Sfda Guide

Saudi Food and Drug Authority, 2008
King Fahd National Library Cataloging-in-Publication Data

Saudi Food and Drug Athority
Saudi package drug insert :SPDI - Riyadh, 2008
1407p ; 30 cm
ISBN: 978-603-00-1550-4
1-Drugs - Handbooks, manuals etc.
2-Drugs- Saudi Arabia I-Title
615.1 dc 1429/6195
L.D. no. 1429/6195
ISBN: 978-603-00-1550-4
Copyright 1429-2008 by Saudi Food and Drug Authority (SFDA)
All rights reserved. No part of this publication may be printed, stored in a

retrival system, or transmitted in any form or by any means, without the
prior written permission of the copyright holder.
First Edition
2008
Printed in:
Saudi Arabia
Copies may obtained from:
Saudi food and Drug Authority

Drug Sector
National Drug and Poison Information Center
3292 Northern Ring Road,
Al Nafal District, Riyadh 13312 - 6288
Kingdom of Saudi Arabia
Tel: +966-1-2759222 Ext. 1302
Fax: +966-1-2757195
www.sfda.gov.sa
Saudi Package Drug Insert (SPDI)
Preface
S audi Package Drug Insert (SPDI) book is a new publication produced by Saudi
Food and Drug Authority (SFDA). This unique reference is produced by SFDA to
provide rapid access to Package Insert (PI) information for drugs registered and
marketed in Saudi Arabia and drug identification atlas for tablets and capsules for
such products.
The SPDI book contains several sections which provide a wide range of information
that health care professionals will find useful in their work. The first section provides
an index for list of pharmaceutical manufacturers with their complete addresses
available in Saudi Arabia.
The second section provides an index for brand names, third section provide index
for generic names and the fourth section provide therapeutic index for each listed
products. Section five provide product identification guide that contains full-size
color photos of tablets and capsules arranged alphabetically by manufacturers'
names.
Section six is the main section of the book and it includes entries for nearly about
3000 pharmaceuticals and is arranged alphabetically by manufacturers' names.
Since leaflets also contain not registered drugs, every not registered drug is marked
as N.R.
The main feature of the SPDI is its availability with two electronic versions one for
the book and other for drug identifier, where both are provided with tablets and
capsules atlas, which can be searched electronically guaranteeing us easy access to
SPDI.
The SPDI main intension is to help our clients, that is, Physicians, Pharmacists,
Nurses and other healthcare professionals by giving the most up to date information
to all registered and marketed drugs before the product is prescribed. It brings to our
readers updated information and complementary medical and pharmaceutical
knowledge for safe prescribing.
Prof. Mohammed AL-Kanhal Prof. Saleh Bawazir

Act. Executive President Vice President for Drug Affairs
Contents
The Saudi Package Drug Insert (SPDI) is highly organized and specially compiled
for the benefit of medical professionals. It focuses primarily on the following:
Part A Page No.

Manufacturers Index. 7
Brand Name Index. 33
Generic Name Index. 59
Therapeutic Index. 85
Product Identification Guide. 111
Part B
Product Information 1
Manufacturer's Index
This index provides an alphabetical directory of a complete list of all the
manufacturers' names participating in SPDI. It is through their courtesy that SPDI is
brought to the Medical profession.
It includes manufacturer's full name with its line of products along with their dosage
forms, generic name, therapeutic category and page number for each product
present in product information section, in side to side column.
Especially the last pages of the book is endowed with brief but comprehensive
information per company in their alphabetical order including its full name with
complete address, phone number and fax number available in the Kingdom of Saudi
Arabia.
Brand Name Index

This index is specially designed to provide brand names in alphabetical order for the
listed products present in product information section. The unique idea here is to
provide brand name together with its generic name, company name, and therapeutic
category all in one roof present in side to side column. This makes our index a search
engine to have all the info. about the products, if one searching any product with its
brand name.
Another highlight of this index is that it provides brand name together with dosage
forms of drugs which are registered in Kingdom of Saudi Arabia .This enables us to
know about all the dosage forms available for a brand and its company name too,
Contents
this info. all in one roof, helps for quick reference than to search individually in
product information section.
The brand names marked with * symbol indicates that their respective photographs
are present in product identification guide.
Generic Name Index

This is designed as a digest for rapid reference of the products through their generic
category.
It includes alphabetical array of generic category along with brand name, dosage
form, company name, therapeutic category and its page number for each product
present in product information section, in side to side column.
This provides key information about different brand names and their respective
company name registered in Kingdom of Saudi Arabia which enables to select the
brand name of choice.
Basic information about the therapeutic category can be known from generic name
through this index.
Therapeutic Index
Therapeutic index aims to provide prescribers, pharmacists and other healthcare
professionals with sufficient therapeutic information for each product.
This index lists therapeutic category of each product alphabetically. Along with
each category you will find their respective brand name, generic name, company
name, and the page number in side to side column.
This enables to find different brands available under the same category and allowing
you to quickly and easily identify all manufacturers of such brand with that
therapeutic use or mechanism of action. Categories are based on the manufacturers'
product information, latest medical terminology and are comprehensively cross-
referenced. Detailed therapeutic category is provided by giving sub-category for
most of the products.
Contents
This index is particularly useful for comparing drugs having same therapeutic action
but sometimes not the same generic category.
Product Identification Guide

This service of identification of tablets & capsules from its image or photograph is
an informational resource designed to assist health practitioner in caring for their
patients and provide consumer with drug specific information
In this section the photographs of the products are arranged by their manufacturer's
name alphabetically. This section includes nearly about 200 photos for tablets and
capsules. Each Photograph of product is listed with info. about its brand name,
active ingredient, prescription category, manufacturer name and page number of
their insert present in the product information section.
Research tell us that people often understand information more easily when it is
processed through visual images. Thus to aid in quick identification, this section
provides full color, shape, imprints, & actual size photographs of tablets & capsules.
The photograph of some of dosage forms included is not of actual size.
Many injuries & death occur each year due to medication errors, some of which may
have been prevented by having the capability to identify an unknown medicine.
Other resources are often incomplete, provide lists with choices from which to make
the tablet & capsule identification & leave the user in doubt. Mistakes can easily be
made. Only SPDI makes a fast positive identification every time.
While every effort has been made to guarantee faithful reproduction of the photos in
this section, but changes in size, color and design are always a possibility as due to
changes brought by manufacturer with time. In such case be sure to confirm product
identity with the manufacturer or your pharmacist.
For more information on any of the product in this section, please turn to the product
information section, or check directly with the manufacturer.
Product Information
This product information section includes inserts for the pharmaceutical products
which are listed in alphabetical order of brand names under their manufacturers
names sequence. This section will provide you details for the entries included in the
Contents
SPDI such as brand name, generic name, prescription category, active and inactive
ingredients, indications, effects, dosages, routes, methods, frequency and duration
of administration, hazards, contraindications, any other relevant warnings, side
effects, precautions etc..
This section is made possible through the courtesy of the manufacturers whose
product appears in it. The information concerning each product has been prepared
based on the data provided by the respective manufacturer / scientific office and
approved by the Ministry of Health, Saudi Arabia.
Guide for N.R.
SPDI book is featured with very important basic idea of keeping only registered
and marketed drugs in Saudi Arabia. But the leaflets contain some more Brands,
Concentrations and Packaging which are not registered here in Saudi Arabia, need to
be separated out. Here in SPDI the word "N.R" is used to represent "Not
Registered". Specifically one can look for either in composition or presentation for
any N.R present in a leaflet.
Disclaimer
The products insert included in this section was provided by the individual
manufacturer of each product. Thus this section is made possible through the
courtesy of the manufacturer whose product appear in it. The insert concerning each
product has been prepared, edited and approved by the medical department, medical
director, and / or medical counsel of its manufacturer. All the data has been carefully
compiled and checked, however, errors may occur. The publisher does not warrant
or guarantee any product. Since the publisher does not perform the individual
analysis of the products insert provided, inclusion of any product in SPDI does not
indicate that publisher advocate the use of any of the drug mentioned in SPDI
All the information given is valid at the time of publication, which will be updated
and published in SPDI supplement for hard copy once in two years while for its soft
copy, i.e. CD once in a year. Kindly consult the supplements before prescribing or
administering any product described in the SPDI.
Guide to Controlled Substance Category

Product insert is accompanied with symbols shown below are subjected to the
Controlled Substance Act 1971. Drug products are categorized according to their
potential for abuse. Here not only controlled drugs are categorized but also specified
for their schedules too.
Contents
Category Interpretation
C-II High potential for abuse.
Use may lead to sever physical or
psychological dependence.
C-III Some potential for abuse.
Use may lead to low-to-moderate physical
dependence or high psychological dependence
C-IV Low potential for abuse.
Use may lead to limited physical or
psychological dependence
C-V Subject to local regulation.
Abuse potential is low
Guide to use-in-pregnancy ratings :
Drugs can have harmful effects on the foetus at any time during pregnancy. It is
important to bear this in mind when prescribing for a women of child bearing
age.
Use in pregnancy rating system weighs the degree to which available

information has ruled out the risk to the foetus against the drugs potential benefit
to the patient. The ratings and its interpretation, are as follows.
Category Interpretation
A Controlled studies show no risk
B No evidence of risk in humans
C Risk can cot be ruled out
D Positive evidence of risk
X Contraindicated in pregnancy
Part A
Manufacturer's Index
Page No. 7-32
Brand Name Index

Page No. 33 - 58
Generic Name Index

Page No. 59 - 84
Therapeutic Index
Page No. 85 - 110
Product Identification Guide

Page No. 111 - 114
MANUFACTURERS INDEX
MANUFACTURER NAME / GENERIC NAME THERAPEUTIC PAGE MANUFACTURER NAME / GENERIC NAME THERAPEUTIC PAGE
BRAND NAME CATEGORY NO BRAND NAME CATEGORY NO
Betagan - Sterile ophthalmic suspension Levobunolol HCl Glaucoma treatment 20
ABBOTT 1 drug, Beta adrenoceptor
blocking drug
Eryderm - Topical solution Erythromycin base Antibiotic, Macrolide 1
Botox - Dried substance for injection Botulinum toxin type A Neurotoxin complex 20
Erythrocin - e.c Tablets Erythromycin stearate Antibiotic, Macrolide 1
Used for strabismus
Erythrocin - Granules for oral suspension Erythromycin ethylsuccinate Antibiotic, Macrolide 1 and blepharospasm
Ethrane - Solution for inhalation Enurane Anaesthetic, General 2 associated with dystonia
Forane - Solution for inhalation Isourane Anaesthetic, Volatile 2 FML Liquilm - Fluorometholone Corticosteroid, Ophthalmic 22
Humira - Solution for injection Adalimumab Anti-rheumatic, Cytokine 2 Sterile ophthalmic suspension
inhibitor FML-Neo Liquilm - Fluorometholone, Neomycin Corticosteroid & 22
Isoptin- f.c Tablets Verapamil hydrochloride Antihypertensive, 4 Sterile ophthalmic suspension sulfate antibiotic, Ophthalmic
Calcium channel blocker Lumigan - Eyedrops Bimatoprost Glaucoma treatment 22
Isoptin - f.c Sustained release tablets Verapamil hydrochloride Antihypertensive, Calcium 5 drug, Prostamide
channel blocker Oox - Eyedrops Ooxacin Antibiotic, Quinolones, 23
Itrin - Tablets Terazosin hydrochloride Antihypertensive, 5 Ophthalmic
treatment of Pred Forte - Prednisolone acetate Anti-inammatory, 23
benign prostatic Sterile Ophthalmic suspension Ophthalmic
hyperplasia(BPH), Zymar - Ophthalmic solution Gatioxacin Antibiotic, Fluoroquinolone, 24
-adrenoceptor blocker Ophthalmic
Klacid - f.c Tablets Clarithromycin Antibiotic, Macrolide 6
Klacid - Granules for oral suspension Clarithromycin Antibiotic, Macrolide 7 ALPHARMA 25
Klacid XL- Tablets Clarithromycin Antibiotic, Macrolide 8 Cyclogest - Pessaries Progesterone Female sex hormone 25
Reductil - Capsules Sibutramine hydrochloride Anti-obesity drug 9 Dumozol - Cream Metronidazole Anti-protozoal, Topical 25
Survanta- Intratracheal suspension Phospholipids Pulmonary surfactant, 9 Dumozol - Oral suspension Metronidazole Anti-protozoal, 25
for respiratory distress Anti-anaerobic
syndrome Dumozol - Tablets Metronidazole Anti-protozoal, 25
Anti-anaerobic
ADVANCED PHARMACEUTICAL INDUSTRIES CO. LTD. 9
Adiprin - E.C Tablets Acetylsalicylic acid NSAID, Platelet aggregati- 9 AMARIYA PHARMA INDUSTRIES 26
-on inhibitor Amrizole - Vaginal suppositories Metronidazole. Anti-protozoal, 26
Candivast - Capsules Fluconazole Antifungal, Triazole 9 Anti-anaerobic
Lowvasc - Capsules Amlodipine besylate Antihypertensive, 10
Amrizole - Rectal suppositories Metronidazole. Anti-protozoal, 26
Calcium channel blocker
Anti-anaerobic
Moven - Capsules Meloxicam NSAID, for treatment 10
Cafamol - Tablets Paracetamol, Doxylamine, NSAID, Antihistaminic, 26
of arthritis & spondylitis
Caffeine Natural stimulant
Nomal - Capsules Tramadol hydrochloride Opioid analgesic 10
Depovit - Injection Hydroxocobalamin Vitamin B12 27
Prevoc - Tablets Ticlopidine hydrochloride Antiplatelet, 11 acetate (Vit-B12)
Anti-thrombotic Ketofan - Tablets Ketoprofen NSAID, Analgesic 27
Ribavin - Capsules Ribavirin Antiviral drug 11 Spasmotalin - Tablets Mebeverine hydrochloride Antispasmodic & Drug 27
Zocin - Capsules Azithromycin dihydrate Antibiotic, Macrolide 12 altering gut motility,
Intestinal smooth muscle
ALCON 12 relaxant
Betoptic - Ophthalmic solution Betaxolol hydrochloride Glaucoma treatment drug 12 AMGEN 27
Beta adrenoceptor
blocker Aranesp - Injection Darbepoetin alfa Erythropoiesis stimulating 27
BSS (Balanced Salt Solution) - Sodium chloride, Potassium Irrigation solution 13 agent, Epoetin derivative.
Irrigation solution chloride ,Calcium chloride
dihydrate, Magnesium chloride APOTEX 31
hexahydrate, Sodium acetate
Apo-Diclo - Tablets Diclofenac sodium NSAID, Antirheumatic, 31
Ciloxan - Ophthalmic solution Ciprooxacin HCl Antibiotic, Quinolone, 13
Antipyretic, Analgesic
Ophthalmic
Apo-Doxy - Capsules Doxycycline hyclate Antibiotic, Tetracycline 34
Cyclogyl - Sterile ophthalmic solution Cyclopentolate hydrochloride Anticholinergic, Mydriatic 14
& Cycloplegic Apo-Glyburide - Tablets Glyburide Antidiabetic drug 36
Oral, Sulphonylurea
Duratears Ocular lubricant ointment Mineral Oil, Anhyd.liquid Tear deciency, Ocular 15
lanolin, White Petrolatum lubricant & astringent Apo-Ranitidine- Tablets Ranitidine Antacid, Ulcer-healing, 37
H2-receptor antagonist
Fenicol - Ophthalmic ointment Chloramphenicol Antibiotic, Ophthalmic 16
Ferriprox - Tablets Deferiprone Iron chelator 40
Iopidine - Ophthalmic solution Apraclonidine hydrochloride Glaucoma treatment drug, 15
Relatively selective
ASTELLAS EUROPE B.V 41
alpha2-adrenergic agonist
Isopto Carpin - Eyedrops Pilocarpine hydrochloride Glaucoma treatment drug, 16 De-Nol - Tablets Bismuth subcitrate Ulcer-healing, 41
Miotic Precipitate forming
Isopto Fenicol - Ophthalmic solution Chloramphenicol Antibiotic, Ophthalmic 16 Flemoxin - Capsules Amoxicillin Antibiotic, 41
Maxitrol - Ophthalmic ointment Dexamethasone, Neomycin Corticosteroid, 16 Broad-spectrum penicillin
sulfate, Polymixin B sulphate Anti-inammatory, Flemoxin - Drops Amoxicillin Antibiotic, 41
Antibacterial prep, Topical Broad-spectrum penicillin
Maxitrol - Ophthalmic solution Dexamethasone, Neomycin Corticosteroid, 16 Flemoxin - Solutab Amoxicillin Antibiotic, 42
sulfate, Polymixin B sulphate Anti-inammatory, Broad-spectrum penicillin
Antibacterial prep,Topical Locoid - Cream Hydrocortisone 17-butyrate Corticosteroid, Topical 42
Mydriacyl - Ophthalmic solution Tropicamide Anticholinergic, Mydriatic 17 Locoid - Lipocream Hydrocortisone 17-butyrate Corticosteroid, Topical 42
& Cycloplegic Locoid - Lotion Hydrocortisone 17-butyrate Corticosteroid, Topical 42
Naphcon A - Eyedrops Naphazoline hydrochloride, Decongestant, 17 Locoid - Ointment Hydrocortisone 17-butyrate Corticosteroid, Topical 42
Pheniramine maleate Antihistamine for
allergic/inammatory Pimafucort - Cream Hydrocortisone, Natamycin, Corticosteroid, 42
condition, Ophthalmic Neomycin base Antibacterial,
Antifungal, Topical
Patanol - Eyedrops Olopatadine hydrochloride Anti-allergic, Selective 17
Pimafucort - Ointment Hydrocortisone, Natamycin, Corticosteroid, 42
H1- receptor
Neomycin base Antibacterial, Antifungal,
antagonist, Ophthalmic
Topical
Statrol - Opthalmic ointment Neomycin sulfate, Antibacterial, Topical 18
Polymyxln B sulfate ASTRAZENECA 42
Statrol - Opthalmic solution Neomycin sulfate, Antibacterial, Topical 18
Polymyxln B sulfate Accolate - Tablets Zarlukast Anti-asthmatic, Leukotriene 42
receptor antagonist
Tears Naturale -Eyedrops Duasorb (Dextran + HPMC) Tear deciency, Ocular 18
lubricant & astringent Arimidex - Tablets Anastrozole Anticancer, Selective non- 43
steroidal aromatase
Travatan - Eyedrops Travoprost Glaucoma treatment drug, 18
inhibitor
Prostaglandin analogue
Atacand - Tablets Candesartan cilexetil Antihypertensive, 45
ALLERGAN 19 Angiotensin-II receptor
antagonist
Acular - Sterile ophthalmic solution Ketorolac tromethamine NSAID, Ophthalmic 19 Atacand Plus - Tablets Candesartan cilexetil, Antihypertensive, 47
Albalon - Sterile ophthalmic solution Naphazoline HCI Vasoconstrictor, 20 Hydrochlorothiazide Angiotensin-II receptor
Ophthalmic antagonist, Diuretic
7
MANUFACTURERS INDEX
Bricanyl - Solution for injection Terbutaline sulphate Anti-asthmatic, Inhibitor 49 0.9%w/v Sodium chloride - Sodium chloride Parenteral preparation 89
of premature labour, Solution for injection as vehicle solution
Selective beta2 agonist Aminoplasmal - 5% E Amino acid Parenteral nutrition of 89
Bricanyl - Syrup Terbutaline sulphate Anti-asthmatic, Selective 50 -Solution for infusion amino acids
beta2 -agonist Aminoplasmal - 10% Amino acid Parenteral nutrition of 90
Crestor - f.c. Tablets Rosuvastatin calcium Lipid-regulating drug, 51 Solution for infusion amino acids
Cholesterol synthesis Aminoplasmal - 15% Amino acid Parenteral nutrition of 91
inhibitor Solution for infusion amino acids
Entocort - Tablet & Solution Budesonide Corticosteroid for 53 Atropine sulphate Injection Atropine sulphate Antimuscarinic 91
for rectal suspension ulcerative colitis, Proctitis (Anticholinergic) drug
Inderal - Tablets Propranolol hydrochloride Antihypertensive, 53 Compound Sodium Lactate IV infusion Sodium chloride, Sodium Parenteral preparation for 92
Anti-anginal, lactate, Potassium chloride, uid & electrolyte supply
Anti-arrythmic, Calcium chloride dihydrate
Beta-adrenoceptor blocker Glycine 1.5% w/v - Irrigation solution Glycine Irrigation solution 93
Inderal - Injection Propranolol hydrochloride Antihypertensive, 53 Heparin Sodium injection Heparin sodium Anticoagulant, Parenteral 93
Anti-anginal,
Lidocaine B. Braun 2% - Injection Lidocaine hydrochloride Anaesthesia, Local 95
Anti-arrythmic,
blocker Lipofundin MCT/LCT 10% - Soya-bean oil, Medium-chain Parenteral nutrition of 96
Emulsion for infusion triglycerides, Medium-chain calories & essential fatty
Kinidin Durules - Tablets Quinidine bisulphate Anti-arrythmic drug 55
triglycerides,Alpha linolenic acids
Losec- powder for solution Omeprazole sodium Antacid, Ulcer-healing, 56 acid
for infusion Proton pump inhibitor
Lipofundin MCT/LCT 20% - Soya-bean Oil, Medium-chain Parenteral nutrition of 97
Losec - Capsules Omeprazole Antacid, Ulcer-healing, 57 Emulsion for infusion triglycerides, Medium-chain calories & essential fatty
Proton pump inhibitor triglycerides,Alpha linolenic acids
Losec Mups - Tablets Omeprazole magnesium Antacid, Ulcer-healing, 58 acid
Proton pump inhibitor Metronidazole Intravenous infusion Metronidazole Anti-protozoal, 98
Meronem IV - Injection or Infusion Meropenem trihydrate Antibiotic, Betalactam 60 Anti-anaerobic
Nexium - Tablets Esomeprazole magnesium Antacid, Ulcer-healing, 62 Nutriex Lipid Peri Total parental nutrition Parenteral nutrition of 99
trihydrate Proton pump inhibitor Emulsion for IV infusion mixture amino acids,
Nexium IV - Injection Esomeprazole sodium Antacid, Ulcer-healing, 63 Carbohydrates, Fats,
Proton pump inhibitor Electrolytes
Nolvadex-D - Tablet Tamoxifen citrate Anticancer, Antioestrogen 65 Nutriex Lipid Plus Total parental nutrition Parenteral nutrition of 100
Emulsion for IV infusion mixture amino acids,
Nolvadex - Tablet Tamoxifen citrate Anticancer, Antioestrogen 65
Carbohydrates, Fats,
Oxis Turbuhaler - Inhalation powder Formoterol fumarate Anti-asthmatic, Selective 66 Electrolytes
dihydrate beta2 -agonist
Potassium Phosphates Injection Dipotassium phosphate, Electrolyte concentrate 102
Plendil S.R - Tablets Felodipine Antihypertensive, Calcium 67 Potassium dihydrogen
channel blocker phosphate
Pulmicort - Nebuliser suspension Budesonide Anti-asthmatic, 68
Corticosteroid BAXTER 102
Pulmicort Turbuhaler - Budesonide Anti-asthmatic, 70 Dextrose Injection 5% Dextrose hydrous Parenteral preparation for 102
Inhalation powder Corticosteroid uid & calorie supply
Seroquel - Tablets Quetiapine fumarate Antipsychotic drug 71 Dextrose Injection 10% Dextrose hydrous Parenteral preparation for 102
Symbicort Turbuhaler - Budesonide, Formoterol Anti-asthmatic, 73 uid & calorie supply
Inhalation powder fumarate dihydrate Corticosteroid & Dextrose Injection 50% Dextrose hydrous Parenteral Preparation for 103
Selective beta2 agonist energy supply &
Tenoretic - Tablets Atenolol, Chlorthalidone Antihypertensive, 75 hypoglycaemia
eta-adrenoceptor Dextrose Injection 70% Dextrose hydrous Parenteral preparation for 103
blocker, Diuretic energy supply &
Tenormin - Tablets / Injection Atenolol Antihypertensive, 76 hypoglycaemia
Anti-anginal, Endobulin S/D - Powder and solvent Human normal Immuno-deciency 104
Anti-arrythmic, for solution for injection immunoglobulin treatment drug
Beta-adrenoceptor blocker
Endoxan - Powder for solution Cyclophosphamide Anticancer, Alkylating 106
Xylocaine Pump Spray - Solution Lidocaine base Anaesthesia, Local 78 monohydrate agent
Zestril - Tablets Lisinopril dihydrate Antihypertensive, 79 Endoxan - Tablets Cyclophosphamide Anticancer, Alkylating 106
ACE inhibitor monohydrate agent
Zoladex - Suspension Goserelin acetate Gonadotrophin 81 Extraneal - Solution for Icodextrin Osmotic agent in 107
releasing hormone peritoneal dialysis Continuous Ambulatory
(Gn-RH)agonist Peritonial Dialysis(CAPD)
Holoxan - Injection Ifosfamide Anticancer, Alkylating 108
B. BRAUN MELSUNGEN AG 82
agent
10% w/v Calcium Gluconate Injection Calcium gluconate, Calcium Calcium supplement 82 Human Albumin - Solution for infusion Human albumin Plasma Protein Fraction 110
D-saccharate tetrahydrate Partobulin SDF - IM injection Anti-D antibody, Anti-D antibody 110
5% w/v Dextrose IV Infusion Glucose monohydrate Parenteral preparation for 83 Human protein
uid & calorie supply Recombinate - Powder and solvent Blood coagulation Antibrinolytic drug and 111
10% w/v Dextrose IV Infusion Glucose monohydrate Parenteral preparation 83 for solution for injection factor VIII. Haemostatic
for energy supply Renamin - Injection Amino acid (Valine, Leucine, Parenteral nutrition of 113
& hypoglycaemia Isoleucine, Phenylalanine, amino acids
40% w/v Dextrose IV Infusion Glucose monohydrate Parenteral preparation for 84 lysine, Histidine, Threonine,
energy supply Tryptophan
& hypoglycaemia Sevourane - Volatile liquid Fluoromethyl 2,2,2, - Anaesthesia, Inhalational 115
50% w/v Dextrose Injection Glucose monohydrate Parenteral preparation for 84 for Inhalation Triuoro-1-(Triuoromethyl)
energy supply ethyl ether
& hypoglycaemia Travasol 10% - Injection Amino acid (essential & Parenteral nutrition of 119
7.45% w/v Potassium chloride Potassium chloride Electrolyte replacement 84 non-essential amino-acid) amino acids
Injection Uromitexan - Tablets Mesna (Sodium 2 - Anticancer, Cytotoxic drug 121
15% w/v Potassium chloride Injection Potassium chloride Electrolyte replacement 85 mercapto ethane sulphonate).
4.2% w/v Sodium bicarbonate Sodium bicarbonate Electrolyte replacement 85 Uromitexan - Injection solution Mesna (Sodium 2 - Anticancer, Cytotoxic drug 122
Intravenous Infusion mercapto ethane sulphonate).
8.4% w/v Sodium bicarbonate Injection Sodium bicarbonate Electrolyte replacement 86 BAYER HEALTHCARE & BAYER SCHERING 122
0.9%w/v Sodium chloride - Sodium chloride Irrigation solution 89
Irrigation Solution Adalat 10- Capsules Nifedipine. Antihypertensive, 122
0.9%w/v Sodium chloride & Sodium chloride, Glucose Parenteral preparation for 89
5%w/v Dextrose IV Infusion uid , electrolyte & Adalat LA-s.r Tablets Nifedipine. Antihypertensive, 123,
glucose supply Calcium channel blocker 125
5.85%w/v Sodium chloride Injection Sodium chloride Electrolyte substitute 87 Adalat Retard - s.r Tablets Nifedipine. Antihypertensive, 126
0.45% w/v Sodium chloride Sodium chloride, Glucose Parenteral preparation for 88
Avalox - Tablets Moxioxacin hydrochloride Antibiotic, Quinolone 127
& 5% w/v Dextrose IV Infusion uid , electrolyte &
glucose supply Avalox - IV solution Moxioxacin hydrochloride Antibiotic, Quinolone 127
0.9%w/v Sodium chloride Sodium chloride Parenteral preparation 87 Ciprobay - Infusion solution Ciprooxacin lactate Antibiotic, Quinolone 133,
IV Infusion (PVC) as vehicle solution 134
8
MANUFACTURERS INDEX
Ciprobay -f.c Tablets Ciprooxacin HCl Antibiotic, Quinolone 136, Micardis Plus - Tablet Telmisartan, Antihypertensive, 169
monohydrate 138, Hydrochlorothiazide Angiotensin-II receptor
141 antagonist/diuretic
Glucobay - Tablets Acarbose Antidiabetic drug, Oral 142 Mobic - Tablets Meloxicam NSAID, for treatment of 171
Levitra -f.c Tablets Vardenal (as HCl trihydrate) Erectile dysfunctioning 143, Arthritis & Spondylitis
treatment drug 144, Mucosolvan - Liquid Ambroxol hydrochloride Mucolytic 172
145 Mucosolvan - Tablets Ambroxol hydrochloride Mucolytic 172
Mycospor - Cream Bifonazole Antifungal, Topical 145 Pharmaton Capsules Ginseng Extract G115, Food supplement, 172
Mycospor - Solution Bifonazole Antifungal, Topical 146 lecithin, Multivitamin, Strength & Vitality drug
Nimotop - Infusion solution Nimodipine Antihypertensive, 146 Minerals and Trace elements.
Calcium channel blocker Pharmaton Kiddi Sirop Multivitamin, Lysine Multivitamin preparation 173
Nimotop - Tablets Nimodipine Antihypertensive, 147 Sifrol - Tablets Pramipexole dihydrochloride Antiparkinsonism, 173
Calcium channel blocker monohydrate dopamine agonist
Silomat - Tablets Clobutinol hydrochloride Antitussive, Non-opioid 174
BIOGEN IDEC. INC. 148
Songha Night - Capsules Extracts of Valerian root and Sedative, Mild 175
Avonex - Injection Interferon beta-1A Immuno-modulator, 148 Extracts of Melissa leaves
Antiviral, Antiproliferative Spiriva - Capsule for inhalation Tiotropium Anticholinergic, 175
Bronchodilator
BIOTEST 151 Viramune - Tablets Nevirapine anhydrate Antiviral drug 176
Biseko - Solution for IV infusion Human serum. Sera 151
B P L (BIO PRODUCTS LABORATORY) 180
Hepatect - Solution for infusion Human hepatitis B Immuno-globulin, 152
immunoglobulin for Human hepatitis B D-Gam - Injection Human Anti-D Gammaglobulin, 180
intravenous administration immunoglobulin Anti-D antibody
(Human Plasma Protein, Dried Factor VIII Fraction, 8Y Factor VIII Von Willebrand Antibrinolytic drug 180
immunoglobulin G, Injection factor and Haemostatic
HBs antibody content) Replenine - VF- Freeze dried conc. Human Factor IX Haemophilia B 182
Human Albumin 5% Human Albumin Plasma protein fraction 153 for injection treatment drug
Solution for IV infusion Vigam Liquid - Infusion liquid Human normal Immuno-deciency 183
Human Albumin 20% Human Albumin Plasma protein fraction 153 immunoglobulin treatment drug
Solution for IV infusion Zenalb 20 - Infusion solution Human albumin Plasma protein fraction 185
Intraglobin F - Solution for infusion Human normal Immuno-deciency 154
immunoglobulin treatment drug, BRISTOL MYERS SQUIBB 186
Human immunoglobulins
Abilify - Tablets Aripiprazole Antipsychotic drug 186
Pentaglobin - Solution for IV infusion Human normal Immuno-deciency 155
Capozide - Tablets Captopril, Antihypertensive, 191
immunoglobulin, treatment drug,
Hydrochlorothiazide ACE inhibitor & Diuretic
Immunoglobulin M (IgM)/ Human immunoglobulins
immunoglobulin A (IgA) Cefzil - Oral suspension Cefprozil Antibiotic, Cephalosporin 195
Plasma Protein Fraction Human 5% Human plasma protein Plasma protein fraction 156 Cefzil - Tablets Cefprozil Antibiotic, Cephalosporin 195
Solution for IV infusion Maxipime - IV/IM Injection Cefepime hydrochloride Antibiotic, Cephalosporin 197
Taxol - Injection Paclitaxel Anticancer, Taxanes 201
BOEHRINGER INGELHEIM 157
Ultracef - Capsules Cefadroxil Antibiotic, Cephalosporin 209
Actilyse Set - Injection Alteplase (Recombinant Thrombolytic agent 157 Ultracef - Powder for suspension Cefadroxil Antibiotic, Cephalosporin 209
human tissue-type Ultracef - Tablets Cefadroxil Antibiotic, Cephalosporin 209
Plasminogen activator)
Zerit - Capsules Stavudine Antiviral drug 209
Alupent - Syrup Orciprenaline sulfate Anti-asthmatic, 159
Selective beta2 -agonist CHAUVIN PHARMACEUTICALS LTD 213
Atrovent - Metered aerosol Ipratropium bromide Anti-asthmatic, 159
Antimuscarinic broncho- Fluorets - Strips Fluorescein sodium Ocular staining & 213
-dilator diagnostic drug
Atrovent - Inhalation solution Ipratropium bromide Anti-asthmatic, 160, Minims Articial Tears - Eyedrops Sodium chloride, Natural tears uid 213
Antimuscarinic broncho- 161 Hydroxyethylcellulose Substitute
-dilator Minims Chloramphenicol - Eyedrops Chloramphenicol Antibiotic, Ophthalmic 213
Bisolvon - Elixir Bromhexine hydrochloride Mucolytic 161 Minims Cyclopentolate hydrochloride Cyclopentolate hydrochloride Mydriatic & Cycloplegic 214
Bisolvon - Solution Bromhexine hydrochloride Mucolytic 161 Eyedrops
Bisolvon - Tablets Bromhexine hydrochloride Mucolytic 161 Minims Fluorescein Sodium - Eyedrops Fluorescein sodium Ocular staining & 214
diagnostic drug
Buscopan - Tablet Hyoscine-N-butylbromide Antispasmodic & Drug 162
altering gut motility, Minims Gentamicin sulphate - Eyedrops Gentamicin sulphate Antibiotic, 214
Antimuscarinic Aminoglycoside, Ophthalmic
Combivent - Metered aerosol Ipratropium bromide Anti-asthmatic, 162 Minims Lidocaine And Fluorescein Lidocaine, Fluorescein Anaesthetic, Staining & 215
monohydrate, Salbutamol Antimuscarinic Eyedrops diagnostic drug,
sulphate bronchodilator & Ophthalmic
beta2 -agonist Minims Oxybuprocaine hydrochloride Oxybuprocaine hydrochloride Anaesthetic, Ophthalmic 215
Combivent - Inhalation solution Ipratropium bromide, Anti-asthmatic, 163 Eyedrops
Salbutamol sulphate Antimuscarinic Minims Phenylephrine hydrochloride Phenylephrine hydrochloride Sympathomimetic, 215
bronchodilator & Eyedrops Mydriatic
beta2 -agonist Minims Pilocarpine nitrate - Eyedrops Pilocarpine nitrate Glaucoma treatment 216
Dulcolax - Coated Tablets Bisacodyl Laxative, Local 164 drug, Miotic
Gincosan - Capsules Extract GK501 Food supplement, 164 Minims Saline - Eyedrops Sodium chloride Irrigation solution, 216
(from Ginkgo biloba tree), Strength & Vitality drug Ophthalmic
Extract G115(from roots of Minims Tetracaine hydrochloride Tetracaine hydrochloride Anaesthetic, Ophthalmic 216
Panax ginseng) Eyedrops
Ginsana G115 - Capsules Ginseng Extract G115 Food supplement, 165 Minims Tropicamide - Eyedrops Tropicamide Mydriatic & Cycloplegic 216
Strength & Vitality drug
Ginsana G115 - Chewable Tablets Ginseng Extract G115 Food supplement, 165 CHIESI FARMACEUTICI S.P.A-PHARMA. 217
Clenil Forte Spray Beclomethasone dipropionate Corticosteroid, 217
Ginsana G115 - Fruit Tonic Ginseng Extract G115 Food supplement, 165 Pressurised inhalation solution Antiasthmatic
Rino Clenil Spray Beclomethasone dipropionate Corticosteroid, Nasal 217
Imukin - Injection Recombinant human Immuno-modulator, 165 Aqueous Suspension decongestant, Topical
interferon Gamma-1b interferons to reduce
frequency of serious DEEF PHARMACEUTICAL INDUSTRIES COMPANY 218
infections in chronic
granulomatous disease Citrin - Syrup Cetirizine hydrochloride Antihistamine, 218
Non-sedating
Kiddi Pharmaton Fizz - Eff. Tablets Lysine, Multivitamin, Multivitamin preparation 166
Minerals and Trace elements Defadol S.F - Syrup Paracetamol NSAID, Analgesic, 218
Antipyretic
Metalyse - Powder for solution Tenecteplase Fibrinolytic drug 166
for injection Defajour - Syrup Loratadine Antihistamine, 219
Non-sedating
Micardis - Tablet Telmisartan Antihypertensive, 168
Angiotensin-II receptor Deforax - Cream Acyclovir Antiviral, Topical 219
antagonist Drof - Shampoo Ketoconazole Antifungal, Topical 219
9
MANUFACTURERS INDEX
Defopan - Syrup Hyoscine -N -butyl Antispasmodic & drug 220
bromide altering gut motility, ELI LILLY AND COMPANY 252
Antimuscarinic
Cialis - Tablets Tadalal Erectile dysfunctioning 252
treatment drug
DR. FALK PHARMA GmbH 220
Forsteo - Solution for injection Teriparatide Osteoporosis treatment 253
Mucofalk Orange - Granules Ispaghula husk Laxative, Bulk-forming 220 drug, Recombinant
Salofalk - Enema Suspension Mesalazine Chronic bowel disorder 220 fraction of parathyroid
treatment drug, hormone
Aminosalicylate Gemzar - Injection Gemcitabine HCl Anticancer, Antimetabolite 256
Salofalk - Tablets Mesalazine Chronic bowel disorder 221 Humalog - Injection solution Insulin Lispro Antidiabetic, Short 261
treatment drug, acting insulin
Aminosalicylate Humalog MIX25 - Suspension Insulin lispro/Insulin lispro Antidiabetic, Intermediate 262
Ursofalk - Capsules Ursodeoxycholic acid Gallstone dissolving drug 222 in cartridge Protamine suspension acting insulin
Humalog MIX50 - Suspension Insulin lispro/Insulin lispro Antidiabetic, Intermediate 262
EBEWE PHARMA 222 in cartridge Protamine suspension acting insulin
5-Fluorouracil Ebewe 5-uorouracil Anticancer, Antimetabolite 222 Prozac - Capsules Fluoxetine hydrochloride Antidepressant, Selective 263
Solution for injection serotonin re-uptake
inhibitor
Alexan - Injection Cytarabine Anticancer, Antimetabolite 223,
Strattera - Hard Capsule Atomoxetine hydrochloride CNS stimulant 264
225
Zyprexa - f.c Tablets Olanzapine Antipsychotic drug 267
Calciumfolinat Ebewe - Solution Calcium folinate Anticancer drug 227
(Antimetabolite) toxicity F. HOFFMANN LA. ROCHE LTD 269
reducer, Synergistic
To 5-uorouracil Anexate - Injection Flumazenil Benzodiazepine antagonist 269
(Anticancer drug) Aurorix - Tablets Moclobemide Antidepressant, 270
Carboplatin Ebewe Carboplatin Anticancer, Platinum 228 Reversible monoamine
Conc. for solution for injection compound oxidase inhibitor
Cisplatin Ebewe Cisplatin Anticancer, Platinum 229 Bactrim - Tablets Sulphamethoxazole, Antibiotic, Co-trimoxazole 271
Conc. for solution for infusion compound Trimethoprim
Doxorubicin Doxorubicin hydrochloride Anticancer, Cytotoxic 230 Bactrim Pediatric - Oral suspension Sulphamethoxazole, Antibiotic, Co-trimoxazole 271
Conc. for solution for infusion antibiotic Trimethoprim
Ebetaxel - Solution Paclitaxel Anticancer, Taxanes 232 Bezalip - Tablets Bezabrate Lipid-regulating drug, 273
Epirubicin Ebewe Epirubicin HCl Anticancer, Cytotoxic 234 Serum triglycerides
Conc. for solution for injection antibiotic reducer
Etoposid Ebewe Etoposide Anticancer, Vinca alkaloid 235 Bezalip Retard - Tablets Bezabrate Lipid-regulating drug, 275
Conc. for solution for infusion Serum triglycerides
reducer
Methotrexat Ebewe - Tablet Methotrexate Anticancer, Antimetabolite 237
Bondronat - Injection Ibandronic acid as Osteoporosis treatment 276
Methotrexat Ebewe Methotrexate Anticancer, Antimetabolite 238
Ibandroante sodium hydrate drug
Solution for injection/infusion
Bonviva - Tablets Ibandronic acid as Osteoporosis treatment 276
Mitoxantron Ebewe Mitoxantrone Anticancer, Cytotoxic 240
Ibandroante sodium hydrate drug
Conc. for solution for infusion antibiotic
Cellcept - Capsules Mycophenolate mofetil Immunosuppressant, 278
Sedacoron - Ampoules Amiodarone hydrochloride Anti-arrythmic drug 241
Antiproliferative
Sedacoron - Tablets Amiodarone hydrochloride Anti-arrythmic drug 244 Cellcept - Tablets Mycophenolate mofetil Immunosuppressant, 278
Tamoxifen Ebewe - Tablet Tamoxifen Anticancer, Antioestrogen 246 Antiproliferative
Copegus - Tablets Ribavirin Antiviral drug 281
EIPICO (EGYPTIAN INT. PHARMACEUTICAL INDUSTRIES CO.) 247
Dilatrend - Tablets Carvedilol Antihypertensive, 286
Betaderm - Cream Betamethasone valerate Corticosteroid, Topical 247 Non selective eta &
Betaderm - Ointment Betamethasone valerate Corticosteroid, Topical 247 lpha1 receptor blocker
Cevitil - Eff. Tablets Ascorbic acid Vitamin C 247 Dormicum - Injection Midazolam Anaesthesia, Short 288
acting barbiturate
Ciprocin - Tablets Ciprooxacin as HCl Antibiotic, Quinolone 247
monohydrate Euglucon - Tablets Glibenclamide Antidiabetic drug oral, 290
Sulphonyl urea
Covit - Capsules Vitamin B complex Vitamin B Complex 247
Fansidar - Tablets Sulfadoxine , Pyrimethamine Antimalarial drug 291
Dexamethasone Sodium Phosphate Dexamethasone phosphate Corticosteroid 247
Injection as sodium salt Inhibace - Tablets Cilazapril Antihypertensive, 292
ACE inhibitor
E-Mox - Capsules Amoxycillin trihydrate Antibiotic, 248
Broad-spectrum penicillin Ismo - Tablets Isosorbide mononitrate Antihypertensive, 294
Anti-anginal, Vasodilator
E-Mox - Dry mix Amoxycillin trihydrate Antibiotic, 248
Broad-spectrum penicillin Konakion - Chewable Dragees Phytomenadione Vitamin K 295
Epental - Powder for injection Thiopental sodium Anaesthetic, 248 Konakion - MM Paediatric Phytomenadione Vitamin K 295
Short acting barbiturate Oral or parenteral solution
Epico - Effervescent salt Magnesium sulphate, Laxative, Mild 249 Konakion - MM - Injection Phytomenadione Vitamin K 295
Sodium bicarbonate, Kytril - Injection Granisetron HCl Anti-emetic, 5-HT3 296
Citric acid receptor antagonist
Epicocillin - Injection Ampicillin soduim Antibiotic, Broad-spectrum 249 Kytril -f.c Tablets Granisetron hydrochloride. Anti-emetic, 5-HT3 296
penicillin receptor antagonist
Epicogel Suspension Dried Aluminium hydroxide Antacid, Antiatulant 249 Lariam - Tablets Meoquine as HCl Antimalarial drug 297
Gel, Dimethicone, Magnesium Lexotanil - Tablets Bromazepam Anxiolytic 299
hydroxide
Madopar - Capsules Levodopa, Benserazide HCl Antiparkinsonism, 300
Epilat - Capsules Nifedipine Antihypertensive, 249 Dopaminergic drug
Madopar - Tablets Levodopa, Benserazide HCl Antiparkinsonism, 300
Epimag - Eff. Granules Magnesium citrate Laxative, Osmotic 250 Dopaminergic drug
Epirazole - Capsules Omeprazole Antacid, Ulcer-healing, 250 Neotigason - Capsules Acitretin Psoriasis treatment drug, 302
Proton pump inhibitor Aromatic analogue of
Furazol - Tablets Metronidazole, Diloxanide Anti-protozoal, 250 retinoic acid
furoate Anti-anaerobic Neupogen - Injection Filgrastim Neutropenia treatment 303
Gastrofait - Tablets Sucralfate Ulcer-healing, Complexing 250 drug, Haematopoietic
agent growth factor
Hydrocortisone Sodium Succinate Hydrocortisone sodium Corticosteroid 251 Pegasys - Injection Peginterferon alfa-2A Immuno-modulator, 306
Injection succinate Antiviral, Antiproliferative
Kapect Oral Suspension Light Kaolin, Pectin Anti-diarrhoeal, Adsorbent 251 Recormon - Injection Epoetin Beta Erythropoesis stimulating 311
& Bulk-forming drug agent, Recombinant
Lactulose - Syrup Lactulose Laxative, Osmotic 251 human erythropoietin
Mucogel Suspension Aluminium hydroxide gel, Antacid, Local surface 252 Rivotril - Injection Clonazepam Anti-epileptic 312
magnesium hydroxide, anaesthetic drug, Benzodiazepine
Oxethazaine Rivotril - Oral drops Clonazepam Anti-epileptic 312
No-Uric - Tablets Allopurinol Gout & Cytotoxic- 252 drug, Benzodiazepine
induced hyperuricaemia Rivotril - Tablets Clonazepam Anti-epileptic 312
treatment drug drug, Benzodiazepine
10
MANUFACTURERS INDEX
Roaccutane - Capsules Isotretinoin Acne treatment, Oral 314 Loceryl - Nail lacquer Amorolne hydrochloride Antifungal, Topical 350
Rocaltrol - Capsules Calcitriol Vitamin D3 316 Neoxidil - Topical solution Minoxidil Hair growth stimulator, 350
Rocephin - Injection Ceftriaxone as disodium Antibiotic, Cephalosporin 317 Topical
Roferon-A - Injection Interferon alfa-2A Immuno-modulator, 319 Retacnyl - Cream Tretinoin Acne treatment, Topical 350
Antiviral, Antiproliferative Rozex - Gel Metronidazole Anti-protozoal, Topical 351
Tamiu - Capsules Oseltamivir phosphate Antiviral drug 322
GE HEALTHCARE 351
Tamiu - Powder for oral suspension Oseltamivir phosphate Antiviral drug 322
Tiberal - Tablets Ornidazole Anti-protozoal, 325 Omnipaque - Solution for injection Iohexol Contrast media 351
Anti-anaerobic Omniscan - Injection Gadodiamide Contrast media 353
Tilcotil - Injection Tenoxicam NSAID, Analgesic, 326 Visipaque - Solution for injection Iodixanol Contrast media 354
Anti-rheumatic
Tilcotil - Suppository Tenoxicam NSAID, Analgesic, 326 GLAXO SMITHKLINE (GSK) 356
Anti-rheumatic
Actifed - Syrup Triprolidine hydrochloride Antihistamine, 356
Tilcotil - Tablets Tenoxicam NSAID, Analgesic, 326 BP, Pseudoephedrine Nasal decongestant
Anti-rheumatic hydrochloride BP
Valcyte - Tablets Valganciclovir HCl Antiviral drug 326 Actifed - Tablets Triprolidine hydrochloride Antihistamine, 356
Valium - Injection Diazepam Tranquiliser, Anxiolytic 330 BP, Pseudoephedrine Nasal decongestant
Valium - Tablets Diazepam Tranquiliser, Anxiolytic 330 hydrochloride BP
Xeloda - Tablets Capecitabine Anticancer, 332 Actifed Compound Linctus - Syrup Triprolidine hydrochloride Antihistamine, Nasal 357
Antimetabolite BP, Pseudoephedrine decongestant, Antitussive
hydrochloride BP, Codeine
Xenical - Capsules Orlistat Anti-obesity drug 334 phosphate
FERRER INTERNATIONAL 336 Alkeran - Tablets Melphalan Anticancer, Alkylating 358
agent
Bronquium Elixir Theophylline, Glyceryl Anti-asthmatic, 336 Amoxil - Injection Amoxicillin sodium Antibiotic, 359
guaiacolate Bronchodilator & Broad-spectrum penicillin
Expectorant Arixtra - Solution for injection Fondaparinux sodium Anti-thrombotic 360
Pulmotropic - Drops Bromhexine HCl Mucolytic 336 Augmentin SR - Tablets Amoxycillin trihydrate, Antibiotic, 369
Pulmotropic - Elixir Bromhexine HCl Mucolytic 336 Potassium clavulanate Broad-spectrum penicillin
Tanidina 150 - Tablets Ranitidine HCl Antacid, Ulcer-healing, 336 Augmentin ES Amoxycillin trihydrate, Antibiotic, 365
H2-receptor antagonist Dry powder for oral suspension Potassium clavulanate Broad-spectrum penicillin
Augmentin Infant Drops Amoxycillin trihydrate, Antibiotic, 367
FERRING PHARMACEUTICALS 336 Potassium clavulanate Broad-spectrum penicillin
Decapeptyl - Injection solution Triptorelin acetate Gonadotrophin 336 Augmentin IV Injection Amoxycillin trihydrate, Antibiotic, 368
releasing Hormone(GnRH) Potassium clavulanate Broad-spectrum penicillin
agonist Augmentin Amoxycillin trihydrate, Antibiotic, 361,
Decapeptyl CR - Injection solution Triptorelin (INN)-GnRH Gonadotrophin 337 Dry powder for oral suspension Potassium clavulanate Broad-spectrum penicillin 362,
Releasing Hormone(GnRH)
agonist Augmentin - Tablets Amoxycillin trihydrate, Antibiotic, 361,
Menogon - Injection Menotrophin Trophic hormone, 338 Potassium clavulanate Broad-spectrum penicillin 364
Fertility agent Avandamet - Tablets Rosiglitazone maleate- Antidiabetic drug oral, 371
Minirin - Nasal spray Desmopressin acetate Antidiuretic hormone 338 Metformin HCl Glitazones
Minirin - Tablets Desmopressin acetate Antidiuretic hormone 339 Avandia - Tablets Rosiglitazone maleate Antidiabetic drug oral, 373
Glitazones
Norprolac - Tablets Quinagolide as Prolactin secretion 340
the hydrochloride inhibitor, Dopamine Avodart - Capsules Dutasteride Anti-androgen, 375
receptor agonist Management of benign
prostatic hyperplasia(BPH)
Pentasa Enema Mesalazine Chronic bowel disorder 341
treatment drug, Bactroban - Nasal ointment Mupirocin calcium Antibacterial, Topical 377
Aminosalicylate Bactroban - Ointment Mupirocin Antibacterial, Topical 377
Pentasa - Slow release Tablets Mesalazine Chronic bowel disorder 341 Beconase Aqueous Nasal Spray Beclomethasone dipropionate Corticosteroid, 377
treatment drug, Anti-inammatory
Aminosalicylate Topical
Pentasa - Suppository Mesalazine Chronic bowel disorder 342 Betnovate-N - Cream Betamethasone as the valerate Corticosteroid, 378
treatment drug, ester, Neomycin sulphate Antibacterial, Topical
Aminosalicylate Betnovate-N - Ointment Betamethasone as the valerate Corticosteroid, 378
ester, Neomycin sulphate Antibacterial, Topical
Tractocile - Solution for injection Atosiban acetate Myometrial relaxant 342,
Betnovate-C - Cream Betamethasone, Clioquinol Corticosteroid, 378
343
Anti-infective, Topical
FRESENIUS KABI 344 Betnovate-C - Ointment Betamethasone, Clioquinol Corticosteroid, 378
Anti-infective, Topical
Addamel N - Injection Trace elements, Electrolytes Parenteral nutrition of 344 Betnovate - Cream Betamethasone as valerate. Corticosteroid, Topical 379
trace elements
Betnovate - Ointment Betamethasone as valerate. Corticosteroid, Topical 379
Haes-Steril 6% - Solution for injection Poly(0-2 Hydroxyethyl) Plasma volume expander 344
Betnovate - Scalp application Betamethasone as valerate. Corticosteroid, Topical 379
starch(HES) with m.wt
Calpol - Oral suspension Paracetamol NSAID, Analgesic, 379
200,000 in NaCl
Antipyretic
Haes-Steril 10% - Solution for injection Poly(0-2 Hydroxyethyl) Plasma volume expander 344
Ceporex - Capsules Cephalexin anhydrous Antibiotic, Cephalosporin 379
starch(HES) with m.wt
200,000 in NaCl Ceporex - Oral suspension Cephalexin anhydrous Antibiotic, Cephalosporin 379
Intralipid 10% - Infusion Linoleic, Alpha Linolenic Parenteral nutrition of 345 Combivir - f.c Tablets Lamivudine, Zidovudine Antiviral drug 380
acid fatty acids Cutivate - Cream Fluticasone propionate Corticosteroid, Topical 381
Intralipid 20% - Infusion Linoleic, Alpha Linolenic Parenteral nutrition of 345 Cutivate - Ointment Fluticasone propionate Corticosteroid, Topical 381
acid fatty acids Dermovate - Scalp application Clobetasol propionate. Corticosteroid, Topical 381
Peditrace - Injection Trace Element Parenteral nutrition of 346 Eltroxin - Tablets Thyroxine sodium anhydrous Thyroid hormone 381
trace elements
Engerix B - Suspension for injection Hepatitis B Surface Vaccine 382
Propofol Fresenius Propofol Anaesthetic, Short acting 346, antigen HBsAg
Emulsion for injection general anaesthetic 347
Epivir - Oral solution Lamivudine Antiviral drug 383
Vamin 18 EF-IV Infusion Amino acid Parenteral nutrition of 348
Eumovate - Cream Clobetasone butyrate Corticosteroid, Topical 384
amino acids
Voluven - Solution for injection Poly(0-2 Hydroxyethyl) Plasma volume expander 348 Eumovate - Ointment Clobetasone butyrate Corticosteroid, Topical 384
starch(HES) with m.wt Flixonase Aqueous Nasal Spray Fluticasone propionate Corticosteroid, Anti-ina- 384
130,000 in NaCl -mmatory, Topical
Flixotide Nebules Fluticasone propionate Anti-asthmatic, 385
GALDERMA 348 Corticosteroid
Flixotide Diskus Fluticasone propionate Anti-asthmatic, 386
Benzac AC - Gel Benzoyl peroxide Acne treatment, Topical 348
Corticosteroid
Differin - Cream Adapalene Acne treatment, Topical 349
Flixotide Evohaler Fluticasone propionate Anti-asthmatic, 387,
Differin - Gel Adapalene Acne treatment, Topical 349 Corticosteroid 388
Efcort - Cream Hydrocortisone aceponate Corticosteroid, Topical 349 Floxapen - Capsules Flucloxacillin sodium Antibiotic, Penicillinase- 390
Efcort - Lipophilic Cream Hydrocortisone aceponate Corticosteroid, Topical 350 resistant penicillin
11
MANUFACTURERS INDEX
Floxapen - Injection Flucloxacillin sodium Antibiotic, Penicillinase- 390 Priorix - Reconst. for injection Schwarz Measles/rit4385 Vaccine 426
resistant penicillin Mumps(derived from Jeryl
Floxapen - Powder for oral suspension Flucloxacillin magnesium Antibiotic, Penicillinase- 390 lynn strain)/Wistar Ra 27/3
resistant penicillin Rubella strain of viruses
Fluarix - Suspension for injection Inactivated inuenza vaccine Vaccine 391 Relanza - Disk Haler Zanamivir Antiviral drug 427
(Split Virion) Relifex - Tablets Nabumetone. NSAID, Anti-arthritis 427
Fortum Ciftazidime(as pentahydrate), Antibiotic, Cephalosporin 392 Retrovir - Capsules Zidovudine. Antiviral drug 428
Powder for solution for injection Sodium carbonate
Retrovir - Oral suspension Zidovudine. Antiviral drug 428
Havrix 1440 Adult Hepatitis A Virus Vaccine 393
Rotarix - Oral Vaccine Live attenuated human Vaccine 429
Suspension for injection
Rotavirus Rix4414 strain
Havrix720 Junior Hepatitis A Virus Vaccine 393
Septrin - Tablets Trimethoprim, Antibiotic, Co-trimoxazole 432
Suspension for injection
Sulphamethoxazole
Hepsera - Tablets Adefovir diplvoxil Antiviral drug 394
Septrin Forte - Tablets Trimethoprim, Antibiotic, Co-trimoxazole 432
Hiberix - Injection Polyribosyl-ribitol-phosphate Vaccine 396 Sulphamethoxazole
Capsular polysaccharide,
Tetanus taxoid Septrin - Ampoules Trimethoprim, Antibiotic, Co-trimoxazole 433
Sulphamethoxazole
Imigran Nasal Spray Sumatriptan Antimigraine drug, 396
5-HT1agonist Septrin - Oral suspension Trimethoprim, Antibiotic, Co-trimoxazole 432
Sulphamethoxazole
Imigran - Injection Sumatriptan, as the Antimigraine drug, 398
succinate salt. 5-HT1agonist Seretide Diskus - Inhaler Salmeterol xinafoate, Anti-asthmatic, 434
Imigran - Tablets Sumatriptan(as succinate) Antimigraine drug, 399 Fluticasone proprionate Selective beta2 agonist
5-HT1 agonist & Corticosteroid
Imuran - Tablet Azathioprine Sodium Immunosuppressant, 400 Seretide Evohaler Salmeterol, Anti-asthmatic, 435
Antimetabolite Fluticasone propionate Selective beta2
agonist & Corticosteroid
Infanrix - HIB Injection Diphtheria toxoid, Tetanus Vaccine 404
toxoid, Three Puried Serevent Diskus Salmeterol (as xinafoate) Anti-asthmatic, 436
Pertussis antigens and Lactose. Bronchodilator,
(PT,FHA,Pertactin) Selective beta2 agonist
Infanrix Hexa - Powder for suspension Tetanus, Pertusis, Vaccine 403 Serevent Inhaler Salmeterol Anti-asthmatic, 437
for injection Diphtheria, Hepatitis B, Polio (as the xinafoate) Bronchodilator,
and Haemophilus vaccine Selective beta2 agonist
Infanrix - Suspension for injection Diphtheria toxoid, Tetanus Vaccine 402 Seroxat CR - Tablets Paroxetine hydrochloride Antidepressant, 438
toxoid, Pertussis toxoid, Selective serotonin
Filamentous Haemagglutinin, re-uptake inhibitor
pertactin Solpadien - Capsules Paracetamol, Caffeine, NSAID, Analgesic, 440
Infanrix - IPV+HIB. Injection Combined Diphtheria- Vaccine 405 Codeine phosphate Antipyretic
Tetanus-Acellular Pertussis, Solpadein Soluble - Tablets Paracetamol, Caffeine, NSAID, Analgesic, 440
Inactivated Polio and Codeine phosphate Antipyretic
Haemophilus Inuenzae
Type B Vaccine. Supravit - Capsules Multivitamins, Folic acid, Multivitamin & 441
Minerals, Essential amino Mineral preparation
Kemadrin - Injections Procyclidine hydrochloride Antiparkinsonism, 406
acids
Antimuscarinic drug
Tracrium - Injection Atracurium besylate Muscle relaxant 441
Kemadrin - Tablets Procyclidine hydrochloride Antiparkinsonism, 406
Antimuscarinic drug Trandate - Injection Labetalol hydrochloride Antihypertensive, 443
Anti-anginal,
Lamictal - Dispersible Tablets Lamatrigine Anti-epileptic drug, 407
Anti-arrythmic,
Phenyltriazine compound
Lamictal - Tablets Lamatrigine Anti-epileptic drug, 407
Trandate - Tablets Labetalol hydrochloride Antihypertensive, 442
Phenyltriazine compound
Anti-anginal, Alpha,
Lanoxin - Injection Digoxin Cardiac glycoside 410
Lanoxin - PG - Elixir Digoxin Cardiac glycoside 410
Tritanrix-HB - Suspension for injection Diphtheria toxoid, Tetanus Vaccine 444
Lanoxin - PG - Tablets Digoxin Cardiac glycoside 410
toxoid, PW, Recombinant
Lanoxin - Tablets Digoxin Cardiac glycoside 410 HbsAG Protein
Lanvis - Tablets Thioguanine Anticancer, Antimetabolite 411 Tritanrix Hb+hiberix Injection Combined Diphtheria, Vaccine 444
Leukeran - Tablets Chlorambucil Anticancer, Alkylating 412 Tetanus, Whole Cell Pertussis,
agent Hepatitis Band Haemophilus
Mencevax ACWY Polysaccharide from Vaccine 413 Inuenzae Type B
Powder for solution for injection Neisseria meninigitis Twinrix Adult - Suspension for injection Inactivated H A Virus, Vaccine 445
Midarine - Injection solution Suxamethonium chloride Muscle relaxant 414 Recombinant HbsAG
Mivacron - Injection Mivacurium chloride Muscle relaxant 415 Typherix - Solution for injection Surface VI Polysaccharide Vaccine 446
Myleran - Tablets Busulphan Anticancer, Alkylating 417 of Salmonella typhii
agent Ultiva - Injection Remifentanil hydrochloride. Opioid Analgesic 447
Nimbex - Injection Cisatracurium besylate Muscle relaxant 419 Valtrex - Tablets Valaciclovir Antiviral drug 450
Otosporin - Eardrops Polymyxin B sulphate, Antibiotic & 420 Varilrix - Injection Live attenuated oka strain Vaccine 451
Neomycin sulphate, Anti-inammatory, Topical of Varicella-zoster Virus
Hydrocortisone
Ventolin - Evoholer Solbutamol sulphate Anti-asthmatic, 452
Panadol Actifast - f.c Tablets Paracetamol, Sodium NSAID, Analgesic, 421 Selective beta2 -agonist
bicarbonate Antipyretic
Ventolin - Injection Salbutamol as sulphate Anti-asthmatic, 453
Panadol Cold & Flu Caplets Paracetamol, NSAID, Analgesic, 421 Management of
Chlorpheniramine maleate, Antipyretic, premature labour,
Pseudoephedrine Sympathomimetic, Selective beta2 agonist
hydrochloride Antihistamine
Ventolin Respirator solution Salbutamol as sulphate. Anti-asthmatic, 452
Panadol Extra - Tablets Paracetamol, Caffeine NSAID, Analgesic, 422
Bronchodilator,
Antipyretic
Selective beta2 agonist
Panadol Night - Caplets Paracetamol, NSAID, Analgesic, 422
Ventolin Diskus - Inhaler Salbutamol as sulphate. Anti-asthmatic, 454
Diphenhydramine Antipyretic, Antihistamine
Bronchodilator,
hydrochloride
Panadol Sinus - Caplets Paracetamol, NSAID, Analgesic, 423
Pseudoephedrine Antipyretic, Ventolin CR - Tablets Salbutamol as sulphate. Anti-asthmatic, 452
hydrochloride Sympathomimetic Bronchodilator,
Panadol Soluble - Tablets Paracetamol NSAID, Analgesic, 423
Antipyretic Ventolin - Rotacap Salbutamol as sulphate. Anti-asthmatic, 455
Bronchodilator,
Panadol - Tablet Paracetamol NSAID, Analgesic, 423
Antipyretic
Ventolin - Syrup Salbutamol as sulphate. Anti-asthmatic, 452
Pentostam - Injection Sodium Stibogluconate Leishmaniasis treatment 424
Bronchodilator,
drug, Pentavalent
Antimony Compound Selective beta2 agonist
Polio Sabin (Oral)suspension Poliomyelitis viruses of Vaccine 425 Ventolin - Tablets Salbutamol as sulphate. Anti-asthmatic, 452
the sabin strains type Bronchodilator,
1 (LSc, 2ab), Type 2 Selective beta2 agonist
(P712 Ch, 2ab) and Type 3 Zantac - EFF. Tablets Ranitidine (as hydrochloride)/ Antacid, Ulcer-healing, 456
(Leon 12a, 1b) sodium H2-receptor antagonist
12
MANUFACTURERS INDEX
Zantac 75 - Tablets Ranitidine (as hydrochloride) Antacid, Ulcer-healing, 455 Fluanxol - Tablet Flupentixol dihydrochloride Antidepressant, 488
H2-receptor antagonist Anti-psychotic
Zantac - Injection Ranitidine (as hydrochloride) Antacid, Ulcer-healing, 456 Fluanxol Depot - Oily injection uid Flupentixol decanoate Antidepressant, 489
H2-receptor antagonist Anti-psychotic
Zantac - Tablets Ranitidine (as hydrochloride) Antacid, Ulcer-healing, 456 Nortrilen - Tablet Nortriptyline hydrochloride Antidepressant, 490
H2-receptor antagonist Tricyclic antidepressant
Zefx - F.C Tablets / Suspension Lamivudine Antiviral drug 457 Saroten Retard - Capsules Amitriptyline hydrochloride Antidepressant, 490
Ziagen - Oral suspension Abacavir sulphate Antiviral drug 458 Tricyclic antidepressant
Ziagen - Tablets Abacavir sulfate. Antiviral drug 460 Truxal - Tablet Chlorprothixene Antipsychotic drug 491
hydrochloride
Zinacef - Suspension for injection Cefuroxime sodium Antibiotic, Cephalosporin 463
Zinnat - Oral suspension Cefuroxime axetil Antibiotic, Cephalosporin 464 HAYATH PHARMA 492
Zinnat - Tablets Cefuroxime axetil Antibiotic, Cephalosporin 464
Acnelin - Cream Tretinoin Acne treatment, Topical 492
Zofran - Injection Ondansetron HCl.dihydrate Anti-emetic, 5-HT3 465
receptor antagonist Ciproquin - Tablets Ciprooxacin HCl Antibiotic, Quinolone 492
Zofran - Tablets Ondansetron HCl.dihydrate Anti-emetic, 5-HT3 465 Clotrex - Ear drops Clotrimazole Antifungal, Otic 492
receptor antagonist Deat - Oral drops Simethicone Antiatulant, Antifoaming 493
agent
Zofran - Syrup Ondansetron HCl.dihydrate Anti-emetic, 5-HT3 466
receptor antagonist Derma Coryl- Cream Econazole nitrate Antifungal, Topical 493
Zovirax DS - Suspension Acyclovir Antiviral drug 468 Gyno Coryl - Ovoules Econazole nitrate Antifungal, Imidazole 493
Zovirax - Ophthalmic ointment Acyclovir Antiviral drug, Ophthalmic 466 Locagel - Gel Diclofenac diethylamine NSAID, Anti-rheumatic, 494
Analgesic, Topical
Zovirax - Injection Acyclovir Antiviral drug 467
Protogyn - Tablets Tinidazole Anti-protozoal, 494
Zovirax - Cream Acyclovir Antiviral drug, Topical 468
Anti-anaerobic
Zovirax - Suspension Acyclovir Antiviral drug 468
Topicort - Cream Hydrocortisone acetate Corticosteroid, Topical 494
Zovirax - Tablets Acyclovir Antiviral drug 468
Zyloric - Tablet Allopurinol Gout & Cytotoxic - 469 HIKMA PHARMACEUTICALS 495
induced hyperuricaemia
Alpax-injection Pancuronium bromide Muscle relaxant 495
treatment drug
Amoclan Forte - Oral suspension Amoxycillin trihydrate and Antibiotic, 495
GLOBAL PHARMA 470 Potassium clavulanate Broad-spectrum penicillin
Amoclan Forte - Tablets Amoxycillin trihydrate and Antibiotic, 495
Emidol - Suspension Paracetamol NSAID, Analgesic, 470 Potassium clavulanate Broad-spectrum penicillin
Antipyretic
Amoclan IV - Injection Amoxycillin sodium and Antibiotic, 496
Emidol -Syrup Paracetamol NSAID, Analgesic, 470 Potassium clavulanate Broad-spectrum penicillin
Antipyretic
Amoclan - Oral suspension Amoxycillin trihydrate and Antibiotic, 495
Emidol -Tablets Paracetamol NSAID, Analgesic, 470 Potassium clavulanate Broad-spectrum penicillin
Antipyretic
Amoclan - Tablets Amoxycillin trihydrate and Antibiotic, 495
Emifen -f.c Tablets Ibuprofen NSAID, Analgesic, 471 Potassium clavulanate Broad-spectrum penicillin
Antipyretic
Atacure - Injection Atracurium besylate Muscle relaxant 497
Emifen - Oral suspension Ibuprofen NSAID, Analgesic, 471
Bucaine - Injection Bupivacaine HCl Anaesthesia, Local 497
Antipyretic
Cefamezin IM/IV - Injection Cefazolin sodium Antibiotic, Cephalosporin 498
Gloclav - f.c Tablets Amoxicillin trihydrate, Antibiotic, 471
Potassium clavulanate Broad-spectrum penicillin Cezox IV/IM Injection Sterile Ceftizoxime sodium Antibiotic, Cephalosporin 498
Glomox - Capsules Amoxicillin trihydrate Antibiotic, 472 Ceftax IV/IM Injection Cefotaxime sodium Antibiotic, Cephalosporin 499
Broad-spectrum penicillin Ciprolon-f.c Tablet Ciprooxacin HCl Antibiotic, Quinolone 499
Glomox - Dispersible Tablets Amoxicillin trihydrate Antibiotic, 472 Ciprolon - Injection Ciprooxacin as lactate Antibiotic, Quinolone 500
Broad-spectrum penicillin Ciptadine - Tablets Cyproheptadine Antihistamine, 500
Glomox - Suspension Amoxicillin trihydrate Antibiotic, 472 hydrochloride Appetite stimulant
Broad-spectrum penicillin (as sesquihydrate)
Glormin - Tablets Atenolol Antihypertensive, 472 Contrasal - Syrup Dextromethorphan Antitussive 501
Anti-anginal, hydrobromide
Anti-arrythmic, Dansetron - Injections Ondansetron as Anti-emetic, 5-HT3 501
Beta-adrenoceptor blocker hydrochloride dihydrate receptor antagonist
Glotac - f.c Tablets Ranitidine hydrochloride Antacid, Ulcer-healing, 473 Diaxine - Tablets Diphenoxylate HCl, Antimotility drug 502
H2-receptor antagonist Atropine sulfate
Glotrizine - Syrup Cetirizine dihydrochloride Antihistamine, 474 Dolomol - Tablets Paracetamol NSAID, Analgesic, 502
Non-sedating Antipyretic
Dolomol - Drop Paracetamol NSAID, Analgesic, 502
GRUNENTHAL GMBH 474 Antipyretic
Procto-Synalar - Ointment Fluocinolone acetonide, Corticosteroid, 474 Dolomol - Suppositories Paracetamol NSAID, Analgesic, 502
Lignocaine hydrochloride Anaesthetic, Local Antipyretic
Proxen -f.c Tablets Naproxen NSAID, 474, Dolomol - Syrup Paracetamol NSAID, Analgesic, 502
Anti- Arthritis, Analgesic 476 Antipyretic
Doral S.F - Injection Cephradine with arginine Antibiotic, 502
Tramal - Ampoules Tramadol hydrochloride Opioid Analgesic 477
Cephalosporin
Tramal - Capsules Tramadol hydrochloride Opioid Analgesic 479
Fendol D.S - Tablets Mefenamic acid NSAID, Analgesic, 502
Tramal Retard - p.r Tablets Tramadol hydrochloride Opioid Analgesic 480 Antipyretic
Tramal - Suppositories Tramadol hydrochloride Opioid Analgesic 481 Fendol - Capsule Mefenamic acid NSAID, Analgesic, 502
Zaldiar - Tablets Tramadol hydrochloride, NSAID, Analgesic, 482 Antipyretic
Paracetamol Antipyretic Fendol - Oral suspension Mefenamic acid NSAID, Analgesic, 502
Antipyretic
H. LUNDBECK A/S 483
Feral - Capsules Ferrous sulfate and Haematinic, Erythropoietic 503
Cipralex - Tablets Escitalopram as oxalate Antidepressant, 483 Folic acid for Iron & Folic acid
Selective serotonin Deciency Anaemia
re-uptake inhibitor Floran - Liquid for inhalation Isourane Anaesthetic, Volatile 503
Cipram - Tablets Citalopram hydrobromide Antidepressant, 485 Flucand - Capsules Fluconazole Antifungal, Triazole 504
Selective serotonin Flucand - Injection Fluconazole Antifungal, Triazole 504
re-uptake inhibitor
Glibil 5 - Tablets Glibenclamide Antidiabetic drug oral, 504
Clopixol - Tablets Zuclopenthixol Antipsychotic drug, 486 Sulphonyl urea
dihydrochloride Thioxanthene Glorion - Tablets Glimepiride Antidiabetic drug oral, 505
Clopixol-Acuphase - Oily injection uid Zuclopenthixol acetate Antipsychotic drug, 486 Sulphonyl urea
Thioxanthene Hikma Midazolam - Injection Midazolam Anaesthesia, 506
Clopixol Depot - Oily injection uid Zuclopenthixol decanoate Antipsychotic drug, 487 Short acting barbiturate
Thioxanthene Hydrosone - Tablets Hydrocortisone Corticosteroid 507
Clopixol - Aqueous injection uid Zuclopenthixol Antipsychotic drug, 486 Hypoten - Tablets Atenolol Antihypertensive, 507
dihydrochloride Thioxanthene Anti-anginal,
Clopixol - Drops Zuclopenthixol Antipsychotic drug, 486 Anti-arrythmic, eta
dihydrochloride Thioxanthene -blocker
13
MANUFACTURERS INDEX
Indomin - Capsule Indomethacin NSAID, Analgesic, 508 Levophed - Injection Norepinephrine bitartrate Adrenergic receptor 528
Antipyretic stimulator in acute
Indomin - Suppository Indomethacin NSAID, Analgesic, 508 hypotension, Cardiac
Antipyretic arrest
Lexin - Capsules Cephalexin monohydrate Antibiotic, Cephalosporin 508 Lidocaine hydrochloride Injection Lidocaine hydrochloride Anti-arrythmic drug 529
Lexin - Oral suspension Cephalexin monohydrate Antibiotic, Cephalosporin 508 Metronidazole Injection Metronidazole Anti-protozoal, 530
Lexin Tablets Cephalexin monohydrate Antibiotic, Cephalosporin 508 Anti-anaerobic
Maxil IV/IM Injection Cefuroxime sodium Antibiotic, Cephalosporin 508 Potassium acetate Injection Potassium acetate Parenteral preparation 532
for potassium deciency
Maxil 750 IM/IV Cefuroxime sodium Antibiotic, Cephalosporin 508
Potassium chloride Injection Potassium chloride Parenteral preparation 533
Miacin - Injection Amikacin sulphate Antibiotic, Aminoglycoside 509
for potassium deciency
Naprox DS- Tablets Naproxen sodium NSAID, Analgesic, 509
Potassium Phosphates Injection Mono & Dibasic Potassium Parenteral preparation 534
Antipyretic
phosphates for potassium deciency
Naprox - Tablets Naproxen sodium NSAID, 509
Precedex- Injection Dexmedetomidine Sedative, Selective 534
Analgesic, Antipyretic
hydrochloride alpha 2- adrenoceptor
Naxone - Injection Naloxone HCl Opioid antagonist 510 agonist
Neurovitan - Tablets Octotiamine, Riboavine (B2), Neuro, Musculotropic 510 Sodium acetate Injection Sodium acetate Parenteral preparation 537
Pyridoxine hydrochloride, vitamin complex
for sodium imbalance
cyanocobalamin (B12)
Sodium bicarbonate Injection Sodium bicarbonate Parenteral preparation of 538
Nidazole - Tablets Metronidazole benzoate Anti-protozoal, 510
electrolyte replenisher,
Anti-anaerobic
Systemic alkalizer
Nidazole - Suspension Metronidazole benzoate Anti-protozoal, 510
Sodium chloride Injection Sodium chloride Parenteral preparation 538
Anti-anaerobic
for uid & electrolyte
Nufen - Tablets Ibuprofen NSAID, Analgesic, 510 imbalance
Antipyretic
Sodium Phosphates Injection Sodium phosphates Parenteral preparation 539
Oprazole - e.c Tablets Omeprazole Antacid, Ulcer-healing, 511 for uid & phosphorous
Proton pump inhibitor deciency
Orvek - Syrup penicillin V potassium Antibiotic, Semisynthetic 511
penicillin IBSA 540
Penamox - Capsules Amoxycillin as trihydrate Antibiotic, 512
Choriomon - Injection Highly puried Human Ovulation inducing drug 540
Broad-spectrum penicillin
Chorionic Gonadotropin(HCG)
Penamox - Oral suspension Amoxycillin as trihydrate Antibiotic, 512
Broad-spectrum penicillin Flector EP Tissugel - Plaster Diclofenac epolamine NSAID, Analgesic, 541
Anti-rheumatic, Topical
Poxidium - Tablets Chlordiazepoxide, Anxiolytic, 512
Clidinium bromide Anti-spasmodic, Fostimon - Injection Highly puried human Ovulation inducing drug 542
Antisecretory follicle stimulating hormone
Prograf - Capsules Tacrolimus Immmuno-suppressive 512 Merional - Injection Human follicular stimulating Human follicular stimulator 543
agent hormone (FSH), Human in infertile women
leutinizing hormone
Purinol - Tablets Allopurinol Gout & cytotoxic- 513
induced hyperuricaemia JAMJOOM PHARMA 544
treatment drug
Restamine - Syrup Loratadine Antihistamine, 514 Aciloc - Capsules Omeprazole Antacid, Ulcer-healing, 544
Non-sedating Proton pump inhibitor
Restamine - Tablets Loratadine Antihistamine, 514 Acnezoyl - Gel Benzoyl peroxide hydrous Acne treatment, Topical 545
Non-sedating
Acretin - Cream Tretinoin Acne treatment, Topical 545
Riabal - Tablets Prinium bromide Antispasmodic & 514
Amvasc - Capsules Amlodipine Antihypertensive, 545
Drug altering gut motility
Anti-anginal,
Rolan 50 - Injection Ranitidine HCl Antacid, Ulcer-healing, 514 Calcium-channel blocker
Azi-Once - Capsules Azithromycin dihydrate Antibiotic, Macrolide 546
Rythinate - Oral Suspension Erythromycin as Antibiotic, Macrolide 515
Azi-Once - Oral suspension Azithromycin dihydrate Antibiotic, Macrolide 546
ethylsuccinate
Betazol- Cream Betamethasone dipropionate, Corticosteroid, Anti-fungal 547
Samixon IV/ IM Injection Ceftriaxone sodium Antibiotic, Cephalosporin 515
Miconazole nitrate & antibacterial prep-topical
Suprax - Capsules Cexime as trihydrate Antibiotic, Cephalosporin 516
Betazol G - Cream Betamethasone dipropionate, Corticosteroid, 547
Suprax - Suspension Cexime as trihydrate Antibiotic, Cephalosporin 516 Gentamicin sulphate, Antibacterial, Topical
Tanatril - Tablets Imidapril HCl Antihypertensive, 516 Miconazole nitrate
ACE inhibitor Ciproxen - f.c Tablets Ciprooxacin hydrochloride Antibiotic, Quinolone 547
Tekam - Injection Ketamine as HCl Anaesthesia, 516 Clara - Syrup Loratadine Antihistamine, 548
Intravenous Non-sedating
Totinal - Syrup Ketotifen as fumarate Anti-asthmatic, 517 Clara - Tablets Loratadine Antihistamine, 548
Anti-histamine Non-sedating
Trifed - Syrup Triprolidine HCl , Antihistamine, 517 Croma - Ophthalmic solution Sodium cromoglicate, Anti-allergic, Ophthalmic 548
Pseudoephedrine HCl Decongestant, Expectorant Tetrahydrozoline
Trifed - Tablets Triprolidine HCl, Antihistamine, 517 hydrochloride
Pseudoephedrine HCl Decongestant, Expectorant Dermizol - Gel Miconazole nitrate Antifungal & Antibacterial, 548
Votrex -Injection Diclofenac sodium NSAID, Analgesic, 517 Topical
Antipyretic, Anti-rheumatic
Dexaox - Ophthalmic suspension Ooxacin, Dexamethasone Corticosteroid, Antibiotic, 548
Votrex - Suppository Diclofenac sodium NSAID, Analgesic, 517 Topical
Dompy - Oral suspension Domperidone Anti-emetic, Dopamine 549
Votrex - Tablets Diclofenac sodium NSAID, Analgesic, 517 receptor antagonist
Dompy - Tablets Domperidone Anti-emetic, Dopamine 549
Zenos - Injections Dexamethasone Corticosteroid, 517 receptor antagonist
phosphate (as sodium) Anti-inammatory
Duracan - Capsules Fluconazole Antifungal, Triazole 549
HOSPIRA 518 Elica-M - Cream Mometasone furoate, Corticosteroid, Antifungal 550
Miconazole nitrate & Antibacterial prep,
4 Trace Elements - Injection Zinc chloride, Cupric Parenteral preparation 518 Topical
chloride, Manganese of trace elements for Elica - Cream Mometasone furoate Corticosteroid, Topical 550
chloride, Chromic Total Parenteral Nutrition
chloride, Sodium chloride. (TPN) Elica - Ointment Mometasone furoate Corticosteroid, Topical 550
10% w/v Calcium chloride Injection Calcium chloride dihydrate Calcium supplement 519 Elicasal - Ointment Mometasone furoate, Corticosteroid, Topical 550
Salicylic acid
Aminophylline - Injection Aminophylline dihydrate Anti-asthmatic, 520
Bronchodilator Fluca - Ophthalmic suspension Sodium cromoglicate, Anti-allergic, Ophthalmic 551
uorometholone
Atropine sulfate - Injection Atropine sulfate monohydrate Antimuscarinic drug 525
Fusibact B - Cream Fusidic acid , Betamethasone Antibacterial, Topical 551
Dextrose 5% Injection Dextrose hydrous Parenteral preparation for 526
valerate
Fluid & Calorie supply
Fusibact - Cream Fusidic acid Antibacterial, Topical 551
Dextrose 10% - Injection Dextrose hydrous Parenteral preparation for 526
Energy supply & Fusibact - Ointment Sodium fusidate Antibacterial, Topical 551
Hypoglycaemia Hyfresh - Ophthalmic solution Sodium hyaluronate Lubricant, Ophthalmic 551
Epinephrine- Injection Epinephrine Sympathomimetic 527 Lamifen - Cream Terbinane hydrochloride Antifungal, Topical 552
14
MANUFACTURERS INDEX
Lamifen - Tablets Terbinane hydrochloride Antifungal, Squalein 552 Haldol - Injection solution Haloperidol Antipsychotic drug 586
epoxidase enzyme Haldol - Oral drops Haloperidol Antipsychotic drug 586
inhibitor
Haldol - Tablets Haloperidol Antipsychotic drug 586
Lisino - Tablets Lisinopril dihydrate Antihypertensive, 552 Imodium - Capsules Loperamide hydrochloride Anti-diarrhoeal, 588
ACE inhibitor Antimotility drug
Loxtra - Ophthalmic suspension Ooxacin, Prednisolone Corticosteroid, Antibiotic, 553 Livostin Eye drops Levocabastine Antihistamine, Ophthalmic 589
acetate, Tetrahydrozoline HCl Topical
Livostin Nasal spray Levocabastine hydrochloride Antihistamine, Topical 589
Meva - Capsules Mebeverine HCl Antispasmodic & drug 553
Motilium Supp for adult Domperidone Anti-emetic, Dopamine 590
altering gut motility,
receptor antagonist
Relaxant Motilium Supp for child Domperidone Anti-emetic, Dopamine 590
receptor antagonist
Momenta - Cream Mometasone, Miconazole Corticosteroid & 554
, Gentamicin Antifungal, Topical Motilium Supp for infants Domperidone Anti-emetic, Dopamine 590
receptor antagonist
Neurocom I.M - Injection Vitamin B1,Vitamin B6, Vitamin B Complex 554
Vitamin B12 Motilium - Suspension Domperidone Anti-emetic, Dopamine 590
receptor antagonist
Optichlor - Ophthalmic solution Chloramphenicol Antibiotic, Ophthalmic 554
Motilium - Tablets Domperidone Anti-emetic, Dopamine 590
Opticin - Ophthalmic solution Ciprooxacin HCl Antibiotic, Quinolone, 554 receptor antagonist
Ophthalmic
Nizoral - Tablets Ketoconazole. Antifungal, Imidazole 591
Optidex T - Ophthalmic suspension Tobramycin, Dexamethasone Antibacterial, Topical 554
Nizoral Cream Ketoconazole Antifungal, Topical 592
Optidrin - Ophthalmic solution Sodium cromoglicate Anti-allergic, Ophthalmic 555
Nizoral Shampoo Ketoconazole Antifungal, Topical 593
Optiox - Ophthalmic solution Ooxacin Antibiotic, Quinolone, 555
Parafon - Capsules Chlorzoxazone, Paracetamol Skeletal muscle relaxant, 593
Ophthalmic
Non-opiod analgesic
Optifresh - Ophthalmic solution Polyvinyl alcohol, Povidone Lubricant, Ophthalmic 555
Pariet - g.r Tablets Rabeprazole sodium Antacid, Ulcer-healing, 594
Optilone - Ophthalmic suspension Fluorometholone, Liquilm Corticosteroid, Topical 555 Proton pump inhibitor
Optimol - Sterile ophthalmic Timolol maleate Glaucoma treatment drug, 556 Pevaryl - Spray powder Econazole Antifungal, Local 596
Suspension Beta 1, 2 Adrenergic Pevaryl - Spray solution Econazole Antifungal, Topical 596
blocker
Pevisone - Cream Econazole nitrate, Antifungal & 597
Optipred Prednisolone acetate Corticosteroid, Ophthalmic 556 Triamcinolone acetonide. Corticosteroid, Topical
Sterile Ophthalmic Suspension
Rapifen-IV Injection Alfentanil hydrochloride Opioid analgesic, 597
Optizolin - Eyedrop Antazoline hydrochloride, Anti Inammatory, 556 Anaesthetic
Tetrahydrozoline Ophthalmic
Reminyl - Oral solution Galantamine hydrobromide Dementia of Alzheimers 599
hydrochloride
disease treatment,
Preslo - f.c Tablets Atenolol Antihypertensive, 556 Reversible
Anti-anginal, anticholinesterase
Anti-arrythmic,
Reminyl - Tablets Galantamine hydrobromide Dementia of Alzheimers 599
1-adrenoceptor blocker
disease treatment,
Relaxon - Capsule Chlorzoxazone, Paracetamol Skeletal Muscle Relaxant, 557 Reversible
Non-opiod Analgesic anticholinesterase
Salibet - Ointment Betamethasone, Salicylic acid Corticosteroid, Topical 557 Retin-A - Cream Tretinoin Acne treatment, Topical 601
Vividrin - Eyedrop Sodium cromoglicate Anti-allergic, Ophthalmic 557 Retin-A- Gel Tretinoin Acne treatment, Topical 601
Voltic - e.c Tablets Diclofenac sodium NSAID, Antirheumatic, 557 Retin-A- Solution Tretinoin Acne treatment, Topical 601
Analgesic, Antipyretic Risperdal Consta - p.r Tablet Risperidone Antipsychotic drug 602
Voltic - Injection Diclofenac sodium NSAID, Antirheumatic, 558 Risperdal - f.c Tablet Risperidone Antipsychotic drug 604
Analgesic, Antipyretic Risperdal - Oral suspension Risperidone Antipsychotic drug 604
Xola - Sterile ophthalmic suspension Dorzolamide hydrochloride Glaucoma treatment drug, 559 Sibelium - Capsules Flunarizine hydrochloride Antimigraine drug 606
Carbonic anhydrase
Sporanox - Capsules Itraconazole Antifungal, Triazole 606
Inhibitor
Stugeron - Tablets Cinnarizine Antihistamine, Nausea & 609
Xolamol Dorzolamide hydrochloride, Glaucoma treatment 559 Vertigo
Sterile ophthalmic suspension Timolol maleate drug, Carbonic anhydrase Sufenta - Aqueous solution Sufentanil citrate Opioid Analgesic, 610
Inhibitor Anaesthetic
Zydac 75 - Tablet Ranitidine HCl Antacid, Ulcer-healing, 560 Sufenta Forte - Aqueous solution Sufentanil citrate Opioid Analgesic, 610
H2-receptor antagonist Anaesthetic
Zydac I.V/I.M - Injection Ranitidine HCl Antacid, Ulcer-healing, 560 Topamax - f.c Tablets Topiramate Anti-epileptic drug 611
H2-receptor antagonist Tylenol Forte - Tablets Paracetamol NSAID, Analgesic, 615
Zydac - Tablets Ranitidine hydrochloride Antacid, Ulcer-healing, 561 Antipyretic
H2-receptor antagonist Tylenol - Suppository Paracetamol NSAID, Analgesic, 615
Antipyretic
JANSSEN CILAG 561
Velcade - Injection Bortezomib Anticancer, Cytotoxic 616
Cilest - Tablets Norgestimate,Ethinyl Combined hormonal 561 drug
estradiol contraceptive, Oral Vermox - Suspension Mebendazole Anthelmintic 619
Concerta - Tablets Methylphenidate CNS Stimulant 564 Vermox - Tablet Mebendazole Anthelmintic 619
hydrochloride
Concerta - e.r Tablets Methylphenidate CNS Stimulant 564 JAZEERA PHARMACEUTICALS INDUSTRIES 620
hydrochloride Anazol - Suspension Metronidazole Anti-protozoal, 620
Daktacort - Cream Miconazole, Hydrocortisone Antifungal & 566 Anti-anaerobic
Corticosteroid, Topical Anazol - Tablets Metronidazole Anti-protozoal, 620
Daktarin - Powder Miconazole nitrate Antifungal & Antibacterial, 566 Anti-anaerobic
Topical Biocef - Suspension Cefaclor as monohydrate Antibiotic, Cephalosporin 620
Daktarin - Cream Miconazole nitrate Antifungal & Antibacterial, 566 Biocef - Capules Cefaclor as monohydrate Antibiotic, Cephalosporin 620
Topical
Cefadin - Capsules Cephradine Antibiotic, Cephalosporin 621
Daktarin - Oral gel Miconazole nitrate Antifungal, Topical 568
Cefadrox - Capsules Cefadroxil as monohydrate Antibiotic, Cephalosporin 621
Daktarin - Topical tincture Miconazole nitrate Antifungal, Topical 566
Cefadrox - Suspension Cefadroxil as monohydrate Antibiotic, Cephalosporin 621
Durogesic - Transdermal patch Fentanyl base Opioid Analgesic 568 Cefaxon - Injection Ceftriaxone sodium Antibiotic, Cephalosporin 622
Eprex - Injection Epoetinum alfa. Erythropoiesis stimulating 570, Cefox - Injection Cefuroxime sodium Antibiotic, Cephalosporin 622
agent, Recombinant 574
Cetamol - Suppositories Paracetamol NSAID, Analgesic, 623

Antipyretic
Evra Transdermal patch Norelgestromin (NGMN) and Combined hormonal 578
Diclomax - Tablets Diclofenac diethylamine NSAID, Analgesic, 623
Ethinylestradiol contraceptive
Fentanyl - Isotonic aqueous solution Fentanyl Opioid Analgesic 581
Diclomax 1% - Emulgel Diclofenac diethylamine NSAID, Anti-rheumatic, 623
Gyno-Daktarin - Vaginal capsules Miconazole nitrate Antifungal & Antibacterial, 582 Analgesic, Topical
Local
Diclomax - Suppositories Diclofenac diethylamine NSAID, Analgesic, 623
Gyno-Daktarin - Vaginal cream Miconazole nitrate Antifungal & Antibacterial, 582 Antipyretic, Anti-rheumatic
Topical
Duspamen - Tablets Mebeverine HCl Antispasmodic & Drug 624
Gyno-Pevaryl - Ovoules Econazole nitrate Antifungal, Local 583 altering gut motility,
Haldol Decanoate Haloperidol decanoate. Antipsychotic drug 584 Intestinal smooth muscle
Solution for injection relaxant
15
MANUFACTURERS INDEX
Evorex - Capsules Fluoxetine as HCl Antidepressant, Selective 624 Zotrim - Suspension Sulfamethoxazole, Antibiotic, Co 634
Serotonin re-uptake Trimethoprim trimoxazole
Inhibitor
Fenam - Tablets Mefenamic acid NSAID, Analgesic, 624 JORIVER(JORDANIAN RIVER PHARMACEUTICAL INDUSTRIES) 634
Antipyretic Fusiver - Ointment Sodium fusidate Antibacterial, Topical 634
Fenam Forte - Tablets Mefenamic acid NSAID, Analgesic, 624 Joam - f.c Tablets Diclofenac potassium NSAID, Antirheumatic, 635
Antipyretic Antipyretic, Analgesic
Fenam - Syrup Mefenamic acid NSAID, Analgesic, 624 Micover H - Cream Miconazole nitrate USP, Antifungal, 635
Antipyretic Hydrocortisone USP Antibacterial &
Fucibet - Cream Fusidic acid and Antibacterial & 625 Corticosteroid, Topical
Betamethasone Corticosteroid preparation, Mucofree - Syrup Bromhexine hydrochloride Mucolytic 635
Topical
Noviral - Cream Acyclovir Antiviral drug, Topical 636
Glucare - Tablets Metformin HCl Antidiabetic drug oral, 625
Biguanide JPM (THE JORDANIAN PHARMACEUTICAL MANUFACTURING CO.) 636
Jazofen - Tablets Ibuprofen NSAID, Analgesic, 625
Antipyretic Amoxipen - Capsule Amoxicillin trihydrate Antibiotic, 636
Loramax - Syrup Loratadine Antihistamine, 625
Non-sedating Amoxipen - Oral suspension Amoxicillin trihydrate Antibiotic, 636
Loramax - Tablets Loratadine Antihistamine, 625
Non-sedating Angiotec - Tablets Enalapril maleate Antihypertensive, 637
ACE inhibitor
Megamox - Suspension Amoxycillin as trihydrate, Antibiotic, 626
Clavulanic acid Broad-spectrum penicillin Asmanore - Syrup Salbutamol sulphate Anti-asthmatic, 637
as Potassium Selective beta2- agonist
Megamox - Tablets Amoxycillin as trihydrate, Antibiotic, 626 Asmanore - Tablets Salbutamol sulphate Anti-asthmatic, Selective 637
Clavulanic acid Broad-spectrum penicillin beta2- agonist
as potassium Bactall - Tablets Ciprooxacin HCl Antibiotic, Quinolone 638
Micetal - Cream Flutrimazole Antifungal, Topical 626 Bendazole - Tablets Mebendazole Anthelmintic 638
Micetal - Gel Flutrimazole Antifungal, Topical 626 Bevacol - Tablets Mebeverine hydrochloride Antispasmodic & Drug 639
Micetal - Ointment Flutrimazole Antifungal, Topical 626 altering gut motility,
Intestinal smooth
Monocef - Capsules Cephalexin Antibiotic, Cephalosporin 627 muscle relaxant
Monocef - Suspension Cephalexin Antibiotic, Cephalosporin 627 Cobal - Tablets Mecobalamin Peripheral neuropathies 639
Normoten - Tablets Atenolol Antihypertensive, 627 treatment,vitamin B12
Anti-anginal, Coenzyme
Anti-arrythmic, Dopanore - Tablets Methyldopa Antihypertensive, 640
Beta-adrenoceptor blocker Centrally acting
Oam - Granules Diclofenac potassium NSAID, Analgesic, 627 Eracid - Tablets Clarithromycin Antibiotic, Macrolide 640
Antipyretic,
Fenadex - Tablets Fexofenadine hydrochloride Antihistamine, 641
Anti-rheumatic
Non-sedating
Omeral - Capsules Omeprazole Antacid, Ulcer-healing, 628
Lowrac - Capsule Amlodipine besylate Antihypertensive, 641
Proton pump inhibitor
Anti-anginal,
Omnicef - Capsules Cefdinir Antibiotic, Cephalosporin 628 Calcium-channel blocker
Omnicef - Suspension Cefdinir Antibiotic, Cephalosporin 628 Methacin - Capsules Indomethacin NSAID, Analgesic, 642
Paraxone - Capsules Chlorzoxazone, Paracetamol Skeletal muscle relaxant, 629 Antipyretic
Non-opiod analgesic Methacin - Suppository Indomethacin NSAID, Analgesic, 642
Pectal - Syrup Guaifenesin Expectorant 629 Antipyretic
Penetrex - Tablets Enoxacin Antibiotic, Quinolone 629 Metrozole - Tablets Metronidazole Anti-protozoal, 642
Ranimax - Tablets Ranitidine HCl Antacid, Ulcer-healing, 630 Anti-anaerobic
H2-receptor antagonist Mezacol - Tablets Mesalazine Chronic bowel disorder 643
Ranimax AC - Tablets Ranitidine HCl Antacid, Ulcer-healing, 630 treatment drug,
H2-receptor antagonist Aminosalicylate
Rectacure - Cream Tribenoside HCl and Anti-haemorrhoidal 630 Monozide - Tablets Hydrochlorothiazide Diuretic(thiazide), 643
Lidocaine Preparation, Local Antihypertensive,
Antiurolithic &
Remox - Suspension Amoxycillin as trihydrate Antibiotic, 630
Antidiuretic in diabetes
insipidus
Remox - Capsules Amoxycillin as trihydrate Antibiotic, 630
Noracin - Tablets Noroxacin Antibiotic, Quinolone 644
Noractone - Tablets Spironolactone Diuretic(potassium sparing) 644
Repaderm - Gel Aescin, Diethylamine Anti-swelling, 630
& Antihypertensive
salicylate Anti-inammatory &
Nortrime - Oral suspension Co-trimoxazole Antibiotic, 645
Analgesic, Topical
Sulphonamide &
Rinofed Plus - Syrup Triprolidine HCl , Antihistamine, 631 Trimethoprim preparation
Pseudoephedrine HCl, Decongestant, Analgesic
Nortrime - Tablets Co-trimoxazole Antibiotic, 645
Paracetamol & Antipyretic
Sulphonamide &
Rinofed Plus - Tablets Triprolidine HCl , Antihistamine, 631 Trimethoprim preparation
Pseudoephedrine HCl, Decongestant, Analgesic
Pylomid - Tablets Metoclopramide Anti-emetic, 646
Paracetamol & Antipyretic
hydrochloride Stimulates gut motility
Rinofed Expectorant - Syrup Triprolidine HCl, Antihistamine, 631
Ranidine - Tablets Ranitidine hydrochloride Antacid, Ulcer-healing, 646
Pseudoephedrine HCl, Decongestant, Expectorant
Guaifenesin
Razon - e.c Tablets Pantoprazole sodium Antacid, Ulcer-healing, 647
Rinofed - Syrup Triprolidine HCl , Antihistamine, 632
Pseudoephedrine HCl Nasal decongestant Proton pump inhibitor
Rinofed - Tablets Triprolidine HCl , Antihistamine, 632 Setral - Tablets Sertraline hydrochloride Antidepressant, Selective 648
serotonin re-uptake
Pseudoephedrine HCl Nasal decongestant
inhibitor
Romin - Syrup Dextromethorphan HBr Cough suppressant 632
Spasmonore - Suppository Hyoscine butylbromide Antispasmodic & drug 648
Solvex - Syrup Bromhexine HCl Mucolytic 632 altering gut motility,
Totam - Injection Cefotaxime sodium Antibiotic, Cephalosporin 632 Antimuscarinic
Xefo - Powder for injection Lornoxicam NSAID, Antirheumatic, 633 Spasmonore - Tablets Hyoscine butylbromide Antispasmodic & drug 648
Analgesic Altering gut
Xefo - Tablets Lornoxicam NSAID, Antirheumatic, 633 motility, Antimuscarinic
Analgesic Talin - Syrup Terbutaline sulphate Anti-asthmatic, Inhibitor 649
Zinopril - Tablets Lisinopril as dihydrate Antihypertensive, 633 of premature labour,
ACE Inhibitior Selective beta2 agonist
Zofen - Syrup Pizotifen Antihistamine, 5-HT 634 Tefanyl - Syrup Ketotifen fumarate Anti-asthmatic, 649
antagonist as appetite Anti-histamine
stimulant, Prophylaxis Tefanyl - Tablets Ketotifen fumarate Anti-asthmatic, 649
of migraine Anti-histamine
Zotrim Forte - Tablet Sulfamethoxazole, Antibiotic, 634 Tenox - Capsules Tenoxicam NSAID, Analgesic, 650
Trimethoprim Co-trimoxazole Antirheumatic
16
MANUFACTURERS INDEX
Vominore - Tablets Meclozine hydrochloride, Anti-emetic, Antivertigo & 650 Cefuzime - Powder for Cefuroxime sodium Antibiotic, Cephalosporin 655
Pyridoxine hydrochloride Motion sickness, suspension for injection
(Vitamin B6) Central anticholinergic Cefuzime - Oral suspension Cefuroxime axetil Antibiotic, Cephalosporin 655
action
Cefuzime - Tablets Cefuroxime axetil Antibiotic, Cephalosporin 655
JULPHAR (GULF PHARMACEUTICAL INDUSTRIES) 650 Cetralon - Syrup Cetirizine HCl Antihistamine, 655
Non-sedating
3V - Injection Vitamin B1, Vitamin B6, Vitamin B Complex 650 Cetralon - Tablets Cetirizine HCl Antihistamine, 655
Vitamin B12 Non-sedating
3V - Tablets Vitamin B1, Vitamin B6, Vitamin B Complex 650 Chlorohistol - Syrup Chlorpheniramine maleate Antihistamine, Sedating 655
Vitamin B12 Chlorohistol - Tablet Chlorpheniramine maleate Antihistamine, Sedating 655
Adol - Caplets Paracetamol NSAID, Analgesic, 651
Clamycin - Tablets Clarithromycin Antibiotic, Macrolide 656
Antipyretic
Clofen Creamagel Diclofenac diethylamine NSAID, Anti-rheumatic, 656
Adol Allergy Sinus - Caplets Paracetamol, NSAID, Analgesic, 651
Analgesic, Topical
Pseudoephedrine, Antipyretic, Nasal
Chlorpheniramine Maleate decongestant, Clofen - Tablets Diclofenac sodium NSAID, Analgesic, 656
Antihistamine Antipyretic, Anti-rheumatic
Adol Chewable- Tablets Paracetamol NSAID, Analgesic, 651 Codaphed - Syrup Ephedrine HCl , Sympathomimetic, 656
Antipyretic Chlorpheniramine maleate, Codeine phosphate 656
Antihistamine,
Adol Cold - Caplets Paracetamol, NSAID, Analgesic, 651
Cough suppressant
Pseudoephedrine HCl, Antipyretic, Nasal
Dextromethorphan HBr decongestant, Cough Cynovit - Injection Cyanocobalamin Vitamin B12 656
suppressant Dexipan - Cream Dexpanthenol Vitamin B7 analogue,
Adol Extra - Caplets Paracetamol, Caffeine NSAID, Analgesic, 651 Disinfectant & Healing
Antipyretic effect on skin diseases,
Topical
Adol PM - Caplets Paracetamol, NSAID, Analgesic, 651
Diphenhydramine HCl Antipyretic, Antihistamine Dialon - f.c Tablets Metformin HCl Antidiabetic drug oral, 656
Biguanide
Adol Sinus - Caplets Paracetamol, NSAID, Analgesic, 651
Pseudoephedrine HCl Antipyretic, Nasal Diazepam - Tablets Diazepam Anxiolytic 657
decongestant Dizinil - Tablets Dimenhydrinate Antihistamine, Sedating 657
Adol - Oral drops Paracetamol NSAID, Analgesic, 651 Duradox - Capsules Doxycycline (as hyclate) Antibiotic, Tetracycline 657
Antipyretic Eromycin Erythromycin ethylsuccinate Antibiotic, Macrolide 657
Adol - Rectal Suppository Paracetamol NSAID, Analgesic, 651 Granules for oral suspension
Antipyretic Eromycin - Tablets Erythromycin stearate Antibiotic, Macrolide 657
Adol - Syrup Paracetamol NSAID, Analgesic, 651 Exedexe (Sedofan) - Syrup Dextromethorphan HBr Antitussive 658
Antipyretic
Exedexe (Sedofan) - Tablets Dextromethorphan HBr Antitussive 658
Albenda - Suspension Albendazole Anthelmintic 652
Ferrous Gluconate - Coated Tablets Ferrous gluconate Haematinic, Iron 658
Albenda - Tablets Albendazole Anthelmintic 652 supplement for Iron
Alfacort - Cream Hydrocortisone. Corticosteroid, Topical 652 deciency anaemia
Alfacort - Ointment Hydrocortisone. Corticosteroid, Topical 652 Fitzecalm - Suspension Carbamazepine Anti-epileptic, 658
Amirone - Tablet Amiodarone HCl Anti-arrythmic drug 652 Antimanic drug
Amydramine - II (Sugar-free) - Syrup Diphenhydramine HCl Antihistamine, Sedating 652 Fitzecalm - Tablets Carbamazepine Anti-epileptic, 658
Antimanic drug
Amydramine (Sugar-free) - Syrup Diphenhydramine HCl, Antihistamine, 652
Ammonium chloride, Expectorant Flutin - Capsules Fluoxetine HCl Antidepressant, 659
Sodium citrate, Menthol Selective serotonin
re-uptake inhibitor
Amydramine Paediatric- Syrup Diphenhydramine HCl, Antihistamine, 652
Sodium citrate, Menthol Cough suppressant Folicum - Tablets Folic acid Erythropoietic, Treats 659
folate megaloblastic
Asmafort - Syrup Ketotifen fumarate Anti - asthmatic, 652
anaemia
Anti-histamine
Futasole - Cream Fusidic acid Antibacterial, Topical 659
Asmafort - Tablet Ketotifen fumarate Anti-asthmatic, 652
Anti-histamine Futasole - Ointment Sodium fusidate Antibacterial, Topical 659
Azomycin - Capsules Azithromycin dihydrate Antibiotic, Macrolide 652 Gamavate - Cream Clobetasol propionate Corticosteroid, Topical 659
Azomycin - Suspension Azithromycin dihydrate Antibiotic, Macrolide 652 Gamavate - ointment Clobetasol propionate Corticosteroid, Topical 659
Beclohale - Inhaler Beclomethasone dipropionate Anti-asthmatic, 653 Gental - Cream Gentamicin sulfate Antibiotic, 659
Corticosteroid Aminoglycoside, Topical
Becovit - Syrup Thiamine mononitrate Vitamin B Complex 653 Gental - Ointment Gentamicin sulfate Antibiotic, 659
(Vitamin B1) Riboavin Aminoglycoside, Topical
(Vitamin B2) Pyridoxine Ginsavit - Syrup Ginseng extract , Multivitamin & Mineral 659
hydrochloride (Vitamin B6) Multivitamin, Minerals Preparation
Nicotinamide, Dexpanthenol Gupisone - Tablets Prednisolone Corticosteroid 659
Becovit - Tablet Vitamin B Complex Vitamin B Complex 653 Gyno-Mikozal - Cream Miconazole nitrate Antifungal & 660
(B1,B2,B6,B12), Nicotinamide, Antibacterial, Topical
Cal.pantothenate
Gyno-Mikozal - Vaginal ovoules Miconazole nitrate Antifungal & 660
Becovit Forte - Tablets Thiamine mononitrate Vitamin B Complex 653 Antibacterial, Local
(Vitamin B1), Riboavin
Histaloc -f.c Tablets Promethazine HCl Antihistamine, 660
(Vitamin B2)
Anti-emetic,
Pyridoxine hydrochloride
Central sedative
(Vitamin B6)
cyanocobalamin Histaloc - Syrup Promethazine HCl Antihistamine, 660
(Vitamin B12), Nicotinamide Anti-emetic,
Calcium pantothenate Central sedative
Betasone - Cream Betamethasone valerate Corticosteroid, Topical 653 Histol - Syrup Pheniramine maleate Antihistamine, 660
Non-sedating
Betasone - Ointment Betamethasone valerate Corticosteroid, Topical 653
Intard - Tablets Diphenoxylate HCl, Antimotility drug 660
Betasone - Tablets Betamethasone Corticosteroid 653
Atropine sulphate
Butalin - Solution for nebuliser Salbutamol sulphate Anti-asthmatic, 654
Julmentin 2X - Oral suspension Amoxycillin trihydrate, Antibiotic, 660
Bronchodilator,
Potassium clavulanate Broad-spectrum penicillin
Julmentin 2X - Tablets Amoxycillin trihydrate, Antibiotic, 660
Butalin - Inhaler Salbutamol Anti-asthmatic, 654
Bronchodilator,
Selective beta2 agonist Julmentin Forte - Oral suspension Amoxycillin trihydrate, Antibiotic, 660
Butalin - Syrup Salbutamol sulphate Anti-asthmatic, 654
Bronchodilator, Julmentin Forte - Tablets Amoxycillin trihydrate, Antibiotic, 660
Selective beta2 agonist Potassium clavulanate Broad-spectrum penicillin
Butalin - Tablet Salbutamol sulphate Anti-asthmatic, 654 Julmentin - Injection Amoxycillin trihydrate, Antibiotic, 660
Bronchodilator, Potassium clavulanate Broad-spectrum penicillin
Selective beta2 agonist Julmentin - Oral suspension Amoxycillin trihydrate, Antibiotic, 660
Captophar - Tablets Captopril Antihypertensive, 654 Potassium clavulanate Broad-spectrum penicillin
ACE inhibitor Julmentin - Tablets Amoxycillin trihydrate, Antibiotic, 660
Cefrin - Capsules Cephalexin monohydrate Antibiotic, 655 Potassium clavulanate Broad-spectrum penicillin
Cephalosporin Julphacef (Eskacef) - Capsule Cephradine Antibiotic, Cephalosporin 661
Cefrin - Oral suspension Cephalexin monohydrate Antibiotic, Cephalosporin 655 Julphacef (Eskacef) - Oral suspension Cephradine Antibiotic, Cephalosporin 661
17
MANUFACTURERS INDEX
Julphamox - Capsules Amoxicillin trihydrate Antibiotic, 661 Pronal - Oral suspension Ibuprofen NSAID, Analgesic, 667
Broad-spectrum penicillin Antipyretic
Julphamox - Oral Drops Amoxicillin trihydrate Antibiotic, 661 Pronal - Tablets Ibuprofen NSAID, Analgesic, 667
Julphamox - Oral Suspension Amoxicillin trihydrate Antibiotic, 661 Pronal XP - Caplets Ibuprofen, Caffeine NSAID, Analgesic, 668
Jusprin 81 -e.c Tablets Aspirin NSAID, Platelet 661 Pyridoxin - Tablets Pyridoxine HCl Vitamin B6 668
aggregation inhibitor Rantag - Ampoule Ranitidine HCl Antacid, Ulcer-healing, 668
Jusprin -e.c Tablets Aspirin NSAID, Analgesic, 662 H2-receptor antagonist
Antipyretic Rantag - Tablets Ranitidine HCl Antacid, Ulcer-healing, 668
Kaptin - Suspension Kaolin , Pectin Anti-diarrhoeal, Adsorbent 662
Recocef - Capsules Cefaclor monohydrate Antibiotic, Cephalosporin 668
& Bulk-forming drug
Recocef - Oral suspension Cefaclor monohydrate Antibiotic, Cephalosporin 668
Kaptin II (Frodac) - Caplets Attapulgite activated Anti-diarrhoeal 662
Risek - Capsule Omeprazole Antacid, Ulcer-healing, 669
Kdiron - Oral drops Ferrous sulphate Haematinic, Iron 662 Proton pump inhibitor
supplement for iron
Risek - Powder for infusion Omeprazole sodium Antacid, Ulcer-healing, 669
deciency anaemia
Kdiron - Syrup Ferrous sulphate Haematinic, Iron 662
Rothacin - Capsules Indomethacin NSAID, Analgesic, 669
supplement for iron
Antipyretic
deciency anaemia
Rubicalm - Cream Diethylamine salicylate, Analgesic, Topical 669
Lanfast - Capsule Lansoprazole Antacid, Ulcer-healing, 662 Chlorbutol, Menthol
Salinal - Chewable Tablets Simethicone Antiatulant, 669
Laxocodyl (Paediatric) - Suppository Bisacodyl Laxative, Stimulant 662 Antifoaming agent
Laxocodyl - e.c Tablet Bisacodyl Laxative, Stimulant 662 Salinal - Drops Simethicone Antiatulant, 669
Laxocodyl - Suppository Bisacodyl Laxative, Stimulant 662 Antifoaming agent
Laxolyne (For Child) - Suppository Glycerin Laxative, Stimulant 663 Salurin - Syrup Furosemide Diuretic, Loop 669
Laxolyne - Suppository Glycerin Laxative, Stimulant 663 Salurin - Tablets Furosemide Diuretic, Loop 669
Lidocaine - Ointment Lidocaine Anaesthesia, Local 663 Sarf - f.c Tablets Ciprooxacin HCl Antibiotic, Quinolone 669
Lomax - Tablets Lomeoxacin HCl Antibiotic, Quinolone 663 Scopinal - Ampoule Hyoscine-N-butylbromide Antispasmodic & Drug 670
Loratin (Lojour) - Syrup Loratadine Antihistamine, 663 altering gut motility,
Antimuscarinic
Non-sedating
Scopinal - f.c Tablets Hyoscine-N-butylbromide Antispasmodic & Drug 670
Lovrak - Cream Acyclovir Antiviral drug, Topical 663
Lovrak - Ointment Acyclovir Antiviral drug, Topical 663 Antimuscarinic
Lovrak - Tablets Acyclovir Antiviral drug 663 Scopinal - Syrup Hyoscine-N-butylbromide Antispasmodic & Drug 670
Mebzol - Suspension Mebendazole Anthelmintic 664 altering gut motility,
Mebzol - Tablets Mebendazole Anthelmintic 664 Antimuscarinic
Mikacin - Injection Amikacin sulphate Antibiotic, 664 Sedofan - Syrup Triprolidine HCl, Antihistamine, 670
Aminoglycoside Pseudoephedrine HCl Nasal decongestant
Mikostat - Cream Nystatin Antifungal, Topical 664 Sedofan - Tablets Triprolidine HCl, Antihistamine, 670
Pseudoephedrine HCl Nasal decongestant
Mikostat - Ointment Nystatin Antifungal, Topical 664
Simvast - Tablets Simvastatin Lipid-regulating drug, 670
Mikostat - Oral suspension Nystatin Antifungal, Polyene 664 Cholesterol synthesis
Mikozal - Cream Miconazole nitrate Antifungal & 664 inhibitor
Antibacterial, Topical Soax - Solution Lactulose Laxative, Osmotic 671
Mixavit - Oral drops Multivitamins Multivitamin Preparation 665 Soolan - Syrup Glyceryl guaiacolate , Expectorant, 671
Mixavit - Syrup Multivitamins Multivitamin Preparation 665 Chlorpheniramine maleate, Antihistaminic preparation
Mixavit - Tablets Multivitamins Multivitamin Preparation 665 Phenylephrine HCl
Mixavit-M - Tablets Vitamin B Complex and Vitamin B Complex 665 Supraproct-S - Ointment Betamethasone valerate, Corticosteroid, Anaesthetic, 671
Minerals & Minerals Cinchocaine HCl Topical
Moxal Plus - Suspension Aluminium hydroxide, Antacid, Antiatulant 665 Tamophar - Tablets Tamoxifen citrate Anticancer, Antioestrogen 671
Magnesium hydroxide , Tensotin - Tablets Atenolol Antihypertensive, 671
Simethicone Anti-anginal,
Anti-arrythmic,
Moxal - Chewable Tablets Aluminium hydroxide dried Antacid 665
Beta blocker
gel, Magnesium hydroxide
Tetracycline - Capsules Tetracycline HCl Antibiotic, Tetracycline 671
Moxal - Suspension Aluminium hydroxide dried Antacid 665
gel, Magnesium hydroxide Tetracycline - Ointment Tetracycline HCl Antibiotic, Tetracycline, 671
Topical
Mucolyte - Syrup Bromhexine HCl Mucolytic 665
Theophar - Syrup Theophylline sodium Anti-asthmatic, 672
Narapril - Tablets Enalapril maleate Antihypertensive, 665 glycinate Bronchodilator
ACE inhibitor
Thiavit - Tablets Thiamine HCl (Vitamin B1) Vitamin B1 672
Nasivin - Nasal drops Oxymetazoline HCl Nasal decongestant, 666
Triaxone (Enoxirt) - IM Injection Ceftriaxone sodium Antibiotic, Cephalosporin 672
Topical
Triaxone (Enoxirt) - IV Injection Ceftriaxone sodium Antibiotic, Cephalosporin 672
Negacef - Injection Ceftazidime Antibiotic, Cephalosporin 666
Trimol - Oral suspension Trimethoprim, Antibiotic, Co-trimoxazole 672
Negazole - f.c Tablets Metronidazole Anti-protozoal, 666 Sulphamethoxazole
Anti-anaerobic
Trimol - Tablets Trimethoprim, Antibiotic, Co-trimoxazole 672
Orcinol - Syrup Clobutinol HCl, Cough Suppressant, 666 Sulphamethoxazole
Orciprenaline sulphate, Selective beta2-
Uroxin - Tablets Noroxacin Antibiotic, Quinolone 672
Ammonium chloride agonist, Expectorant
Oxytetracycline - Ointment Oxytetracycline HCl Antibiotic, Tetracycline 666 Valopin - Syrup Sodium valproate Anti-Epileptic drug, 673
Aliphatic carboxylic acid
Panderm - Cream Nystatin, Neomycin Corticosteroid, 666
Vancolon IV - Injection Vancomycin HCl Antibiotic, Macrolide 673
sulphate, Gramicidin, Antifungal,antibacterial,
Triamcinolone acetonide Topical Vit A+D - Oral drops Vitamin A (as palmitate), Vitamin A & D 674
Vitamin D
Panderm - Ointment Nystatin, Neomycin Corticosteroid, Antifungal, 666
Vit C (VC) - Chewable Tablets Vitamin C Vitamin C 674
sulphate, Gramicidin, Antibacterial, Topical
Triamcinolone acetonide Vitamin B - Complex-f.c Tablets Thiamine mononitrate, Vitamin B Complex 674
Riboavin, Pyridoxine
Potencort - Cream Fluticasone propionate Corticosteroid, Topical 667
hydrochloride, Calcium
Potencort - Ointment Fluticasone propionate Corticosteroid, Topical 667 pantothenate, Nicotinamide
Premosan - Drops Metoclopramide HCl Anti-emetic, Stimulates 667 Xylolin - Nasal spray Xylometazoline HCl Nasal decongestant, 674
gut motility Topical
Premosan - Injection Metoclopramide HCl Anti-emetic, Stimulates 667
gut motility KAHIRA PHARMA. & CHEMICAL INDUSTRIES. CO. CAIRO-EGYPT 674
Premosan - Syrup Metoclopramide HCl Anti-emetic, Stimulates 667 Algibaume - Cream Diethylamine salicylate NSAID, Analgesic, 674
gut motility Anti-rheumatic, Topical
Premosan - Tablets Metoclopramide HCl Anti-emetic, Stimulates 667 Anallerge 4 - Tablets Chlorpheniramine maleate Antihistamine, Sedating 674
gut motility Ceviline - Oral drops Ascorbic acid Vitamin C 674
Primocef I.M/I.V - Injection Cefotaxime sodium Antibiotic, Cephalosporin 667 Chemotrim - Tablet Sulphamethoxazole, Antibiotic, Co-trimoxazole 675
Pronal - Gel Ibuprofen NSAID, Analgesic, 667 Trimethoprim
Topical (Co-trimoxazole)
18
MANUFACTURERS INDEX
Citro Mag - Eff. Tablets Light magnesium oxide, Laxative, Mild 675 Methylprednisolone Sodium Succinate Methylprednisolone Corticosteroid 692
Sodium bicarbonate, Injection Sodium succinate
Citric acid, Saccharin Naloxone hydrochloride - Injection Naloxone hydrochloride Opioid antagonist 693
Colifuran - Tablets Nitrofurantoin Antibacterial, For 675 Phenytoin - Injection Phenytoin sodium Anti-epileptic drug, 694
Genito-urinary tract Hydantoin
infection
Sodium nitroprusside - Injection Sodium nitroprusside Antihypertensive, 694
Colmediten - Tablets Colchicine Gout induced 676
Vasodilator
hyperuricaemia treatment
drug Vancomycin hydrochloride - Injection Vancomycin hydrochloride Antibiotic, Macrolide 695
Flagicure - Tablets Metronidazole Anti-protozoal, 676 Vinblastine sulphate - Injection Vinblastine sulphate Anticancer, Vinca alkaloid 695
Anti-anaerobic Vincristine sulphate - Injection Vincristine sulphate Anticancer, Vinca alkaloid 696
Flatidyl - Chewable Tablets Activated Dimethicone Antiatulant, Antifoaming 676
(Simethicone) agent MEDPHARMA- PHARMA & CHEMICAL INDUSTRIES 696
Prisoline - Nasal & Eyedrops Naphazoline hydrochloride, Nasal decongestant, 677 Betamed - N Cream Betamethasone valerate, Corticosteroid 696
Chlorpheniramine maleate Antihistaminic Neomycin sulphate & Antimicrobial, Topical
Rivo - Tablets Acetylsalicylic acid NSAID, Analgesic, 677 Betamed - N Ointment Betamethasone valerate, Corticosteroid 697
Antipyretic Neomycin sulphate & Antimicrobial, Topical
Tinea Cure - Cream Tolnaftate Antifungal, Topical 677 Betamed - Cream Betamethasone valerate Corticosteroid, Topical 696
Tinea Cure - Paint Tolnaftate Antifungal, Topical 677 Betamed - Ointment Betamethasone valerate Corticosteroid, Topical 696
Tussilar - Tablets Dextromethorphan Antitussive 677 Candizole - Cream Miconazole nitrate Antifungal & Antibacterial, 697
hydrobromide Topical
Urisept - Tablets Phenazopyridine Urological analgesic 677 Candizole - Powder Miconazole nitrate Antifungal & Antibacterial, 697
hydrochloride Topical
Vioderm Cream Iodochlorhydroxyquin Antibacterial, Antifungal, 677 Cefaxine - Capsule Cephalexin monohydrate Antibiotic, Cephalosporin 697
Antieczematous, Ceframed - Capsule Cephradine monohydrate Antibiotic, Cephalosporin 698
Antipruritic, Topical Clarazole - Shampoo Ketoconazole Antifungal, Topical 698
LEO PHARMACEUTICALS PRODUCTS 678 Diclon - Emulgel Diclofenac diethylamine NSAID, Analgesic, 698
Anti-rheumatic, Topical
Burinex - Injection Bumetanide Diuretic, Short Acting 678 Diphelin - Adult Syrup Diphenhydramine Antihistamine, 699
Burinex - Tablets Bumetanide Diuretic, Short Acting 678 hydrochloride, Sodium Cough suppressant
Daivobet - Ointment Calcipotriol , Betamethasone Vitamin D derivative 678 citrate, Menthol
& Corticosteroid for Diphelin - Paediatric Syrup Diphenhydramine Antihistamine, Cough 699
treatment of psoriasis, hydrochloride, Sodium suppressant
Topical citrate, Menthol
Daivonex - Cream Calcipotriol Vitamin D derivative for 678 Fungyzole - Cream Miconazole nitrate Antifungal & Antibacterial, 699
treatment of psoriasis, Topical
Topical Medacef - Capsules Cefaclor monohydrate Antibiotic, Cephalosporin 700
Daivonex - Ointment Calcipotriol Vitamin D derivative for 678 Medacef - Oral Suspension Cefaclor monohydrate Antibiotic, Cephalosporin 700
treatment of psoriasis, Medacid - Chewable Tablets Aluminum hydroxide, Antacid 700
Topical Magnesium hydroxide
Fucicort - Cream Fusidic acid, Betamethasone Corticosteroid & 679 Medacid - Suspension Aluminum hydroxide, Antacid 700
Antibiotic, Topical Magnesium hydroxide
Fucidin - Gel Fusidic acid Antibiotic, Topical 679 Medacid Plus - Chewable Tablets Aluminum hydroxide, Antacid, Antiatulant 700
Fucidin - Ointment Sodium fusidate Antibiotic, Topical 679 Magnesium hydroxide,
Fucidin H - Cream Fusidic acid, Hydrocortisone Corticosteroid & 679 Simethicone
acetate Antibiotic, Topical Medacid Plus - Suspension Aluminum hydroxide, Antacid, Antiatulant 700
Fucithalmic - Eyedrops Fusidic acid Antibiotic, Ophthalmic 679 Magnesium hydroxide,
Simethicone
Innohep - Injection Tinzaparin sodium Anticoagulant, Low 680
molecular weight heparin Medacin T - Topical Solution Clindamycin phosphate Antibiotic, Topical 701
Medafen 100 - Paediatric Suspension Ibuprofen NSAID, Analgesic, 701
One-Alpha - Capsules Alfacalcidol Calcium and Phosphate 680
Antipyretic
homeostasis regulator
Medamol - Caplets Paracetamol NSAID, Analgesic, 702
One-Alpha - Injection Alfacalcidol Calcium and Phosphate 680
Antipyretic
Medamol - Syrup Paracetamol NSAID, Analgesic, 702
One-Alpha - Oral drops Alfacalcidol Calcium and Phosphate 680
Antipyretic
Medroxol - Syrup Ambroxol hydrochloride Mucolytic 702
One-Alpha - Solution Alfacalcidol Calcium and Phosphate 680
homeostasis regulator Pheniram - Syrup Chlorpheniramine maleate Antihistamine, Sedating 702
Pheniram - Tablet Chlorpheniramine maleate Antihistamine, Sedating 702
MAYNE PHARMA 680 Salbutamed - Syrup Salbutamol sulphate Anti-asthmatic, Selective 703
beta2- agonist
Amikacin - Injection Amikacin (as sulphate) Antibiotic, Aminoglycoside 680
Anzatax - Injection Paclitaxel Anticancer, Taxanes 681 MEDICAL UNION PHARMACEUTICALS (MUP) 703
Atracurium besilate - Injection Atracurium besilate Muscle relaxant 683
Acicone - Chewable Tablets Magaldrate Antacid 703
Calcium folinate Calcium folinate Anticancer drug 683
Solution for injection (Antimetabolite) toxicity Acicone - Oral suspension Magaldrate Antacid 703
reducer, Synergistic Acicone-S - Chewable Tablets Magaldrate, Simethicone Antacid, Antiatulant 703
To 5-uorouracil Acicone-S - Oral suspension Magaldrate, Simethicone Antacid, Antiatulant 703
(Anticancer drugs) Bronex - Oral drops Guaiphenesin, Expectorant, Decongestant 704
Carboplatin - Injection Carboplatin Anticancer, Platinum 685 Pseudoephedrine
compound hydrochloride
Cisplatin - Injection Cisplatin Anticancer, Platinum 685 Hi-Cal - Syrup Calcium glubionate Calcium supplement 704
compound Laxolac-Syrup Lactulose Laxative, Osmotic 704
DBL Aciclovir Sterile Concentrate Aciclovir Antiviral drug 686 Miconaz - Cream Miconazole nitrate Antifungal & Antibacterial, 704
Injection Topical
DBL Cytarabine - Injection Cytarabine Anticancer, Antimetabolite 685 Miconaz - Powder Miconazole nitrate Antifungal & Antibacterial, 704
Dobutamine hydrochloride - Injection Dobutamine hydrochloride Inotropic 687 Topical
Sympathomimetic, Rhinostop - Oral drops Pseudoephedrine Decongestant 705
Cardiac stimulant hydrochloride, Carbinoxamine
Dopamine - Injection Dopamine hydrochloride Inotropic 688 Sorbit - Powder Sortibol Laxative, Osmotic 705
Sympathomimetic,
Cardiac stimulant MEPHA LTD 705
Erythromycin Lactobionate- Erythromycin lactobionate Antibiotic, Macrolide 688
Gasec 20, Gastrocaps Omeprazol Antacid, Ulcer-healing, 705
IV infusion Proton pump inhibitor
Fluorouracil - Injection Fluorouracil Anticancer, Antimetabolite 689 Mephaquin Lactab Meoquine hydrochloride Antimalarial drug 707
Fluphenazine decanoate - Injection Fluphenazine decanoate Antipsychotic drug 690 Mesporin Ceftriaxone sodium Antibiotic, Cephalosporin 709
Glyceryl Trinitrate - Injection Glyceryl trinitrate Antihypertensive, 690 Powder & Solvent for IV solution
Anti-anginal, Vasodilator Mesporin - Powder for IV perfusion Ceftriaxone sodium Antibiotic, Cephalosporin 709
Methotrexate IM/IV - Injection Methotrexate Anticancer, Antimetabolite 691 Mesporin - Ceftriaxone sodium, Antibiotic, Cephalosporin 709
692 Powder & Solvent for IM solution Lidocaine HCl
19
MANUFACTURERS INDEX
Neurorubine - Forte Lactab Thiamine nitrate (Vitamin B1) Vitamin B 711 Neo-Haemorrhan - Suppository Ruscus extract, Prednisolone Anti-haemorrhoidal 732
Pyridoxine hydrochloride Complex acetate, Lignocaine HCl, preparation with
(Vitamin B6), Cyanocobalamine Aluminium acetate, Corticosteroid, Local
(Vitamin B12) Zinc oxide
Olfen-1% Gel Diclofenac sodium NSAID, Antirheumatic, 712 Paramol - Syrup Paracetamol NSAID, Analgesic, 732
Analgesic, Local Antipyretic
Olfen-25 Lactab Diclofenac sodium NSAID, Antirheumatic, 712 Paramol - Tablets Paracetamol NSAID, Analgesic, 732
Antipyretic, Analgesic Antipyretic
Olfen-50 Lactab Diclofenac sodium NSAID, Antirheumatic, 712 Promantine - Syrup Promethazine hydrochlorlde Antihistamine, Anti-emetic, 733
Antipyretic, Analgesic Central sedative
Olfen-50 Rectocaps Diclofenac sodium NSAID, Antirheumatic, 712 Vitop - Capsules Multivitamins, Minerals & Multivitamin & Mineral 733
Antipyretic, Analgesic Folic acid preparation
Olfen-75 - IM Injection Diclofenac sodium, NSAID, Antirheumatic, 712
Lidocaine hydrochloride Antipyretic, Analgesic MSD (MERCK SHARP & DOHME B.V) 733
Olfen-100 Depocaps Diclofenac sodium NSAID, Antirheumatic, 712 Aggrastat - Conc. for solution Tiroban hydrochloride Myocardial 733
Antipyretic, Analgesic for inj monohydrate infarction preventive
Olfen-100 Rectocaps Diclofenac Sodium NSAID, Antirheumatic, 712 drug, Glycoprotein
Antipyretic, Analgesic inhibitor
Salipax - Capsules Fluoxetine hydrochloride Antidepressant, Selective 714 Arcoxia -f.c Tablets Etoricoxib. NSAID, Anti-rheumatic, 736
serotonin re-uptake Anti-gout
inhibitor Cancidas - Powder for concentrate Caspofungin (as acetate) Antifungal drug 739,
for solution for injection 741
MERCK SERONO 716
Co-Renitec - Tablets Enalapril maleate, Antihypertensive, ACE 744
Concor Cor - Tablets Bisoprolol fumarate Antihypertensive, 716 Hydrochlorothiazide inhibitor, Diuretic
eta-receptor blocker Cosopt - Eyedrops Dorzolamide hydrochloride, Glaucoma treatment drug, 746
Concor 5 Plus - Tablets Bisoprolol fumarate, Antihypertensive, 717 Timolol maleate Topical carbonic
Hydrochlorothiazide eta-receptor blocker, anhydrase inhibitor &
Diuretic eta blocker
Concor 5 - Tablets Bisoprolol fumarate Antihypertensive, 719 Cozaar - f.c Tablets Losartan potassium. Antihypertensive, 748
Anti-anginal, -receptor Angiotensin-II receptor
blocker antagonist
Concor 10 - Tablets Bisoprolol fumarate Antihypertensive, 719 Ezetrol - Tablets Ezetimibe Cholesterol absorption 749
Anti-anginal, -receptor inhibitor
blocker Fortzaar 100/25 - f.c Tablets Losartan potassium, Antihypertensive, 752
Cytobion - Injection Cynocobalamin Vit B12 Vitamin B12 719 Hydrochlorothiazide. Angiotensin-II receptor
Euthyrox - Tablets Levothyroxine Sodium Thyroid hormone 719, antagonist, Diuretic
720, Fosamax Once Weekly - Tablets Alendronic acid as Bone resorption 754
Alendronate sodium inhibitor, Biphosphonate
721,
trihydrate
722
HB-VAX-DNA - Suspension for Inj. Hepatitis B (Recombinant) Vaccine 755
Evion - Tablets All-rac-alpha-tocopheryl Vitamin E 723 Vaccine
acetate (Vit E)
Hyzaar 50/12.5 - f.c Tablets Losartan potassium, Antihypertensive, 756
Glucophage -f.c Tablets Metformin hydrochloride Antidiabetic drug oral, 724, Hydrochlorothiazide Angiotensin-II receptor
Biguanide 726 antagonist, Diuretic
Glucovance - f.c Tablets Metformin hydrochloride, Antidiabetic drug oral, 725 Inegy - Tablets Ezetimibe, Simvastatin Lipid regulating drug, 758
Glibenclamide Biguanide & Cholesterol absorption
Sulphonylurea & synthesis inhibitor
Gonal-F - Injection Follitropin alfa Human follicle stimulating 727
hormone for fertility M-M-R II - Powder Living virus for the Vaccine 762
for injection liquid vaccination against Measles
Neurobion - Injection Vitamin B1, Vitamin B6, Vitamin B Complex 728
(Morbilli), Mumps and
Vitamin B12
Rubella
Neurobion - Tablets Vitamin B1, Vitamin B6, Vitamin B Complex 728
Vitamin B12 Moduretic - Tablets Hydrochlorothiazide, Antihypertensive, 764
Amiloride hydrochloride Diuretic (Potassium
Rebif - Solution for injection Interferon beta-1A Immuno-modulator, 728
Sparing & Thiazide)
Antiviral, Antiproliferative
Noroxin - Tablets Noroxacin Antibiotic, Quinolone 765
Saizen - Dry substance Somatropin (Recombinant Human growth hormone 729
for reconstitution for injection human growth-hormone) Pepcidin - Tablets Famotidine Antacid, Ulcer-healing, 767
MID PHARMA 730 Propecia - Tablets Finasteride Male pattern baldness 768
treatment drug in male,
Betixim - Capsules Cexime trihydrate Antibiotic, Cephalosporin 730 5-alpha reductase
Betixim - Suspension Cexime trihydrate Antibiotic, Cephalosporin 730 Inhibitor
Cipromid -f.c Tablets Ciprooxacin hydrochloride Antibiotic, Quinolone 730 Proscar - Tablets Finasteride Benign prostatic 769
monohydrate hyperplasia treatment
Lansomid - Capsules Lansoprazole Antacid, Ulcer-healing, 730 drug, 5-alpha reductase
Proton pump inhibitor inhibitor
Lapril - Tablets Enalapril maleate Antihypertensive, 731 Renitec - Tablets Enalapril maleate Antihypertensive, 769
ACE inhibitor ACE inhibitor
Midaex - Capsules Cephalexin monohydrate Antibiotic, 731 Sinemet Plus - Tablets Carbidopa, Levodopa Antiparkinsonism, 772
Cephalosporin Dopaminergic drug
Midaex - Oral suspension Cephalexin monohydrate Antibiotic, Cephalosporin 731 Sinemet - Tablets Carbidopa, Levodopa Antiparkinsonism, 772
Dopaminergic drug
Midrone Extra - Tablets Paracetamol, Caffeine NSAID, Analgesic, 731
anhydrous Antipyretic Singulair Paediatric Montelukast (as sodium) Anti-asthmatic, 774
Chewable Tablets Leukotriene receptor
Midroxil - Capsules Cefadroxil monohydrate Antibiotic, Cephalosporin 731
antagonist
Midroxil - Oral suspension Cefadroxil monohydrate Antibiotic, Cephalosporin 731
Singulair - Granules Montelukast (as sodium) Anti-asthmatic, 776
Leukotriene receptor
MISR CO. FOR PHARMA INDUSTRIES S.A.E 731
antagonist
Baumalgine - Ointment Diethylamine salicylate, Analgesic, Rubicient 731 Singulair - Tablets Montelukast (as sodium) Anti-asthmatic, 778
Methyl nicotinate Leukotriene receptor
ColiUrinal - Eff. Granules Piperazine as citrate, Diuretic, Antiseptic, 732 antagonist
Hexamine, Khellin Antispasmodic Tienam I.V - Sterile Powder Imipenem monohydrate, Antibiotic, Carbapenem 779
Dermocort Cream Iodochlorhydroxyquin, Antibacterial, Antifungal, 732 for Injection Cilastatin sodium
Hydrocortisone as acetate Anti-inammatory, Timoptol - Eyedrops Timolol maleate Glaucoma treatment 782
Anti-allergic, Topical drug, Beta 1, 2 adrenergic
Indomethacin - Capsules Indomethacin NSAID, Analgesic, 732 blocker
Antipyretic Trusopt - Eyedrops Dorzolamide hydrochloride Glaucoma treatment drug, 783
Neo-Haemorrhan - Ointment Ruscus Extract, Prednisolone Anti-haemorrhoidal 732 Topical carbonic
acetate, Lignocaine HCl, preparation with anhydrase inhibitor
Aluminium acetate, Corticosteroid, Local Vaqta Adult Strain Cr 326f Hepatitis Vaccine 785
Zinc oxide Suspension for injection A virus, Inactivated
20
MANUFACTURERS INDEX
Vaqta Junior Strain Cr 326f Hepatitis Vaccine 786 Prelloran - Gel Heparinoid & Ethylene glycol Anti-inammatory, 801
Suspension for injection A Virus, Inactivated salicylate Analgesic, Decongestant,
Zocor - Tablets Simvastatin Lipid-regulating drug, 787 Topical
Cholesterol synthesis Procto-Glyvenol - Cream Tribenoside, Lidocaine Anti-haemorrhoidal 801
inhibitor hydrochloride preparation, Local
Procto-Glyvenol - Suppository Tribenoside , Lidocaine Anti-haemorrhoidal 802
NEBO A/S 790 hydrochloride preparation, Local
Cosmofer - Solution for Inj. and Inf. Iron (III)-hydroxide Dextran Haematinic, Parenteral 790 Tavegyl - Syrup Clemastinum Antihistamine, Antipruritic 802
Complex iron Venoruton - Capsules O-(-hydroxy-ethyl)-rutoside Venous disorder 802
treatment drug
NILE CO. FOR PHARMACEUTICALS AND CHEMICAL INDUSTRY 792 Venoruton - Gel O-(-hydroxy-ethyl)-rutoside Venous trauma 803
Codilar - Syrup Dextromethorphan Antitussive, Decongestant, 792 treatment drug, Local
hydrobromide, Phenyl Antihistaminic
NOVARTIS PHARMA 803
ephrine hydrochloride,
Chlorpheneramine maleate Aclasta - Solution for injection Zoledronic acid monohydrate Bone resorption inhibitor 803
Isilin - Syrup Diphenhydramine Antihistamine, Expectorant 792 Adelphane Esidrex - Tablets Reserpine, Dihydralazine Antihypertensive with 804
hydrochloride, Ammonium sulphate and Central action, Peripheral
chloride, Sodium citrate, Hydrochlorothiazide vasodilation & Diuretic
Menthol effect
Panthenol - Injection D-Panthenol Vitamin B7 Analogue, 792 Anafranil - Tablets Clomipramine hydrochloride Antidepressant drug, 807
Disinfectant for aloepecia, Tricyclic antidepressant
burns, wounds & ulcers, Apresoline - Powder Hydralazine HCl Antihypertensive, 807
Prophylaxis/treatment for solution for inj Peripheral vasodilator
of paralytic ileus
Aredia- Injection Pamidronate disodium Bone resorption inhibitor 811
Phosphalugel - Sachet Colloidal aluminium Antacid, Gastro-mucosal 792 anhydrous
phosphate, Sorbic acid, protective
Brinerdin - Tablets Dihydroergocristine Antihypertensive, 812
Methyl Parahydroxybenzoate,
(as the mesylate),Clopamide, Centrally acting
Propyl Parahydroxybenzoate,
Reserpine.
Sucrose, Aroma Gel q.s
Certican - Tablets Everolimus Immunosuppressive agent 813
Senna Lax - Tablets Calcium salts of puried Laxative, Stimulant 793
Certican - Dispersible Tablet Everolimus Immunosuppressive agent 813
Senna extract (Senna
glycosides) Cibacen - f.c Tablets Benazepril hydrochloride Antihypertensive, 816
ACE inhibitor
Tri-B - Injection Combined Vitamins Vitamin B Complex 793
B1, B6, B12 Co-Diovan -f.c Tablets Valsartan, Antihypertensive, 818
Hydrochlorothiazide Angiotensin-II receptor
Tri-B - Tablets Combined Vitamins B1, B6, Vitamin B Complex 793
antagonist & Diuretic
B12 and Folic acid
Comtan -f.c Tablets Entacapone Antiparkinsonism, 820
Zymogen - Tablets Lipase, Amylase, Protease, Digestive enzymes 793
Dopaminergic drug
pepsin (1: 2500),
Dehydrochloric acid, Desferal - Freeze dried powder Deferoxamine mesilate Iron Chelator 822
Hemicellulase Diovan - f.c Tablets Valsartan Antihypertensive, 824
Angiotensin-IIreceptor
NIPPON KAYAKU CO. LTD. 793 antagonist
Efemoline - Eyedrop Fluorometholone, Tetryzoline Corticosteroid, 826
Bleocin-Lyophilised powd. for inj. Bleomycin hydrochloride Anticancer, Cytotoxic 793
hydrochloride Anti-allergic-ophthalmic
antibiotic
Elidel 1% - Cream Pimecrolimus Atopic dermatitis 827
NORGINE LTD 795 treatment drug
Esidrex - Tablets Hydrochlorothiazide Diuretic, Thiazide 829
Camcolit - Tablets Lithium carbonate Manic depressive 795
Estracomb TTS Oestradiol hemihydrate, Female sex hormone 831
illness (MDI) treatment
(Oestradiol hemihydrate &
drug norethisterone acetate)
Movicol - Powder Polyethylene glycol, Sodium Laxative, Osmotic 795 Estraderm MX-TTS Oestradiol hemihydrate Female sex hormone 833
chloride, Sodium bicarbonate, Exelon - Capsules Rivastigmine hydrogen Dementia of alzheimer 836
Potassium chloride tartrate & parkinsonism disease
Normacol - Granules Sterculia Laxative, Bulk-forming 796 treatment drug, Reversible
Normacol Plus - Granules Sterculia, Frangula Laxative, Bulk-forming 796 anticholinesterase
Spasmonal - Capsule Alverine citrate Antispasmodic & 796 Exjade - Dispersible Tablets Deferasirox Iron (III) Chelator 838
drug altering gut Famvir -f.c Tablets Famciclovir Antiviral drug 839
motility, Antimuscarinic Femara -f.c Tablets Letrozole Anticancer, Selective 840
non-steroidal aromatase
NOVARTIS CONSUMER HEALTH 796 inhibitor
Calcium - Sandoz Forte Calcium carbonate, Calcium supplement 796 Foradil - Capsules of inhalation powder Formoterol fumarate Anti-asthmatic, Selective 842
- Eff. Tablets Calcium lactate gluconate dihydrate beta2 -agonist
Cortiphenol - H Eye Ointment Hydrocortisone acetate, Corticosteroid & 797 Glivec - Capsules Imatinib mesilate Anticancer, Protein- 844
Chloramphenicol Antibiotic, Ophthalmic tyrosine kinase inhibitor
Eurax - Cream Crotamiton Acaricide, Antipruritic, 797 Glivec -f.c Tablets Imatinib mesilate Anticancer, Protein- 847
Pediculoside, Topical tyrosine kinase inhibitor
Eurax - Lotion Crotamiton Acaricide, Antipruritic, 797 Hydergine - Tablets Co-dergocrine mesilate Cerebral Vasodilator, 849
Pediculoside, Topical lpha-adrenergic receptor
Fenistil 24 - Capsules Dimethindene maleate Antihistamine, 798 blocker
Antipruritic, Antiallergic Hygroton - Scored Tablets Chlortalidone Diuretic, Thiazide 850
Fenistil - Gel Dimethindene maleate Antihistamine, 799 Infectoam - Eye ointment Fluorometholone, Gentamicin Corticosteroid, 851
Antipruritic, Antiallergic sulphate Anti-bacterial,ophthalmic
Fenistil - Oraldrops Dimethindene maleate Antihistamine, 798 Infectoam - Eyedrop Fluorometholone, Gentamicin Corticosteroid, 851
Antipruritic, Antiallergic sulphate Anti-bacterial,ophthalmic
Fenistil - Tablets Dimethindene maleate Antihistamine, 798 Lamisil - Tablets Terbinane hydrochloride. Antifungal, Squalein 852
Antipruritic, Antiallergic epoxidase enzyme
inhibitor
Lamisil - Cream Terbinane hydrochloride. Antifungal, Topical 799
Lamprene - Capsule Clofazimine Antileprotic drug 854
Lamisil - Solution Terbinane hydrochloride. Antifungal, Topical 799
Leponex - Tablets Clozapine Antipsychotic drug 855
Lamisil - Spray Terbinane hydrochloride. Antifungal, Topical 799
Lescol Retard(XL) -p.r Tablets Fluvastatin sodium Lipid-regulating drug, 858
Nicotinell-10 - Transdermal patch Nicotine CNS stimulant 799
Cholesterol synthesis
Orofar - Lozenges Benzoxonium chloride, Antibiotic, Local 800 Inhibitor
Lidocaine hydrochloride anaesthetic for Lescol - Capsules Fluvastatin sodium Lipid-regulating drug, 858
Buccopharyngeal cavity Cholesterol Synthesis
Pilka - Oral Drops Extracts of : Thyme, Antitussive, Expectorant, 801 inhibitor
Pinguicula and Drosera Antimicrobial Lioresal - Tablets Baclofen Skeletal muscle relaxant, 861
Prelloran - Cream Heparinoid & Ethylene glycol Anti-inammatory, 801 Depresses monosynaptic
salicylate Analgesic, Decongestant, and polysynaptic
Topical reex transmission
21
MANUFACTURERS INDEX
Locacorten with neomycin-Ointment Flumetasone pivalate; Corticosteroid, 862 Syntocinon - Solution for injection Oxytocin Uterine smooth muscle 902
Neomycin (as sulphate) Anti-bacterial, Topical contracting & milk release
Locacorten Vioform - Cream Flumetasone pivalate, Corticosteroid, 863 facilitating hormone,
Clioquinol Anti-infective, Topical Posterior pituitary
hormone
Locacorten Vioform - Ointment Flumetasone pivalate, Corticosteroid, 863
Clioquinol Anti-infective, Topical Tavegyl - Injection Clemastinum Antihistamine, Antipruritic 903
Locacorten - Cream Flumetasone pivalate Corticosteroid, Topical 862 Tavegyl - Tablets Clemastinum Antihistamine, Antipruritic 903
Locacorten - Ointment Flumetasone pivalate Corticosteroid, Topical 862 Tegretol - Chewable Tablets Carbamazepine Anti-epileptic, Neurotropic 904
agent
Locasalen - Ointment Flumetasone pivalate, Corticosteroid, Topical 864
Salicylic acid Tegretol - CR Tablet Carbamazepine Anti-epileptic, Neurotropic 904
agent
Lomir Tablets Isradipine Antihypertensive, 865
Calcium channel blocker Tegretol - Syrup Carbamazepine Anti-epileptic, Neurotropic 904
agent
Lopresor - f.c Tablets Metoprolol tartrate Antihypertensive, 866
Anti-anginal, Tegretol - Tablet Carbamazepine Anti-epileptic, Neurotropic 904
Anti-arrythmic, agent
Antimigraine, Teoptic - Eyedrop Carteolol hydrochloride Glaucoma treatment drug, 906
Beta-adrenoceptor blocker Beta 1, 2 Adrenergic
Lopresor Retard (Divitabs) Metoprolol tartrate Antihypertensive, 866 blocker
s.r Tablets Anti-anginal, Tofranil - Tablet Imipramine hydrochloride Antidepressant drug, 907
Anti-arrythmic, Tricyclic antidepressant
Antimigraine, Trileptal - f.c Tablet Oxcarbazepine Anti-epileptic drug, 909
Beta-adrenoceptor blocker Tricyclic compound
Ludiomil - Tablets Maprotiline hydrochloride Antidepressant drug 868 Trileptal - Oral suspension Oxcarbazepine Anti-epileptic drug, 909
Methergin - Solution for injection Methylergometrine maleate Oxytocic drug 870 Tricyclic compound
Methergin - Tablets Methylergometrine maleate Oxytocic drug 870 Ultracortenol - Eye drops Prednisolone acetate Corticosteroid, Ophthalmic 912
Miacalcic - Injection Salmon calcitonin Bone resorption inhibitor 871, Ultracortenol - Eye ointment Prednisolone pivalate Corticosteroid, Ophthalmic 912
872 Viscotears - Eye gel Carbomer 980 Tear deciency, Ocular 913
Miacalcic - Nasal spray Salmon calcitonin Bone resorption inhibitor 872 lubricant & astringent
Mosegor - Tablets Pizotifen hydrogen maleate Antihistamine, Appetite 873 Visudyne - Powder for solution for inj. Verteporn Photosensitizer, 913
stimulant, Mood elevator, Treatment of patients
Anti-migraine with age related
muscle degeneration
Mosegor - Syrup Pizotifen hydrogen maleate Antihistamine, Appetite 874
Ophthalmic
stimulant, Mood elevator,
Anti-migraine Voltaren Retard - Tablets Diclofenac sodium NSAID, Analgesic, 915
Myfortic -f.c Tablets Mycophenolic acid Immunosuppressant, 874
as Sodium salt Antiproliferative Voltaren - Coated Tablet Diclofenac sodium NSAID, Analgesic, 915
Navoban - Capsules Tropisetron hydrochloride Anti-emetic, 5-HT3 876
receptor antagonist Voltaren - Injection Diclofenac sodium NSAID, Analgesic, 917
Navoban - Injection Tropisetron hydrochloride Anti-emetic, 5-HT3 876
receptor antagonist Voltaren - Suppository Diclofenac sodium NSAID, Analgesic, 915
Nitroderm TTS Glyceryl trinitrate Antihypertensive, 877
Anti-anginal, Vasodilator Voltaren Ophtha - CD Eyedrop Diclofenac sodium NSAID, Analgesic, 918
Ophthalmic
Nyolol Eye Gel Timolol maleate Glaucoma treatment 878
drug, Beta 1, 2 Voltaren Ophtha - SDU Eyedrops Diclofenac sodium NSAID, Analgesic, 918
Adrenergic blocker Xolair - Powder and solvent for inj. Omalizumab Anti-asthmatic, 919
Oculosan - Eyedrops Naphazoline nitrate, Zinc Anti-allergic, 879 Recombinant human
sulphate heptahydrate, Anti-inammatory, monoclonal antibody
Witch Hazel, Orange Astringent, Ophthalmic Zaditen - Ophtha Eyedrops Ketotifen (as the hydrogen Antihistamine, Ophthalmic 922
Flower oil, Lavender oil, fumarate)
Euphrasia (Eyebright) Zaditen - Ophtha SDU Eyedrops Ketotifen (as the hydrogen Antihistamine, Ophthalmic 922
tincture fumarate)
Okacin - Eyedrops Lomeoxacin HCl Antibiotic, Quinolone, 880 Zelmac - Tablets Tegaserod Gut motility normalizer, 922
Ophthalmic 5-HT4 receptor partial
Parlodel - Tablet Bromocriptine mesilate Prolactin Secretion 880 agonist
Inhibitor, Dopamine Zometa - Conc. for solution forinj. Zoledronic acid (as Bone resorption inhibitor 924
receptor stimulant Zoledronic acid
Pursennid - Tablets Extracts of senna Laxative, Stimulant 882 monohydrate)
Ritalin - Tablets Methylphenidate CNS Stimulant 882
NOVO NORDISK A/S 925
hydrochloride
Sandimmun - Conc. for IV infusion Ciclosporin Immunosuppressive agent 884 Actrapid HM - Solution for injection Insulin Human, rDNA Antidiabetic, Short 925
Sandimmun Neoral - Capsules Ciclosporin Immunosuppressive agent 886 acting insulin
Sandimmun Neoral - Oral solution Ciclosporin Immunosuppressive agent 886 Actrapid Novolet Insulin Human, rDNA Antidiabetic, Short acting 927
Solution for injection insulin
Sandostatin - Injection Octreotide acetate Inhibitor of growth 890
Actrapid HM Penll - Solution Insulin Human, rDNA Antidiabetic, Short acting 929
hormone(GH) & Peptide
for injection insulin
hormone of
gastro-enteropancreatic Glucagen Hypokit - Powder and Glucagon Hypoglycaemia treatment 930
(GEP) System solvent for solution for inj. drug
Sandostatin LAR - Depot Injection Octreotide acetate Inhibitor of growth 892 Insulatard Novolet - Suspension for inj Insulin human isophane Antidiabetic, 931
Long acting insulin
hormone(GH) & Peptide
Insulatard Penll - Suspension for inj Insulin human isophane Antidiabetic, 933
hormone of
Long acting insulin
gastro-enteropancreatic
(GEP) System Insulatard HM - Injection Insulin human isophane Antidiabetic, 934
Long acting insulin
Simulect - Powder and solvent for inj. Basiliximab Corticosteroid & 894
Immunosuppressant Levemir Flexpen Insulin detemir, rDNA Antidiabetic, 936
Solution for injection Long acting insulin
Sirdalud - Tablets Tizanidine hydrochloride Skeletal muscle relaxant, 896
Levemir Penll - Solution for injection Insulin detemir, rDNA Antidiabetic, 938
Selective alpha 2-
Long acting insulin
adrenoceptor agonist
Mixtard 50 Novolet Insulin(dissolved), Isophane Antidiabetic, Combined 939
Spersadex Comp. - Eyedrops Chloramphenicol, Antibacterial, 897 suspension for inj. insulin fast acting & long
Dexamethasone sodium Corticosteroid-ophthalmic acting insulin
phosphate
Mixtard 30 Novolet Insulin(dissolved), Isophane Antidiabetic, Combined 941
Spersallerg - Eyedrops Antazoline hydrochloride, Antihistamine, Ophthalmic 897 suspension for inj. insulin fast acting & long
Tetryzoline hydrochloride acting insulin
Stalevo -f.c Tablets Levodopa, Carbidopa Antiparkinsonism, 898 Mixtard 30 - Injection Insulin(dissolved), Isophane Antidiabetic, Combined 943
monohydrate, Entacapone Dopaminergic drug insulin fast acting & long acting
Synacthen Depot - Suspension Tetracosactide hexaacetate Glauco, Minerocorticoids 901 Insulin
for injection & to a lesser extent Mixtard 30 Penll Insulin(dissolved), Isophane Antidiabetic, Combined 944
androgens biosynthesis suspension for inj. insulin. fast acting & long acting
stimulator Insulin
22
MANUFACTURERS INDEX
Mixtard 40 Novolet - Suspension Insulin(dissolved), Isophane Antidiabetic, Combined 946 Esmeron - Solution for injection Rocuronium bromide Muscle relaxant 986
for Inj. insulin fast acting & long acting Gracial - Tablets Desogestrel, Ethinylestradiol Combined hormonal 989
Insulin contraceptive, Oral
Mixtard 40 Penll - Suspension for inj. Insulin(dissolved), Isophane Antidiabetic, Combined 948 Implanon - Implant for subdermal use Etonogestrel Hormonal contraceptive, 991
insulin fast acting & long acting Oral
Insulin
Livial - Tablets Tibolone Hormone replacement 993
Mixtard 50 Penll - Suspension for inj. Insulin(dissolved), Isophane Antidiabetic, Combined 949 therapy drug
insulin fast acting & long
acting insulin Marvelon - Tablets Ethinyl estradiol, Desogestrel Combined hormonal 994
contraceptive, Oral
Norditropin Nordilet Somatropin (Recombinant Human growth hormone 950,
Solution for injection human growth-hormone) 952, Norcuron - Powder and solvent for Vecuronium bromide Muscle relaxant 996
954 solution for inj.
Norditropin Simplex Somatropin Human growth hormone 956, Oradexon - Tablets Dexamethasone Corticosteroid 998
Solution for injection 957, Oradexon - Injection Dexamethasone Corticosteroid 999
958 Orgalutran - Solution for injection Decapeptide ganirelix Anti-gonadotrophic 1000
Novomix 30-Flexplen Insulin aspart, Insulin aspart Antidiabetic, Combined 959 releasing Hormone(GnRH)
Solution for injection protamine fast acting & intermediate Orgametril - Tablets Lynestrenol. Hormone, Progestagen 1001
Pavulon - Solution for injection Pancuronium bromide Muscle relaxant 1002
Novomix 30 - Penll Insulin aspart, Insulin aspart Antidiabetic, Combined 960 Pregny - Powder and solvent Human chorion gonadotropin Gonadotrotrophic 1003
Solution for injection protamine fast acting & intermediate for solution for inj. hormone for fertility
Puregon - Powder and solvent for inj. Follitropin beta, Human follicle 1004
Solvent (Sodium chloride, stimulating hormone for
Novonorm - Tablets Repaglinide Antidiabetic drug oral, 962, Water for injection) fertility
Sulphonyl urea 963 Puregon - Solution for injection Follitropin beta Human follicle 1005,
Novorapid - Flexpen Insulin aspart Antidiabetic, 964 stimulating hormone 1006
Suspension for Inj Short acting insulin for fertility
Novorapid Penll - Suspension for inj Insulin aspart Antidiabetic, Short 966 Remeron -f.c Tablets Mirtazapine Antidepressant, 1007
acting insulin Presynaptic alpha2-
antagonist
Novoseven - Powder and solvent Eptacog Alfa (Recombinant Coagulation factor, VIIA 968
for solution for inj. coagulation factor VIIa) Sustanon - Solution for injection Testosterone propionate, Male sex hormone 1008
Testosterone
Vagifem - Vaginal Tablets Estradiol hemihydrate Female sex hormone 970
phenylpropionate,
OCTAPHARMA 971 Testosterone isocaproate,
Testosterone decanoate
Albumin Human Human albumin Plasma protein fraction 971,
Solution for infusion. 972 PFIZER SAUDI ARABIA PHARMACEUTICAL 1009
Octagam - Solution for infusion. Human normal Immuno-deciency 973 Amlor - Capsules Amlodipine besylate Antihypertensive, 1009
immunoglobulin treatment drug, Anti-anginal,
Human Immunoglobulins
Calcium-channel blocker
Octanate - Powder and solvent Human coagulation Anti-haemorrhagic, Blood 974
Caduet - Tablets Amlodipine besylate, Antihypertensive, 1010
for solution for inj. Factor VIII coagulation factor VIII
Atorvastatin calcium Anti-anginal,
for Haemophilia A
Calcium-channel
Octanine F - Powder and solvent Human coagulation Anti-haemorrhagic, 976 blocker, Lipid
for solution for inj. factor IX Blood coagulation regulating drug
factor IX for
Haemophilia B Cardura - Tablets Doxazosine mesylate Antihypertensive, 1016
Treatment of benign
Octaplas - Solution for infusion. Human plasma proteins Plasma protein fraction 978
prostatic hyperplasia(BPH),
Rhesonativ - Powder and solvent Human Anti-D Immuno-globulin 979 -adrenoceptor blocker
for solution for iInj. immunoglobulin against D(Rh) antigen
Cefobid - Injection Cefoperazone sodium Antibiotic, Cephalosporin 1016
of human erythrocyte
Fasigyn - Tablets Tinidazole Anti-protozoal, 1017
OM PHARMA 980 Anti-anaerobic
Feldene - Suppository Piroxicam NSAID, Analgesic, 1018
Dicynone - Injection Etamsylate Anti-haemorrhagic, 980 Antipyretic
Angioprotective drug
Relpax - Tablets Eletriptan hydrobromide Antimigraine drug, 1020
Dicynone - Tablet Etamsylate Anti-haemorrhagic, 980 5-HT1 receptor agonist
Angioprotective drug
Unasyn - Injection Sulbactam , Ampicillin Antibiotic, penicillin 1021
OMAN PHARMACEUTICAL PRODUCTS CO. L.L.C 980 Vfend Voriconazole Antifungal, Triazole 1022
Powder for solution for inhalation
Atormin - Tablet Atenolol Antihypertensive, 980
Vfend - Tablets Voriconazole Antifungal, Triazole 1026
Anti-anginal,
Anti-arrhythmic & Viagra - f.c Tablets Sildenal citrate Erectile dysfunctioning 1029
Myocardial infarction treatment drug
drug, Beta-adrenoceptor Vibramycin - Tablets Doxycycline monohydrate Antibiotic, Tetracycline 1032
blocker Zithromax - Powder for IV infusion Azithromycin dihydrate Antibiotic, Macrolide 1034
Bevason - Cream Betamethasone valerate Corticosteroid, Topical 981
Zithromax - Oral Suspension Azithromycin dihydrate Antibiotic, Macrolide 1037
Bevason - Ointment Betamethasone valerate Corticosteroid, Topical 981
Zithromax - Capsule Azithromycin dihydrate Antibiotic, Macrolide 1039
Clofast - Gel Diclofenac diethylamine NSAID, Analgesic, 981
Anti-rheumatic,topical PHARCO PHARMACEUTICALS COMPANY 1040
Dimetor - Tablet Metformin hydrochloride Antidiabetic drug oral, 982
Biguanide Aspinol - Tablets Acetylsalicylic acid, Caffeine NSAID, Analgesic, 1040
Fudion - Cream Fusidic acid Antibacterial, Topical 982
Omezyn - Capsule Omeprazole Antacid, Ulcer-healing, 982 Chloroquine - Phosphate Syrup Chloroquine phosphate Antimalarial, Antiamoebic, 1040
Proton pump inhibitor Anti-rheumatic
Opizole B - Cream Clotrimazole, Betamethasone Antifungal & 983 Dermatin - Powder Clotrimazole Antifungal, Topical 1040
dipropionate Corticosteroid, Topical Dermatin - Cream Clotrimazole Antifungal, Topical 1040
Opizole - Cream Clotrimazole Antifungal, Topical 983 Dermatin - Soliotion Clotrimazole Antifungal, Topical 1040
Pmol - Caplets Paracetamol NSAID, Analgesic, 983 Farcolin - Respiratory solution Salbutamol sulphate Anti-asthmatic, Selective 1040
Antipyretic beta2 -agonist
Pmol - Syrup Paracetamol NSAID, Analgesic, 983 Fawar Lemon - Powder Sodium bicarbonate, Tartaric Antacid, Antiatulant, 1041
Antipyretic acid , Citric acid Urine alkalizer
Viscodril Expectorant - Syrup Diphenhydramine Antihistamine, 984 Fawar Fruit - Powder Sodium bicarbonate, Antacid, Antiatulant, 1041
hydrochloride, Ammonium Expectorant Tartaric acid, Citric acid Urine alkalizer
chloride
Sine-up Syrup Chlorpheniramine maleate, Antihistamine, 1041
Zynovate - Cream Mometasone furoate Corticosteroid, Topical 984 Phenylephrine HCl Nasal decongestant
Zynovate - Ointment Mometasone furoate Corticosteroid, Topical 984 V-2 Capsules Vitamins, Minerals, Folic Multivitamin & 1041
ORGANON 985 acid, Nicotinamide, Iron Mineral preparation
Inositol
Andriol Testocaps Testosterone undecanoate Male sex hormone 985 V-2 Plus Capsules Ginseng ext,Vitamins, Multivitamin, 1042
Cerazette - Tablets Desogestrel Hormonal contraceptive, 985 Minerals, Essential Phospholipids & Mineral
Oral preparation
23
MANUFACTURERS INDEX
Peritoneal Dialysis Solution (CAPD2) Sodium chloride, Sodium Peritoneal dialysis 1052
PHARMA INTERNATIONAL 1042 Lactate, Calcium chloride, solution for chronic
Cefutil -f.c Tablets Cefuroxime (Axetil) Antibiotic, Cephalosporin 1042 Magnesium chloride, renal disease
Dextrose monohydrate
Nadine - f.c Tablets Ranitidine HCl Antacid, Ulcer-healing, 1042
H2-receptor antagonist Peritoneal Dialysis Solution (CAPD3) Sodium chloride,sodium Peritoneal dialysis 1052
Lactate ,calcium chloride, solution for chronic
Kenazole - Shampoo Ketoconazole Antifungal, Topical 1043
Magnesium chloride, renal disease
PHARMACEUTICAL SOLUTION INDUSTRY 1043 Dextrose monohydrate
Peritoneal Dialysis Solution (CAPD4) Sodium chloride,sodium Peritoneal dialysis 1053
Atropine sulphate Injection Atropine sulphate Antimuscarinic drug 1043 Lactate, Calcium chloride, solution for chronic
Babylyte - Oral solution Sodium, Potassium, Chloride, Oral rehydration solution 1044 Magnesium chloride, renal disease
Citrate,Dextrose monohydrate Dextrose monohydrate
Balanced Salt Solution Sodium chloride, Potassium Irrigation solution 1044 Peritoneal Dialysis Sodium chloride, sodium Peritoneal dialysis 1053
Irrigation Solution chloride,. Calcium chloride Solution with 1.5% Dextrose acetate, calcium chloride, solution for chronic
dihydrate Magnesium (Low sodium) Magnesium chloride, renal disease
chloride hexahydrate. Anhydrous dextrose
Sodium acetate trihydrate monohydrate, Sodium Ion
Sodium citrate dihydrate
Peritoneal Dialysis Sodium chloride, Sodium Peritoneal dialysis 1053
10%w/v Calcium gluconate Calcium gluconate Calcium supplement, 1044 Solution with 4.25% Dextrose acetate, Calcium chloride, solution for chronic
IV/IM Injection Parenteral (Low sodium) Magnesium chloride, renal disease
Cipro-Sol - Infusion solution Ciprooxacin lactate Antibiotic, Quinolone 1045 Anhydrous dextrose
Compound Sodium Lactate Sodium lactate Sodium Parenteral preparation 1046 monohydrate, Sodium Ion
IV infusion chloride, Potassium chloride to prevent, Treat metabolic Potassium chloride Potassium chloride Parenteral preparation 1054
Calcium chloride acidosis Injection concentrate for potassium deciency
6% w/v Dextran 70 in 0 .9%w/v Dextran 70, Sodium chloride Plasma substitute 1046
Ringers IV Infusion solution Sodium chloride, Parenteral preparation 1054
Sodium chloride Infusion
Potassium chloride, for uid & electrolyte
6%w/v Dextran 70 in 5%w/v Dextran 70 , Dextrose Plasma substitute 1046 Calcium chloride dihydrate, imbalance
Dextrose-IV infusion monohydrate
Sodium bicarbonate Sodium bicarbonate Parenteral preparation 1054
10% w/v Dextran 40 in 0.9%w/v Dextran 40, Sodium Plasma substitute 1047
5% w/v-IV infusion to prevent/treat metabolic
Sodium chloride-IV infusion chloride
acidosis
10% w/v Dextran 40 in 5%w/v Dextran 40, Dextrose Plasma substitute 1047
Dextrose-IV infusion monohydrate Sodium bicarbonate Sodium bicarbonate Parenteral preparation 1054
5%, 10%, 20%, 25%, 40%, 50%, Dextrose monohydrate Parenteral preparation 1047 7.5% w/v -IV infusion to prevent/treat metabolic
70%w/v Dextrose-IV infusion for energy supply acidosis
& hypoglycaemia Sodium bicarbonate Sodium bicarbonate Parenteral preparation 1054
20%, 25%, 40%, 50% w/v Dextrose monohydrate Parenteral preparation 1047 8.4% w/v-IV infusion to prevent/treat Metabolic
Dextrose-IV injection for energy supply acidosis
& hypoglycaemia 0.18%w/v Sodium chloride Sodium chloride, Parenteral preparation for 1055
2.5% w/v Dextrose in 1/2 Dextrose monohydrate, Parenteral preparation for 1057 and 4.3%w/v Dextrose-IV infusion Dextrose monohydrate uid & electrolyte
Normal Saline-IV infusion Normal saline uid & electrolyte imbalance
imbalance 0.18%w/v Sodium chloride Sodium chloride Parenteral preparation for 1055
4% w/v Dextrose in 0.18% w/v Dextrose monohydrate, Parenteral preparation 1055 IV infusion fluid & electrolyte
Normal Saline-IV infusion Normal saline for fluid & electrolyte imbalance
imbalance
0.225% w/v Sodium chloride Sodium chloride Parenteral preparation for 1056
5% w/v Dextrose in 0.18% w/v Dextrose monohydrate in 1/5 Parenteral preparation 1055 IV infusion fluid & electrolyte
Normal Saline-IV infusion Normal saline for uid & electrolyte
imbalance
imbalance
0.45% w/v Sodium chloride Sodium chloride Parenteral preparation for 1056
5% w/v Dextrose in 0.225% w/v Dextrose monohydrate in Parenteral preparation 1056
IV Infusion fluid & electrolyte
Normal Saline - IV infusion Normal saline for uid & electrolyte
imbalance imbalance
5% w/v Dextrose in Dextrose monohydrate , Parenteral preparation 1057 0.9% w/v Sodium chloride Sodium chloride Parenteral preparation 1057
Normal Saline-IV infusion Sodium chloride for uid & electrolyte IV Infusion for fluid & electrolyte
imbalance imbalance
5% w/v Dextrose in 0.45% w/v Dextrose monohydrate in Parenteral preparation 1057 3% w/v Sodium chloride Sodium chloride Parenteral hypertonic 1057,
Normal Saline-IV infusion Normal saline for uid & electrolyte injection Solution solution in 1058
imbalance hyponatraemia/
5% w/v Dextrose in Hartmanns Dextrose monohydrate, Parenteral preparation 1048 hypochloraemia
Solution-IV infusion Anhydrous Dextrose sodium for uid & electrolyte 5%w/v Sodium chloride Sodium chloride Parenteral hypertonic 1058
lactate, Sodium chloride, imbalance Injection solution solution in
Potassium chloride Calcium hyponatraemia/
chloride hypochloraemia
5% w/v Dextrose and Compound Dextrose monohydrate Parenteral preparation 1048 5.85%w/v Sodium chloride Sodium chloride Parenteral hypertonic 1058
Sodium Lactate-IV infusion anhydrous Dextrose, Sodium for uid & electrolyte Hypertonic solution solution in
lactate, Sodium chloride, imbalance
hyponatraemia/
Potassium chloride, Calcium
hypochloraemia
chloride
7.5% w/v Sodium chloride Sodium chloride Parenteral hypertonic 1058
10% w/v Dextrose in 0.18% w/v Dextrose monohydrate in Parenteral preparation 1056 Injection Solution solution in
Normal Saline-IV infusion 1/5 Normal Saline for uid & electrolyte hyponatraemia/
imbalance hypochloraemia
10% w/v Dextrose in 0.45% w/v Dextrose monohydrate, Parenteral preparation 1057 10% w/v Sodium chloride Sodium chloride Parenteral hypertonic 1059
Normal Saline-IV infusion 1/2 Normal Saline for uid & electrolyte Hypertonic solution solution in
imbalance hyponatraemia/
1.5% w/v Glycine Irrigation solution Glycine(aminoacetic acid ) Irrigation solution 1048 hypochloraemia
Hartmanns Solution - IV infusion Sodium lactate, Sodium Parenteral preparation 1049 Sodium chloride for Irrigation Sodium chloride Irrigation solution 1059
chloride, Potassium chloride, for uid & electrolyte Sodium Lactate 1/6 Molar-IV infusion Sodium lactate Parenteral preparation 1059
Calcium chloride imbalance to prevent/treat metabolic
Lidocaine hydrochloride 1%, 2%w/v Lidocaine hydrochloride Anaesthesia, Local 1049 acidosis
Injection anhydrous, Sodium chloride
Water for Injection Sterilized distilled water Sterile water for injection 1059
Magnesium Sulfate Injection Magnesium sulfate Parenteral nutritional 1049
Water for Irrigation Sterilized distilled water Sterile water for irrigation 1059
heptahydrate supplement to
prevent/treat
hypomagnesemia, Acute PHARMADRUG PRODUCTION GMBH 1059
nephritis, Anti convulsant
Lignocaine Jelly Lidocaine hydrochloride Anaesthesia, Local 1059
Mannitol IV infusion Mannitol Diuretic, Osmotic 1050
Metronidazole -IV infusion Solution Metronidazole, Sodium Anti-protozoal, 1050 PHILADELPHIA PHARMACEUTICALS 1060
chloride, Sodium Anti-anaerobic
Monohydrogen Phosphate, Crotaphil - Cream Crotamiton Acaricide, Antipruritic, 1060
Citric acid monohydrate Pediculoside, Topical
Peritoneal Dialysis Solution (CAPD) Sodium chloride,sodium Peritoneal dialysis 1051 Crotaphil - Lotion Crotamiton Acaricide, Antipruritic, 1060
acetate ,calcium chloride, Solution for chronic Pediculoside, Topical
Magnesium chloride, renal disease
anhydrous Dextrose Ibuphil - Gel Ibuprofen NSAID, Analgesic, 1061
monohydrate,calcium Ion Topical
24
MANUFACTURERS INDEX
Panthophil - Ointment Dexpanthenol Vitamin B7 analogue, 1061 Disprin 81 - e.c. Tablets Acetylsalicylic acid NSAID, Platelet 1072
Disinfectant & Healing aggregation inhibitor
effect on skin diseases, Doxagen - Tablets Doxazosin mesilate Antihypertensive, 1072
Topical Treatment of benign
Philaquin Forte - Topical cream Hydroquinone Skin bleaching agent, 1061 prostatic hyperplasia
Topical (BPH), - adrenoceptor
Philazole - Shampoo Ketoconazole Antifungal, Topical 1061 blocker
Philazole - Cream Ketoconazole Antifungal, Topical 1061 Doxycin - Capsules Doxycycline hyclate Antibiotic, Tetracycline 1072
Salidex - Ointment Dexamethasone acetate , Corticosteroid preparation, 1061 Earcalm - Eardrops Phenazone, Benzocaine Analgesic, Anaesthetic, 1072
Salicylic acid Topical Local
Salidex - Topical solution Dexamethasone acetate , Corticosteroid preparation, 1061 Famogen - f.c Tablets Famotidine Antacid, Ulcer-healing, 1073
Salicylic acid Topical
Feromin - Oral drops Ferrous sulphate Haematinic, Iron 1074
Salimist - Nasal drops Sodium chloride Nasal moisturizing & 1062 supplement for
soothing, Normal saline iron deciency
Uciderm Gel Fusidic acid Antibacterial, Topical 1062 Anaemia
Uciderm Cream Fusidic acid Antibacterial, Topical 1062 Feromin - Tablets Ferrous sulphate Haematinic, Iron 1074
Uciderm Ointment Sodium fusidate Antibacterial, Topical 1062 Supplement for iron
Uciderm-B Cream Fusidic acid, Betamethasone Antibacterial & 1062 deciency anaemia
valerate Corticosteroid preparation, Flamazine - Cream Silver sulfadiazine Antibacterial, Topical 1074
Topical Flozak - Capsules Fluoxetine hydrochloride Antidepressant, Selective 1074
Vocort - Cream Isoconazole nitrate, Antifungal, Topical 1062 serotonin re-uptake
Diucortolone valerate inhibitor
Xylophil - Gel Lidocaine hydrochloride Anaesthesia, Local 1062 FluCare - Syrup Triprolidine hydrochloride, Antihistamine, 1075
Pseudoephedrine Nasal decongestant
RECKITT BENCKISER COMPANY 1063 hydrochloride
Flucin - Ointment Flumethasone pivalate, Corticosteroid, 1075
Brufen - Tablets Ibuprofen NSAID, Analgesic, 1063 Neomycin sulphate Antibacterial, Topical
Antipyretic
Flumed DM Adult - Syrup Chlorpheniramine maleate, Antihistamine, 1075
Gaviscon Peppermint Liquid Sodium alginate, Sodium Antacid, Heartburn pain 1063 Pseudoephedrine Decongestant, Antitussive
Oral Suspension bicarbonate, Calcium reliever hydrochloride,
carbonate Dextromethorphan
Junifen Paediatric suspension Ibuprofen NSAID, Analgesic, 1063 Hydrobromide
Antipyretic Flumed DM Paed - Syrup Chlorpheniramine maleate, Antihistamine, 1075
Pseudoephedrine Decongestant, Antitussive
RECORDATI S.P.A 1063 hydrochloride,
Dextromethorphan
Derma-Lomexin - Cream Fenticonazole nitrate Antifungal, Topical 1063
hydrobromide
Derma-Lomexin - Spray Fenticonazole nitrate Antifungal, Topical 1063
Flumed - Syrup Chlorpheniramine maleate, Antihistamine, 1075
Genurin Semplice Fort - Tablets Flavoxate hydrochloride Antispasmodic on 1064 Pseudoephedrine Decongestant
urogenital smooth muscles hydrochloride
Gyno-Lomexin - Vaginal Cream Fenticonazole nitrate Antifungal, Topical 1064 Flumetol - Eye ointment Fluorometholone Corticosteroid, Ophthalmic 1076
Gyno-Lomexin - Vaginal Suppository Fenticonazole nitrate Antifungal, Topical 1064 Folic acid - Tablets Folic acid Erythropoietic, Treats 1076
Theo-Dur - Tablets Theophylline anhydrous Anti-asthmatic, 1064 folate megaloblastic
Bronchodilator anaemia
Gastrozole - Capsules Omeprazole Antacid, Ulcer-healing, 1076
RIYADH PHARMA 1065 Proton pump inhibitor
Acicare 75 - f.c Tablets Ranitidine hydrochloride Antacid, Ulcer-healing, 1065 Genprid - Capsules Sulpiride Antipsychotic drug, 1077
H2-receptor antagonist Antidepressant
Acicare- f.c Tablets Ranitidine hydrochloride Antacid, Ulcer-healing, 1065 Genprid - Tablets Sulpiride Antipsychotic drug, 1077
H2-receptor antagonist Antidepressant
Acivir - Cream Acyclovir Antiviral drug, 1066 Gentacin - Eye drops Gentamicin sulphate Antibiotic, 1077
Topical Aminoglycoside, Topical
Asthalin - Syrup Salbutamol sulphate Anti-asthmatic, 1066 Gentacin - Eye ointment Gentamicin sulphate Antibiotic, 1077
Bronchodilator, Aminoglycoside,
Selective beta2 agonist Ophthalmic
Balad - Cream Fusidic acid Antibacterial, Topical 1066 Guafedrin - Syrup Guaifenesin, Pseudoephedrine Expectorant & 1077
Balad - Gel Fusidic acid Antibacterial, Topical 1066 hydrochloride Decongestant
Balad - Ointment Fusidic acid Antibacterial, Topical 1066 Guaphan DM - Syrup Guaifenesin, Expectorant & 1078
Dextromethorphan Cough preparation
Betachol - Eyedrops Betamethasone sodium Corticosteroid & 1067 Hydrobromide
phosphate, Chloramphenicol Antibacterial, Ophthalmic
micronized Guaphan - Syrup Guaifenesin Expectorant 1078
Betagen - Tablets Betahistine hydrochloride Nausea & Vertigo drug, 1067 Histofen - Eyedrops Ketotifen hydrogen fumarate Antihistamine, 1078
Histamine substitute Ophthalmic
Calcinate - Tablets Calcium carbonate Calcium supplement 1067 Histofen - Syrup Ketotifen hydrogen fumarate Anti-asthmatic, 1078
Anti-histamine
Chloroquine - Syrup Chloroquine phosphate Antimalarial, Antiamoebic, 1067
Anti-rheumatic Homapin - Eyedrops Homatropine hydrobromide Mydriatic & Cycloplegic 1079
Chloroquine - Tablets Chloroquine phosphate Antimalarial, Antiamoebic, 1067 Isobid - m.r Capsules Isosorbide dinitrate Antihypertensive, 1079
Anti-rheumatic Anti-anginal, Vasodilator
Chlorpheniramine - Syrup Chlorpheniramine maleate Antihistamine, Sedating 1068 Lorahist - Syrups Loratadine Antihistamine, 1079
Non-sedating
Ciprocin - Eye Drops Ciprooxacin hydrochloride Antibiotic, Quinolone, 1068
Ophthalmic Lorahist - Tablets Loratadine Antihistamine, 1079
Non-sedating
Ciprocin - Eye Ointment Ciprooxacin hydrochloride Antibiotic, Quinolone, 1068
Ophthalmic Mebagen - Tablets Mebeverine hydrochloride Antispasmodic & drug 1080
Ciprogen - Tablets Ciprooxacin hydrochloride Antibiotic, Quinolone 1069
intestinal smooth muscle
Citalogen - f.c Tablets Citalopram hydrobromide Antidepressant, Selective 1069 Relaxant
serotonin re-uptake
Nazophen - Nasal drops Naphazoline hydrochloride, Nasal decongestant, 1080
inhibitor
Chlorpheniramine maleate Antihistamine
Clarimac - f.c Tablets Clarithromycin Antibiotic, Macrolide 1070
Noscam - Nasal drops Antazoline sulphate, Antihistamine, 1080
Cliocort - Ointment Hydrocortisone acetate, Corticosteroid, Topical 1070 Naphazoline nitrate Decongestant, Topical
Clioquinol
Ocugesic - Eyedrops Diclofenac sodium NSAID, Analgesic, 1080
Clobederm - Cream Clobetasol propionate Corticosteroid, Topical 1070 Ophthalmic
Clobederm - Ointment Clobetasol propionate Corticosteroid, Topical 1070 Oculac - Eyedrops Sodium chloride, Natural tears uid 1081
Coxicam - Tablets Meloxicam NSAID, for treatment 1071 Hypromellose substitute
of arthritis & spondylitis Ocumol - Eyedrops Timolol maleate Glaucoma treatment 1081
Dermolar - Cream Fluocinolone acetonide Corticosteroid, Topical 1071 drug, Beta 1, 2 adrenergic
Dermolar - Ointment Fluocinolone acetonide Corticosteroid, Topical 1071 blocker
DermolarN - Cream Fluocinolone acetonide, Corticosteroid, 1071 Ocured - Eyedrops Antazoline sulphate, Antihistamine, 1081
Neomycin sulphate Antibacterial,topical Naphazoline nitrate Decongestant, Ophthalmic
25
MANUFACTURERS INDEX
Optasone - Eyedrop Betamethasone sodium Corticosteroid, 1081 Riyadhformin - f.c Tablets Metformin hydrochloride Antidiabetic drug oral, 1093
phosphate Ophthalmic Biguanide
Oxacin - Eye drops Ooxacin Antibiotic, Quinolone, 1082 Rumafen - e.c Tablets Diclofenac sodium NSAID, Analgesic, 1094
Ophthalmic Antipyretic, Anti-rheumatic
Phorpain - Gel Ibuprofen NSAID, Analgesic, 1082 Rumafen - Gel Diclofenac diethyl ammonium NSAID, Analgesic, 1094
Topical Antirheumatic, Topical
Pilotina - Eyedrops Pilocarpine hydrochloride Glaucoma treatment drug, 1082 Simvagen - Tablets Simvastatin Lipid-regulating drug, 1094
Miotic Cholesterol Synthesis
Protoprazole - e.c Tablets Pantoprazole sodium Antacid, Ulcer-healing, 1082 Inhibitor
Proton pump inhibitor Teracin - Eye ointment Tetracycline hydrochloride Antibacterial, Ophthalmic 1095
Proxepain -f.c Tablets Naproxen sodium NSAID, Analgesic, 1083 Theoped - s.r Tablets Theophylline Anti-asthmatic, 1095
Antipyretic Bronchodilator
Pyralvex - Solution Anthraquinone glycosides, Analgesic, 1083 Theoped - Syrups Theophylline Anti-asthmatic, 1095
Salicylic acid Antiphlogistic, Antibacterial Bronchodilator
Rhinofrin - Nasal drops Phenylephrine hydrochloride Nasal decongestant, 1083 Ultrazole - Capsules Lansoprazole Antacid, Ulcer-healing, 1096
Sympathomimetic Proton pump inhibitor
Riabroxol - Syrup Ambroxol hydrochloride Mucolytic 1084 Vascodipine - Tablets Amlodipine besilate Antihypertensive, 1096
Anti-anginal, Calcium-
Riabroxol - Tablets Ambroxol hydrochloride Mucolytic 1084
channel blocker
Riacetamid - Eyegel Sulphacetamide Antibacterial, Ophthalmic 1084
Waxsol - Otic Drops Docusate sodium Wax Softener 1096
Riacetamid-10 - Eyedrops Sulphacetamide sodium Antibacterial, Ophthalmic 1084 Xylomet Adult - Nasal drops Xylometazoline Nasal decongestant, 1097
Riacetamid-20 - Eyedrops Sulphacetamide sodium Antibacterial, Ophthalmic 1084 hydrochloride Topical
Riachol - Eyedrops Chloramphenicol Antibiotic, Ophthalmic 1084 Xylomet Paed - Nasal drops Xylometazoline Nasal decongestant, 1097
Riachol - Eye-Ointment Chloramphenicol Antibiotic, Ophthalmic 1084 hydrochloride Topical
Riacort - Cream Hydrocortisone acetate Corticosteroid, Topical 1085 Zertazine -f.c Tablets Cetirizine hydrochloride Antihistamine, 1097
Riacort - Ointment Hydrocortisone acetate Corticosteroid, Topical 1085 Non-sedating
Zertazine - Syrup Cetirizine hydrochloride Antihistamine, 1097
Riafampicin - Tablets Rifampicin Antibiotic, 1085
Non-sedating
Antituberculosis,
Antileprotic & Brucellosis Zolpigen - f.c Tablets Zolpidem tartrate Sedative, Treats insomnia 1097
Riagesic - Oral drops Paracetamol NSAID, Analgesic, 1085 SAJA PHARMACEUTICALS 1098
Antipyretic
(SAUDI ARABIAN JAPANESE PHARMA. CO. LTD)
Riagesic - Syrup Paracetamol NSAID, Analgesic, 1085,
Antipyretic 1086 Amopres - Capsules Amlodipine besylate Antihypertensive, Calcium 1098
Riagesic - Tablets Paracetamol NSAID, Analgesic, 1085 channel blocker
Antipyretic Azomax - Capsules Azithromycin dihydrate Antibiotic, Macrolide 1099
Rialac - Liquid Lactulose Laxative, Osmotic 1086 Clarex - Tablets Clarithromycin Antibiotic, Macrolide 1099
Rialocaine - Eyedrop Lidocaine hydrochloride Anaesthesia, Ophthalmic 1086 Duspatalin - Tablets Mebeverine Antispasmodic & drug 1100
Rialocaine - Gel Lidocaine hydrochloride Anaesthesia, Local 1086
Rialocaine - Ointment Lidocaine hydrochloride Anaesthesia, Local 1087 relaxant
Rialol - Eyedrops Betaxolol hydrochloride Glaucoma treatment drug, 1087 Flonazol - Capsules Fluconazole Antifungal, Triazole 1100
Floxacin - Tablets Ciprooxacin hydrochloride Antibiotic, Quinolone 1100
Rialox Plus - Suspension Aluminum hydroxide, Antacid, Antiatulant 1087
Itrazol - Capsules Itraconazole Antifungal, Triazole 1101
Magnesium hydroxide,
Simethicone Josaxin - Tablets Josamycin Antibiotic, Macrolide 1102
Olmetec - Tablets Olmesartan medoxomil Antihypertensive, 1102
Rialox - Suspension Aluminum hydroxide, Antacid 1088
Angiotensin-II receptor
Magnesium hydroxide
blocker
Rialox - Tablets Aluminum hydroxide, Antacid 1088
Omeprex - Capsules Omeprazole Antacid, Ulcer-healing, 1104
Magnesium hydroxide
Riamide - Syrup Metoclopramide Anti-emetic, 1088
Omnic - m.r Capsules Tamsulosin hydrochloride Benign prostatic 1104
hydrochloride Stimulates gut motility hyperplasia(BPH) &
Rianest - Cream Nystatin Antifungal, Topical 1088 Urination disorders
Rianest - Ointment Nystatin Antifungal, Topical treatment drug,
Rianest - Suspension Nystatin Antifungal, Polyene 1088 Alpha1-receptor blocker
Pantomax -e.c Tablets Pantoprazole sodium Antacid, Ulcer-healing, 1105
Riaphan - Syrup Dextromethorphan Antitussive 1089
Sesquihydrate Proton pump inhibitor 1106
hydrobromide
Roxonin - Tablets Loxoprofen sodium NSAID, Analgesic, 1106
Riapril - Tablets Enalapril maleate Antihypertensive, 1089
Antipyretic
ACE inhibitor
Simvaten - f.c Tablets Simvastatin. Lipid-regulating drug, 1107
Riaprofen - f.c Tablets Ibuprofen NSAID, Analgesic, 1089
Antipyretic inhibitor
Riaprofen FM -f.c Tablets Ibuprofen NSAID, Analgesic, 1090 Vasopril Tablets Enalapril maleate Antihypertensive, 1108
Antipyretic ACE inhibitor
Riaproxen - Tablets Naproxen NSAID, Analgesic, 1090 Yutopar - Tablets Ritodrine hydrochloride Uterine myometrial 1108
Antipyretic relaxant, beta2 - agonist
Riaspasm - Syrup Hyoscine- N-butylbromide Antispasmodic & Drug 1091 Yutopar - Injection Ritodrine hydrochloride Uterine myometrial 1108
altering gut relaxant, beta2 - agonist
motility, Antimuscarinic
Riaspasm - Tablets Hyoscine- N-butylbromide Antispasmodic & Drug 1091 SANDOZ 1109
Altering gut
Artamin - Capsules Penicillamine Anti-rheumatoid, 1109
motility, Antimuscarinic
Heavy metal antagonist
Riatropine - Eye Ointment Atropine sulphate Mydriatic & Cycloplegic 1091
Baneocin - Ointment Bacitracin zinc, Antibiotic, Topical 1110
Riatropine - Eyedrops Atropine sulphate Mydriatic & Cycloplegic 1091 Neomycin sulphate
Riavate - Cream Betamethasone valerate Corticosteroid, Topical 1091 Baneocin - Powder Bacitracin zinc, Antibiotic, Topical 1110
Riavate - Ointment Betamethasone valerate Corticosteroid, Topical 1091 Neomycin sulphate
Riaxine - Syrup Bromhexine hydrochloride Mucolytic 1092 Biodroxil - Tablets Cefadroxil monohydrate Antibiotic, Cephalosporin 1110
Riazem - Capsules Diltiazem hydrochloride Antihypertensive, 1092 Biodroxil - Capsules Cefadroxil monohydrate Antibiotic, Cephalosporin 1110
Anti-anginal, Biodroxil - Oral suspension Cefadroxil monohydrate Antibiotic, Cephalosporin 1110
Calcium-channel blocker Cefazolin - Injection Cefazolin as sodium Salt Antibiotic, Cephalosporin 1111
Riazem -f.c Talets Diltiazem hydrochloride Antihypertensive, 1092 Curam - f.c-Tablets Amoxycillin trihydrate, Antibiotic, 1113,
Anti-anginal, Potassium clavulanate Broad-spectrum penicillin 1114
Calcium-channel blocker Curam - Oral suspension Amoxycillin trihydrate, Antibiotic, 1114
Riazole - suspension Metronidazole benzoate Anti-protozoal, 1093 Potassium clavulanate Broad-spectrum penicillin
Anti-anaerobic Exoderil - Cream Naftine hydrochloride Antifungal, Topical 1116
Riazole - Tablets Metronidazole Anti-protozoal, 1093 Lisdene - Tablets Lisinopril dihydrate Antihypertensive, 1116,
Anti-anaerobic ACE inhibitor 1118,
Riazolin - Eyedrops Naphazoline nitrate Decongestant, Ophthalmic 1093 1119
26
MANUFACTURERS INDEX
Ospamox - Capsules Amoxicillin trihydrate Antibiotic, 1120 Lantus - Solution for injection Insulin glargine Antidiabetic, Long 1161,
Broad-spectrum penicillin acting insulin 1163
Ospamox -f.c Tablet Amoxicillin trihydrate Antibiotic, 1121 Lantus Optiset - Solution for injection Insulin glargine Antidiabetic, Long 1164
Broad-spectrum penicillin acting insulin
Ospamox - Oral suspension Amoxicillin trihydrate Antibiotic, 1122 Lanzor - Capsules Lansoprazole Antacid, Ulcer-healing, 1166,
Broad-spectrum penicillin Proton pump inhibitor 1167
Ospen 200 - Granules for oral susp. Phenoxy methyl penicillin Antibiotic, Semisynthetic 1123 Lasix - Injection solution Furosemide Diuretic, Loop 1167
potassium penicillin Lasix - Tablets Furosemide Diuretic, Loop 1169
Ospen 400 - Granules for oral susp. Phenoxy methyl penicillin Antibiotic, Semisynthetic 1124 Lasix - Infusion solution Furosemide Diuretic, Loop 1170
potassium penicillin Mono-Tildiem - Capsules Diltiazem hydrochloride Antihypertensive, 1171
Ospen 500 - Tablets Phenoxy methyl penicillin Antibiotic, Semisynthetic 1125 Antianginal, Calcium
potassium penicillin channel blocker
Ospen 1000 - Tablets Phenoxy methyl penicillin Antibiotic, Semisynthetic 1125 Plaquenil Tablets Hydroxychloroquine sulphate Anti-rheumatoid arthritis, 1172
potassium penicillin Anti- erythematous
Ospexin - Oral suspension Cephalexin Antibiotic, Cephalosporin 1126 Plavix - Tablets Clopidogrel hydrogen Antiplatelet, 1172
Ospexin - Tablets Cephalexin Antibiotic, Cephalosporin 1127 sulphate Atherothrombotic inhibitor
penicillin G Sodium - Injection Benzylpenicillin Sodium Antibiotic, Penicillin 1128 Primperan - Suppository Metoclopramide Anti-emetic, Stimulates 1174,
Retarpen - Injection Benzathine benzyl penicillin Antibiotic, 1130 gut motility 1176
Broad-spectrum penicillin Primperan - Solution for injection Metoclopramide HCl Anti-Emetic, Stimulates 1175
Standacillin - Injection Ampicillin as sodium salt Antibiotic, 1131 gut motility
Broad-spectrum penicillin Primperan - Tablets Metoclopramide HCl Anti-emetic, Stimulates 1175
Thiopental - Injection Thiopental sodium Anaesthetic, 1132 gut motility
Short acting barbiturate Profenid - Suppository Ketoprofen NSAID, Analgesic 1177
Profenid - Freeze-dried powder Ketoprofen NSAID, Analgesic 1177
SANOFI AVENTIS 1133 Profenid - Coated Tablets Ketoprofen NSAID, Analgesic 1178
Adenocor - Solution for injection Adenosine Anti-Arrythmic drug 1133 Profenid LP - Coated Tablets Ketoprofen NSAID, Analgesic 1178
Amaryl - Tablets Glimepiride Antidiabetic drug oral, 1134 Rhinathiol 2% Carbocisteine Mucolytic 1179
Sulphonyl urea Children & Infants syrup
Apidra Optipen Insulin glulisine Antidiabetic, Fast acting 1135 Rhinathiol 5% - Adult syrup Carbocisteine Mucolytic 1179
Solution for injection in cartridge Insulin Rhinathiol Promethazine Syrup Carbocisteine, Promethazine Mucolytic, Antihistaminic 1180
Apidra Optiset - Solution for injection Insulin glulisine Antidiabetic, Fast acting 1137 hydrochloride
Insulin Rifadin - Capsules Rifampicin Antibiotic, 1180
Aprovel - Tablets Irbesartan Antihypertensive, 1139, Antituberculosis,
Angiotensin-II receptor 1140 Antileprotic & Brucellosis
antagonist Rulid - Tablets Roxithromycin Antibiotic, Macrolide 1181
Aspegic Injectable DL-Lysine acetylsalicylate Analgesic, Antipyretic, 1141 Sabril - Tablets Vigabatrin Anti-epileptic drug, 1182
Anti-inammatory Gaba transaminase
Bi-Tildiem - Tablets Diltiazem hydrochloride Antihypertensive, 1141, Inhibitor
Anti-anginal, Calcium 1142 Solian - Tablets Amisulpride Antipsychotic drug 1183,
channel blocker 1184,
Calcium Resonium - Powder Calcium polystyrene Potassium removal 1142 1185
sulphonate drug, Ion exchange resin
Sorbitol Delalande Sorbitol Laxative, Osmotic 1185
Claforan - Injection Cefotaxime sodium Antibiotic, Cephalosporin 1143, Powd. for oral solution in sachet
1144 Stilnox - Tablets Zolpidem hemitartrate Hypnotic and Sedative 1186
Clexane - Solution for injection Enoxaparin sodium Anti-thrombotic agent 1145 Surgam - Tablets Tiaprofenic acid NSAID, Analgesic 1186
Clomid - Tablets Clomifene citrate Ovulation inducer, 1146 Targocid - Powder and Teicoplanin Antibiotic, Glycopeptide 1187
Antioestrogen
solvent for solution for inj
Co-Aprovel - Tablets Irbesartan and Antihypertensive, 1147
Tarivid - I.V infusion Ooxacin hydrochloride Antibiotic, Fluoroquinolone 1188
Hydrochlorothiazide Angiotensin-II receptor
antagonist & Thiazide Tarivid - Tablets Ooxacin Antibiotic, Fluoroquinolone 1190
diuretic Taxotere - Concentration Docetaxel Anticancer, Taxoid 1193
Cordarone - Solution for injection Amiodarone hydrochloride Anti-arrythmic drug 1148 for solution for infusion
Cordarone - Tablets Amiodarone hydrochloride Anti-arrythmic drug 1149 Tavanic - I.V infusion Levooxacin Antibiotic, Fluoroquinolone 1194
Danol - Capsules Danazol Gonadotrophin secretion 1150 Tavanic - Tablets Levooxacin Antibiotic, Fluoroquinolone 1194
inhibitor for Telfast - Tablets Fexofenadine hydrochloride Antihistamine, 1195,
endometriosis, Breast pain Non-sedating 1196
Daonil - Tablets Glibenclamide Antidiabetic drug oral, 1151 Tiapridal - Solution for injection Tiapride Antipsychotic, 1196
Sulphonyl urea Neuroleptic
Depakine - Syrup Sodium valproate Anti-epileptic drug, 1151 Tiapridal - Tablets Tiapride Antipsychotic, 1196
Aliphatic carboxylic acid Neuroleptic
Depakine - g.r Tablets Sodium valproate Anti-epileptic drug, 1152, Ticlid - Tablets Ticlopidine hydrochloride Antiplatelet, 1197
Aliphatic carboxylic acid 1155 Anti-thrombotic
Depakine - Oral solution Sodium valproate Anti-epileptic drug, 1153 Tildiem - Tablets Diltiazem hydrochloride Antihypertensive, 1198
Aliphatic carboxylic acid Antianginal, Calcium
Depakine - Injection Sodium valproate Anti-epileptic drug, 1154 channel blocker
Aliphatic carboxylic acid Trental - f.c Tablets Pentoxifylline Peripheral vasodilator 1198
Depakine Chrono - s.r Tablets Sodium valproate Anti-epileptic drug, 1155 Xatral - s.r Tablets Alfuzosin hydrochloride Benign prostatic 1199
Aliphatic carboxylic acid hyperplasia treatment
Dogmatil - Syrup Sulpiride Antipsychotic drug 1156 drug, Alpha-blocker
Dogmatil - Capsules Sulpiride Antipsychotic drug 1157 Xatral XL -p.r Tablets Alfuzosin hydrochloride Benign prostatic 1199
hyperplasia treatment
Dogmatil - Solution for injection Sulpiride Antipsychotic drug 1157
drug, Alpha-blocker
Dogmatil - Tablets Sulpiride Antipsychotic drug 1158
Eloxatin Oxaliplatin Anticancer, Platinum 1159 SANOFI PASTEUR 1200
Concentration for solution for infusion compound
Act-Hib - Powder & solvent Haemophilus Inuenzae Vaccine 1200
for solution for inj. Type B Polysaccharide
Flagyl - Tablets Metronidazole Anti-protozoal, 1159 Conjugated to tetanus protein
Anti-anaerobic
Fumafer - Tablets Ferrous fumarate Haematinic, Iron 1160 Actacel - Suspension for injection Pertussis toxoids (PT), Vaccine 1200
supplement for Iron Filamentous Haemagglutinin
deciency anaemia (FHa), Fimbriae (Agg 2 + 3),
Hemoclar Cream Pentosan sulphuric polyester Minor trauma drug, 1160 pertactin (69kda Protein),
Anti-inammatory in diphtheria toxoids,
acute venous condition tetanus toxoids
Hept-A-Myl - Oral solution Heptaminol Cardiac stimulant, 1160 Avaxim 160U Hepatitis A Virus Vaccine 1201
Vasodilator Suspension for injection (Gbm Strain), Inactivated
Kerlone - Tablets Betaxolol hydrochloride Antihypertensive, 1161 Avaxim 80U Paediatric Hepatitis A Virus Vaccine 1201
Antianginal, Beta blocker Suspension for inj. (Gbm Strain), Inactivated
27
MANUFACTURERS INDEX
D.T.Coq/D.T.P - Powder & diluent Puried Diphtheria toxoid, Vaccine 1202 Perderm - Cream Alclometasone dipropionate Corticosteroid, Topical 1228
for susp. for inj Puried Tetanus toxoid, Perderm - Ointment Alclometasone dipropionate Corticosteroid, Topical 1228
Bordetella Pertussis
Polaramine - Repetabs Dexchlorpheniramine maleate Antihistamine, Sedating 1229
Polysaccharide Meningococcal Polysaccharide of Neisseria Vaccine 1202
Polaramine Expectorant - Syrup Dexchlorpheniramine Antihistamine, 1229
A+C Vaccine-injection Meningitidis Group A /
maleate, Pseudoephedrine Decongestant, Expectorant
Polysaccharide of Neisseria
sulfate, Guaifenesin
Meningitidis Group C
Polaramine - Syrup Dexchlorpheniramine maleate Antihistamine, Sedating 1229
Opvero - Oral suspension Poliovirus Type 1,2 & 3 Vaccine 1203
Remicade - Injection Iniximab Human Monoclonal 1230
Pneumo 23 Polysaccharides of Vaccine 1203
Antibody
Solution for injection Streptococcus Pneumoniae
Serotypes 1, 2, 3, 4, 5, 6B, Tinaderm - Solution Tolnaftate Antifungal, Topical 1235
7F, 8, 9N, 9V, 10A, 11A, 12F, Trilafon - Tablets Perphenazine Antipsychotic drug, 1235
14, 15B, 17F, 18C, 19A, 19F, Anxiolytic, Anti-emetic
20, 22F, 23F, 33F
Rouvax - Suspension for injection Live attenuated Measles Vaccine 1204
SERVIER 1236
virus(Schwarz Strain) Bi Preterax - Tablets Perindopril Tert-butylamine, Antihypertensive, ACE 1236
Tetavax - Suspension for injection Tetanus Toxoid Vaccine 1204 Indapamide inhibitor & Diuretic
Tetract-HIB - Suspension for injection Haemophilus Inuenzae Vaccine 1205 Coversyl - Tablets Perindopril Tert-butylamine Antihypertensive, 1237,
Type B Polysaccharide, ACE inhibitor 1238
Puried Diphtheria toxoid, Daon-f.c Tablets Diosmin, Hesperidin Vascular protector, 1239
Puried Tetanus toxoid, Venous Tonic
Bordetella Pertussis
Diamicron - Tablets Gliclazide Antidiabetic drug oral, 1239
Tripacel - Solution for injection Pertussis toxoids (PT)/ Vaccine 1205 Sulphonyl urea
lamentous Haemagglutinin
Diamicron MR Tablets Gliclazide Antidiabetic drug oral, 1239
(FHa)/mbriae (Agg 2+3)/
Sulphonyl urea
pertactin (69kda Protein)/
diphtheria Toxoids /tetanus Hyperium - Tablets Rilmenidine Antihypertensive, 1241
Toxoids Centrally Acting
Typhim VI - Solution for injection Polysaccharides of Salmonella Vaccine 1206 Natrilix - s.r Tablets Indapamide Diuretic(thiazide) & 1241
typhi Ty2 strain Antihypertensive
Natrilix - Tablets Indapamide Diuretic(thiazide) & 1241
SCHERING-PLOUGH CORPORATION 1206 Antihypertensive
Preterax - Scored Tablets Perindopril Tert-butylamine, Antihypertensive, 1242
Celestoderm-V Garamycin - Cream Betamethasone valerate, Corticosteroid, 1206
Indapamide ACE inhibitor/diuretic
Gentamicin sulfate Antibacterial, Topical
Procoralan -f.c Tablets Ivabradine HCl Anti-anginal drug 1242
Celestoderm-V Garamycin - Ointment Betamethasone valerate, Corticosteroid, 1206
Gentamicin sulfate Antibacterial, Topical Protelos - Granules for oral susp. Strontium ranelate Bone breakdown 1243
anhydrate inhibitor & Stimulates
Celestone Chronodose - Injection Betamethasone sodium Corticosteroid 1207 bone rebuilding
Phosphate , Betamethasone
acetate Stablon - Coated Tablets Tianeptine sodium Antidepressant drug 1244
Celestone - Tablets Betamethasone Corticosteroid 1209 Trivastal Retard 50 - s.r Tablets Pirbedil Antiparkinsonism, 1244
Dopamine receptor
Clarinase - Repetabs Loratadine, Pseudoephedrine Antihistamine, 1210 Stimulant
sulfate Decongestant
Vastarel - Tablets Trimetazidine Anti-anginal drug 1244
Diprofos - Injection Betamethasone dipropionate, Corticosteroid 1211 dihydrochloride
Betamethasone sodium
Vastarel MR Tablets Trimetazidine Anti-anginal drug 1245
phosphate
dihydrochloride
Diprogenta - Cream Betamethasone dipropionate, Corticosteroid, 1212
Gentamicin sulfate. Antibacterial, SHAPHACO PHARMACEUTICAL INDUSTRIES 1245
Topical
Diprogenta - Ointment Betamethasone dipropionate, Corticosteroid, 1212 Amol Extra - Tablets Paracetamol, Caffeine NSAID, Analgesic, 1245
gentamicin sulfate. Antibacterial, Topical anhydrous Antipyretic
Diprolene - Cream Betamethasone dipropionate Corticosteroid, Topical 1213 Amol - Oral drops Paracetamol NSAID, Analgesic, 1245
Antipyretic
Diprolene - Ointment Betamethasone dipropionate Corticosteroid, Topical 1213
Amol - Syrup Paracetamol NSAID, Analgesic, 1245
Diprosalic - Lotion Betamethasone dipropionate, Corticosteroid Preparation, 1214 Antipyretic
Amol - Tablets Paracetamol NSAID, Analgesic, 1245
Diprosalic - Ointment Betamethasone dipropionate, Corticosteroid Preparation, 1214 Antipyretic
Augmoks - f.c Tablets Amoxycillin trihydrate, Antibiotic, 1246
Diprosone - Cream Betamethasone dipropionate Corticosteroid, Topical 1215 Potassium clavulanate Broad-spectrum penicillin
Diprosone - Ointment Betamethasone dipropionate Corticosteroid, Topical 1215 Betonate - Cream Betamethasone Corticosteroid, Topical 1246
Diprosone - Lotion Betamethasone dipropionate Corticosteroid, Topical 1215 Betonate - Ointment Betamethasone Corticosteroid, Topical 1246
Disophrol - s.r Tablets Dexbrompheniramine Antihistamine, 1215 Betonate N - Cream Betamethasone, Corticosteroid, 1246
maleate, Pseudoephedrine Decongestant Neomycin sulphate Antibacterial,topical
sulfate Betonate N - Ointment Betamethasone, Corticosteroid, 1246
Elocom - Cream Mometasone furoate Corticosteroid, Topical 1216 Neomycin sulphate Antibacterial, Topical
Elocom - Lotion Mometasone furoate Corticosteroid, Topical 1216 Ranzin - f.c Tablets Ranitidine HCl Antacid, Ulcer-healing, 1247
Elocom - Ointment Mometasone furoate Corticosteroid, Topical 1216 H2-receptor antagonist
Eulexin - Tablets Flutamide Anticancer, Anti-androgen 1216 SCHERING COMPANY S.p.A 1247
for Prostate cancer
Garamycin - Cream Gentamicin sulfate Antibiotic, 1217 Advantan - Cream Methylprednisolone Corticosteroid, Topical 1247
Aminoglycoside, Topical aceponate.
Garamycin - Ointment Gentamicin sulfate Antibiotic, 1217 Advantan - Ointment Methylprednisolone Corticosteroid, Topical 1247
Aminoglycoside, Topical aceponate.
Garamycin - Eye/ Ear drops Gentamicin sulfate Antibiotic, 1217 Androcur - Tablets Cyproterone acetate Anti-Androgen 1248
Aminoglycoside, Betaferon - Powder & solvent Interferon beta-1b Immuno-modulator, 1249
Ophthalmic, Otic for solution for injection Antiviral, Antiproliferative
Garasone - Eye/ Ear drops Gentamicin sulfate, Antibiotic & 1218 Bonefos - Concentrate Disodium Clodronate Bone resorption 1251
Betamethasone sodium Corticosteroid for solution for infusion inhibitor, Biphosphonate
phosphate treatment, Ophthalmic Bonefos - Capsules Disodium Clodronate Bone resorption 1252
Intron-A - Injection solution Highly puried interferon Immuno-modulator, 1218 inhibitor, Biphosphonate
Alfa-2b Antiviral, Antiproliferative Climen - Tablets Estradiol Valerate, Hormone replacement 1252
Cyproterone acetate therapy drug
Lotriderm - Cream Clotrimazole/ Corticosteroid, Antifungal, 1221
Betamethasone dipropionate Topical Diane-35 - Tablets Cyproterone acetate/ Anti-androgen & Female 1253
ethinylestradiol sex hormone,
Nasonex - Nasal spray Mometasone furoate Corticosteroid, Topical 1222
Treats androgenisation in
monohydrate
females requiring
Netromycine - Injection Netilmicin sulfate Antibiotic, Aminoglycoside 1222 hormone therapy
Nitro-Dur Nitroglycerin Antihypertensive, 1224 Dopergin - Tablets Acid lisuride maleate Antiparkinsonism, 1256
Transdermal infusion system Anti-anginal, Vasodilator Dopaminergic agonist
Peg-Intron - Powder & solvent Peginterferon Alfa-2b Immuno-modulator, 1225 Fludara - Powder for Fludarabine phosphate Anticancer, Antimetabolite 1256
for solution for inj. Antiviral, Antiproliferative solution for injection
28
MANUFACTURERS INDEX
Gastrogran - Oral aqueous solution Sodium amidotrizoate, Contrast media 1258
Meglumine amidotrizoate SPIMACO ADDWAEIH 1286
Gynera - Tablets Gestodene,Ethinylestradiol Hormonal contraceptive, 1259 Aerius - Syrup Desloratadine Antihistamine, 1286
Oral Non-sedating
Isovist - Solution for injection Iotrolan Contrast media 1260 Aerius - Tablets Desloratadine Antihistamine, 1287
Magnevist - Aqueous solution Gadopentetic acid, Contrast media 1262 Non-sedating
Dimeglumine salt Amikin - Injection Amikacin sulfate Antibiotic, 1287
Microlut - Tablets Levonorgestrel Hormonal contraceptive, 1263 Aminoglycoside
Oral Amlopine - Capsules Amlodipine besylate Antihypertensive, 1289
Mirena - IUS Levonorgestrel Hormonal contraceptive, 1263 Anti-anginal,
IUS Calcium-channel blocker
Nerisone Cream Diucortolone valerate Corticosteroid, Topical 1264 Amoxil - Capsule Amoxycillin trihydrate Antibiotic, 1289
Broad-spectrum penicillin 1289
Nerisone Ointment Diucortolone valerate, Corticosteroid, Topical 1264
Amoxil - Syrup Amoxycillin trihydrate Antibiotic,
Broad-spectrum penicillin 1289
Nerisone C Cream Diucortolone valerate, Corticosteroid, 1265
Amoxil Forte - Syrup Amoxycillin trihydrate Antibiotic,
Chlorquinaldol Antiseptic preparation,
Topical
Augmentin - Syrup Amoxycillin trihydrate, Antibiotic, 1290
Primolut N - Tablets Norethisterone. Female sex hormone 1265
Progyluton - Tablets Estradiol valerate, Norgestrel Female sex hormone 1266
Augmentin - Tablets Amoxycillin trihydrate, Antibiotic, 1290
Proluton-Depot - Oil solution for inj. Hydroxyprogesterone Progesterone hormone 1266 Potassium clavulanate Broad-spectrum penicillin
caproate Bactrim Forte - Tablets Trimethoprim, Antibiotic, Co-trimoxazole 1290
Proviron - Tablets Mesterolone Male sex hormone 1267 Sulfamethoxazole
Skinoren - Cream Azelaic acid Acne treatment, Topical 1268 Bactrim - Syrup Trimethoprim, Antibiotic, Co-trimoxazole 1290
Sulfamethoxazole
Testoviron-Depot - Oil solution for inj. Testosterone oenanthate Male sex hormone 1268
Betamet - Ointment Betamethasone Valerate Corticosteroid, Topical 1292
Travocort - cream Isoconazole nitrate, Antifungal, Topical 1268
Bevit - Syrup Vitamin B1, Vitamin B 2, Vitamin B Complex 1292
Diucortolone valerate
Vitamin B 6, Nicotinamide,
Ultravist - Contrast medium Iopromide Contrast media 1269 Dexpanthenol
Yasmin - Tablets Drospirenone, Combined hormonal 1270 Buspar - Tablets Buspirone hydrochloride Anti-anxiety drug 1293
Ethinylestradiol contraceptive, Oral Capoten - Tablets Captopril Antihypertensive, 1294
ACE inhibitor
SHIFA 1271 Capril - Tablets Captopril Antihypertensive, 1294
ACE inhibitor
Cinokort - Injection Triamcinolone acetonide Corticosteroid 1271
Cardol - Tablets Atenolol Antihypertensive, 1295
Clafo 500,1000 - Injection Cefotaxime sodium Antibiotic, Cephalosporin 1272 Anti-anginal,
Cloxa 500,1000 - Injection Cloxacillin Antibiotic, penicillinase 1272 Anti-arrythmic,
resistant penicillin Beta-adrenoceptor blocker
Diclorism 75-injection Diclofenac sodium NSAID, Analgesic, 1272 Carvidol - Tablets Carvedilol Antihypertensive, 1296
Antipyretic, Anti-rheumatic Anti-anginal,
Genta 20, 40, 80 - Injection Gentamicin sulfate Antibiotic, 1273 Beta-adrenoceptor
Aminoglycoside blocker
Ogmant - Injection Amoxycillin sodium, Antibiotic, 1273 Ceclor - Capsule Cefaclor monohydrate Antibiotic, 1296,
Potassium clavulanate Broad-spectrum penicillin Cephalosporin 1297
Shifa Piroxicam - Injection Piroxicam NSAID, Analgesic, 1273 Ceclor - Oral suspension Cefaclor monohydrate Antibiotic, 1296,
Antipyretic Cephalosporin 1297
Shifa Ranitidine - Injection Ranitidine HCl Antacid, Ulcer-healing, 1273 Ceclor M.R. - Tablets Cefaclor monohydrate Antibiotic, 1298
H2-receptor antagonist Cephalosporin
Zidacef 500,1000 - Injection Ceftazidime pentahydrate Antibiotic, Cephalosporin 1274 Cetro - Syrup Cetirizine dihydrochloride Antihistamine, 1299
Non-sedating
SOLVAY PHARMACEUTICALS 1274 Cetro - Tablets Cetirizine dihydrochloride Antihistamine, 1299
Non-sedating
Androgel - Gel Testosterone Male sex hormone 1274 Cipromax - Eye / Ear Drops Ciprooxacin HCl Antibiotic, 1299
Betaserc - Tablets Betahistine Nausea 1275 monohydrate Quinolone, Ophthalmic,
dihydrochloride & Vertigo drug, Otic
Histamine substitute Cipromax - Eye Ointment Ciprooxacin HCl Antibiotic, Quinolone, 1299
Duphaston - Tablets Dydrogesterone Hormone progestogen in 1276 monohydrate Ophthalmic
Hormone replacement Cipromax - Tablets Ciprooxacin HCl Antibiotic, Quinolone 1299
therapy & progesterone monohydrate
deciency Claritine - Syrup Micronized Loratadine Antihistamine, 1300
Duspatalin 135 - Tablets Mebeverine hydrochloride Antispasmodic & Drug 1276 Non-sedating
altering gut motility, Claritine - Tablets Micronized Loratadine Antihistamine, 1300
Intestinal smooth muscle Non-sedating
relaxant
Clovir - Cream Acyclovir Antiviral drug, Topical 1301
Duspatalin Retad - Capsules Mebeverine hydrochloride Antispasmodic & Drug 1277
Clovir - Tablets Acyclovir Antiviral drug 1301
Intestinal smooth muscle Coldact - Syrup Triprolidine hydrochloride, Antihistamine, 1301
relaxant Pseudoephedrine Decongestant
hydrochloride
Faverin - Tablets Fluvoxamine Maleate Antidepressant, Selective 1277
Cortiderm - Cream Micronised Hydrocortisone Corticosteroid, Topical 1302
serotonin re-uptake
inhibitor Cortimax - Cream Clobetasol Propionate Corticosteroid, Topical 1302
Femoston - f.c Tablets Estradiol (Orange Tab.) & Hormone replacement 1278 Cortimax - Ointment Clobetasol Propionate Corticosteroid, Topical 1302
Estradiol/Dydrogesterone therapy drug Cromonal - Nasaldrops Sodium Cromoglycate Anti-inammatory in 1302
(Yellow Tab.) Allergic rhinitis
Femostan 1/10 - f.c Tablets Estradiol Hemihydrate Hormone replacement 1279 Diamet - Tablets Glibenclamide, Antidiabetic drug oral, 1302
(White Tab.) & Estradiol therapy drug Metformin HCl Sulphonyl urea &
hemihydrate/dydrogesterone Biguanide
(Gray Tab.) Diatab - Tablets Glibenclamide Antidiabetic drug oral, 1303
Femoston Conti - f.c Tablets Estradiol, Dydrogesterone Hormone replacement 1281 Sulphonyl urea
therapy drug Enapril - Tablets Enalapril maleate Antihypertensive, 1304
Inuvac - Suspension for inj. Haemagglutinin, Vaccine 1282 ACE inhibitor
neuraminidase Exylin Paediatric - Syrup Diphenhydramine HCl, Antihistamine, Antitussive 1304
Pankreoat - Tablets Pancreatin, Antiatulant, 1283 Menthol
Dimethylpolysiloxane Antifoaming agent Exylin - Syrup Diphenhydramine HCl Antihistamine, Antitussive 1304
Physiotens - tablets Moxonidine Antihypertensive, 1283 Famocid 10 - Tablets Famotidine Antacid, Ulcer-healing, 1305
Centrally acting H2-receptor antagonist
Teveten - Tablets Eprosartan mesylate Antihypertensive, 1284 Famocid - Tablets Famotidine Antacid, Ulcer-healing, 1304
dihydrate Angiotensin-II receptor H2-receptor antagonist
antagonist Feldene - Gel Piroxicam NSAID, Analgesic, 1305
Teveten Plus - Tablets Eprosartan mesylate Antihypertensive, 1285 Topical
dihydrate, Angiotensin-II receptor Feldene - Injection Piroxicam NSAID, Analgesic, 1306
Hydrochlorothiazide. antagonist/ Diuretic Antipyretic
29
MANUFACTURERS INDEX
Feldene - Capsules Piroxicam NSAID, Analgesic, 1306 Metaz - Lotion Mometasone furoate Corticosteroid, Topical 1320
Antipyretic Metaz - Ointment Mometasone furoate Corticosteroid, Topical 1320,
Feldene Dispersible Tablets Piroxicam NSAID, Analgesic, 1306
Antipyretic
Metosil - Tablets Metoclopramide HCl Anti-emetic, Stimulates 1321
Ferosac - Injection Iron (III) hydroxide Haematinic, Parenteral iron 1307 gut motility
Saccharate complex
Nazix - Nasal drops Xylometazoline Nasal decongestant, 1321
Ferose - Drops Iron hydroxide-polymaltose Haematinic, Iron 1308 hydrochloride Topical
Complex supplement for Iron
Nazix - Nasal spray Xylometazoline Nasal decongestant, 1321
deciency anaemia
hydrochloride Topical
Ferose - Chewable Tablets Iron hydroxide-polymaltose Haematinic, Iron 1308
Neorin Syrup Desloratadine. Antihistamine, 1321
Complex Supplement for iron
Non-sedating
deciency anaemia
Neorin Tablet Desloratadine. Antihistamine, 1322
Ferose-F - Tablets Ferric hydroxide Polymaltose, Haematinic, Erythropoietic 1308
Non-sedating
Folic acid for iron &folic acid
deciency anaemia Nospasm - Tablets Hyoscine -N -Butylbromide Antispasmodic & drug 1323
altering gut
Ferose - Syrup Iron hydroxide-Polymaltose Haematinic, Iron 1308
Complex Supplement for Iron motility, Antimuscarinic
Deciency Anaemia Ospen - Tablets Phenoxy methyl penicillin Antibiotic, Semisynthetic 1323
Fevadol - Syrup Paracetamol NSAID, Analgesic, 1308 Potassium penicillin
Antipyretic Ospen - Oral Suspension Phenoxy methyl penicillin Antibiotic, Semisynthetic 1324
Fevadol - Tablets Paracetamol NSAID, Analgesic, 1308 Potassium penicillin
Antipyretic Peptazol - Capsules Lansoprazole Antacid, Ulcer-healing, 1325
Fevadol Extra - Tablets Paracetamol , Caffeine NSAID, Analgesic, 1308 Proton pump inhibitor
Antipyretic Pevaryl - Cream Econazole nitrate Antifungal, Topical 1325
Fevadol Plus - Tablets Paracetamol, Codeine NSAID, Analgesic, 1309 Proton -e.c Tablets Pantoprazole sodium Antacid, Ulcer-healing, 1326
Phosphate, Caffeine Antipyretic Proton pump inhibitor
Fevadol (Sugar Free) - Syrup Paracetamol NSAID, Analgesic, 1309 Rofenac - Tablets Diclofenac sodium NSAID, Analgesic, 1326
Antipyretic Antipyretic, Anti-rheumatic
Fevadol - Suppository Paracetamol NSAID, Analgesic, 1309 Rofenac - Injection Diclofenac sodium NSAID, Analgesic, 1326
Antipyretic Antipyretic, Anti-rheumatic
Flocazole - Capsule Fluconazole Antifungal, Triazole 1309 Rofenac-D - Dispersible Tablets Diclofenac sodium NSAID, Analgesic, 1326
Flutab - Tablets Paracetamol, NSAID, Analgesic, 1310 Antipyretic, Anti-rheumatic
Pseudoephedrine HCl , Antipyretic, Decongestant, Rofenac Ophtha- Eyedrops Diclofenac sodium NSAID, Analgesic, 1327
Diphenhydramine HCl Antihistamine Ophthalmic
Formit - Tablets Metformin hydrochloride Antidiabetic drug oral, 1310 Rofenac - Gel Diclofenac sodium NSAID, Analgesic, 1327
Biguanide Anti-rheumatic, Topical
Fusiderm-B - Cream Fusidic acid, Betamethasone Corticosteroid, 1310 Rofenac - Suppository Diclofenac sodium NSAID, Analgesic, 1328
valerate Antibacterial, Topical Antipyretic, Anti-rheumatic
Fusiderm - Cream Fusidic acid Antibacterial, Topical 1311 Salamat - Syrup Salbutamol sulphate Anti-asthmatic, 1328
Fusiderm - Ointment Sodium fusidate Antibacterial, Topical 1311 Selective beta2 -agonist
Gentam - Ear/eye drops Gentamicin sulphate Antibiotic, 1311 Salamat - Tablets Salbutamol sulphate Anti-asthmatic, 1328
Aminoglycoside, Selective beta2 -agonist
Ophthalmic,Otic Sapofen - Gel Ibuprofen NSAID, Analgesic, Topical 1328
Gentam - Injection Gentamicin sulphate Antibiotic, Aminoglycoside 1311 Sapofen Plus - Tablets Ibuprofen , Pseudoephedrine NSAID, Analgesic, 1329
Gentam - Ointment Gentamicin sulphate Antibiotic, Aminoglycoside, 1311 hydrochloride Antipyretic, Decongestant
Topical Sapofen - Tablets Ibuprofen NSAID, Analgesic, 1329
Glaze - Tablets Gliclazide Antidiabetic drug oral, 1312 Antipyretic
Sulphonyl urea Sapofen Junior - Oral suspension Ibuprofen NSAID, Analgesic, 1329
Histop - Syrup Chlorpheniramine maleate Antihistamine, Sedating 1312 Antipyretic
Histop - Tablets Chlorpheniramine maleate Antihistamine, Sedating 1312 Sinofree - Tablets Paracetamol / NSAID, Analgesic, 1329
Hymox - Capsule Amoxycillin trihydrate Antibiotic, 1312 Pseudoephedrine HCl Antipyretic, Decongestant
Broad-spectrum penicillin Sna - Tablets Tadalal Erectile dysfunctioning 1329
Hymox - Syrup Amoxycillin trihydrate Antibiotic, 1312 treatment drug
Broad-spectrum penicillin Sortiva - Tablets Losartan potassium Antihypertensive, 1331
Kafosed - Syrup Dextromethorphan Antitussive 1313 Angiotensin-II receptor
Hydrobromide antagonist
Keex - Oral suspension Cephalexin monohydrate Antibiotic, Cephalosporin 1313 Staril - Tablets Fosinopril sodium Antihypertensive, 1332
Keex - Tablets Cephalexin monohydrate Antibiotic, Cephalosporin 1313 ACE inhibitor
Kenacomb - Cream Triamcinolone acetonide, Corticosteroid, 1314 Tempra - Syrup Acetaminophen NSAID, Analgesic, 1333
Neomycin sulphate, Antibacterial & Antifungal, Antipyretic
gramicidin, Nystatin Topical Tracon - Capsule Itraconazole Antifungal, Triazole 1333
Kenacomb - Ointment Triamcinolone acetonide, Corticosteroid, 1314 Verine - Tablets Mebeverine hydrochloride Antispasmodic & drug 1335
Neomycin sulphate, Antibacterial & Antifungal, altering gut motility,
Gramicidin,Nystatin Topical Intestinal smooth muscle
Klavox - Oral drops Amoxycillin trihydrate, Antibiotic, 1315 Relaxant
Potassium clavulanate Broad-spectrum penicillin Zaditen - Syrup Ketotifen hydrogen fumarate Anti-asthmatic, 1335
Klavox - Oral suspension Amoxycillin trihydrate, Antibiotic, 1314, Anti-histamine
Potassium clavulanate Broad-spectrum penicillin 1315 Zaditen - Tablets Ketotifen hydrogen fumarate Anti-asthmatic, 1335
Klavox - Syrup Amoxycillin trihydrate, Antibiotic, 1314, Anti-histamine
Potassium clavulanate Broad-spectrum penicillin 1315 Zimax - Capsule Azithromycin dihydrate Antibiotic, Macrolide 1335
Klavox - Tablets Amoxycillin trihydrate, Antibiotic, 1314, Zimax - Oral Suspension Azithromycin dihydrate Antibiotic, Macrolide 1335
Potassium clavulanate Broad-spectrum penicillin 1315
Lipostat - Tablets Pravastatin sodium Lipid-regulating drug, 1316 STIEFEL LABORATORIES LTD 1336
inhibitor Isotrex - Gel Isotretinoin Acne treatment, Topical 1336
Lorinase - Syrup Loratadine, Pseudoephedrine Antihistamine, 1317 Isotrexin - Gel Erythromycin , Isotretinoin Acne treatment, Topical 1337
sulfate Nasal decongestant Panoxyl Acnegel Benzoyl Peroxide Acne treatment, Topical 1337
Lorinase - Tablets Loratadine, Pseudoephedrine Antihistamine, 1318 Panoxyl - Lotion Benzoyl Peroxide Acne treatment, Topical 1337
sulfate Nasal decongestant Polytar Liquid Pine tar, Juniper tar, Coal Antidandruff & 1337
Lorine - Syrup Loratadine Antihistamine, 1318 tar Antiseborrhoeic dermatitis,
Non-sedating Topical
Lorine - Tablets Loratadine Antihistamine, 1318 Stiemycin - Topical Solution Erythromycin Antibiotic, Macrolide 1337
Non-sedating Stieprox - Shampoo Cyclopirox olamin Antidandruff & 1338
Lustral -f.c Tablets Sertraline hydrochloride Antidepressant, 1319 Antiseborrhoeic
Selective serotonin dermatitis, Topical
re-uptake inhibitor Wartec - Cream Podophyllotoxin Antiviral drug, Topical 1338
Mafepain - Tablets Mefenamic acid NSAID, Analgesic, 1320
Antipyretic TABUK PHARMACEUTICAL MANUFACTURING COMPANY 1338
Metaz - Cream Mometasone furoate Corticosteroid, Topical 1320, Acidal - Chewable Tablets Dried Aluminum hydroxide, Antacid 1338
Magnesium hydroxide
30
MANUFACTURERS INDEX
Acidal - Oral Suspension Dried Aluminum hydroxide, Antacid 1338 Metfor - Tablets Metformin hydrochloride Antidiabetic drug oral, 1352
Magnesium hydroxide Biguanide
Artiz - f.c Tablets Cetirizine hydrochloride Antihistamine, 1338 Metfor XR - F.C Tablets Metformin hydrochloride Antidiabetic drug oral, 1352
Non-sedating Biguanide
Aspicard - Tablets Aspirin NSAID, Platelet 1339 Micozol - Cream Miconazole nitrate Antifungal & Antibacterial, 1352
aggregation inhibitor Topical
Omiz - Capsules Omeprazole Antacid, Ulcer-healing, 1353
Avolen - Syrup Theophylline anhydrous Anti-asthmatic, 1339 Proton pump inhibitor
Bronchodilator Orthocam - Gel Piroxicam NSAID, Analgesic, 1353
Avolen SR - Tablets Theophylline anhydrous Anti-asthmatic, 1339 Antirheumatic, Topical
Bronchodilator Orthocam - Capsule Piroxicam NSAID, Analgesic, 1353
Calcitec - Nasal spray Calcitonin salmon Hormone, Calcium 1339 Antipyretic, Anti-rheumatic
metabolism regulator Orthocam DT - Dispersible Tablets Piroxicam NSAID, Analgesic, 1353
Canar - Tablets Atenolol Antihypertensive, 1340 Antipyretic, Anti-rheumatic
Anti-anginal, Prof -f.c Tablets Ibuprofen NSAID, Analgesic, 1354
Anti-arrythmic, Antipyretic
Prof - Oral suspension Ibuprofen NSAID, Analgesic, 1354
Candeur - Capsule Fluconazole Antifungal, Triazole 1340 Antipyretic
Cephalex - Capsule Cephalexin anhydrous Antibiotic, Cephalosporin 1341 Quinox - f.c Tablets Ciprooxacin hydrochloride Antibiotic, Quinolone 1354
Cephalex - Oral suspension Cephalexin anhydrous Antibiotic, Cephalosporin 1341 Ranacid - Syrup Ranitidine hydrochloride Antacid, Ulcer-healing, 1354
Cephradine Tabuk-injection Cephradine anhydrous Antibiotic, Cephalosporin 1341 H2-receptor antagonist
Claritt -f.c Tablets Clarithromycin Antibiotic, Macrolide 1342 Ranacid - Tablets Ranitidine hydrochloride Antacid, Ulcer-healing, 1354
Claritt - Oral suspension Clarithromycin Antibiotic, Macrolide 1342 H2-receptor antagonist
Claritt XL - e.r Tablets Clarithromycin Antibiotic, Macrolide 1342 Rapidus - Tablet Diclofenac potassium NSAID, Antirheumatic, 1355
Clozole - Vaginal cream Clotrimazole Antifungal, Topical 1342 Antipyretic, Analgesic
Derma-T - Topical lotion Clindamycin phosphate Antibiotic, Topical 1343 Rifacin - Capsule Rifampicin Antibiotic, 1355
Antituberculosis,
Derma-T - Topical Solution Clindamycin phosphate Antibiotic, Topical 1343 Antileprotic & Brucellosis
Dermal - Cream Clobetasol propionate Corticosteroid, Topical 1343 Roxil - Capsule Cefadroxil anhydrous Antibiotic, Cephalosporin 1356
Divido - Capsule Diclofenac sodium NSAID, Antirheumatic, 1343 Roxil - Oral suspension Cefadroxil anhydrous Antibiotic, Cephalosporin 1356
Antipyretic, Analgesic
Sinaten - Ointment Nystatin Antifungal, Topical 1356
Enervit - Tablets Multivitamin with Mineral Multivitamin & 1344
elements Mineral Preparation Sinaten - Oral suspension Nystatin Antifungal, Polyene 1356
Eptol - Oral Solution Carbamazepine Anti-epileptic, 1344 Sinaten - Vaginal Tablets Nystatin Antifungal,polyene 1357
Antimanic drug Tabeta - Scalp application Betamethasone valereate Corticosteroid, Topical 1357
Eptol - Tablets Carbamazepine Anti-epileptic, 1344 Tabeta - Ointment Betamethasone valereate Corticosteroid, Topical 1357
Antimanic drug Tabiclor MR - Tablets Cefaclor monohydrate Antibiotic, Cephalosporin 1358
Esopress - Tablets Enalapril maleate Antihypertensive, 1345 Tabiclor - Capsule Cefaclor anhydrous Antibiotic, Cephalosporin 1357
ACE inhibitor Tabiclor - Oral Suspension Cefaclor anhydrous Antibiotic, Cephalosporin 1357
Ezilax - Powder Lactulose Laxative, Osmotic 1345 Tabiex - Suppository Diclofenac sodium NSAID, Antirheumatic, 1358
Ezilax - Syrup Lactulose Laxative, Osmotic 1345 Antipyretic, Analgesic
Ezipect - Syrup Diphenhydramine Expectorant & 1345 Tabiex - Tablets Diclofenac sodium NSAID, Antirheumatic, 1358
hydrochloride, Ammonium Demulcent Cough Antipyretic, Analgesic
chloride, Sodium citrate, Preparation Tabiex Cool - Gel Diclofenac diethylamine NSAID, Anti-rheumatic, 1359
Menthol Analgesic, Topical
Fexodine - Tablets Fexofenadine HCl Antihistamine, 1346 Tabiex Retard - Tablet Diclofenac sodium NSAID, Anti-rheumatic, 1359
Non-sedating Analgesic, Anti pyretic
Flazol - Tablets Metronidazole Anti-protozoal, 1346 Tabigesic - Oral suspension Mefenamic acid NSAID, Analgesic, 1360
Anti-anaerobic Antipyretic
Flazol - Oral Suspension Metronidazole benzoate Anti-protozoal, 1346 Tabigesic - Tablets Mefenamic acid NSAID, Analgesic, 1360
Anti-anaerobic Antipyretic
Folivita - Tablets Folic acid Erythropoietic, Treats 1346 Tabigesic Forte - Tablets Mefenamic acid NSAID, Analgesic, 1360
folate megaloblastic Antipyretic
Anaemia
Tabocine - Capsule Doxycycline hyclate Antibiotic, Tetracycline 1360
Foxime Injection Cefotaxime sodium Antibiotic, Cephalosporin 1347
Tazoline - Injection Cefazolin sodium Antibiotic, Cephalosporin 1360
Foxitin - Injection Cefoxitin sodium Antibiotic, Cephalosporin 1347
Toprazole - e.c Tablets Pantoprazole sodium Antacid, Ulcer-healing, 1361
Glizide- Tablets Gliclazide Antidiabetic drug oral, 1347 Sesquihydrate Proton pump inhibitor
Sulphonyl urea
Triaxone - Injection Ceftriaxone sodium Antibiotic, Cephalosporin 1361
Gripine - Syrup Chlorpheniramine maleate Antihistamine, Sedating 1348
Valirec - Syrup Sodium valproate Anti-epileptic drug, 1362
Histafed - Syrup Triprolidine hydrochloride, Antihistamine, 1348 Aliphatic carboxylic acid
Pseudoephedrine Decongestant
hydrochloride Vasta - f.c Tablets Simvastatin Lipid-regulating drug, 1362
Histafed - Tablets Triprolidine hydrochloride, Antihistamine, 1348 inhibitor
Pseudoephedrine Decongestant
hydrochloride Vavo - Cream Ketoconazole Antifungal, Topical 1363
HydrocortisoneTabuk - Cream Hydrocortisone Corticosteroid, Topical 1349 Vavo - Shampoo Ketoconazole Antifungal, Topical 1363
Hyoban- Tablets Hyoscine butylbromide Antispasmodic & drug 1349 Velosef - Injection Cephradine Antibiotic, Cephalosporin 1363
altering gut Vintec - Respirator solution Salbutamol sulphate Anti-asthmatic, 1364
motility, Antimuscarinic Selective beta2 -agonist
Ketofen - Syrup Ketotifen fumarate Anti-asthmatic, 1349 Vintec - Syrup Salbutamol sulphate Anti-asthmatic, 1364
Anti-histamine Selective beta2 -agonist
Ketofen - Tablets Ketotifen fumarate Anti-asthmatic, 1349 Vita-C - Chewable Tablets Ascorbic acid, Vitamin C 1365
Anti-histamine Sodium Ascorbate
Linz - Capsule Fluoxetine HCl Antidepressant, 1349 Vitakid - Oral drops Vitamin A USP Multivitamin Preparation 1365
Selective serotonin (as Palmitate),vitamin D3
re-uptake inhibitor (Cholecalciferol USP)
Vitamin B1 (Thiamine
Lopra - Tablets Citalopram HBr Antidepressant, 1350
hydrochloride
Selective serotonin
USP) vitamin B2
re-uptake inhibitor
(Niacinamide USP)
Lotense - Capsule Amlodipine besylate Antihypertensive, 1350 Vitamin C
Anti-anginal, (Ascorbic acid USP)
Calcium-channel blocker
Vitanerve - f.c Tablets Vitamin B1 Vitamin B Complex 1365
Meiact - f.c Tablets Cefditoren pivoxil Antibiotic, Cephalosporin 1351 (Thiamine Mononitrate
Mentex - Syrup Diphenhydramine Antihistamine, 1351 USP) , Vitamin B2
hydrochloride, Antitussive, Systemic (Riboavin USP)
Dextromethorphan nasal decongestant, Vitamin B6 (Pyridoxine
hydrobromide, hydrochloride USP)
Pseudoephedrine Calcium Pantothenate USP
hydrochloride Niacinamide USP
31
MANUFACTURERS INDEX
Vonal - Oral drops Paracetamol NSAID, Analgesic, 1365 Gyno-Candizol - Vaginal ovoules Miconazole nitrate Antifungal & 1377
Antipyretic Antibacterial, Local
Vonal - Suppository Paracetamol NSAID, Analgesic, 1365 Histazin - Syrup Promethazine hydrochloride Antihistamine, Anti-emetic, 1378
Antipyretic Central sedative
Vonal - Syrup Paracetamol NSAID, Analgesic, 1365 Low-Lip - Tablets Gembrozil Lipid-regulating drug, 1378
Antipyretic Serum triglycerides
Vonal - Tablets Paracetamol NSAID, Analgesic, 1365 reducer
Antipyretic Miniten - Tablets Captopril Antihypertensive, 1379
ACE inhibitor
Winex - Capsules Cexime trihydrate Antibiotic, Cephalosporin 1366
Novecin - Tablets Ooxacin Antibiotic, Quinolone 1379
Winex - Oral Suspension Cexime trihydrate Antibiotic, Cephalosporin 1366
Prolar - Syrup Ketotifen hydrogen fumarate Anti-asthmatic, 1380
Wormazol - Chewable Tablets Mebendazole Anthelmintic 1366
Anti-histamine
Wormazol - Tablets Mebendazole Anthelmintic 1366
Ruxid - f.c Tablets Roxithromycin Antibiotic, Macrolide 1380
Zeta-Cort - Cream Fusidic acid, Betamethasone Corticosteroid, 1366
Unicam - Capsules Piroxicam NSAID, Analgesic, 1381
valerate Antibacterial, Topical
Antipyretic
Zetron - Capsule Azithromycin Antibiotic, Macrolide 1367
Unidox - Capsule Doxycycline hyclate Antibiotic, Tetracycline 1382
Zetron - Oral suspension Azithromycin Antibiotic, Macrolide 1367
Unifed DM - Syrup Triprolidine HCl, Antihistamine, 1383
Zidime - Injection Ceftazidime anhydrous Antibiotic, Cephalosporin 1367 Pseudoephedrine HCl and Decongestant, Anti-tussive
Zinoxime - Injection Cefuroxime sodium Antibiotic, Cephalosporin 1368 Dextromethorphan HBr
Zinoximor -f.c Tablets Cefuroxime axetil Antibiotic, Cephalosporin 1368 Unifed Expectorant - Syrup Triprolidine HCl, Antihistamine, 1383
Pseudoephedrine HCl and Decongestant, Expectorant
THE NATIONAL ANTIVENOM & VACCINE PRODUCTION CENTER 1369 Guaiphenesin
Bivalent Naja/Walterinnesia Snake Antivenom Containing Snake antivenom 1369 Unifed - Syrup Triprolidine HCl, Antihistamine, 1383
Antivenom (Equine) - Injection F(Ab)2 fractions of Ig immunoglobulins Pseudoephedrine HCl Decongestant
against Naja haje arabicus, Univit-A - Forte-capsules Vitamin A Palmitate Vitamin A 1384
walterinnesia aegyptia Univit-E - Capsules Vitamin E Vitamin E 1384
Polyvalent Snake Antivenom Antivenom Containing Snake antivenom 1369
(Equine) - Injection F(Ab)2 fractions of Ig immunoglobulins URSAPHARMA 1385
against Bitis arietans,
Hylo-Comod - Eye drops Sodium hyaluronate Ocular lubricant 1385
Cerastes cerastes, Echis
caritus, Echis coloratus, Naja
haje, Walterinnesia aegyptia VALEANT PHARMACEUTICALS INTERNATIONAL (ICN) 1385
Polyvalent Scorpion Antivenom Containing Scorpion antivenom 1370 Disatyl - Oral drops Simethicone Antiatulant, Antifoaming 1385
Antivenom (Equine) - Injection F(Ab)2 fractions of Ig immunoglobulins agent
against Scorpion venom.
Disatyl - Tablets Simethicone Antiatulant, Antifoaming 1385
TILLOTS PHARMA AG 1370 agent
Eldopaque 2% - Cream Hydroquinone Skin Bleaching agent, 1386
Asacol - f.c Tablets Mesalazine Chronic Inammatory 1370 Topical
Bowel disorder
Eldopaque Forte - Cream Hydroquinone Skin Bleaching agent, 1386
treatment drug,
Topical
Aminosalicylate
Eldoquin 2% - Cream Hydroquinone Skin Bleaching agent, 1386
Asacol - Suppository Mesalazine Chronic bowel disorder & 1370
Haemorrhoids Topical
treatment drug, Eldoquin Forte - Cream Hydroquinone Skin Bleaching agent, 1387
Aminosalicylate Topical
Colpermin - Capsules Natural peppermint oil Antispasmodic & 1371 Fefol Spansules Ferrous sulphate, Folic acid Haematinic, Erythropoietic 1387
Carminative for iron & folic acid
deciency anaemia
UCB S.A PHARMA SECTOR 1371 Oxsoralen - Capsules Methoxsalen Photoactive agent, Treats 1387
Cirrus - Tablets Cetirizine dihydrochloride, Antihistamine, 1371 psoriasis & repigmentation
Pseudoephedrine Nasal decongestant of vitiligo
hydrochloride Oxsoralen - Lotion 1% Methoxsalen Photoactive agent, 1390
Keppra -f.c Tablets Levetiracetam Anti-epileptic drug 1371, Repigmentation of vitiligo,
1372 Topical
Navidoxine - Tablets Meclozine hydrochloride, Anti-emetic, Antivertigo 1372
Pyridoxine hydrochloride & motion sickness,
WEIMER PHARMA GMBH 1391
Central anticholinergic Lidocaton 2% 1:100.000 Lidocaine hydrochloride, Anaesthetic, Local 1391
action Solution for injection Epinephrine
Nootropil - Capsules Piracetam Psychotropic drug, 1373 Lidocaton 2% 1:80.000 Lidocaine hydrochloride, Anaesthetic, Local 1392
Improves telencephalon Solution for injection Epinephrine
function
Mepicaton 3% - Solution for injection Mepivacaine hydrochloride Anaesthetic, Local 1393
Nootropil - f.c Tablets Piracetam Psychotropic drug, 1373
Improves telencephalon WYETH CONSUMER 1394
function
Nootropil - Injection Piracetam Psychotropic drug, 1373 Robitussin - Syrup Guaifenesin Expectorant 1394
Improves telencephalon
function WEYTH PHARMACEUTICALS 1395
Nootropil - Solution Piracetam Psychotropic drug, 1373 Advil - Tablets Ibuprofen NSAID, Analgesic, 1395
Improves telencephalon Antipyretic
function
Advil Cold And Sinus Caplets Ibuprofen, Pseudoephedrine NSAID, Analgesic, 1395
Xyzal - f.c Tablets Levocetirizine Antihistamine, 1373
Dihydrochloride Non-sedating HCl Decongestant
Zyrtec -f.c Tablets Cetirizine Antihistamine, 1374 Efexor XR -p.r Tablets Venlafaxine hydrochloride Antidepressant & 1395
hydrochloride Non-sedating depression accompanied
by anxiety
Zyrtec - Oral Solution Cetirizine hydrochloride Antihistamine, 1374
Non-sedating Enbrel Etanercept Anti-rheumatic, 1397
Powder for solution for injection Cytokine inhibitor
UNITED PHARMACEUTICALS MANUFACTURING CO.LTD. 1375 Minulet - Tablets Ethinyl Estradiol and Combined hormonal 1399
Gestodene Contraceptive, Oral
Clindacin T - Topical solution Clindamycin phosphate Antibacterial, Anti-acne, 1375
Prevenar- Suspension for injection Pneumococcal Vaccine 1401
Topical
Polysaccharide serotype
Cloderm - Cream Clobetasol propionate Corticosteroid, Topical 1375 4(PPS)/PPS 6B/PPS 9V/PPS
Cloderm - Ointment Clobetasol propionate Corticosteroid, Topical 1375 14/PPS 18 C/PPS 19 F/PPS
Diaphage - Tablets Metformin HCl Antidiabetic drug oral, 1375 23 F/conjugated to the
Biguanide CRM197 Carrier Protein
Diclofen - Cremogel Diclofenac diethylamine NSAID, Analgesic, 1376 Tazocin Piperacillin sodium, Antibiotic, Penicillin 1402
Anti-rheumatic, Topical Lyophilised Powder for IV infusion Tazobactam sodium
Droxil - Capsule Cefadroxil Antibiotic, Cephalosporin 1376
ZLB BEHRING GMBH 1404
Glibemide - Tablets Glibenclamide Antidiabetic drug oral, 1376
Sulphonyl urea Streptase - Injection Streptokinase Fibrinolytic drug 1404
32
33
C
34
.
35
M
36
D
37
38
T
HT
39
40
41
42
43
44
T
45
DNA
P DNA
46
USP
USP
47
U
I.M
48
R
49
50
51
52
53
54
55
A
56
57
58
Part B
Product Information
Page No. 1 - 1405
ABBOTT
SPDI
erythryaea. (formerly Streptomyces erythraeus) and belongs to the treatment for primary syphilis in patients allergic to the penicillins.
ABBOTT macrolide group of antibiotics. It is basic and readily forms salts In treatment of primary syphilis, spinal uid examinations should
P.O.BOX: 20628, RIYADH: 11465 with acids. be done before treatment and as part of follow up after therapy.
SAUDI ARABIA The base. the stearate salt, and the esters are poorly soluble in Corynebacterium diphtheriae: As an adjunct to antitoxin, to
water, and are suitable for oral administration. prevent establishment of carriers, and to eradicate the organism
TEL: 01-2180180, FAX: 01-2180200 in carriers.
Erythromycin stearate tablets contain the stearate salt of the
antibiotic in a unique lm coating. Corynebacterium minutissimum: For the treatment of
ERYDERM Topical Solution erythrasma.
CLINICAL PHARMACOLOGY
Entamoeba histolytica: In the treatment of intestinal amebiasis
Microbiology only. Extra-enteric amebiasis requires treatment with other
(Erythromycin) Biochemical tests demonstrate erythromycin inhibits protein agents.
synthesis of the pathogen without directly affecting nucleic Listeria monocytogenes: Infections due to this organism.
COMPOSITION acid synthesis. Antagonism has been demonstrated between
Neisseria gonorrhoeae: Erythromycin lactobionate LV. in
Topical solution containing 2% erythromycin base. clindamycin and erythromycin.
conjunction with stearate orally, as an alternative drug in treatment
INDICATIONS Erythromycin binds to the 50 S ribosomal subunits of susceptible of acute pelvic inammatory disease caused by N. gonorhoeae in
bacteria and suppresses protein synthesis. female patients with a history of sensitivity to penicillin. Before
Topical control of acne vulgaris.
Disc Susceptibility Tests: Quantitative methods require treatment of gonorrhea, patients who are suspected of also having
CONTRAINDICATIONS measurement of zone diameters .give the most precise estimates syphilis should have a microscopic examination for T. pallidum (by
In known hypersensitivity to erythromycin. of antibiotic susceptibility. One recommended procedure uses immunouorescence or dark eld) before receiving erythromycin,
erythromycin class discs for testing susceptibility; interpretations and monthly serologic tests for a minimum of 4 months.
SIDE EFFECTS/PRECAUTIONS
correlate Zone diameters of this disc test with MlC values for Bordetella pertussis: Erythromycin is effective in eliminating the
Dryness, pruritus, erythema, desquamation and burning sensation. erythromycin. With this procedure, a report from the laboratory of organism from the nasopharynx of infected individuals, rendering
DOSAGE AND ADMINISTRATION susceptible indicates the infecting organism is likely to respond them noninfectious. Some clinical studies suggest erythromycin
to therapy. A report of resistant indicates the infective organism may be helpful in the prophylaxis of pertussis in exposed
Apply twice daily after the skin is thoroughly washed with warm
S not likely to respond to therapy. A report of intermediate susceptible individuals.
water and soap.
susceptibility indicates the result be considered equivocal, and, Legionnaires Disease: Although no controlled clinical efcacy
PACKAGING if the pathogen is not fully susceptible to alternative clinically studies have been conducted, in vitro and limited preliminary
b: 60 ml. feasible drugs, the test should be repeated. This category provides clinical data suggest erythromycin may be effective in treating
a buffer zone which prevents small, uncontrolled technical factors Legionnaires Disease.
from causing major discrepancies in interpretation.
ERYTHROCIN Drops (N.R) NOTE: Many strains of Hemophilus inuenzae are resistant to CONTRAINDICATIONS
ERYTHROCIN Granules erythromycin atone, but are susceptible to erythromycin and Erythromycin stearate is contraindicated in patients with known
sulfonamides together. Staphylococci resistant to erythromycin hypersensitivity to erythromycin.
may emerge during a course of erythromycin therapy. Culture and Erythromycin is contraindicated in patients taking terfenadine,
(Erythromycin Ethylsuccinate) susceptibility testing should be performed. astemizole, or cisapride (see PRECAUTIONS, Drug
Pharmacokinetics; Interactions).
ERYTHROCIN Filmtabs Orally administered erythromycin stearate is readily and reliably WARNINGS
absorbed. Optimal serum levels of erythromycin are reached
Hepatic dysfunction including increased liver enzymes and
when the drug is taken in the fasting state or immediately before
hepatocellular and/or cholestatic hepatitis, with or without
(Erythromycin Stearate) meals. Erythromycin diffuses readily into most body uids. Only
jaundice, has been infrequently reported with erythromycin.
low concentrations are normally achieved in the spinal uid, but
COMPOSITION passage of the drug across the blood_ brain barrier increases There have been reports suggesting erythromycin does not
in meningitis. In the presence of normal hepatic function. reach the fetus in adequate concentration to prevent congenital
[Drops: contain erythromycin ethylsuccinate which, after syphilis. Infants born to women treated during pregnancy with
reconstitution, contain 100 mg of erythromycin activity per 2.5 ml erythromycin is concentrated in the liver and excreted in the bile;
the effect of hepatic dysfunction on excretion of erythromycin by oral erythromycin for early syphilis should be treated with an
of suspension (N.R.)]. appropriate penicillin regimen. .
the liver into the bile is not known. Less than 5% of the orally
Granules: contain erythromycin ethylsuccinate which, after Pseudomembranous colitis has been reported with nearly all
administered dose of erythromycin is excreted in active form in
reconstitution, contain 200 mg of erythromycin activity per 5 ml antibacterial agents, including macrolides, and may range in
the urine.
of suspension. severity from mild to life threatening.
Filmtabs: lm-coated tablets containing erythromycin stearate INDICATIONS
Rhabdomyolysis with or without renal impairment has been
equivalent to 250 mg or 500 mg of erythromycin activity per Streptococcus pyogenes: Upper and lower respiratory tract, skin reported in seriously ill patients receiving erythromycin
tablet. and soft tissue infections of mild to moderate severity. concomitantly with lovastatin.
INDICATIONS Streptococcal pharyngitis and longterm prophylaxis:
PRECAUTIONS
In upper and lower respiratory tract infections, mild to moderate Although injectable benzathine penicillin G is considered by
General: Erythromycin is principally excreted by the liver.
skin and soft tissue infections and chlamydial infections. many experts to be the drug of choice, erythromycin is an alternate
Caution should be exercised when erythromycin is administered
drug of choice when oral medication is preferred for treatment
CONTRAINDICATIONS to patients with impaired hepatic function (see CLINICAL
of streptococcal pharyngitis and in long-term prophylaxis of
PHARMACOLOGY and WARNINGS).
In patients with known hypersensitivity to erythromycin. rheumatic fever. When oral medication is given, the importance
of strict adherence by the patient to the prescribed dosage regimen Prolonged or repeated use of erythromycin may result in an
SIDE EFFECTS overgrowth of nonsusceptible bacteria or fungi. If superinfection
must be stressed. A therapeutic dose should be administered for
Mainly gastrointestinal disturbances. at least 10 days. occurs, erythromycin should be discontinued and appropriate
therapy instituted.
PRECAUTIONS Alpha hemolytic streptococci (viridans group):
When indicated, incision and drainage or other surgical procedures
Caution in patients with impaired hepatic function. Serum Although no controlled clinical efcacy trials have been
should be performed in conjunction with antibiotic therapy.
theophylline levels may be increased. conducted, oral erythromycin has been suggested for use in a
regimen for prophylaxis against bacterial endocarditis in patients There have been reports erythromycin may aggravate the weakness
DOSAGE AND ADMINISTRATION hypersensitive to penicillin who have congenital heart disease, of patients with myasthenia gravis.
Drops & granules: 30-50 mg/kg/day in 2, 3 or 4 equally divided or rheumatic or other acquired valvular heart disease when they Laboratory Tests: Erythromycin interferes with the uorometric
doses. undergo dental procedures and surgical procedures of the upper determination of urinary catecholamines.
Tablets: Usual dose: 250 mg every 6 hours or 500 mg every 12 respiratory tract. Erythromycin is not suitable prior to genitourinary Drug Interactions: Erythromycin use in patients who are
hours. or gastrointestinal tract surgery. Staphylococcus aureus: Acute receiving high doses of theophylline may be associated with an
For details see insert. infections of skin and soft tissue of mild to moderate severity. increase in serum theophylline levels and potential theophylline
Resistant Streptococcus pneumonia: Upper respiratory tract toxicity. In case of theophylline toxicity and/or elevated serum
Up to 4 g per day may be administered depending on the severity
infections (e.g.. otitis media, pharyngitis) and lower respiratory theophylline levels. the dose of theophylline should be reduced
of infection.
tract infections (e.g., pneumonia) of mild to moderate degree. while the patient is receiving concomitant erythromycin therapy.
PACKAGING Mycoplasma pneumoniae(Eaton agent, PPLO): For respiratory There have been published reports suggesting when oral
[dp: 30 ml, 50 ml (N.R.)] infections due to this organism. erythromycin is given concurrently with theophylline there is
gr: 60 ml, 100 ml Hemophilus inuenzae: For upper respiratory tract infections a signicant decrease in erythromycin serum concentrations.
of mild to moderate severity. Not all strains of this organism are This decrease could result in subtherapeutic concentrations of
t: 250 mg - 12s (N.R.), 20s,
susceptible to erythromycin at concentrations achieved with usual erythromycin.
10 x 10 strips
500 mg - 16s (N.R.), 20s, 100s (N.R.). therapeutic doses; Concomitant administration of erythromycin and digoxin has been
resistant strains may require concomitant therapy with reported to result in elevated digoxin serum levels.
sulfonamides. There have been reports of increased anticoagulant effects when
ERYTHROCIN STEARATE Tablet
Chlamydia trachomatis: Erythromycin is indicated for treatment erythromycin and oral anticoagulants were used concomitantly.
of the following infections caused by Chlamydia trachomatis, Concurrent use of erythromycin and ergotamine. or
conjunctivitis of the newborn, pneumonia of infancy and urogenital dihydroergotamine has been associated in some patients with
(Erythromycin Stearate) infections during pregnancy. acute ergot toxicity characterized by severe peripheral vasospasm
ERYTHROMYCIN STEARATE TABLETS, USP When tetracyclines are contraindicated or not tolerated, and dysesthesia.
erythromycin is indicated for the treatment of uncomplicated Erythromycin has been reported to decrease the clearance of
FilmtabTablet
urethral, endocervical, or rectal infections in adults due to triazolam, midazolam and zopiclone and thus may increase the
DESCRIPTION Chlamydia trachomatis. pharmacologic effect of these drugs.
Erythromycin is produced by a strain of Sacchoropolysporo Treponema pallidum: Erythromycin is an alternate choice of The use of erythromycin in patients concurrently taking drugs me-
Book_01.indd 1 6/4/2008 2:16:46 PM

ABBOTT
SPDI
tabolized by the cytochrome P450 system may be associated with total daily dose may be given every 12 hours in the fasting state INDICATIONS
elevations in serum levels of these drugs. There have been reports or immediately before meals. For the treatment of more severe For general anaesthesia.
of interactions of erythromycin with carbamazepine, cyclosporine, infections the total daily dose may be doubled.
hexobarbital, phenytoin, alfentanil, disopyrarnide, bromocrip- In the treatment of streptococcal infections: A therapeutic CONTRAINDICATIONS
tine, valproate, tacrolimus, quinidine, lovastatin, terfenadine and dosage of erythromycin should be administered for at least 10 If previous use has led to hyperthermia.
astemizole. Serum concentrations of drugs metabolized by the days. In continuous prophylaxis of streptococcal infections in Cross sensitivity between it and other halogenated anesthetic
cytochrome P450 system should be monitored closely in patients persons with a history of rheumatic heart disease, the dose is 250 agents.
concurrently receiving erythromycin. mg twice a day.
SIDE EFFECTS/PRECAUTIONS
Erythromycin signicantly alters the metabolism of astemizole For prophylaxis against bacterial endocarditis in patients
when taken concomitantly. Rare cases of serious cardiovascular allergic to penicillin with congenital heart disease, or Hypotension, respiratory depression. Shivering, nausea and
adverse events including cardiac arrest, torsade de pointes rheumatic or other acquired valvular heart disease when vomiting after recovery are minor in nature.
and other ventricular arrhythmias have been observed. (See undergoing dental procedures or surgical procedures of DOSAGE AND ADMINISTRATION
CONTRAINDICATIONS and ADVERSE REACTIONS). the upper respiratory tract: I g (20 mg/kg for children) orally
Maintenance concentrations range from 1-2.5%.
Erythromycin signicantly alters the metabolism of terfenadine 2 hours before the procedure, and then, 500 mg (10 mg/kg for
when taken concomitantly. Rare cases of serious cardiovascular children) 6 hours after the initial dose. PACKAGING
adverse events including death,cardiac arrest, torsades de pointes For conjunctivitis of the newborn caused by Chlamydia b: 100 ml.
and other ventricular arrhythmias have been observed (see trachomatis: Oral erythromycin suspension 50 mg/kg/day in 4
CONTRAINDICATIONS and ADVERSE REACTIONS). divided doses for at least 2 weeks.
HUMIRA Solution for Injection
Elevated cisapride levels have been reported in patients receiving For pneumonia of infancy caused by Chlamydia trachomatis:
erythromycin and cisapride concomitantly. This may result in Although the optimal duration of therapy has not been established,
QT prolongation and cardiac arrhythmias including ventricular the recommended therapy is oral erythromycin suspension 50 mg/ (Adalimumab)
tachycardia, ventricular brillation and torsade de pointes. kg/day in 4 divided doses for at least 3 weeks.
Carcinogenesis, Mutagenesis, Impairment of Fertility: For urogenital infections during pregnancy due to Chlamydia NAME OF THE MEDICINAL PRODUCT
Long-term (2 year) oral studies conducted in rats with erythromycin trachomatis: Although the optimal dose and duration of therapy
have not been established, the suggested treatment is erythromycin HUMIRA 40 mg solution for injection in pre-lled syringe
ethylsuccinate and erythromycin base did not provide evidence of
tumorigenicity. Mutagenicity studies have not been conducted. 500 mg, by mouth, 4 times a day on an empty stomach for at least COMPOSITION
There was no apparent effect on male or female fertility in rats fed 7 days. For women who cannot tolerate this regimen. a decreased Each 0.8 ml single dose pre-lled syringe contains 40 mg of
erythromycin (base) at levels up to 0.25% of diet. dose of 250 mg, by mouth, 4 times a day should be used for at adalimumab.
least 14 days.
Pregnancy: There is no evidence of teratogenicity or any other Adalimumab is a recombinant human monoclonal antibody
adverse effect on reproduction in female rats fed erythromycin base For adults with uncomplicated urethral, endocervical, or
expressed in Chinese Hamster Ovary cells.
(up to 0.25% of diet) prior to and during mating, during gestation, rectal infections caused by Chlamydia trachomatis in whom
and through weaning of 2 successive litters. There are however, no tetracyclines are contraindicated or not tolerated: 500 mg, by PHARMACEUTICAL FORM
adequate and well controlled studies in pregnant women. Because mouth, 4 times a day for at least 7 days. Solution for injection in pre-lled syringe.
animal reproduction studies are not always predictive of human For treatment of primary syphilis: 30 to 40 g given in divided
doses over a period of to to 15 days. CLINICAL PARTICULARS
response, this drug should be used during pregnancy only if clearly
needed. Erythromycin has been reported to cross the placental For treatment of acute pelvic inammatory disease caused THERAPEUTIC INDICATIONS
barrier in humans, but fetal plasma levels are generally low. by N. gonorrhoeae: 500 mg Erythrocin lactobionate LV. every 6 Rheumatoid Arthritis
Labor and Delivery: The effect of erythromycin on labor and hours for 3 days, followed by 250 mg erythromycin stearate every HUMIRA in combination with methotrexate, is indicated for:
delivery is unknown. 6 hours for 7 days. the treatment of moderate to severe, active rheumatoid arthritis
Nursing Mothers; Erythromycin is excreted in breast milk, For intestinal amebiasis: Adults: 250 mg 4 times daily for to to in adult patients when the response to disease-modifying anti-
therefore, caution should be exercised when erythromycin is 14 days. Children: 30 to 50 mglkg/day in divided doses for 10 to rheumatic drugs including methotrexate has been inadequate.
administered to a nursing woman. 14 days. the treatment of severe, active and progressive rheumatoid
Pediatric Use: See INDICATIONS and DOSAGE AND For use in pertussis: Although optimal dosage and duration have arthritis in adults not previously treated with methotrexate.
ADMINISTRATION. not - been established, doses of erythromycin utilized in reported HUMIRA can be given as monotherapy in case of intolerance
clinical studies were 40 to 50 mglkg/day, given in divided doses
to methotrexate or when continued treatment with methotrexate
ADVERSE REACTIONS for 5 to 14 days.
is inappropriate.
The most frequent side effects of oral erythromycin preparations For treatment of Legionnaires Disease: Although optimal doses
HUMIRA has been shown to reduce the rate of progression
are gastrointestinal and are dose.related.They include nausea, have not been established, doses utilized in reported clinical data
of joint damage as measured by X-ray and to improve physical
vomiting, abdominal pain, diarrhea and anorexia. were 1 to 4 g daily in divided doses.
function, when given in combination with methotrexate.
Symptoms of hepatic dysfunction including hepatitis and/or HOW SUPPLIED Psoriatic Arthritis
abnormal liver function test results may occur (see WARNINGS).
Erythrocin Stearate Filmtab, 250 mg Bottles of 12(N.R), 20, HUMIRA is indicated for the treatment of active and progressive
Pseudomembranous colitis has been rarely reported in association 100 (N.R) and 500 (N.R) tablets and ABBO-PAC of unit dose strip psoriatic arthritis in adults when the response to previous disease-
with erythromycin therapy. packages of 100 tablets (N.R). modifying anti-rheumatic drug therapy has been inadequate.
There have been isolated reports of transient central nervous Erythrocin Stearate Filmtab, 500 mg Bottles of 16 (N.R), 20, and
system side effects including confusion,hallucinations, seizures, POSOLOGY AND METHOD OF ADMINISTRATION
100 tablets (N.R.)
and vertigo; however, a cause and effect relationship has not been HUMIRA treatment should be initiated and supervised by
established. specialist physicians experienced in the diagnosis and treatment
Erythromycin has been associated with the production of ETHRANE Solution for Inhalation of rheumatoid arthritis.
potentially life-threatening ventricular arrhythmias, including After proper training in injection technique, patients may self-
ventricular tachycardia and torsade de pointes,in individuals with inject with HUMIRA if their physician determines that it is
prolonged QT interval (see CONTRAINDICATIONS). (Enurane) appropriate and with medical follow-up as necessary.
Allergic reactions ranging from urticaria and mild skin eruptions Adults
to anaphylaxis have occurred. Skin reactions ranging from mild COMPOSITION
Rheumatoid Arthritis
eruptions to erythema multifonne,Stevens-Johnson syndrome and Enurane for inhalation.
toxic epidermal necrolysis have rarely been reported. The recommended dose of HUMIRA for adult patients with
INDICATIONS rheumatoid arthritis is 40 mg adalimumab administered every other
There have been isolated reports of reversible hearing loss For induction and maintenance of general anesthesia. week as a single dose via subcutaneous injection. Metholrexate
occurring chiey in patients with renal insufciency and in should be continued during treatment with HUMIRA.
To be used for outpatients and for dental anesthesia.
patients receiving high doses of erythromycin.
CONTRAINDICATIONS Glucocorticoids, salicylates, nonsteroidal anti-inammatory drugs,
OVERDOSAGE or analgesics can be continued during treatment with HUMIRA.
In known hypersensitivity to enurane. Regarding combination with disease modifying anti-rheumatic
In case of overdosage, erythromycin should be discontinued.
Overdosage should be handled with the prompt elimination of SIDE EFFECTS/PRECAUTIONS drugs other than methotrexate (See Special Warnings and Special
unabsorbed drug and all other appropriate measures should be Motor activity, hypotension, respiratory depression and Precautions, and Pharmacodynamics Properties).
initiated. arrhythmias have been reported. In monotherapy, some patients who experience a decrease in their
Erythromycin is not removed by peritoneal dialysis or Nausea, vomiting, hiccups or shivering may occur occasionally. response to HUMIRA may benet from an increase in dose
hemodialysis. intensity to 40 mg adalimumab every week.
DOSAGE AND ADMINISTRATION Available data suggest that the clinical response is usually
DOSAGE AND ADMINISTRATION Surgical levels of anaesthesia may be obtained with 1.5-3% achieved within 12 weeks of treatment. Continued therapy should
Optimal serum levels of erythromycin are reached when concentrations. Maintenance concentration should not exceed be carefully reconsidered in a patient not responding within this
erythromycin stearate is taken in the fasting state or immediately 3%. time period.
before meals.
PACKAGING Psoriatic Arthritis
Adults: The usual dosage is 250 mg every 6 hours; or 500mg
b: 250 ml. The recommended dose of HUMIRA for patients with psoriatic
every 12 hours, taken in the fasting state or Immediately before
arthritis is 40 mg adalimumab administered every other week as a
meals. The total daily dose may be taken in 2 divided doses. once
single dose via subcutaneous injection.
every 12 hours. Up to 4 g per day may be administered, depending FORANE Solution for Inhalation
upon the severity of the infection. Elderly patients
Children: Age, weight and severity of the infection are important No dose adjustment is required.
factors in determining the proper dosage. For the treatment of mild (Isourane) Children and adolescents
to moderate infections the usual dosage is 30 to 50 mg/kg/day in HUMIRA has not been studied in this patient population.
3 or 4 divided doses. COMPOSITION Therefore, use of HUMIRA cannot be recommended in patients
When dosage is desired on a twice.a.day schedule, onehalf of the Isourane for inhalation. aged below 18 years until further data becomes available.
Book_01.indd 2 6/4/2008 2:18:46 PM

ABBOTT
SPDI
Impaired renal and/or hepatic function estimation. With the current knowledge, a possible risk for the female, 91% were Caucasian and had moderate to severely active
HUMIRA has not been studied in these patient populations. No development of lymphomas or other malignancies in patients rheumatoid arthritis. Most patients received 40 mg HUMIRA
dose recommendations can be made. treated with a TNF-antagonist cannot be excluded. every other week
No studies have been conducted that include patients with a history The proportion of patients who discontinued treatment due to
CONTRAINDICATIONS
of malignancy or that continue treatment in patients who develop adverse events during the double-blind, placebo controlled portion
Hypersensitivity to the active substance or to any of the malignancy while receiving HUMIRA. Thus additional caution of Studies I, II, III and IV was 6.6% for patients taking HUMIRA
excipients. should be exercised in considering HUMIRA treatment of these and 4.2% for placebo-treated patients.
Active tuberculosis or other severe infections such as sepsis, patients (See Undesirable Effects). Adverse events at least possibly causally-related to adalimumab,
and opportunistic infections (See Special Warnings and Special Sixty-one patients with rheumatoid arthritis were given both clinical and laboratory, are displayed by system organ class
Precautions). pneumococcal vaccinations against a background of HUMIRA and frequency (very common > 1/10; common > 1/100 < 1/10;
Moderate to severe heart failure (NYHA class Ill/TV) (See Special and methotrexate therapy. Most patients receiving HUMIRA uncommon > 1/1000 < 1/100) in Table 1 below.
Warnings and Special Precautions). were able to mount effective B-cell immune responses to
Table 1 Undesirable Effects in Clinical Studies.
pneumococcal polysaccharide vaccine. Since no data are available,
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS concurrent administration of live vaccines and HUMIRA is not Body System Frequency Adverse events
FOR USE recommended. Neoplasia Uncommon Skin benign neoplasm
Hemic and Common Decreased hemoglobin
INFECTIONS Congestive heart failure Lymphatic system Uncommon Granulocytopenia, coagulation
Patients must be monitored closely for infections including In a clinical trial with another TNF antagonist worsening time increased, antinuclear
tuberculosis, before, during and after treatment with HUMIRA. congestive heart failure and increased mortality due to congestive antibody present, leukopenia,
Because the elimination of adalimumab may take up to ve heart failure have been observed. HUMIRA should be used lymphadenopathy, lymphocytosis,
months, monitoring should be continued throughout this period. with caution in patients with mild heart failure (NYHA class l/ll). platelet count decreased, purpura
Treatment with HUMIRA should not be initiated in patients HUMIRA is contraindicated in moderate or severe heart failure. Metabolic and Common Hyperlipidemia
Treatment with HUMIRA must be discontinued in patients who Nutritional Uncommon Hypercholesterolemia, alkaline
with active infections including chronic or localized infections
develop new or worsening symptoms of congestive heart failure. Disorders phosphatase increased, BUN
until infections are controlled.
increased, hyperuricamia,
Patients who develop a new infection while undergoing treatment Autoimmune processes peripheral edema, weight gain,
with HUMIRA should be monitored closely. Administration Treatment with HUMIRA may result inthe formation of creatinine phosphokinase
of HUMIRA should be discontinued if a patient develops a autoimmune antibodies. The impact of long-term treatment with increased, healing abnormal,
new serious infection until infections are controlled Physicians HUMIRA on the development of autoimmune diseases is hypokalemia, lactic
should exercise caution when considering the use of HUMIRA unknown. dehydrogenase increased
in patients with a history of recurring infection or with underlying Concurrent administration of TNF-alpha inhibitor and Psychiatric Uncommon Depression, somnolence,
conditions which may predispose patients io infections. Disorders insomnia, agitation
anakinra
Nervous System Common Headache, dizziness Paresthesia,
Serious infections, sepsis, and opportunistic infections, including Concurrent administration of etanercept (another agent that inhibits Uncommon vertigo, hypesthesia,
fatalities, have been reported with HUMIRA. Tuberculosis has TNFoc) and anakinra (a recombinant, non-glycosylated form of neuralgia, tremor
been observed in patients treated with HUMIRA. the human interieukin-1 receptor antagonist) has been associated Special senses Uncommon Conjunctivitis, eye disorder*,
All patients recovered after standard antimicrobial therapy. No with an increased risk of serious infections, an increased risk of otitis media, taste perversion,
deaths due to tuberculosis occurred during the clinical trials. neutropenia and no additional benet compared to these medicinal abnormal vision, blurred vision,
Before initiation of therapy with HUMIRA, all patients must be products alone The safety and efcacy of anakinra used in dry eye, ear disorder*, eye pain
evaluated for both active or inactive (latent) tuberculosis infection. combination with adalimumab has not been established. Therefore Cardiovascular Uncommon Hypertension, vasodilatation,
This evaluation should include a detailed medical history with combination of adalimumab and anakinra is not recommended. System chest pain, migraine
a personal history of tuberculosis or possible previous exposure Surgery Hemorrhage Uncommon Ecchymosis
to patients with active tuberculosis and previous and/or current Respiratory Common Upper respiratory infection,
There is limited safety experience of surgical procedures in patients
immunosuppressive therapy. Appropriate screening tests, i.e. System rhinitis, sinusitis, bronchitis,
treated with HUMIRA. The long -half-life of adalimumab should
cough increased, pneumonia
tuberculin skin test and chest x-ray, should be performed in all be taken into consideration if a surgical procedure is planned. Pharyngitis, dyspnea, lung
patients (local recommendations may apply), it is recommended A patient who requires surgery while on HUMIRA should be disorder*, asthma
that the conduct of these tests should be recorded in the patient closely monitored for infections, and appropriate actions should Digestive System Common nausea, diarrhea, sore throat
alert card. Prescribers are reminded of the risk of false negative be taken. There is limited safety experience in patients undergoing Uncommon Liver function test abnormal,
tuberculin skin test results, especially in patients who are severely arthroplasty while receiving HUMIRA. SGPT increased, SGOT ncreased,
ill or immunocompromised. mouth ulceration, esophagilis,
INTERACTION WITH OTHER MEDICINAL PRODUCTS
If active tuberculosis is diagnosed, HUMIRA therapy must vomiting, dyspepsia, constipation,
AND OTHER FORMS OF INTERACTION gastrointestinal pain, tooth
not be initiated (See Contraindications). If latent tuberculosis
is diagnosed, appropriate anti-tuberculosis prophylaxis in HUMIRA has been studied both in rheumatoid arthritis patients disorder*, gastritis, gastroenteritis,
accordance with local recommendations must be initiated before taking HUMIRA as monotherapy and those taking concomitant tongue disorder*, oral moniliasis,
methotrexate. Antibody formation was low (< 1 %) when aphthous stomatitis, dysphagia,
starting treatment with HUMIRA. In this situation, the benet/
HUMIRA was given together with methotrexate in comparison stomatitis, ulcerative stomatitis
risk balance of therapy with HUMIRA should be very carefully
with use as monotherapy. Administration of HUMIRA without Skin and Common Rash, pruritis, herpes simplex
considered. Appendages Uncommon Skin disorder*, herpes zoster,
methotrexate resulted in increased formation of antibodies and
Patients should be instructed to seek medical advice if signs/ increased clearance of adalimumab (See Pharmacodynamic maculopapular rash, nail
symptoms (eg, persistent cough, wasting/weight loss, low grade Properties). disorder*, dry skin, sweating
fever) suggestive of a tuberculosis infection occur during or after increased, alopecia, ungal
There is no experience with the efcacy and safety in patients dermatitis, urticaria, skin nodule,
therapy with HUMIRA.
previously treated with other TNF-antagonists. skin ulcer, eczema, subcutaneous
Neurolooical events
hematoma
TNF-antagonists including HUMIRA have been associated PREGNANCY AND LACTATION
Musculo-skeletal Uncommon Arthralgia, muscle cramps,
in rare cases with exacerbation of clinical symptoms and/or For adalimumab, there is no experience in pregnant women.
System myalgia, joint disorder, synovitis,
radiographic evidence of demyelinating disease. Prescribers In a developmental toxicity study conducted in monkeys, tendon disorder*
should exercise caution in considering the use of HUMIRA in there was no indication of maternal toxicity, embryotoxicity or Urogenital Common Urinary tract infection
patients with pre-existing or recent-onset central nervous system teratogenicity. Preclinical data on postnatal toxicity and fertility System Uncommon Vaginal moniliasis, hematuria,
demyelinating disorders. effects of adalimumab are not available. cystitis, menorrhagia, proteinuria,
Allergic reactions Due to its inhibition of TNFa, adalimumah administered increased urinary requency
during pregnancy could affect normal immune responses in the Body as a whole Common Laboratory test abnormal,
Serious allergic adverse reactions have not been reported with asthenia, clinical are eaction, u
subcutaneous administration of HUMIRA during clinical newborn. Administration of adalimumab is not recommended
syndrome, abdominal pain,
trials. Non-serious allergic reactions associated with HUMIRA during pregnancy. Women of childbearing potential are strongly
infection:ever, mucous membrane
were uncommon during clinical trials. In postmarketing, serious recommended to use adequate contraception to prevent pregnancy disorder*, pain in extremity, face
allergic reactions including anaphylaxis have been reported very and continue its use for at least ve months after the last edema, back pain, cellulitis,
rarely following HUMIRA administration. If an anaphylactic HUMIRA treatment. chills, sepsis, surgery
reaction or other serious allergic reaction occurs, administration of Use during lactation Injection Site Very Common injection site pain
HUMIRA should be discontinued immediately and appropriate It is not known whether adalimumab is excreted in human milk or Reaction Common injection site reaction, injection
therapy initiated. absorbed systemically after ingestion. site hemorrhage, njection site
eruption
Immunosuppression However, because human immunoglobulins are excreted in milk, Hypersensitivity, Uncommon Allergic reaction
In a study of 64 patients with rheumatoid arthritis that were treated women must not breast-feed for at least ve months after the last general
with HUMIRA, there was no evidence of depression of delayed- HUMIRA treatment. * (not otherwise specied)
type hypersensitivity, depression of immunoglobulin levels, or
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
change in enumeration of effector T-and B cells and NK-cells, Injection site reactions
monocyte/macrophages, and neutrophils. No studies on the effects on the ability to drive and use machines
In placebo-controlled trials, 20% of patients treated with
have been performed.
Malignancies and Ivmphoproliferative disorders HUMIRA developed injection site reactions (erythema and/or
In the controlled portions of clinical trials of TNF-antagonists, UNDESIRABLE EFFECTS CLINICAL TRIALS itching, haemorrhage, pain or swelling), compared to 14% of
more cases of lymphoma have been observed among patients HUMIRA was studied in 2334 patients in placebo-controlled patients receiving placebo. Injection site reactions generally did
receiving a TNF-antagonist compared with control patients. trials and in long term follow-up studies, including 2073 patients not necessitate discontinuation of the medicinal product.
However, the occurrence was rare, and the follow up period of exposed for six months and 1497 patients exposed for greater than In placebo-controlled trials, the rate of infection was 1 per patient
placebo patients was shorter than for patients receiving TNF- one year. The data in the table is based on the adequate and well- year in the HUMIRA treated patients and 0.9 per patient year in
antagonist therapy. Furthermore, there is an increased background controlled studies I, II, III and IV involving 1380 patients receiving the placebo-treated patients. The incidence of serious infections
lymphoma risk in rheumatoid arthritis patients with long-standing, adalimumab during the placebo-controlled period by randomised was 0.04 per patient year in HUMIRA treated patients and
highly active, inammatory disease, which complicates the risk treatment. The population had a mean age of 54.5 years, 77% were 0.02 per patient year in placebo-treated patients. The infections
Book_01.indd 3 6/4/2008 2:18:47 PM

ABBOTT
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consisted primarily of upper respiratory tract infections, Following subcutaneous administration of 40 mg of HUMIRA recommended alternatives. On long-term treatment a daily dose
bronchitis and urinary tract infections. Most patients continued on every other week the mean steady-state trough concentrations of 480 mg should not be exceeded;short-term dose increases are
HUMIRA after the infection resolved. were approximately 5 u.g/ml (without concomitant methotrexate) possible only when directed by the physician.
Malignancies and Ivmphoproliferative disorders and 8 to 9 u.g/ml (with concomitant methotrexate), respectively. The following doses are recommended for the treatment of
The serum adalimumab trough levels at steady-state increased tachyarrhythmia in children:
In the 4 pivotal trials, 21 malignancies were reported in 1380
roughly proportionally with dose following 20,40 and 80 mg every
HUMIRA treated patients observed for 785 patient-years, and Older pre-school children aged up to 6 years are given 1 lm
other week and every week subcutaneous dosing.
2 malignancies were reported in 690 placebo treated patients coated tablet of ISOPTIN 40 mg 2-3 times daily; school children
observed for 362 patient-years. This included 2 lymphomas in Population pharmacokinetic analyses with data from over 1300 take 1 -3 lm coated tablets of ISOPTIN 40 mg 2-3 times daily
the HUMIRA treated patients and no lymphomas in the placebo patients revealed a trend toward higher apparent clearance of (maximum daily dose 360 mg).
treated patients. adalimumab with increasing body weight. After adjustment for
weight differences, gender and age appeared to have a minimal In patients with impaired hepatic function, depending on the
In controlled trials and in open label extension studies, a total of 80 severity of the liver disease, the effect of verapamil is intensied
effect on adalimimab clearance. The serum levels of free
malignancies were observed in 2468 rheumatoid arthritis patients and prolonged due to diminished drug metabolism. In these cases
adalimumab (not bound to anti-adalimumab antibodies, AAA)
treated in clinical trials for a mean of 24 months (4870 patient- dosage should be adjusted with special care starting with low
were observed to be lower in patients with measurable AAA.
years of therapy). This included 32 non-melanoma skin cancers. doses (e.g. in patients with hepatic cirrhosis with 1 lm coated
HUMIRA has not been studied in children or in patients with
The expected rates of non-melanoma skin cancers cannot be tablet of ISOPTIN 40 mg twice daily). ISOPTIN 40 mg is
hepatic or renal impairment.
reliably estimated Forty-eight other malignancies were observed particularly useful when titrating these patients.
and overall rates and incidences of malignancies in these patients PHARMACEUTICAL PARTICULARS
was similar to that expected for an age and gender matched Incompatibilities CONTRA INDICATIONS
population. Among these other malignancies, 10 lymphomas were ISOPTIN 40 mg should not be given in the following cases:
In the absence of compatibility studies, this medicinal product
observed. In post-marketing experience from January 2003 to June Cardiovascular shock, complicated acute myocardial infarction
must not be mixed with other medicinal products.
2004, with an estimated exposure of 40100 patient-years, a total (bradycardia, marked hypotension, left ventricular failure); severe
of 70 malignancies, including 13 lymphomas, have been reported, SHELF LIFE conduction disorders (2rxl and 3a degree AV block, sinoatrial
predominately in patients with rheumatoid arthritis (See Special 18 months block) and sick sinus syndrome (bradycardia-tachycardia
Warnings and Special Precautions). syndrome].
Special precautions for storage
Autoantibodies
Store in a refrigerator (2C - 8C). Keep the syringe in the outer SIDE EFFECTS
Patients had serum samples tested for autoantibodies at multiple carton. Do not freeze.
time points. In the adequate and well-controlled trials, 12.6% of Particularly when given in high doses or in the presence of
patients treated with HUMIRA and 7.3% of placebo-treated HOW SUPPLIED previous damage, some cardiovascular effects of verapamil
patients that had negative baseline anti-nuclear antibody litres HUMIRA 40 mg solution for injection in single-use pre-lled may occasionally be greater than therapeutically desired:
reported positive litres at week 24. One patient out of 2334 syringe (type I glass) for patient use is available in packs of: bradycardic arrhythmias, such as sinus bradycardia, sinus arrest
treated with HUMIRA developed clinical signs suggestive of [1 pre-lled syringe (0.8 ml sterile solution) with 1 alcohol pad with asystole, 2nd and 3ra degree AV block or bradyarrhythmia
new-onset lupus-like syndrome. The patient improved following in a blister (N.R.)]. in atrial brillation, hypotension, development or aggravation of
discontinuation of therapy. No patients developed lupus nephritis 2 pre-lled syringes (0.8 ml sterile solution), each with 1 heart failure. Constipation has been reported frequently. In rare
or central nervous system symptoms. alcohol pad, in a blister. cases nausea, vertigo or dizziness, headache, ushing, fatigue,
Information from further rheumatoid arthritis clinical trials nervousness, ankle oedemas, erythromelalgia and paraesthesia
[4 pre-lled syringes (0.8 ml sterile solution), each with 1
may occur. In very rare cases, there may be myalgia and arthralgia.
HUMIRA has been studied in 542 patients with early rheumatoid alcohol pad, in a blister (N.R.)].
Single cases of allergic skin reactions (exanthema, pruritus,
arthritis (disease duration less than 3 years) who were methotrexate [6 pre-lled syringes (0.8 ml sterile solution), each with 1
urticaria, angioneurotic oedema, Stevens-John son syndrome) have
naive (Study V). In the methotrexate monotherapy group, 3.9% of alcohol pad, in a blister (N.R.)].
been reported, in addition to a reversible increase of transaminases
subjects had ALT values 3 x ULN (Study V) compared with 2.9%
and/or alkaline phosphatase, which is probably a sign of allergic
in HUMIRA inonotherapy and 8.6% in the combination arm ISOPTIN 40 mg Tablet
(methotrexate plus HUMIRA). hepatitis.
Psoriatic Arthritis In very rare cases gynaecomastia, which so far has been fully
reversible in all cases following discontinuation of the drug, has
HUMIRA has been studied in 395 patients with psoriatic (Verapamil Hyclrochloride) been observed in elderly patients under long-term treatment. Rises
arthritis. Elevations in ALT were more common in these patients
in prolactin levels have been reported.
compared with patients in rheumatoid arthritis clinical studies. COMPOSITION
On extremely rare occasions gingival hyperplasia, which is fully
Additional Adverse Reactions from Postmarketinq Film Coated Tablet contains 40 mg of verapamil hydrochloride. reversible when the drug is discontinued, may occur under long-
Surveillance or Phase IV Clinical Trials
MODE OF ACTION term treatment.
Anaphylaxis has been reported very raiely. Cutaneous vasculitis
has been reported rarely. Verapamil inhibits the transmembrarie inux of calcium ions INTERACTIONS
into the heart and vascular smooth muscle cell. The myocardial The simultaneous administration of ISOPTIN 40 mg and other
OVERDOSE oxygen demand is lowered directly as a result of the effect on the
cardioactive drugs (e.g. belareceptor blockers, anti-arrhythmias)
No dose-limiting toxicity was observed during clinical trials of energy consuming metabolic processes of the myocardial cell and
or inhalation anaesthetics may lead to a mutual enhancement of the
rheumatoid arthritis patients. The highest dose level evaluated has indirectly due to a reduction of the afterload.
cardiovascular effects (AV blockade, bradycardia, hypotension,
been multiple intravenous doses of 10 mg/kg. Due to the calcium-antagonistic effect on the smooth vascular heart failure). When given in combination with quinidine to
muscles of the coronaries, ISOPTIN enhances myocardial blood patients with hypertrophic obstructive cardiomyopathy, single
PHARMACOLOGICAL PROPERTIES
ow, even in poststertotic areas, and relieves coronary spasms. cases of hypotension and pulmonary oedema were observed.
PHARMACODYNAMIC PROPERTIES
These properties contribute to the anti-ischemic and anti-anginal Intravenous betareceptor blockers should not be given to patients
Mechanism of action efcacy of ISOPTIN in all types of coronary artery disease. under treatment with ISOPTIN 40 mg.
Adalimumab binds specically to TNF and neutralizes the The antihypertensive effect of ISOPTIN stems from a decrease ISOPTIN 40 mg may intensify the blood pressure-lowering
biological function of TNF by blocking its interaction with the p55 in peripheral vascular resistance - without an increase in heart rate effect of other antihypertensives.
and p75 cell surface TNF receptors. as a reex response. As early as day 1 of treatment, blood pressure
Rises in digoxin plasma levels under concomitant administration
Adalimumab also modulates biological responses that are induced falls; the effect is found to persist also in long-term therapy.
or regulated by TNF, including changes in the levels of adhesion of verapamil have been reported. Physicians should be on the
ISOPTIN is suitable for the treatment of all types of hypertension: alert for symptoms of possible digoxin toxicity. The digitalis level
molecules responsible for leukocyte migration (ELAM-1, VCAM- for monotherapy in mild to moderate hypertension, combined with
1, and ICAM-1 with an IC50 of 1-2 X 1010 M). should be determined and the glycoside dose reduced, if required.
other antihypertensives - in particular with diuretics and, according There have also been occasional reports on interactions with
PHARMACODYNAMIC EFFECTS to more recent ndings, with ACE inhibitors - in more severe types carbamazepine (potentiated by verapamil, neurotoxic side effects),
of hypertension. Its effect on normal blood pressure is negligible.
After treatment with HUMIRA, a rapid decrease in levels of lithium (attenuated by verapamil, enhanced rteurotoxicity),
acute phase reactants of inammation (C-reactive protein (CRP) ISOPTIN has a marked anti-arrhythmic effect, particularly in cyclosporin, theophylline (rise of plasma level by verapamil),
and erythrocyte sedimentation rate (ESR)) and serum cytokines supraventricular arrhythmias. It delays impulse conduction in the rifampicin, phenvtoin and phenobarbital (reduced plasma level
(IL-6) was observed compared to baseline in patients with AV node. Owing to this, sinus rhythm is restored and/or ventricular and effects of verapamil attenuated). Verapamil plasma levels may
rheumatoid arthritis. Serum levels of matrix metalloproteinases rate is normalized, depending on the type of arrhythmia. Normal be increased under concomitant administration of cimetidine. The
(MMP-1 and MMP-3) that produce tissue remodelling responsible heart rate is either not affected or only minimally lowered effect of muscle relaxants may be potentiated.
for cartilage destruction were also decreased after HUMIRA INDICATIONS PRECAUTIONS
administiation. Patients treated with HUMIRA usually
Chronic coronary insufciency and long-term treatment of angina When treating hypertension with ISOPTIN 40 mg, monitoring
experienced improvement in haematological signs of chronic
pectoris, coronary spasms - vasospastic angina, Angina pectoris of the patients blood pressure at regular intervals is required.
inammation.
after myocardiai infarction. Depending on individual susceptibility, the patients ability to
PHARMACOKINETIC PROPERTIES Hypertension. drive a vehicle or operate machinery may be impaired. This is
After subcutaneous administration of a single 40 mg dose, Tachyarrhythmia, such as paroxysmal supraventricular tachycardia, particularly true in the initial stages of treatment, when changing
absorption and distribution of adalimumab was slow, with atrial brillation/utter with rapid ventricular response (except in over from another drug, and also with respect to the consumption
peak serum concentrations being reached about 5 days after WPW syndrome, see precautions), premature ventricular beats. of alcohol.
administration. The average absolute bioavailability of Care should be taken in:
adalimumab estimated from three studies following a single DOSAGE AND MODE OF ADMINISTRATION
40 mg subcutaneous dose was 64%. After single intravenous The doses of ISOPTIN 40 mg, individualized according to the 1st degree AV block, bradycardia < 50 beats/min, hypotension
doses ranging from 0.25 to 10 mg/kg, concentrations were dose severity of the disease, are to be taken regularly as prescribed by < 90 mm Hg systolic pressure, atrial brillation/ utter and
proportional. After doses of 0.5 mg/kg (-40 mg), clearances ranged the physician. The lm coated tablets are to be swallowed whole simultaneous pre-excitation syndrome, e.g. WPW syndrome (risk
from 11 to 15 ml/hour, the distribution volume (Vss) ranged from 5 with some liquid, preferably with or shortly after meals. ot inducing ventricular tachycardia), heart failure (compensation
to 6 litres and the mean terminal phase half-life was approximately Unless otherwise instructed, the dose for adults is 1-2 lm with cardiac glycosides, for example, before initiating treatment).
two weeks. Adalimumab concentrations in the synovia! uid from coated tablets of ISOPTIN 40 mg, 3-4 times a day. If higher ISOPTIN 40 mg should not be given during pregnancy
several rheumatoid arthritis patients ranged from 31-96% of those doses or fewer administrations are necessary, ISOPTIN 80 (especially in the rst trimester) and lactation unless, in the
in serum. mg, ISOPTIN 120 mg and slow-release ISOPTIN are physicians judgement, it is essential for the patients well-being.
Book_01.indd 4 6/4/2008 2:18:47 PM

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EXPIRY DATE lactation unless, in the physicians judgement, it is essential for the oral administration. The hypotensive action of the drug produced
Do not use beyond the expiry date indicated on the carton. patients well-being. by its daily single dose is clinically manifested in an appreciable
way during the whole period of 24 hours. The reduction of blood
TRADE PACKS SIDE EFFECTS
pressure following the oral daily dose manifests itself gradually;
20 lm coated tablets Particularly when given in high doses or in the presence of the eventual occurrence of orthostatic effects during the rst day
Store the drug carefully! previous damage, some cardio-vascuar effects of verapamil of therapy is comparable to that observed with other quinazoline
may occasionally be greater than therapeutically desired: derivatives. Terazosin has proved to possess the same efciency
Keep out of the reach of children!
bradycardiac arrhythmias, such as sinus bradycardia, sinus arrest as other antihypertensive preparations with a clear therapeutic
with asystole, 2nd and 3rd degree AV block or bradyarrhythmia activity.
ISOPTIN SR 240 mg Tablet in atrial brillation, hypotension, development or aggravation of
BPH and Hypertension
heart iailure. Constipation has been reported frequently. In rare
cases nausea, vertigo or dizziness, headache, ushing, fatigue, On long-term therapy, terazosin did not induce tolerance for either
(Verapamil Hydrochloride) nervousness, ankle oedemas, erythromelalgia and paraesthesia may of the two indications. It is known that quinazoline derivatives, like
occur, In very rare cases, there may be myalgia and arthralgia. terazosin, induce positive effects on the serum lipids, decreasing
COMPOSITION signicantly total cholesterol, LDL, VLDL, and LDL/cholesterol
Single cases of allergic skin reactions (exanthema, pruritus,
ratio and a favorable reduction of the triglyceride levels. This
1 lm-coated tablet contains 240 mg of verapamil hydro- urticaria, angioneurotic oedema, Stevens-Johnson syndrome) have
action represents an advantage with respect to diuretics and beta-
chloride. been reported, in addition to a reversible increase of transaminases
blocking drugs which, as known, have unfavorable effects on these
and/or alkaline phosphatase, which is probably a sign of allergic
INDICATIONS parameters.
hepatitis. In very rare cases gynaecomastia, which so far has been
Hypertension. fully reversible in all cases following discontinuation of the drug, Since the arterial hypertension and the increase of serum lipids are
has been observed in elderly patients under long-term treatment. strictly related to the pathology of the coronary, the positive effect
DOSAGE AND MODE OF ADMINISTRATION exerted by terazosin both on the arterial pressure and on the lipids,
Rises in prolactin levels have been reported. On exlremely rare
The doses of ISOPTIN SR 240 mg, individualized according to occasions gingival hyper-plasia, which is fully reversible when the may result in reduction of the risk factors for coronary pathies.
the severity of the disease, are to be taken regularly as prescribed drug is discontinued, may occur under long-term treatment, The long-term therapy with terazosin does not produce any
by the physician. The lm-coated tablets are to be swallowed clinical signicant changes in the most important laboratory
whole with some liquid, preferably with or shortly after meals. MODE OF ACTION parameters as (glycemia, uricemia, creatininemia, azotemia and
Unless otherwise instructed, the daily dose for adults is 1 lm- The calcium antagonist verapamil inhibits the transmembrane transamina-semia); therefore, the drug can be safely used in
coated tablet in the morning (patients requiring particularly inux of calcium ions into the heart and vascular smooth muscle diabetics, hyperuricemics, and elderly patients. Interactions with
gradual pressure lowering should be started on half a tablet taken cell. The antihypertensive effect of ISOPTIN stems from a the following drugs were never observed: thiazide diuretics,
in the morning). If after about 2 weeks of treatment a dose increase decrease in peripheral vascular resistance -without an increase beta-blocking drugs, analgesics, non-steroidal anti-inammatory
is found to be necessary the dose can be raised to a maximum of 2 in heart rate as a reex response. As early as day 1 of treatment drugs, hypoglycaemic drugs, antibiotics, anxiolytics and
lm-coated tablets daily (additionally 1 half to 1 lm-coated tablet blood pressure falls; the effect is found to persist also in long-term bronchodilatores.
in the evening after an interval of about 12 hours). therapy. ISOPTIN is suitable for the treatment of all types of
hypertension; for monotherapy in mild to moderate hypertension, PHARMACOKINETICS
On long-term treatment a daily dose of 480 mg should not be
combined with other antihypertensives - in particular with diuretics Terazosin administered orally is proved to be completely absorbed
exceeded; short-term dose increases are possible only when in man. The effect of food on the absorption of the drug is negligible.
and, according to more recent ndings, with ACE inhibitors-in
directed by the physician. The plasma levels of the drug reach the peak concentration within
more severe types of hypertension.
For children and adults requiring smaller doses of verapamil, one hour after oral administration, and then decline with a half-life
Due to the calcium-antagonistic effect on the smooth vascular
ISOPTIN 40 mg and 80 mg are available. of approximately 12 hours, thus maintaining levels of therapeutic
muscles of the coronaries, ISOPTIN enhances myocardial blood
In patients with impaired hepatic function the effect of verapamil ow, even in poststenotic areas, and relieves coronary spasms. effect allowing the drug to be administered only once daily.
is intensied and prolonged depending on the severity of the liver
ISOPTIN has a marked antiarrhythmic effect, particularly in INDICATIONS
disease due lo diminished drug metabolism. In these cases dosage
supravenlricular arrhythmias. It delays impulse conduction in the Terazosin hydrochloride is indicated in the symptomatic treatment
should be adjusted with special care starting with low closes (e.g.
AV node. Owing to this, sinus rhythm is restored and/or ventricular of Benign Prostatic Hyperplasia (BPH) and in the therapy of mild
in patients with hepatic cirrhosis with 1 tablet of ISOPTIN 40
rate is normalized, depending on the type of arrhythmia. to moderate hypertension as single therapy or associated with
mg 2-3 times daily.
EXPIRY DATE other antihypertensive drugs.
CONTRAINDICATIONS
Do not use beyond the expiry date indicated on the carton. CONTRAINDICATIONS
ISOPTIN SR 240 rng should not be given in the following
cases: TRADE PACKS Ascertained or presumed hypersensitivity to quinazoline
derivatives, history of orthostatic hypotension and in pregnancy
Cardiovascular shock, complicated acute myocardial infarction 20 lm-coated tablets
and lactation.
(bradycardia, marked hypotension, left ventricular failure), severe
OTHER FORMS
conduction disorders (2a and 3 degree AV block, sinoatrial block) UNDESIRABLE EFFECTS
and sick sinus syndrome (bradycardia-tachycardiasyndrome). ISOPTIN SR 120 mg (N.R.), lm-coated tablets ISOPTIN
Benign Prostatic Hyperplasia (BPH):
SR 180 mg (N.R.), lm-coated tablets
INTERACTIONS The following side effects have been reported: asthenia,
Store the drug carefully!
palpitations, nausea, dizziness, somnolence, nasal congestion
The simultaneous administration of ISOPTIN SR 240 rng and Keep out of the reach of children! and blurred vision. Like all quinazoline derivatives, it can cause
cardioactive drugs (e.g. betareceptor blockers, antiarrhythmics) or
orthostatic hypotension, particularly associated with the rst
inhalation anaesthetics may lead to a mutal enhancement of the
cardiovascular effects (AV blockade, bradycardia, hypotension, ITRIN Tablet dose.
heart failure). When given in combination with quinidine to Hypertension:
patients with hypertrophic obstructive cardiomyopathy single The following side effects have been reported: vertigo, headache,
cases of hypotension and pulmonary oedema were observed. (Terazosin Hydrochloride) fever outsets; abdominal, cervical and thoracic pains. In most
Intravenous beta-receptor blockers should not be given to patients cases such symptoms disappear by carrying on the therapy without
under treatment with ISOPTIN SR 240 rng. Isoplin SR 240 DESCRIPTION & COMPOSITION requiring reduction of dosage.
mg may intensify the blood pressure-lowering effect of other Terazosin hydrochloride is a selective blocking drug with a long- As with all quinazoline derivatives, troubles of postural nature
antihypertensives. lasting action towards the adrenergic receptors alpha-1. Chemically can occur, especially with the rst dose. Also other symptoms
Rises in digoxin plasma levels under concomitant administration it is a derivative of quinazoline having the following formula: 2- have been reported, but they are not distinguishable clearly from
of verapamil have been reported. Physicians should be on the [4-(tetrahydro-2-furanyl)-carbonyl] 1-piperazinyl 6,7-dimethoxy- those possibly occurring by themselves in hypertensive subjects
alert for symptoms of possible digoxin toxicity. The digitalis level 4-quinazolineamine monohydrochloride dihydrate. not under terazosin therapy, particularly: depression, insomnia,
should be determined and the glycoside dose reduced, if required. irritability and paresthesia.
PHARMACOLOGICAL ACTIONS
There have also been occasional reports on interactions with PHARMACODYNAMICS DOSAGE AND ADMINISTRATION
carbamazepine (potentiated by verapamil, neurotoxic side Benign Prostatic Hyperplasia (BPH):
Terazosin is a competitive/selective a1-blocking agent producing
effects), lithium (attenuated by verapamil, enhanced neuro-
reduction of the peripheral vascular resistance and smooth muscle The usual recommended dose range is 5 to 10 mg administered
toxicity),cyclosporin, theophylline, (rise of plasma level by
relaxation. once a day. Treatment should always be initiated with 1 mg dose
verapamil), rifampicin. phenytoin and phenobarbital (reduced
Benign Prostatic Hyperplasia (BPH): (half of 2 mg tablet) given at bed time, then the daily dose should
plasma level and effects of verapamil attenuated). Verapamil
The symptoms associated with BPH are related to bladder outlet be doubled every two weeks up to 5 mg or 10 mg per day.
plasma levels may be increased under concomitant administration
of cimetidine. The effect of muscle relaxants may be potentiated. obstruction, which is comprised of two underlying components: a If the drug administration is discontinued for several days, therapy
static component due to an increase in prostate size and a dynamic should be reinstituted using the initial dosage regimen.
PRECAUTIONS component which is due to an increase in smooth muscle tone in Hypertension
When treating hypertension with ISOPTIN SR 240 mg, the prostate and bladder neck, leading to constriction of the bladder The dosage of ITRIN must be adjusted following the behaviour
monitoring of the patients blood pressure at regular intervals is outlet. Since the bladder body contains few alpha-1 adrenoreceptors of the blood pressure values. It is advisable to start treatment with
-required.--Depending on individual susceptibility, the patients while the bladder neck and the prostate contain high density of 1 mg (half -2 mg tablet) at bedtime as a starting dose.
ability to drive a vehicle or operate machinery may be impaired. alpha-1 adrenoreceptors, selective alpha-1 blockade following
After one to two weeks of treatment, the daily single dose can be
This is particularly true in the initial stages of treatment, when administration of terazosin decrease the dynamic component of
increased to 2 mg, and then to 5 or 10 mg daily, until the desired
changing over from another drug, and also with respact to the BPH by decreasing bladder outlet resistance without impairing
value of the blood pressure is achieved. In case of complementing
consumption of alcohol. bladder contraction and decreasing prostate muscular tone leading
the therapy with a thiazide diuretic or a beta-blocking agent, it may
Care should be taken in: 15 degree AV block, bradycardia to reduction in symptoms of BPH and improvement of urine ow
be necessary to reduce the ITRIN dose, according to doctors
< 50 beats/ min, hypotension < 90 mmHg systolic pressure, atrial rates. Clinical studies have demonstrated that the size of the
instructions.
brillation/utter and simultaneous pre-exciiation syndrome, prostate does not correlate with the severity of BPH.
e.g. WPW syndrome (risk of inducing ventricular tachycardia), Hypertension: Since terazosin develops a selective WARNINGS
heart failure (compensation with cardiac glycosides, for example, alpha-1 blocking action, it causes a decrease in blood pressure Safety and effectiveness in children have not been ascertained.
before initiating treatment). ISOPTIN SR 240 mg should not by decreasing total peripheral vascular resistance. Terazosin Since, in some cases, signs of drowsiness or vertigo have been
be given during pregnancy (especially in the rst trimester) and decreases blood pressure gradually within 15 minutes following manifested, it is recommended to be careful when driving motor
Book_01.indd 5 6/4/2008 2:18:48 PM

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cars and/or operating machinery requiring particular attention for and tacrolimus) may be associated with elevations in serum
at least 12 hours after the administration of the starting dose or levels of these drugs. Rhabdomyolysis, coincident with the co- KLACID 500 mg Tablet
when the dose is increased. In case of overdosage and consequent administration of clarithromycin and lovastatin or simvastatin
hypotension, keep the patient lying on his back with the head in a has been reported. The administration of KLACID to patients
downward position. who are receiving theophylline has been associated with increased (Clarithromycin)
While treating BPH, should ITRIN be administered in serum theophylline levels and potential theophylline toxicity.
combination with antihypertensive drugs, their dosage should be The use of KLACID in patients receiving warfarin may result
DESCRIPTION:
adjusted, following the physicians advice. in potentiation of the effects of warfarin. Prothrombin time
Yellow, ovaloid, lm coated tablet containing 500mg of
Keep out of reach of children. should be frequently monitored in these patients. The effects of
clarithromycin
digoxin may be potentiated with concomitant administration
HOW SUPPLIED of KLACID. Monitoring of serum digoxin levels should be PHARMACOLOGICAL ACTIONS :
Tab: 2 mg x 30 (blisters) considered. Macrolides have been reported to alter the metabolism PHARMACODYRNAMICS:
5 mg x 14 (blisters). of terfenadine, cisapride and pimozide resulting in increased Clarithromycin is a semi - synthetic derivative of erythromycin A.
plasma levels of these drugs. This may result in QT prolongation It exerts Its antl-bacterial action by binding to the 50s ribosomal
KLACID 250 mg Tablet and cardiac arrhythmias including ventricular tachycardia, sub-unit of susceptible bacteria and suppresses protein synthesis.
ventricular brillation and torsade de pointes. Similar effects have It is highly potent against a wide variety of aerobic and anaerobic
been observed with concomitanl administration of astemizole gram-positive and gram-negative organisms. The minimum
and other macrolides. KLACID may potentiate the effects inhibitory concentrations (MICs) of clarithromycin are generally
(Clarithromycin) of carbamazepine due to a reduction in the rate of excretion. two-fold lower than the MICs ot erythromycin. The 14 - hydroxy
Simultaneous oral administration of KLACID TABLETS and metabolite of clarithromycin also has anti microbial activity. The
DESCRIPTION :
zidovudm to HIV-infected adults may result in decreased steady MICs of this metabolite are equal or two-fold higher than the
Yellow, ovaloid lm-coated tablets containing 250mg of state zidovudine levels. This can be largely avoided by staggering MICs of the parent compound, except for H-Inuenzae where the
clarithromycin. the doses of KLACID and zidovudine by 1-2 hours. No such 14-hydroxy metabolite is two-fold more active than the parent
PHARMACOLOGICAL ACTIONS : reaction has been reported in children. Ritonavir increases the compound. KLACID is usually active against the following
area under curve (AUC), C and Cm. of clarithromycin when organisms in vitro:
PHARMACODYNAMICS:
administered concurrently. Because of the large therapeutic Gram-positive Bacteria: Staphylococus aureus (methiclllln
Clarithromycin is a new macrolide antibiotic. It exerts its window for clarithromycin, no dosage reduction should be susceptible), Strepto coccus pyogenes [Group A beta-hemolytic
antibacterial activity by means of inhibition of protein synthesis, necessary in patients with normal renal function. However, for streptococci), alpha-hemolytic streptococci (viridans group).
linking to the 50S ribosomal subunit of susceptible bacteria. patients with renal impairment, the following dosage adjustment Streptococcus (Diplocoxus) pneumonias. Streptococcus agafacae,
Clarithromycin is highly potent against a wide variety of aerobic should be considered: For patients with CLcn 30 to 60 ml / min the Listens monocytogenes.
and anaerobic, gram-positive and gram-negative organisms. It is dose of clarithromycin should be reduced by 50% Foi patients with Gram-negative Bacteria: Haemophilus inuenzaes. Haemophilia
active against the following organisms in vitro: Streptococcus CLcn< 30 ml / min the dose of clarithromycin should be decreased paraintuenzae, Moraxella (Branhamella) Catarrhalis, Neisseria
agalactiae, Streptococcus pyogenes. Streptococcus viridans, by 75%. Doses of clarithromycin greater than 1g/day should not be gonorrhoeas, Leglonella pneuntophlla, Bordet&tfa pertussis,
Streptococcus pneumoniae, Haemophilus inuenzae, Haemophilus co-administered with ritonavir Although the plasma concentrations Helicobacter pylori, Campylobacter jejuni.
parainuenzae. Neisseria gonorrheae, Listeria monocytogenes, of clarithromycin and omeprazole may be increased when they
Legionella pneumophila, Mycoplasma pneumoniae, Helicobacter Mycoplasma: Mycoplasma pneumoniae, Ureaplasma urealyti-
are administered concurrently, no adjustment to the dosage is cum.
pylori. Campylobacter jejuni, Chlamydia trachomatis, Moraxilla necessary. At the dosages recommended, there is no clinically
(Branhamella) catarrhalis, Bordetelia pertussis, Staphylococcus Other Organisms: Chlamydia trachomatis, Mycobacterium
signicant interaction between clarithromycin and lansoprazole.
aureus, Propionibacterium acnes Mycobactenum avium, M. avium, M. leprae. M.Kansasii, M.Chelonae. M Fortuitum, M.
Increased plasma concentrations of clarithromycin may also
leprae, M. kansasii, M. chelonae, M. fortuitum, M. intracellulare. intracellulare.
occur when it is co-administered with Maalox or Ranitidine. No
adjustment to the dosage is necessary Anaerobes: Macrolide-susceptible Bacteroides fragills,
PHARMACOKINETICS:
Clostridium petringens, peptococcus species. Peptostreptococcus
Clinical studies have demonstrated that plasma level peaks SIDE EFFECTS : species, Propionibacterium acnas. Clarithromycin also has
appear two hours after administration of a single oral dose of bactericidal activity against several bacterial strains. These
Clarithromycin is generally well tolerated. Side effects reported
100 mg of Clarithromycin with values of 0.35 meg/ml, and 3.97 organisms include H. inuenzas. Streptococcus pneumonias.
include nausea, dyspepsia, diarrhoea, vomiting, abdominal pain
mcryml after an oral dose of 1200 mg. Drug half-life appears to Streptococcus pyogenes. Streptococcus agalactiae, moraxella
and paraesthesia. Stomatitis, glossitis, oral monilia and tongue
be dose dependent. Moreover, meals have failed to demonstrate a (Branhaamella) Catarrhalis, neissseria gonorhoea. Helicobacter
discolouration have been reported. Other side gffects include
signicant inuence on drug bioavailability in this pharmaceutical pylori and Campylobacter spp. The activity of clarithromycin
headache, arthralgia, myalgia and allergic reactions ranging from
form. After absorption Clarithromycin rapidly diffuses in the against H. pylori is greater at neutral pH than at acid pH.
urticaria, mild skin eruptions and angioedema to anaphylaxis and
majority of tissues, excluding CMS, without signicant differences
rarely Stevens-Johnson syndrome / toxic epidermal necrolysis. FURTHER INFORMATION:
in concentration. Clarithromycin is metabolized by the liver,
Reports of alteration of the sense of smell, usually in conjunction
the most important metabolite being 14-hydroxy-N-desmethyl- Helicobacter Pylori (H. pylori) Is associated with acid peptic
with taste perversion have also been received. There have disease including duodenal ulcer and gastric ulcer In which about
Clarithromycin, which peaks in plasma at 0.5 meg/ml and 1.2
been reports of tooth discolouration in patients treated with 95% and 80% of patients respectively are infected with this agent.
meg/ml after 2-4 hours from administration of 250 and 1200 mg
clarithromycin. Tooth discolouration is usually reversible with H. Pylori is also implicated as a major contributing factor in the
respectively. Only after administration of 1200 mg, low plasma
professional dental cleaning There have been reports of transient development of gastritis and ulcer recurrence in such patients.
levels of descladinosyl-Clarithromycin have been identied.
central nervous system side effects including dizziness, vertigo, Recent evidence further suggests a causative link between H. pytori
Metabolic process tends towards saturation with higher doses.
anxiety, insomnia, bad dreams, tinnitus, confusion, disorientation, and gastric carcinoma. In a well controlled study, clarithromycin
Within 5 days from oral or I.V. administration of radiolabelled
hallucination, psychosis and depersonalisation. There have been 500mg tid for 14 days administered with omeprazole 40 mg od
C14-Clarithromycin, 36% of the dose is excreted in the urine and
reports of hearing loss with clarilhromycin. which is usually for 28 days eradicated In excess ot 80% of H. pylori isolates in
52% in the stool.
reversible upon withdrawal of therapy. Pseudomembranous colitis patients with duodenal ulcer, clarithrornycin has been used In
INDICATIONS : has been reported rarely with clarithromycin. and may range in small numbers or patients in other treatment regimens. Possible
Treatment of infections caused by pathogens sensitive to severity from mild to life threatening. There have been rare reports kinetic interactions have not been fully investigated. These
Clarithromycin. Indications include: Infections of nasopharyngeal of hypoglycaemia, some of which have occurred in patients on regirnens include, clarithromycin plus tinidazole and omeprazole;
tract (tonsillitis, pharyngitis), and of paranasal sinuses. Infections concomitant oral hypoglycaemic agents or insulin. Isolated cases darithromycin plus tetracycline, bismuth subsaftcylate and
of the lower respiratory tract: bronchitis, bacterial pneumonia of leukopenia and thrombocytopenia have been reported. As with ranitidine; clarithromycin plus ranitidine alone. Clinical studies
and atypical pneumonia. Skin infections: impetigo, erysipelas, other macrolides. hepatic dysfunction (which is usually reversible) using various different W. pytori eradication regimens have shown
folliculitis, furunculosis and septic wounds. including altered liver function tests, hepatitis and cholestasis with that eradication of H. pylori prevents ulcer recurrence.
or without jaundice, has been reported. Dysfunction may be severe
CONTRAINDICATIONS : and very rarely fatal hepatic failure has been reported Cases of PHAMACOKINETICS:
KLACID is contra-indicated in patients with known increased serum creatinine, interstitial nephritis, renal failure, Clarithromycin Is rapidly and well absorbed from the
hypersensitivity to macrolide antibiotic drugs. It is also pancreatitis and convulsions have been reported rarely. As with gastrointestinal tract after oral administration of KLACID tablet.
contraindicated in pregnant and lactating women, and in patients other macrolides, QT prolongation, ventricular tachycardia and The microbioligically active metabolite14-hydroxy clarithromycin
with severe liver insufciency. KLACID and ergot derivatives Torsade de Pointes have been rarely reported with clarithromycin. is formed by the rst pass metabolism. KLACID may be given
should not be co-administered. Concomitant administration of without regard to meals, as food does not affect the extent of
clarithromycin and any of the following drugs is contraindicated: OVERDOSAGE: bioavailability of KLACID TABLETS. Food does slightly delay
cisapride, pimozide and terfenadine (see precautions - drug In case high dosages of Clarithromycin have been ingested, the onset of absorption of claritnromycin and formation of the 14
interactions). G.I. disturbances can occur A systemic reaction can also follow, - hydroxy metabolite. The pharmacokinetics of clarithromycin
to be readily treated by means of gastric lavage and supportive are non- linear: however, steady state is attained within 2 days of
WARNINGS AND PRECAUTIONS measures. Providing that Clarithromycin cannot be removed by dosing. At 250mg twice daily 20% of unchanged drug is excreted
Clarithromycin is principally excreted by the liver and kidney. haemodialysis or peritoneal dialysis, a rapid action is needed In the urine. With 500mg twice dally dosing urinary excretion
Caution should be exercised in administering this antibiotic to aimed to eliminate the amount of drug not yet absorbed, applying is greater (approximately 36%). The 14-hydroxy clarithromycin
patients with impaired hepatic or enal function and to elderly at the same time a suitable symptomatic therapy. Is the major urinary metabolite and accounts for 10-15% of the
patients (> 65 years). Prolonged or repeated use of KLACID dose. Most of the remainder of the dose is eliminated in the faeces,
may result in an overgrowth of non susceptible bacteria or fungi. DOSAGE AND ADMINISTRATION : primarily via the bile. 5-10 % ot the parent drug is recovered
If super-infection occurs, KLACID should be discontinued and Clarithromycin recommended dosage in adults is one 250 mg from the faeces. When clarithromycin 500mg is given three times
appropriate therapy instituted. H pylori organisms may develop tablet every 12 hours. In cases of severe infections, dosage can daily, the clarithromycin plasma concentrations are Increased
resistance to clarithromycin in a small number of patients. be increased up to 500 mg every 12 hours. Administration must with respect to the 500mg twice daily dosage. KLACID
be continued, accordng to severity of infection, up to 6-14 days. provides tissue concentrations that are several times higher than
INTERACTIONS: In patients with renal impairment with creatinine clearance less the circulating drug levels. Increased levels have been found In
KLACID has been shown not to interact with oral contraceptives. than 30 ml/min, the dosage should be reduced by one-half. Dosage both tonsillar and lung tissue. clarithromycin is 80% bound to
As with other macrolide antibiotics, the use of clarithromycin in should not be continued beyond 14 days in these patients. plasma proteins at therapeutic levels. KLACID also penetrates
patients concurrently taking drugs metabolised by the cytochrome the gastric mucosa. Levels of clarithromycin In gastric mucus and
P450 system (eg. warfarin., ergot alkaloids, triazolam, midazolam, HOW SUPPLIED : gastric tissue are higher when clarithromycin is co- administered
disopyramide, lovastatin, rifabutin, phenytoin, cyclosporin Blisters containing 14 coated tablets of 250 mg each. with omeprazole than when clarithromycin is administered alone.
Book_01.indd 6 6/4/2008 2:18:49 PM

ABBOTT
SPDI
INDICATIONS : SIDE EFFECTS :
KLACID is indicated In the treatment of infections caused by Clarithromycin Is generally Well tolerated. Side effects reported KLACID Granules for oral suspension
susceptible organisms. Include nausea, dyspepsia, diarrhoea, vomiting, abdominal pain
Indications include: and paraesthasia. Stomatitis, glossitis, oral monilia and tongue
Lower respiratory tract Infections for example, acute and discolouration have been reported. Other side effects include (Clarithromycin)
chronic bronchitis, and pneumonia. headache, arthralgia. myalgia and allergic reactions ranging from
urticaria, mild skin eruptions and angioedema to anaphylaxis and DESCRIPTION :
Upper respiratory tract infections for example, sinusitis and
rarely Stevens-Johnson syndrome/toxic epidermal necrolysis. White to off-white granules for oral suspension. After mixing,
pharyngitis.
Reports of alteration of the sense of smell, usually in conjunction each 5ml of the suspension contains 125mg Clarithromycin.
KLACID is appropriate for Initial therapy in community with taste perversion have also been received. There have
acquired respiratory infections and has been shown to be active been reports of tooth discolouration in patients treated with PHARMACOLOGICAL ACTIONS :
in vitro against common and atypical respiratory pathogens as clarithromycin. Tooth discolouration is usually reversible with PHARMACODYNAMICS:
listed in the pharmacodynamics section. professional dental cleaning. There have been reports of transient Clarithromycin is a new macrolide antibiotic. It exerts its
KLACID is also Indicated in skin and soft tissue infections of central nervous system side effects Including dizziness, vertigo, antibacterial activity by means of inhibition of protein synthesis,
mild to moderate severity. anxiety, Insomnia, bad dreams, tinnitus, confusion, dlsorientation. linking to the SOS ribosomal subunit of susceptible bacteria.
KLACID in the presence of acid suppression effected by hallucination, psychosis and depersonalisation. There have been Clarithromycin is highly potent against a wide variety of aerobic
omeprazole or lansoprazole is also Indicated for the eradication reports of hearing loss with darithromycin which is usually and anaerobic, gram-positive and gram-negative organisms. It is
ot H.pylori In patients with duodenal ulcers (See Dosage and reversible upon withdrawal of therapy. Pseudomembranous colitis active against the following organisms in vitro: Streptococcus
Administration section). has been reported rarely with clarithromycin, and may range in agalactiae, Streptococcus pyogenes, Streptococcus viridans,
severity from rnild to life threatening. There have been rare reports Streptococcus pneumoniae, Haemophilus inuenzae, Haemophilus
CONTRAINDICATIONS :
of hypoglycaemia, some of which have occurred in patients on parainuenzae, Neisseria gonorrheae, listeria monocytogenes,
KLACID is contra-indicated in patients with known concomitant oral hypoglycaemlc agents or insulin. Isolated cases Legionella pneumophila, Mycoplasma pneumoniae, Helicobacter
hypersensitivity to macrolide antibiotic drugs. KLACID and of leukopenia and thrombocytopenla have been reported. As with pylori, Campylobacter jejuni, Chlamydia trachomatis, Moraxilla
ergot derivatives should not be co - administered. Concomitant other macrolides, hepatic dysfunction (which is usually reversible) (Branhamella) catarrhalis, Bordetella pertussis, Staphylococcus
administration of clarithromycin and any of the following drugs Including altered liver function tests, hepatitis and cholestasis aureus, Propionibacterium acnes, Mycobacterium avium, M.
Is contraindicated: cisapride, pimozide and terfenadine (see with or without jaundice, has been reported. Dysfunction may leprae, M. kansasii, M. chelonae, M. fortuitum, M. intracellulare.
precautions - drug interactions. be severe and very rarely fatal hepatic failure has been reported.
Cases of increased serum creatinine, interstitial nephritis, PHAMACOKINETICS:
WARNINGS AND PRECAUTIONS :
renal failure, pancreatitis and convulsions have been reported Clinical studies in adults have demonstrated that plasma level
Clarithromycin is principally excreted by the liver and kidney.
rarely. As with other macrolides, QT prolongation, ventricular peaks appear three hours after administration of a single oral dose
Caution should be exercised in administering this antibiotic to
tachycardia and Torsade de Pointes have been rarely reported with of 250 mg of Clarithromycin with values of 1.46 0.27 meg/ml.
patients with impaired hepatic or renal function. Prolonged or
repeated use of KLACID may result In an overgrowth of non - Clarithromycin. Drug half-life appears to be dose dependent, and appears to be
susceptible bacteria or fungi. If super -infection occurs, KLACID 3-4 hours after repeated administrations of 250 mg b.i.d. These
OVER DOSAGE :
should be discontinued and appropriate therapy instituted. H. clinical studies demonstrated the bioequivalence between tablets
Reports indicate that the ingestion of large amounts ol and suspension. Moreover, meals have failed to demonstrate a
pylori organisms may develop resistance to clarithromycin in a
clarilhromycin can be expected to produce gastro-intestinal signicant inuence on drug bioavailability in this pharmaceutical
small number of patients.
symptoms. Adverse reactions accompanying overdosage should form. After absorption, Clarithromycin rapidly diffuses in the
INTERACTIONS: be treated by gastric lavage and supportive measures. One majority of tissues, excluding CNS, without signicant differences
KLACID has been shown not to Interact with oral contraceptives. patient who had a history of bisplar disorder Ingested 8 grams in concentration. Clarithromycin is metabolized in the liver.
As with other macrolide antibiotics, the use of clanthromycin in of clarithromycin and showed altered mental status, paranoid The principal metabolite of Clarithromycin in man and other
patients concurrently taking drugs metabolised by the cytochrome behaviour, hypokalemla and hypoxemla. As with other rnacrolides. primates is a microbiologically active metabolite, 14-hydroxy-
P450 system (eg. warfarin,, ergot alkaloids, triazolam. midazolam, clarithromycin serum levels are not expected to be affected by Clarithromycin, which peaks in plasma at 0.5 meg/ml after 2-4
disopyramide, lovastatin, rifabutin, phenytoin, cyclosporin and haemodialysls or peritoneal dialysis. hours from administration of 250 mg. Only after administration
tacrolimus) may be associated with elevations in serum levels DOSAGE AND ADMINISTRATION : of 1200 mg, low plasma levels of descladinosyl-Clarithromycin
of these drugs. Rhabdomyolysis, coincident with the co-ad mi have been identied. Metabolic process tends towards saturation
Respiratory tract/skin and soft tissue infections
nisi ration of darithromycin and lovastatin or simvastalin has with higher doses. Within 5 days from oral administration of
been reported. The administration ol KLACID to patients who Adults: The usual dose is 250 mg twice daily for 7 days although radiolabelled C14-Clarithromycin, 36% of the dose is excreted in
are receiving theophylline has been associated with increased this may be Increased to 500 mg twice daily for up to 14 days In the urine and 52% in the stool.
serum theophylline levels and potential theophylline toxicity. severe Infections.
The use ol KLACID in patients receiving warfarin may result Children older than 12 years : As for Adults. INDICATIONS :
in potentiation of the effects of warfarin. Prothrornbin time Children younger than 12 years : Use KLACID Treatment of infections caused by pathogens sensitive to
should be frequently monitored in these patients. The effects of Paediatric Suspension. Clarithromycin. Indications include: Infections of nasopharyngeal
digoxin may be potentiated with concomitant administration tract (tonsillitis, pharyngitis), of paranasal sinuses and acute otitis
Eradication of H. pylori In patients with duodenal ulcer media. Infections of lower respiratory tract: bronchitis, bacterial
ol KLACID. Monitoring of serum digoxin levels should be
considered. Macroiides have been reported to alter the metabolism Adults: pneumonia and atypical pneumonia. Skin infections: impetigo,
of terfenadine. cisapride and pimozide resulting in increased DUAL THERAPY : The usual dose of Clarithromycin is 500mg erysipelas, folliculitis, furunculosis and septic wounds.
plasma levels of these drugs. This may result in QT prolongation three times dairy for 14 days. KLACID should be administered
CONTRAINDICATIONS :
and cardiac arrhythmias including ventricular tachycardia, with oral omeprazole 40mg once dally . The pivotal study was
ventricular brillation and torsade da pointes. Similar effects have conducted with omeprazole 40 mg once daily for 28 days. KLACID is contra-indicated in patients with known
been observed with concomitant administration of astemizole Supportive studies have been conducted with omeprazole 40mg hypersensitivity to macrolide antibiotic drugs and other
and other macrolides. KLACID may potentiate the effects once daily for 14 days. ingredients. It is also contraindicated in pregnant and lactating
of carbamazepine due to a reduction in the rate of excretion. women, and in patients with severe liver insufciency KLACID
Simultaneous oral administration of KLACID TABLETS and TRIPPLE THERAPY (7 - 14 days) : and ergot derivatives should not be co-administered. Concomitant
zidovudin 10 HIV-infected adults may result in decreased steady KLACID 500mg twice daily and lansoprazole 30mg twice daily administration of Clarithromycin and any of the following drugs
state zidovudine levels. This can be largely avoided by staggering should be given with amoxycillln 1000mg twice daily tor 7-14 is contraindicated: cisapride, pimozide and terfenadine (see
the doses of KLACID and zidovudine by 1-2 hours. No such days. precautions - drug interactions).
reaction has been reported in children. Ritonavir increases the TRIPPLE THERAPY (7 days): WARNING AND PRECAUTIONS :
area under curve (AUC), Cmax, and Cmin of clarithromycin
when administered concurrently. Because of the large therapeutic 1. KLACID 500mg twice dally and lansoprazole 30mg twice Clarithromycin is principally excreted by the liver and kidney.
window for clarithromycin, no dosage reduction should be daily should be given with metronidazole 400mg twice dally Caution should be exercised in administering this antibiotic
necessary in patients with normal renal function. However, for for 7 days. to patients with impaired hepatic or renal function. Attention
patients with renal impairment, the following dosage adjustment 2. KLACID 500mg twice daily and omeprazole 40mg daily should also be paid to the possibility of cross resistance between
should be considered: For patients with CLcr 30 to 60 ml / mln should be given with amoxycillin 1000mg twice daily or Clarithromycin and other macrolides, such as lincomycin and
the dose of clarithromycin should be reduced by 50%. For patients rnetronidazole 400mg twice daily for 7 days. clindamycin. Prolonged or repeated use of KLACID may
with CLcr < 30ml/min the dose of clarithromycin should be result in an overgrowth of non - susceptible bacteria or fungi. If
TRIPPLE THERAPY (10 days): super - infection occurs, KLACID should be discontinued and
decreased by 75%. Doses of clarithromycin greater than Ig/day
should not be co - administered with ritonavir. Although the KLACID 500mg twice daily should be given with amoxycillln appropriate therapy instituted.
plasma concentrations of clarithromycin and omeprazole may be 1000mg twice daily and omeprazole 20mg dally for 10 days.
INTERACTIONS:
increased when they are administered concurrently, no adjustment Elderly : As adults.
As with other macrolide antibiotics, the use of Clarithromycin in
to the dosage is necessary. At the dosages recommended, there is Renal Impairment: Dosage adjustments are not usually required patients concurrently taking drugs metabolised by the cytochrome
no clinically signicant Interaction between clarithromycin and except in patients with severe renal Impairment (creatinine P450 system (eg. warfarin, ergot alkaloids, triazolam, midazolam,
lansoprazole. Increased plasma concentrations of clarithromycin clearance < 30 ml/min). II adjustment is necessary, the total dally disopyramide, lovastatin, rifabutin, phenytoin, cyclosporin
may also occur when it is co-administered with Maalox or dosage should be reduced by half, e.g. 250 mg once daily or 250
Ranitidine. No adjustment lo the dosage is necessary and tacrolimus) may be associated with elevations in serum
mg twice daily In more severe infections. levels of these drugs. Rhabdomyolysis, co-incident with the co-
USE IN PREGNANCY AND LACTATLNG WOMEN: KLACID may be given without regard to meals, as food does administration of Clarithromycin and lovastatin or simvastatin
Tha safety of KLACID during pregnancy and breast feeding of not affect the extent of bioavailability. has been reported. The administration of KLACID to patients
infants has not been established. KLACID should thus not be HOW SUPPLIED : who are receiving theophylline has been associated with increased
used during pregnancy or lactation unless the benet is considered serum theophylline levels and potential theophylline toxicity. The
KLACID 500 mg tablets are available In blister packs
to outweigh the risk. Some animal studies have suggested an use of KLACID Paediatric Suspension in patients receiving
containing:
embryotoxlc effect but only at dose levels which are clearly toxic digoxin, warfarin and carbamazepine may result in potentiation
to mothers. Clarithromycin has been found in the milk of lactating 14 tablets & of their effects due to a reduction in the rate of excretion.
animals and in human breast milk. 20 tablets (N.R.) Prothrombin time should be frequently monitored in patients
Book_01.indd 7 6/4/2008 2:18:50 PM

ABBOTT
SPDI
receiving warfarin. Monitoring of serum digoxin levels should be KLACID XL is indicated for acute exacerbations of chronic
considered. Ritonavir increases the AUC (Area Under the Curve) KLACID XL Tablets bronchitis and acute maxillary sinusitis.
of Clarithromycin when administered concurrently. Because of the
CONTRAINDICATIONS
large therapeutic window for clarithromyicn, no dosage reduction
should be necessary in patients with normal renal unction. (Clarithromycin) Clarithromycin is contraindicated in patients with known
hypersensitivity to macrolide antibiotic drugs.
However, for patients with renal impairment, the following dosage
adjustments should be considered: For patients with CLfjR 30 to 60 DESCRIPTION Clarithromycin and ergot derivatives should not be co-administered.
ml/min the dose of Clarithromycin should be reduced by 50%. For A yellow, ovaloid tablet containing 500 mg clarithromycin in a As the dose cannot be reduced from 500 mg daily, KLACID XL
patients with CL^30 < ml/min the dose of Clarithromycin should modied-release preparation. is contraindicated in patients with creatinine clearance less than 30
be decreased by 75%. Doses of Clarithromycin greater than 1g/day ml/min. Concomitant administration of clarithromycin and any of
PHARMACOLOGICAL ACTION the following drugs is contraindicated: cisapride, pimozide and
should not be co - administered with ritonavir. Macrolides have
PHARMACODYNAMICS terfenadine (see precautions - drug interactions).
been reported to alter the metabolism of terfenadine, cisapride and
pimozide resulting in increased plasma levels of these drugs. This Clarithromycin is a semi-synthetic derivative of erythromycin A. WARNINGS AND PRECAUTIONS
may result in QT prolongation and cardiac arrhythmias including It exerts its anti-bacterial action by binding to the 50s ribosomal
Clarithromycin is principally excreted by the liver and kidney.
ventricular tachycardia, ventricular brillation and torsade de subunit of susceptible bacteria and suppresses protein synthesis.
Caution should be exercised in administering this antibiotic to
pointes. Similar effects have been observed with concomitant It is highly potent against a wide variety of aerobic and anaerobic
patients with impaired hepatic and renal function. Prolonged
administration of astemizole and other macrolides. Simultaneous Gram-positive and Gram-negative organisms. The minimum
or repeated use of clarithromycin may result in an overgrowth
inhibitory concentrations (MICs) of clarithromycin are generally
oral administration of KLACID Tablets and zidovudine to HIV- of non-susceptible bacteria or fungi. If superinfection occurs,
two-fold lower than the MICs of erythromycin. The 14-hydroxy-
infected adults may result in decreased steady-state zidovudine clarithromycin should be discontinued and appropriate therapy
metabolite of clarithromycin also has antimicrobial activity. The
levels. To date, this interaction does not appear to occur in instituted.
MICs of this metabolite are equal or two-fold higher than the
paediatric HIV infected patients taking KLACID Paediatric
MICs of the parent compound, except for H. inuenzae where INTERACTIONS
Suspension with zidovudine or dideoxyinosine. the 14-hydroxy-metabolite is two-fold more active than the parent Clarithromycin has been shown not to interact with oral
SIDE EFFECTS : compound. contraceptives. As with other macrolide antibiotics the use of
Clarithromycin s generally well tolerated. Side effects reported Clarithromycin is usually active against the following organisms clarithromycin in patients concurrently taking drugs metabolised
include nausea, dyspepsia, diarrhoea, vomiting, abdominal pain in vitro: by the cytochrome P450 system (e.g. warfarin, ergot alkaloids,
and paraesthesia. Stomatitis, glossitis, oral monilia and tongue Gram-positive Bacteria: Staphylococcus aureus (methicillin triazolam, midazolam, disopyramide, levastatin, phenytoin and
discolouration have been reported. Other side effects include susceptible); Strepto-coccus pyogenes (Group A beta-hemolytic cyclosporin) may be associated with elevations in serum levels
streptococci); alpha-hemolytic streptococci (viridans group); of these other drugs. Rhabdomyolysis, coincident with the co-
headache, arthralgia, myalgia and allergic reactions ranging from
Streptococcus (Diplococcus) pneumoniae; Streptococcus administration of clarithromycin and lovastain and simvastatin has
urticaria, mild skin eruptions and angioedema to anaphylaxis and
agalactiae; Listeria monocytogenes. been reported.
rarely Stevens-Johnson syndrome / toxic epidermal necrolysis.
Reports of alteration of the sense of smell, usually in conjunction Gram-negative Bacteria: Haemophilus inuenzae, Haemophilus The administration of clarithromycin to patients who are receiving
with taste perversion have also been received. There have parainuezae, Moraxella (Branhamella) catarrhalis, Neisseria theophylline has been associated with an increase in serum
gonorrhoeae, Legionella pneumophila, Bordetella pertussis, theophylline levels and potential theophylline toxicity. The use
been reports of tooth discolouration in patients treated with
Campylo-bacter jejuni. of clarithromycin in patients receiving warfarin may result in
Clarithromycin. Tooth discolouration is usually reversible with
potentiation of the effects of warfarin.
professional dental cleaning. There have been reports of transient Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.
central nervous system side effects including dizziness, vertigo, Prothrombin time should be frequently monitored in these patients.
Other Organisms: Chlamydia trachomatis, Mycobacterium
anxiety, insomnia, bad dreams, tinnitus, conusion, disorientation, The effects of digoxin may be potentiated with concomitant
avium; M. leprae; M. kansasii; M. chelonae; M. fortuitum; M.
administration of clarithromycin. Monitoring of serum digoxin
hallucination, psychosis and depersonalisation. There have been Intracellulare; Chlamydia pneumoniae.
levels should be considered. Macrolides including clarithromycin
reports of hearing loss with Clarithromycin, which is usually Anaerobes: Clostridium perfringens; Peptococcus species; have been reported to alter the metabolism of terfenadine, cisapride
reversible upon withdrawal of therapy. Pseudomembranous colitis Peptostreptococ-cus species; Propionibacterium acnes. and pimozide resulting in increased plasma levels of these drugs.
has been reported rarely with Clarithromycin, and may range in Clarithromycin also has bactericidal activity against several
severity from mild to life threatening. There have been rare reports This may result in QT prolongation and cardiac arrhythmias
bacterial strains. These organisms include H. inuenzae, including ventricular tachycardia, ventricular brillation, and
of hypoglycaemia, some of which have occurred in patients on Streptococcus pneumoniae, Streptococ-cus pyogenes; torsade de pointes. Similar effects have been observed with
concomitant oral hypoglycaemic agents or insulin. Isolated cases Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, concomitant administration of astemizole and other macrolides.
of leukopenia and thrombocytopenia have been reported. As with Neisseria gonorrhoeae, and Campylo-bacter spp. Clarithromycin may potentiate the effects of carbamazepine due
other macrolides, hepatic dysfunction (which is usually reversible)
PHARMACOKINETICS to a reduction in the rate of excretion. Interaction studies have
including altered liver function tests, hepatitis and cholestasis not been conducted with KLACID XL and zidovudine. If
with or without jaundice, has been reported. Dysfunction may The kinetics of orally administered modied-release
concomitant administration of clarithromycin and zidovudine is
be severe and very rarely fatal hepatic failure has been reported. clarithromycin have been studied in adult humans and compared
required, then an immediate release formulation of clarithromycin
Cases of increased serum creatinine. interstitial nephritis, with clarithromycin 250 mg and 500 mg immediate release tablets.
should be used. Ritonavir increases the area under the curve
renal failure, pancreatitis and convulsions have been reported The extent of absorption was found to be equivalent when equal
(AUC), Cmax and Cmin of clarithromycin when administrated
rarely. As with other macrolides, QT prolongation, ventricular total daily doses were administered. The absolute bioavailability
concurrently. Because of the large therapeutic window for
tachycardia and Torsade de Pointes have been rarely reported with is approximately 50%. Little or no unpredicted accummulation
clarithromycin, no dosage reduction should be necessary in
was found and the metabolic disposition did not change in any
Clarithromycin. patients with normal renal function. However, for patients with
species following multiple dosing. Based upon the nding of
renal impairment an immediate release form of clarithromycin
OVERDOSAGE: equivalent absorption the following in vitro and in vivo data are
should be used. Doses of clarithromycin greater than 1 g/day
In case high dosages of Clarithromycin have been ingested, G.I. applicable to the modied-release formulation.
should not be co-administrated with ritonavir.
disturbances can occur. A systemic reaction can also follow, to be In vitro: Results of in vitro studies showed that the protein
readily treated by means of gastiic lavage and supportive measures. binding of clarithromycin in human plasma averaged about 70% USE IN PREGNANCY AND LACTATION
Provided that Clarithromycin cannot be removed by haemodialysis at concentrations of 0.45 - 4.5 g/ml. A decrease in binding to The safety of clarithromycin during pregnancy and breast-feeding
or peritoneal dialysis, a rapid action is needed aimed to eliminate 41% at 45.0 g/ml suggested that the binding sites might become of infants has not been established. Clarithromycin should thus
the amount of drug not yet absorbed, applying at the same time a saturated, but this only occurred at concentrations far in excess of not be used during pregnancy or lactation unless the benet
suitable symptomatic therapy. therapeutic drug levels. is considered to outweigh the risk. Some animal studies have
In vivo: Clarithromycin levels in all tissues, except the central suggested an embryotoxic effect, but only at dose levels which are
DOSAGE AND ADMINISTRATION : nervous system, were several times higher than the circulating clearly toxic to mothers.
For Infants, 6 months and above the recommended daily dosage drug levels. The highest concentrations were found in the liver Clarithromycin has been found in the milk of lactating animals and
of Clarithromycin Pediatric Suspension is 15 mg/kg/day in two and lung tissue, where the tissue to plasma ratios reached 10 to in human breast milk.
divided doses. The dose can be increased according to the severity 20.
SIDE EFFECTS
of illness and physicians opinion. The pharmacokinetic behaviour of clarithromycin is non-linear. In
fed patients given 500 mg clarithromycin modied-release daily, Clarithromycin is generally well tolerated. Side effects reported
Child Weight (kg) Twice daily include nausea, dyspepsia, diarrhea, vomiting and abdominal pain
the peak steady state plasma concentration of clarithromycin and
5-10 1/2 spoon 14-hydroxy clarithromycin were 1.3 and 0.48 mg/ml respectively. and paraesthesia. Stomatitis, glossitis, oral monilia and tongue
11 -20 1 spoon When the dosage was increased to 1000 mg daily, these steady-state discolouration have been reported. Other side effects include
21 -30 1 1/2 spoon values were 2.4 mg/ml and 0.67 mg/ml respectively. Elimination headache, arhralgia, myalgia and allergic reactions ranging from
half-lives of the parent drug and its metabolite were approximately urticaria, mild skin eruptions and angioedema to anaphylaxis and
In patients with renal impairment with creatinine clearance less 5.3 and 7.7 hours respectively. rarely Stevens-Johnson syndrome / toxic epidemal necrolysis.
than 30 ml/min, the dosage should be reduced by one-half. Dosage Reports of alteration of the sense of smell, usually in conjunction
The apparent half-lives of both clarithromycin and its 14-hydroxy with taste prevention have also been received. There have
should not be continued beyond 14 days in these patients. metabolite tended to be longer at higher doses. Urinary excretion been reports of tooth discolouration in patients treated with
SUSPENSION PREPARATION : accounted for approximately 40% of the clarithromycin dose. clarithromycin. Tooth eiscolouration is usually reversible with
Fecal elimination accounts for approximately 30%. professional dental cleaning. There have been reports of transient
To prepare KLACID suspension, add water to the granules
contained in the bottle until the line impressed on it. Shake well. INDICATIONS central nervous system side-effects including dizziness, vertigo,
Add again water until the line. Such a prepared suspension has KLACID XL is indicated for treatment of infections caused by anxiety, insomnia, bad dreams, tinnitus, confusion, disorientation,
a 2.5% concentration, and can be stored at room temperature for susceptible organisms. Indications include: hallucination, psychosis and depersonalisation. There have been
reports of hearing loss with clarithromycin, which is usually
14 days. Lower respiratory tract infections for example, acute and chronic reversible upon withdrawal of therapy. Pseudomembranouscolitis
bronchitis and pneumonia. have been reported rarely with clarithromycin, and may range in
HOW SUPPLIED :
Upper respiratory tract infections for example, sinusitis and severity from mild to life threatening. There have been rare reports
60 ml bottle with dispenser.
pharyngitis. of hypoglycaemia, some of which have occurred in patients on
100 ml bottle with dispenser (N.R.).
KLACID XL is also indicated in skin and soft tissue infections concomitant oral hypoglycaemic agents or insulin. Isolated cases
KEEP ALL MEDICAMENTS OUT OF REACH OF of mild to moderate severity, for example folliculitis, cellulitis and of leukopenia and thrombocytopenia have been reported. As with
CHILDREN erysipelas. other macrolides, hepatic dysfunction (which is usually reversible)
Book_01.indd 8 6/4/2008 2:18:50 PM

ADVANCE PHARMACEUTICAL INDUSTRIES CO. LTD.
SPDI
including altered liver function tests, hepatitis and cholestasis in the liver. The simultaneous use of several drugs each of which or u symptoms before a doctor is consulted about Reyes
with or without jaundice, have been reported. Dysfunction may increases levels of serotonin in the blood may give rise to serious Syndrome.
be severe and very rarely fatal hepatic failure has been reported. interactions. This phenomenon is called serotonin syndrome. - If ringing in the ear, or loss of hearing occurs, consult a doctor
Causes of increased serum creatinnie, interstitial nephritis, Acting as a SNRI, REDUCTIL should not be used by patients before taking any more of the product.
renal failure, pancreatitis and convulsions have been reported taking other drugs, which also raise serotonin levels. REDUCTIL - Acetylsalicylic acid is classied as pregnancy category C
rarely. As with other macrolides, QT prolongation, ventricular does not impair the effectiveness of oral contraceptives. during the rst and second trimesters and should be used
tachycardia and Torsade de Pointes have been rarely reported with cautiously, however low-dose Acetylsalicylic acid may help
DOSAGE AND ADMINISTRATION
clarithromycin. prevent toxemia of pregnancy and may be benecial in pregnant
The starting dose is one REDUCTIL 10mg capsule once
OVERDOSAGE daily in the morning. Patients who respond unsatisfactorily to women with inadequate uteroplacental blood ow.
Reports indicate that the ingestion of large amounts of REDUCTIL 10mg (i.e. less than 2 kg weight loss in 4 weeks) - Children below 12 years of age should not use ADIPRIN.
clarithromycin can be expected to produce gastrointestinal may be switched to one capsule of REDUCTIL 15mg once - ADIPRIN should not be used in case of glucose-6-phosphate
symptoms. One patient who had a history of bipolar disorder daily. Treatment with REDUCTIL should not exceed one year. dehydrogenase enzyme deciency.
ingested 8 grams of clarithromycin and showed altered mental - Breast-feeding mothers should not use ADIPRIN.
PACKAGING
status, paranoid behaviour, hypokalemia and hypoxemia. Adverse - ADIPRIN may increase the risk of chronic kidney problems.
Cap : 10mg x 28s (Blister)
reactions accompanying overdosage should be treated by gastric
Cap: 15 mg x 28s (Blister). DRUG INTERACTIONS:
lavage and supportive measures. As with other macrolides,
clarithromycin serum levels are not expected to be appreciably - Concurrent use of Acetylsalicylic acid with NSAIDs or
affected by hemodialysis or peritoneal dialysis. SURVANTA Intratracheal Suspension anticoagulants may increase the risk of bleeding.
- Antacids and H2-receptor blockers may cause premature
DOSAGE AND ADMINISTRATION dissolution and loss of protective effects of enteric coated
Adults: The usual recommended dosage of KLACID XL in (Phospholipids) Acetylsalicylic acid
adults is one 500 mg modied-release tablet daily to be taken with - Co-administration of Acetylsalicylic acid with insulin or oral
food. In more severe infections, the dosage can be increased to antidiabetic agents may lead to the potentiation of these agents.
COMPOSITION
two 500 mg modied-release tablets daily. The usual duration of - ADIPRIN may increase Methotrexate and valproic acid,
treatment is 7 to 14 days. Each ml of SURVANTA Intratracheal suspension contains 25
mg of phospholipids in 8 ml and 4 ml (N.R.) single-use vials. serum level.
Children older than 12 years: As for adults.
INDICATIONS ADVERSE EFFECT:
Children younger than 12 years: Use KLACID Pediatric
Prevention and treatment of respiratory distress syndrome (RDS) - Enteric coated Acetylsalicylic acid exhibits fewer gastrointestinal
Suspension.
in premature infants. adverse effects than uncoated Acetylsalicylic acid .
Renal Impairment: KLACID XL should not be used in
- Acetylsalicylic acid may cause blood disorders especially in
patients with renal impairment (creatinine clearance < 30 ml/min). CONTRAINDICATIONS high doses.
KLACID immediate-release tablets may be used in this patient None Known. - Acetylsalicylic acid may provoke various reactions in patients
population. (See contraindications).
SIDE EFFECTS/PRECAUTIONS with asthma, chronic rhinitis, or chronic urticaria.
HOW SUPPLIED - Acetylsalicylic acid may cause hepatotoxicity, particularly in
Transient bradycardia, oxygen desaturation.
KLACID XL Tablets are available in blister packs containing patients with connective tissue disorders.
The use of SURVANTA should be restricted to highly supervised
7 tablets and 14 tablets.
clinical setting. DOSAGE AND ADMINISTRATION:
- For anti-thrombotic effect: ADIPRIN is given as one tablet
REDUCTIL 10 mg Capsule DOSAGE AND ADMINISTRATION
once daily.
The dose is generally 100 mg phospholipid /kg birth weight. In
- For analgesic, antipyretic and anti-inammatory effect:
premature infants weighing 1250 g, or in those with evidence
ADIPRIN is given as one to three tablets 3 to 4 times daily.
(Sibutramine hydrochloride monohydrate) of surfactant deciency give SURVANTA within 15 minutes of
birth. In RDS conrmed by X-ray, give SURVANTA as soon as PRESENTATIONS AVAILABLE:
possible (by 8 hours of age). ADIPRIN is available as 100mg enteric coated tablet in 30 and
COMPOSITION
REDUCTIL 10 mg: 1 capsule contains: 10mg of sibutramine PACKAGING 100 tablets pack.
hydrochloride monohydrate (active substance). Vial : 25 mg/ml x 8 ml. (single-use vials).
REDUCTIL 15 mg: 1 capsule contains: 15mg of sibutramine CANDIVAST Capsule
hydrochloride.
ADVANCED PHARMACEUTICAL
INDICATIONS (Fluconazole)
REDUCTIL is for supportive treatment within a weight INDUSTRIES CO. LTD.
management programme of patients with alimentary obesity and a P.O. BOX 215, RIYADH 11411 COMPOSITION:
BMI of 30kg/m2 or above and of patients with alimentary excess SAUDI ARABIA CANDIVAST 150mg: Each capsule contains 150mg
weight and a BMI of 27 kg/m2 or above who have obesity-related TEL: 2150428, FAX: 2151005 Fluconazole.
risk factors like type II diabetes or dyslipidaemia.
CANDIVAST 50mg: Each capsule contains 50mg Fluconazole.
CONTRAINDICATIONS ADIPRIN-EC Tablets EXCIPIENTS:
Known hypersensitivity to sibutramine, obesity caused by organic
dysfunction, eating disorders such as anorexia nervosa and others,
OTC Colloidal silicon dioxide, FD & C blue 1, gelatin, lactose
(Acetylsalicylic Acid) monohydrate, magnesium stearate, sodium starch glycolate.
concomitant use of MAOIs or other CNS active drugs or other
centrally acting weight reducing agents, history of CAD, CHF, PROPERTIES:
arrhythmia, occlusive artery disease or cerebrovascular disease, COMPOSITION:
Fluconazole is a systemic antifungal agent belonging to the triazole
inadequately controlled high blood pressure, hyperthyroidism, ADIPRIN 100mg: Each enteric coated tablet contains 100mg class. It inhibits the conversion of 14 - methyl sterol to
severely impaired liver or kidney function, benign prostatic Acetylsalicylic acid.
ergosterol, leading to alteration in fungal membrane functions and
hyperplasia, phaeochromocytoma, narrow angle glaucoma, misuse
PROPERTIES: leakage of essential elements. Fluconazole is active against
of drugs, medicine or alcohol, pregnancy and breast-feeding,
persons under 18 and above 65 years. Acetylsalicylic acid, a prototype of salicylates, is a non-steroidal, a wide range of fungi including Candida spp. Cryptococcus
anti-inammatory agent, used for pain, fever, inammation, neoformans, Trychophyton, Microsporum and others.
SIDE EFFECTS prevention of myocardial infarction and stroke.
INDICATIONS:
In > 10% loss of appetite, constipation, dry mouth, insomnia. The use of enteric coated tablets reduces the potential for
In 1- 10% tachycardia, palpitations, raised blood pressure/ CANDIVAST is used to treat:
gastrointestinal SIDE EFFECTS, especially in long term
hypertension, vasodilation (ush), nausea, haemorrhoids, antiplatelet therapy. Vaginal candidiasis, mucosal candidiasis, cryptococcal infections,
dizziness, paraesthesias, headache, anxiety, sweating and taste systemic candidiasis, as a maintenance therapy to prevent
disturbance. PHARMACOKINETICS: relapse of cryptococcal disease in AIDS patients.
Cardiovascular changes: A mean increase in resting blood pressure The absorption of orally administered enteric coated Acetylsalicylic
acid is generally delayed but almost complete. DOSAGE AND ADMINISTRATION:
of between 1 and 3 mmHg and a mean increase in pulse rate of 3 to
7 beats per minute have been observed. After absorption, Acetylsalicylic acid is rapidly converted to Adults:
salicylate. The elimination half-life of Acetylsalicylic acid in 1 - Vaginal candidiasis: 150mg single oral dose.
WARNINGS AND PRECAUTIONS plasma is approximately 15-20 minutes. 2 - Mucosal candidiasis :
REDUCTIL should be used with caution in patients prone to Almost all of the ingested dose is excreted in the urine as free Oropharyngeal: 50mg once daily for 7-14 days. Treatment
epileptic ts or seizures and in patients with mild-to- moderate salicylic acid and conjugated metabolites. can be extended in severe cases.
impairment of liver or kidney function. Women of childbearing Atrophic oral candidiasis: 50mg once daily for 14 days,
potential should use a suitable form of contraception while taking INDICATIONS: concomitantly administered with local antiseptic to the
REDUCTIL. Blood pressure and pulse rate must be closely ADIPRIN is indicated for prevention of myocardial infarction denture.
monitored in all patients on REDUCTIL. Treatment is to be and stroke. Others: 50mg once daily for 14-30 days.
stopped in patients with blood pressure above the 145/90 mm Hg
CONTRAINDICATIONS: 3 - Cryptococcal infections: Initial dose 400 mg on day one
threshold in two consecutive readings. Caution is required when
ADIPRIN is contraindicated in the following cases: followed by 200 mg once daily. Duration of treatment
REDUCTIL is taken along with medications which prolong the
- Hypersensitivity to Acetylsalicylic acid. depends on the clinical and mycological response but
QTc-interval and in patients with conditions liable to prolong the
usually not less than 6-8 weeks in cryptococcal meningitis.
QT interval, such as hypokalaemia and hypomagnesaemia. - Ulcer disease.
4 - Systemic candidiasis: Initial dose 400 mg on day one,
- Blood clotting disorders.
INTERACTIONS followed by 200 mg once daily.
Caution should be exercised on concomitant administration of PRECAUTIONS / WARNINGS: Dosage can be increased to 400 mg daily and duration of
REDUCTIL with certain medicines that are also metabolized - Children should not use Acetylsalicylic acid for chicken pox treatment depends on the clinical response.
Book_01.indd 9 6/4/2008 2:18:51 PM

SPDI
5- Prevention of relapse in cryptococcal meningitis: A dose of necessary, the daily dosage may be increased to a maximum of Gastrointestinal Risk: - NSAIDs cause an increased risk of
at least 100 mg daily should be given indenitely. 10mg once daily. Small, fragile, or elderly individuals or patients serious gastrointestinal adverse events including bleedingn
Renal Impairment: In patient with renal impairment the with hepatic insufciency may be started on 2.5mg once daily and ulceration, and perforation of the stomach or intestines, which can
dosage schedule should be adjusted according to the the dose may be used when adding amlodipine besylate to other be fatal.
following table : anti hypertensive therapy. Lowvasc can be taken with, before or - These events can occur at any time during use and without
after meals. warning symptoms.
Creatinine Clearance (ml / min) Dosage interval / daily dose
>40 24 hours (normal regimen). CONTRAINDICATIONS: - Elderly patients are at greater risk for serious gastrointestinal
LOWVASC is contraindicated in patients with hypersensitivity events (FDA, 2005)
21-40 48 hours or half normal daily
dose. to Amlodipine. DURG INTERACTIONS:
10-20 72 hours or one third normal PRECAUTIONS: No interactions were seen with meloxicam when administered
daily dose * As with any other vasodilator, caution should be exercised concomitantly with food and drugs such as cimetidine, antacids,
Patients receiving regular One recommended dose after when administering Amlodipine to patients with severe Aortic methotrexate, furosemide, digoxin, warfarin and aspirin.
Haemodialysis each dialysis Stenosis. However, caution should be exercised when meloxicam is given
concomitantly with oral hypoglycemic agents, anticoagulants,
Children: Dosage has not been established for children under the * In general, all calcium channel blockers should be used with
antiplatelets antihypertensives, diuretics, and lithium.
age of 16, however imperative, a dose of 3-6 mg /Kg /day can be caution in patients with heart failure, although Amlodipine
used in systemic candidiasis improved the symptoms of heart failure in patients with NYHA SIDE EFFECTS:
class II and III. The most common reported side effects were nausea, abdominal
CONTRAINDICATIONS:
* No dosage adjustment is required in patients with renal pain, dyspepsia, diarrhea, skin rash and pruritis.Other side effect
Fluconazole is contraindicated in patients with known insufciency. such as hematemesis, duodenal or gastric ulcer, uid retention,
hypersensitivity to triazole compounds. anemia and elevated liver enzymes have also been reported.
* There are no adequate and well controlled studies in pregnant
Use in pregnancy is contraindicated. women, therefore Amlodipine should be used only if clearly
DOSAGE AND ADMINISTRATION:
WARNINGS: needed.
* Rheumatoid arthritis: Meloxicam is given 15mg orally once
In some patients particularly those with serious underlying * It is recommended to discontinue nursing while Amlodipine is daily; which can be reduced to 7.5mg if not tolerated.
disease such as AIDS and cancer, abnormalities of hepatic, administered.
* Osteoarthritis: Meloxicam can be given 7.5-15mg once daily.
renal, hematological function tests have been observed during DURG INTERACTIONS: * Dosage for children and adolescents has not been established.
the treatment with Fluconazole, but the clinical signicance and
Azole antifungals may inhibit the metabolism of amlodipine, PRESENTATION AVAILABLE:
relationship to treatment is uncertain.
cyclosporine levels may increase by amlodipine, rifampicin may
Patients with AIDS are more prone to the development of severe MOVEN is available as 7.5mg capsule in 10 and 30 capsules
decrease its effects. pack.
cutaneous reactions to many drugs. A small number of AIDS
patients have developed such reactions usually while Fluconazole SIDE EFFECTS: MOVEN is available as 15mg capsule in 10 and 30 capsules
concomitantly used with other agents known to be associated with The most commonly encountered side effects were peripheral pack.
severe exfoliation. If rash develops which is considered attributable edema, headache, ushing, and hypotension.
to Fluconazole-therapy with this agent should be discontinued. Other side effects may include male sexual dysfunction, nausea, NOMAL Capsule
dyspepsia, muscle cramps and pulmonary edema. C-II
PRECAUTIONS:
The concurrent use of Fluconazole with sulfonylurea hypoglycemic OVERDOSAGE: (Tramadol Hydrochloride)
agents, may increase the plasma concentrations of such agents, Supportive and symptomatic treatment including IV uids and
hypoglycemia has been noted and the dose of oral hypoglycemic Trenedelenberg positioning should be initiated as intoxication COMPOSITION:
may need to be reduced. maycause hypotension. Heartblock may respond to isoproterenol, NOMAL 50mg capsules: Each capsule contains 50mg Tramadol
Fluconazole does not affect the endogenous steroid levels. atropine, or calcium although a temporary pace maker may be Hydrochloride.
required.
SIDE EFFECTS: PROPERTIES:
Fluconazole is generally well tolerated, and most reported SIDE PRESENTATIONS AVAILABLE:
Tramadol, a centrally acting analgesic is structurally related to
EFFECTS are associated with symptoms such as gastrointestinal LOWVASC is available as 2.5mg tablet in 28 tablets pack. codeine. Its analgesic effects are mediated via both the stimulation
disturbances, nausea, diarrhea and atulence. (N.R) of -opioid receptors and indirect modulation of central
LOWVASC is available as 5mg tablet in 28 tablets pack.(N.R) monoaminergic inhibitory pain pathways.
DURG INTERACTIONS:
LOWVASC is available as 5mg capusle in 14 (N.R)and 28 Following oral administration absorption is rapidly achieved within
Concomitant use of rifampicin with Fluconazole results in reduced capsules pack. 15-45 minutes and peak plasma concentrations are attained within
Fluconazole serum levels. 2 hours. The duration of analgesia is 3-6 hours and maximum pain
OVER DOSAGE: MOVEN Capsule relief was reported at 1-4 hours. Oral bioavailability after a single
dose is 68% and increased 90-100% with multiple dosing.
Supportive measures and symptomatic treatment with gastric
lavage (if necessary) may be adequate. Tramadol has a high tissue afnity with low plasma protein binding
Haemodialysis decreases plasma levels by 50%.
(Meloxicam) of 20%. Elimination half life is 5-6 hours. Tramadol is 85%
metabolized in the liver as N- and O- demethylated compounds.
PRESENTATIONS AVAILABLE: COMPOSITION: 90% is excreted by the kidney, and 10% inthe faeces. Tramadol
CANDIVAST is available as 150mg capsules in one capsule MOVEN 7.5mg capsules: Each capsule contains 7.5mg passes through placenta and its concentration in the umbilical
pack. meloxicam. veins reaches to about 80% of that in the mother's veins. About
0.1% of Tramadol is excreted in breast milk.
CANDIVAST is available as 50mg capsules in 7 capsules pack. MOVEN 15mg capsules: Each capsule contains 15mg
meloxicam. INDICATIONS:
LOWVASC PROPERTIES: NOMAL is indicated for the relief of moderate to moderately
severe pain.
Meloxicam is an enolic class nonsteroidal anti-inammatory drug
which has a greater inhibitory action against the inducible isoform CONTRAINDICATIONS:
(Amlodipine Besylate) of cyclo-oxygenase (COX-2), which is implicated in inammatory - Hypersensitivity to Tramadol or opioids.
response, than against the constitutive form of this enzyme (COX- - Patients who suffer cases of acute intoxication with alcohol,
COMPOSITION: 1), inhibition of which is associated with gastric and renal side hypnotics, centerally acting analgesics, opioids or psychotropic
LOWVASC 2.5mg: Each tablet contains Amlodipine 2.5mg as effects. drugs.
(Amlodipine Besylate).(N.R)
INDICATIONS: - Patients receiving MAO inhibitors.
LOWVASC 5mg(N.R): Each tablet contains Amlodipine 5mg as
Meloxicam is indicated for the acute and chronic symptomatic - Patients with less than 10 ml/min creatinine clearance.
(Amlodipine Besylate).(N.R)
treatment of osteoarthritis and rheumatoid arthritis. WARNINGS:
LOWVASC 5mg: Each capsule contains Amlodipine 5mg as
- Seizure risk: Seizures have been reported in patients receiving
(Amlodipine Besylate). CONTRAINDICATIONS:
Tramadol within the recommended dosage range.
PROPERTIES: Meloxicam is contraindicated in the following cases:
- Risk of convulsions may also increase in patients with a
- Known hypersensitivity to meloxicam, aspirin or NSAIDs. recognized risk seizure.
Amlodipine is a dihydropyridine, a long acting calcium channel
blocker, that inhibits selectively calcium inux across cell - Active gastrointestinal bleeding. - Serious and rarely fatal anaphylactic reactions have been
membranes in cardiac and vascular smooth muscles with a greater - Pregnant and breast-feeding women. reported in patients receiving therapy with Tramadol.
effect on vascular smooth muscles. Following oral administration, - Severe hepatic or renal dysfunction. These reactions often occur with the rst dose. Patients with a
it is well absorbed with peak plasma levels achieved within 6- WARNINGS / PRECAUTIONS: history of anaphylactic reactions to codeine and other opioids
12 hrs. Elimination from the plasma is biphasic with a terminal may be at increased risk and therefore should not receive
Use with caution in patients with history of gastrointestinal
elimination half-life of about 30-50 hrs. The steady state plasma Tramadol.
bleeding, impaired cardiac function, hypertension, volume
levels are reached after 5-7 days of consecutive administration. - Patients with a tendency to opioid abuse or opioid dependence,
depleted patients, mild to moderate renal impairment, and in
treatment with Tramadol is not recommended.
INDICATIONS: patients receiving anticoagulants antiplatelets.
- Tramadol should be used with caution and in reduced dosages
* LOWVASC is indicated as rst-line treatment of the following Cardiovascular Risk: - NSAIDs may cause an increased risk of
when administered to patients receiving CNS depressants
conditions: Hypertension Chronic stable anginaVasospastic serious cardiovascular thrombotic events, myocardial infarction,
including, alcohol.
angina (Prinzmetals or Variant angina). and stroke, which can be fatal. This risk may increase with
* LOWVASC can be used alone or, if necessary, in combination duration of use. Patients with cardiovascular disease or risk factors PRECAUTIONS:
with other agents. for cardiovascular disease may be at greater risk (FDA, 2005). - Tramadol should be administered cautiously in patients at risk
- Diclofenac is contraindicated for the treatment of peri for respiratory depression.
DOSAGE AND ADMINISTRATION: operative pain in the setting of coronary artery bypass graft - Tramadol should be used with caution in patients with increased
The recommended dose of LOWVASC is 5mg once daily. If (CABG) surgery (FDA, 2005). intracranial pressure or head injury.
10
Book_01.indd 10 6/4/2008 2:18:52 PM

SPDI
- The administration of Tramadol may complicate the clinical WARNINGS / PRECAUTIONS: - Ribavirin capsules are contraindicated in patients with a
assessment of patients with acute obdominal conditions. - Neutropenia and / or thrombocytopenia:Complete blood count history of hypersensitivity to ribavirin or any component of the
- In patients with creatinine clearance of less than 30ml/min, with white cell differential test should be performed before capsule.
or with advanced cirrhosis of the liver, dosing reduction is treatment and then every two weeks for the rst three months - Patients with autoimmune hepatitis must not be treated with
recommended. of therapy and should be monitored for another two weeks if combination (ribavirin/ Interferon alfa, recombinant) therapy
- Tramadol is not recommended for patients who are dependent therapy was discontinued within the initial three months. because using these medicines can make the hepatitis worse.
on opioids. In case of severe neutropenia (< 1200 neutrophils / mm3) or - Patients with hemoglobinopathies (e.g. thalassemia major,
- Withdrawal symptoms may occur, if Tramadol is discontinued thrombocytopenia (< 80,000 platelet / mm3) the drug therapy sickle cell anemia) should not be treated with ribavirin.
abruptly. should be discontinued. WARNINGS:
- Tramadol is not recommended during pregnancy and breast - Prolonged bleeding time: patients should be monitored for signs
feeding. Based on results of clinical trials ribavirin monotherapy is not
and symptoms of bleeding. Ticlopidine should be used with effective for the treatment of chronic hepatitis C virus infection;
DRUG INTERACTIONS: caution in patients who may be at risk for increased bleeding therefore, ribavirin must not be used alone. The safety and efcacy
- Concomitant administration of Tramadol with carbamazepine from trauma, surgery, or other pathological conditions. For of ribavirin have only been established when used together
causes a signicant increase in Tramadol metabolism. patients who are undergoing elective surgical dental procedures. with interferon alfa, recombinant) or with peg-interferon alfa,
- Coadministration of Tramadol with quinidine or inhibitors of it is recommended to discontinue Ticlopidine therapy 10 to 14 recombinant. There are signicant adverse events caused by
cytochrome P450 2D6 could result in some inhibition of days prior to procedure. ribavirin/interferon alfa, recombinant) or with ribavirin/peg-
the metabolisn of Tramadol, and thereby increases Tramadol - Severe renal function impairment:Caution and close monitoring interferon alfa, recombinant therapy, including severe depression
serum concentration. are recommended, and reduction of dosage may be required. suicidal ideation, hemolytic anemia, suppression of bone marrow
- Post - marketing surveillance has revealed rare reports of - Pregnancy:Adequate and well controlled studies have not been function, autoimmune and infectious disorders, pulmonary
digoxin toxicity and alteration of warfarin effect, including performed in pregnant women. FDA pregnancy category B. dysfunction, pancreatitis and diabetes.
elevation of prothrombin times. Pregnancy:
DURG INTERACTIONS:
- Interactions with MAO inhibitors, due to interference with Ribavirin capsules may cause birth defects and/or death of
Concurrent use of Ticlopidine with anticoagulants, platelet
detoxication mechanisms. exposed fetus. Ribavirin is contraindicated for use in women who
aggregation inhibitors, thrombolytics. and NSAIDs increases the
- CNS depressants, including alcohol may augment the central are pregnant or in men whose female partners are pregnant.
risk of bleeding. Ticlopidine increases plasma levels of phenytoin
effects of Tramadol. Ribavirin has demonstrated signicant teratogenic effect and/or
and theophylline when used concomitantly.
embryocidal effects in all animal species in which adequate studies
SIDE EFFECTS:
SIDE EFFECTS: have been conducted. Pregnancy testing should be performed
Very rarely orthostatic dysregulation, tachycardia and skin monthly during ribavirin therapy and for six months after therapy
The most common reported side effects were skin rash and
reactions. has stopped.
gastrointestinal disturbances (nausea, vomiting, diarrhea, and
The most common CNS effects include dizziness, vomiting, dyspepsia).Neutropenia and thrombocytopenic thrombotic purpura Anemia:
nausea, sedation, headache, dry mouth and sweating.
can occur less frequently. It rarely causes thrombocytopenia, The primary toxicity of ribavirin is hemolytic anemia, which
DOSAGE AND ADMINISTRATION: hepatitis, and cholestatic jaundice. was observed in approximately 10% of ribavirin/interferon alfa,
NOMAL should be titrated according to the pain intensity and Increased serum cholesterol and triglyceride concentration. recombinant-treated patients in clinical trials. Fatal and non-
the response of the individual patients. Hypersensitivity reactions including angioedema. fatal myocardial infarctions have been reported in patients with
NOMAL capsules: 50-100mg can be given 4 times daily with anemia caused by ribavirin. Patients should be assessed for
or without food. DOSAGE AND ADMINISTRATION: underlying cardiac disease before initiation of ribavirin. Patients
PREVOC 250mg is given orally twice daily with food. with pre-existing cardiac disease should have electrocardiograms
Total daily dose should not exceed 400mg. administered before therapy and should be appropriately monitored
Driving or operating machinery should be avoided until the effect PRESENTATION AVAILABLE: during therapy. If there is any deterioration of cardiovascular
of drug wears off. PREVOC is available as 250mg lm coated tablet in 20 tablets status, therapy should be suspended or discontinued. (See dosage
PRESENTATION AVAILABLE: packs. and administration: Guidelines for dose modication).
NOMAL is available as 50mg capsule in 10 capsules pack. Because cardiac disease may be worsened by drug induced
RIBAVIN Capsule anemia, patients with a history of signicant or unstable cardiac
disease should not use ribavirin.
PREVOC Tablet Ribavirin and interferon alfa, recombinant or peg-interferon
(Ribavirin) alfa, recombinant should be suspended in patients with signs
(Ticlopidine Hydrochloride) and symptoms of pancreatitis and discontinued in patients with
DESCRIPTION: conrmed pancreatitis.
COMPOSITION: Is a nucleoside analog. The chemical name of RIBAVIN is 1-- Ribavirin should not be used in patients with creatinine clearance
PREVOC 250mg : Each lm coated tablet contains 250mg D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide. <50ml/min.
Ticlopidine Hydrochloride. PRECAUTIONS:
COMPOSITION:
PROPERTIES: The safety and efcacy of ribavirin/interferon alfa, recombinant
RIBAVIN: Each capsule contains 200mg ribavirin.
Ticlopidine, a thienopyridine derivative, is a platelet-aggregation and ribavirin/peg-interferon alfa, recombinant therapy for the
inhibitor. It inhibits adenosine diphosphate (ADP)-induced CLINICAL PHARMACOLOGY: treatment of HIV infection, adenovirus, RSV, parainuenza, or
PHARMACOKINETICS: inuenza infections have not been established.
binding of brinogen to the platelet membrane at the glycoprotein
llb-llla complex site. Ticlopidine inhibits platelet aggregation in Ribavirin was rapidly and extensively absorbed following oral The safety and efcacy of ribavirin/interferon alfa, recombinant
administration. However, due to rst-pass metabolism, the absolute therapy has not been established in liver or other organ transplant
a dose dependent manner and prolongs bleeding time. Inhibition of
bioavailability averaged 64%. There was a linear relationship patients, patients with decompensated liver disease due to hepatitis
platelet aggregation is detectable within 2 days of repeated
between dose and AUC tf (AUC from time zero to last measurable C infection, patients who are nonresponders to interferon therapy,
doses of 250mg given twice daily. Ticlopidine-induced inhibition or patients coinfected with HBV or HIV.
of platelet aggregation persists for the life of the platelet. concentration) following single doses of 200-1200mg ribavirin.
The relationship between dose and Cmax was curvilinear. Upon ADVERSE REACTIONS:
PHARMACOKINETICS:
multiple oral dosing, based on AUC 12hr, a six fold accumulation The primary toxicity of ribavirin is hemolytic anemia, reductions
Ticlopidine HCI is rapidly and almost completely absorbed
of ribavirin was observed in plasma. Following oral dosing with in hemoglobin levels occurred within the rst 1-2 weeks of oral
from the gastrointestinal tract. It is extensively bound to plasma
600mg BID, steady state was reached by approximately 4 weeks. therapy. (See warnings). Cardiac and pulmonary events associated
proteins.
Upon discontinuation of dosing, the mean half-life was 298 with anemia occurred approximately 10% of patients (See
The terminal elimination half-life reaches 4-5 days with chronic hours, which probably reects slow elimination from non-plasma warnings).
dosing. Ticlopidine is extensively metabolized in the liver. compartment. OVERDOSAGE:
Approximately 60% of the administered dose is excreted in the Effect of antacid on ribavirin absorption:
urine and 23% in the feces. In ribavirin/interferon alfa, recombinant tharapy, the maximum
Coadministration with an antacid containing Magnesium, overdose reported was a dose of 39 million units of interferon alfa
INDICATIONS: aluminum and simethicone resulted in a 14% decrease in mean (13 subcutaneous injections of 3 million IU each) taken with 10gm
- PREVOC is indicated to reduce the risk of fatal or nonfatal ribavirin AUC tf . The clinical relevance of these results is of ribavirin (fty 200mg capsules). The patient was observed for 2
thrombotic stroke in patients who have had either a previous unknown. days in the emergency room during which time no adverse events
completed thrombotic stroke or stroke precursors such as from the overdose was noted.
transient ischemic attack, transient monocular blindness, INDICATIONS:
reversible ischemic neurological decit (RIND), or minor - Ribavirin capsules are indicated in combination with DOSAGE AND ADMINISTRATION:
stroke. (Interferon alfa, recombinant) injection for the treatment of RIBAVIN/interferon alfa, recombinant therapy:
- PREVOC is used to prevent major ischemic events, mainly chronic hepatitis C in patients with compensated liver disease The recommended dose of RIBAVIN depends on the patient's
coronary, in patients with peripheral arterial disease with previously untreated with alpha interferon or who have relapsed body weight. The recommended dose of RIBAVIN is provided
symptoms of intermittent claudication. following alpha interferon therapy. in the following table:
- PREVOC is used to prevent platelet loss during extracorporeal - Ribavirin capsules are indicated in combination with (peg- Recommended dose
circulatory procedures. interferon alfa, recombinant) injection for the treatment of Body weight RIBAVIN
chronic hepatitis C in patients with compensated liver disease
CONTRAINDICATIONS: < 75 kg 2 x 200 mg Capsules AM,
who have not been previously treated with interferon alpha and
- Hypersensitivity to Ticlopidine. 3 x 200 mg Capsules PM daily p.o.
are at least 18 years of age.
- Presence of hematopoietic disorders such as neutropenia and > 75 kg 3 x 200 mg Capsules AM,
thrombocytopenia. CONTRAINDICATIONS:
3 x 200 mg Capsules PM daily p.o.
- Presence of a hematostatic disorder or active pathological - Ribavirin capsules may cause birth defects and/or death of
bleeding (such as bleeding peptic ulcer or intracranial exposed fetus. Ribavirin is contraindicated for use in women RIBAVIN may be administered without regard to food, but
bleeding). who are pregnant or in men whose female partners are should be administered in a consistent manner with respect to food
- Patients with severe liver impairment. pregnant. intake.
11
Book_01.indd 11 6/4/2008 2:18:52 PM

SPDI
The recommended duration of treatment for patients previously INDICATIONS: CLINICAL PHARMACOLOGY:
untreated with interferon is 24 to 48 weeks. The duration of ZOCIN is indicated for the treatment of: Betaxolol HCI a cardio selective (beta-l -adrenergicl receptor
treatment should be individualized to the patient depending * Upper respiratory tract infections including pharyngitis, blocking agent, does not have signicant membrane-
on baseline disease characteristics, response to therapy and tonsillitis, sinusitisand otitis media. stabilizing (local anesthetic) activity and is devoid at intrinsic
tolerability of the regimen. After 24 weeks of treatment virologic sympathomimetic action.
* Lower respiratory tract infections including bronchitis and
response should be assessed. Treatment discontinuation should When instilled in the eye. BETOPTIC Ophthalmic Solution
pneumonia.
be considered in any patient who has not achieved an HCV RNA has the action of reducing elevated as well as normal intraocular
below the limit of detection of the assay by 24 weeks. There are no * Skin and soft tissue infections.
pressure whether or not accompanied by glaucoma.
safety and efcacy data on treatment for longer than 48 weeks in * Sexuallytransmitted diseases (non-gonococcal urethritis and
cervicitis). In three way masked cross over studies compairing ophthalmic
the previously untreated patient population.
betaxolol, timolol and placebo, BETOPTIC Ophthalmic
In patients who relapse following interferon therapy, the DOSAGE AND ADMINISTRATION: Solution was found to have minimal effect on pulmonary and
recommended duration of treatment is 24 weeks. There are no ZOCIN should be administered as a single daily dose at least one cardiovascular parameters in contrasts timolol signicantly
safety and efcacy data on treatment for longer than 24 weeks in hour before or two hours after meals. decreased pulmonary function and produced a lowering of the
the relapse patient population. mean heart rate.
Adults: Respiratory tract infections: a single 500 mg once daily
Ribavin/Peg-interferon alfa, recombinant therapy: for 3 days. CLINICALSTUDIES:
The recommended dose of ribavin is 800mg/day in 2 divided Skin and soft tissue infections: a single 500 mg once daily for 3 BETOPTlC Ophthalmic Solution has been used succesfully in
doses. days. glaucoma patients who have undergone a laser trabeculoplasty
Dose modications: Sexually-transmitted diseases: 1gram given as a single dose. and have needed additional long term hypotensive therapy.
If severe adverse reactions or laboratory abnormalities develop BETOPTIC Ophthalmic Solution has also been well tolerated
Children: The usual dose for Zocin is 10 mg/kg body weight
drug combination Ribavin/interferon alfa, recombinant therapy in glaucoma patients wearing hard or soft contact lenses and in
given as a single dose for 3 days.
the dose should be modied or discontinued if appropriate, until aphakic patients.
General dosing guidelines (once-daily for 3 days):
the adverse reactions abate. If intolerance persists after dose BETOPTIC Ophthalmic Solution does not produces miosis
adjustment, Ribavin/interferon alfa, recombinant therapy should No information is available on children under 6 months of age or accomadative spasm . as frequently seen with miotic agents.
be discontinued. Age Weight Dose The blurred vision and and night blindness often associated
Ribavirin should be administered with caution to patients with 6 months to 2 years < 15kg 10 mg/kg with standard miotic therapy are not associated with ophthalmic
pre-existing cardiac disease. Patients should be assessed before 2 - 5 years 15 - 25 kg 5ml (200mg) betaxolol. Thus patients with central lenticular opacities avoid the
commencement of therapy and should be appropriately monitored visual impairment caused by a constricted pupil.
5 - 11 years 26 - 35 kg 7.5ml (300mg)
during therapy. If there is any deterioration of cardiovascular 11 - 14 years 36 - 45 kg 10ml (400mg) INDICATIONS AND USAGE:
status, therapy should be stopped.
BETOPTIC Ophthalmic Solution has been shown to be
For patients with a history of stable cardiovascular disease, a CONTRAINDICATIONS:
effective in lowering intraocular pressure and is indicated in the
permanent dose reduction is required if the hemoglobin decreases ZOCIN is contraindicated in patients with a known treatment of:
by 2g/dl during any 4-weeks period. In addition, for these cardiac hypersensitivity to Azithromycin or any of the macrolide
1. Patients with chronic open-angle glaucoma.
history patients, if the hemoglobin remains <12g/dl after 4 weeks antibiotics.
on a reduced dose, the patient should discontinue combination 2. Patients with elevated intraocular pressure (ocular
WARNINGS: hypersensitive patients).
RIBAVIN/interferon alfa, recombinant therapy.
Because of the theoretical possibility of ergotism. Azithromycin 3. Patients with glaucoma or ocular hypertension who have
It is recommended that a patient whose hemoglobin level falls and ergot derivatives should not be co-administered.
below 10g/dl has his/her ribavirin dose reduced to 600mg daily reactive airway disease.
(1x200 mg capsule AM, 2X 200mg capsule PM). A patient whose PRECAUTIONS: 4. Patients with glaucoma or ocular hypertension who are
hemoglobin level falls below 8.5g/ dl should be permenantly The use of broad-spectrum antibiotics may lead to overgrowth of currently on multiple-antiglaucoma therapy
discontinued before ribavirin therapy. non-susceptible organisms. No dosage adjustment is required in CONTRAINDICATIONS
Guidelines for dose modications and discontinuation patients with mild renal impairment. Caution should be exercised
Hypersensitivity to any component of this product. BETOPTIC
for anemia when administering Azithromycin to patients with more severe
Ophthalmic Solution is contraindicated in patients with sinus
renal impairment. Azithromycin should be used with caution in
Hemoglobin Dose reduction Permanent bradycardia greater than a rst degree atrioventicular pressure
patients with impaired hepatic function. Rare serious allergic
Ribavin 600mg daily discontinuation of block, cardiogenic shock or patients with a history of overt cardiac
reactions including angioedema and anaphylaxis have been
Ribavin treatment failure.
reported in patients on macrolide therapy. There are no adequate
No cardiac history <10g/dl <8.5g/dl and well-controlled studies in pregnant women, however, studies PRECAUTIONS
Cardiac history 2g/dl decrease <12g/dl after 4 on animals provide no evidence of harm to the fetus (pregnancy Patients who are receiving beta adrenergic blocking agent orally
weeks of dose category B). No data on secretion of Azithromycin in breast
patients during any and BETOPTIC Ophthalmic Solution should be observed for
reduction milk is available, Therefore, caution should be exercised when
4-week period a potential additive effect either on the intraocular pressure or on
Azithromycin is given to nursing mothers.
the known systemic effects of beta blockade.
during treatment
SIDE EFFECTS: While BETOPTIC Ophthalmic Solution has demonstrated a
PRESENTATIONS AVAILABLE: Azithromycin is well tolerated with a low incidence of side effects. low potential for systemic effects, it should be used with caution
The majority of side effects were gastrointestinal origin such as in patients with diabetes (especially labile diabetes) or in patients
RIBAVIN is available as 200mg capsule in 60 capsules pack.
nausea, abdominal discomfort, vomiting, atulence and diarrhea. suspected of developing thyrotoxicosis.
As with other macrolides, allergic reactions and reversible Consideration should be given to the gradual withdrawal of beta-
ZOCIN elevations in liver transaminases were reported. adrenergic blocking agent pnor to general anesthesia because of
No clinically signicant durg interactions were reported. the reduced ability of the heart to respond to beta-adrenergically
medicated sympathetic reex stimuli.
Overdosage: No data on overdosage is available. Gastric lavage
(Azithromycin dihydrate) and general supportive measures are indicated . Pulmonary :
BETOPTIC OPHTHALMIC SOLUTION, cardio selective
COMPOSITION: PRESENTATIONS AVAILABLE :
beta blocker has produced only minimal effects in patients with
ZOCIN 250mg capsule: Each capsule contains 250mg ZOCIN is available as 250mg capsule in 6 capsules pack. reactive air way disease . However , caution should be exercised
Azithromycin as Azithromycin dihydrate ZOCIN is available as 200mg/5ml suspension in 15ml bottle.(N.R) in the treatment of patients with excessive restriction of pulmonary
ZOCIN 200mg suspension: Each 5ml contains 200mg ZOCIN is available as 300mg/7.5ml suspension in 22.5ml function.
bottle. (N.R) Drug interactions:
Azithromycinb as Azithromycin dihydrate.(N.R)
ZOCIN 300mg suspension:Each 7.5ml contains 300mg Although BETOPTIC Ophthalmic Solution used alone
Azithromycin as Azithromycin dihydrate.(N.R) has little or no effect on pupil size, mydriasis resulting from
ALCON concomitant therapy with BETOPTIC Ophthalmic Solution
PROPERTIES: P.O. BOX 405, JEDDAH 21411 and epinephrine has been reported occasionally.
Azithromycin is an azalide, a subclass of macrolide antibiotics. SAUDI ARABIA Close observation of the patients recommended when beta blocker
Following oral administration, Azithormycin is rapidly absorbed TEL: 02-6570957, FAX: 02-6571743 is administered to patients receiving catecholamine depleting
and widely distributed into tissues causing a signicantly higher drugs such as reserpine because of possible additive effect and the
concentration in tissues than in plasma (up to 50 times the production of hypotension and / or bradycardia .Caution should be
maximum observed concentration in plasma). Concentrations in BETOPTIC Opthalmic Solution excercised in patients using concomitant adrenergic psychotropic
target tissues such as lung, tonsils and prostate exceed the MIC90 drugs.
for likely encountered pathogens after a single dose of 500mg. A
Ocular: In patients with angle. closure glaucoma, the immediate
mean terminal serum elimination half-life of 57 hours has been (Betaxolol Hydrochloride) treatment objective is to re-open the angle by constriction of the
reported for Azithromycin. ZOCIN demonstrates in vitro activity
pupil with a miotic agent. Betaxolol has no effect on the pupil:
against a wide range of Gram-positive and Gram-negative bacteria DESCRIPTION
therefore, BETOPTlC Ophthalmic Solution should be used
including: Staphylococcus aureus, Streptococcus pneumoniae, BETOPTIC (BETAXOLOL) Ophthalmic Solution contains with a miotic to reduce elevated intraocular pressure in angle-
Streptococcus pyogenes, Streptococcus agalactiae, Hemophilusm Betaxolol Hydrochloride a cardio selective beta adrenergic closure glaucoma.
inuenzae and parainuenzae, Moraxella catarrhalis, Escherichia receptor blocking receptor blocking agent. In a preserved, sterile
coli, Bordetella pertussis and parapertussis, Borrelia burgdorferi, As with the use of Other anti-glaucoma drugs, diminished
isotonic solution.
Hemophilus ducreyi, Neisseria gonorrhoeae and Chlamydia responsiveness to BETOPTIC Ophthalmic Solution after
Each ml contains: prolonged therapy has been responed in same patients. However,
trachomatis. ZOCIN also demonstrates in vitro activity aganist
Active: 0.56% Betaxolol Hydrochloride (0.5% Betaxolol as in one long-term study in which 250 patients have been followed
Legionella pneumophilia, Mycoplasma pneumonia, Mycoplasma
base.) for up to three years, no signicant difference in mean-intraocular
hominis, Campylobacter spp., Toxoplasma gondii, Treponema
pallidum, Ureaplasma urealyticum as well as anaerobes including Preservative: Benzalkonium chloride 0.01% pressure has bean observed after initial stabilization.
Bacteroides fragilis. Beta-Lactamase production should have no Inactives: Edetate Disodium, Sodium Chloride, Hydrochloric Acid Usage in Pregnancy and Nursing Mothers:
effect on ZOCIN activity. and/or Sodium Hydroxide (to adjust pH), and Puried water. As with any drug, BETOPTIC OPHTHALMICSOLUTION
12
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SPDI
should be used by women who are pregnant or nursing only when NOT FOR INJECTION OR INTRAVENOUS INFUSION. range gram-negative and gram-positive organisms. The bactericidal
the anticipated benets outweigh the risks. action of ciprooxacin results plasma from interference with the
PRECAUTIONS:
Usage in Children: enzyme DNA gyrase which is needed for the synthesis of bacterial
This solution contains preservative and should not be used for DNA.
Clinical studies to establish the safety and efcacy in children have more than one patient. Prior to use, check Following; tip should
not been performed. Ciprooxacin has been shown to be active against most strains of
be rmly in place ,irrigating needle should be properly seated; the following organisms both in vitro and in clinical infection (see
ADVERSE REACTIONS: squeeze out several drops before inserting into anterior chamber. INDICATIONS AND USAGE).
The needle should be removed from the anterior chamber prior to
The following adverse reactions have been reported in clinical Gram-Positive:
releasing pressure to prevent suction.
trials of up to 4 years of patient experience with BETOPTIC Staphylococcus aureus (including methicillin-susceptible and
OPHTHALMIC SOLUTION. The addition of any medication to BSS solution may result in
methicillin-resistant strains)
damage to intraocular tissue. Studies suggest that the intraocular
Ocular: Staphylococcus epidermidis
irrigating solutions which are iso osmotic with normal aqueous
BETOPTIC Ophthalmic Solution has been well tolerated uids should be used with caution in diabetes patients undergoing Staphylococcus pneumoniae
,Discomfort short duration may be experienced in some patients vitrectomy since operative lens changes have been observed. Staphylococcus (Viridans Group)
upon instillation and occasional tearing has been reported .Rare
There have been reports of corneal clouding or edema following Gram Negative:
instances of decreased corneal sensitivity , erythema , itching
ocular surgery in which BSS solution was used as an irrigating Pseudomonas aeruginosa
sensation ,corneal punctuate staining ,keratitis ,anisocoria and
solution. As in all surgical procedures appropriate measures
photophobia have been reported. Serratia marcescens
should be taken to minimize trauma to the cornea and other ocular
Systemic: tissues. Ciprooxacin has been shown to be active in vitro against
Systemic reactions following topical administration of most strains of the following organisms; however, the clinical
ADVERSE REACTIONS: signicance of these data is unknown:
BETOPTIC Ophthalmic Solution have been reported rarely
(e.g. insomnia and depressive neurosis). When the corneal endothelium is abnormal, irrigation or any Gram Positive:
other trauma may result in bullous keratopathy. Post operative Enterococcus faecalis (many strains are only moderately
DOSAGE AND ADMINISTRATION: inammatory reactions as well as reactions as incidents of corneal susceptible)
The usual dose is one drop of BETOPTIC Ophthalmic Solution edema and corneal decompensation have been reported. Their
relationship to the use of BSS solution has not been established Staphylococcus haemolyticus
in the affected eye(s) twice daily. in some patients, the intraocular
pressure lowering response to BETOPTIC Ophthalmic Staphylococcus hominis
Solution may require a few weeks to stabilize. Staphylococcus saprophylicus
The adapter plug is designed to accept an irrigating needle. Tissue
Clinical fallow up should include a determination of the intraocular Staphylococcus pyogenes
may be irrigated by attaching the needle to the DROPTAINER
pressure during the rst month of treatment with BETOPTIC Gram Negative:
bottle as explained below. External irrigation may be done without
OPHTHALMIC SOLUTION. Thereafter, intraocular pressures Acinetobacter Proteus mirabilis
the irrigating needle. Escherichia coli
should be determined on an individual basis at the judgement of calcoaceticus
the physician. Method of using Adapter Plug for LUER-LOK Hub Ophthalmic
Irrigating Needle: subsp. Anitratus Haemophilus ducreyi Proteus vulgaris
When a patient is transferred from a single anti glaucoma agent Aeromonas Providencia
1. Aseptically remove DROPTAlNER bottle from blister by Haemophilus
already used and add drop BETOPTIC OPHTHALMIC caviae rengeri
peeling paper backing. inuenzae
SOLUTION
2. Snap on surgeon's sterile irrigation needle. Push until rmly Aeromonas Haemophilus Providencia stuartii
In the effected eyes(S) twice a day, on the following day discontinue hydrophila parainuenzae
in place and twist slightly
the previous anti glaucoma agent completely and continue with
BETOPTIC OPHTHALMIC SOLUTION 3. Test assembly for proper function before use. Brucella melitensis Klebsiella oxytoca Salmonella
enteritidis
If the intraocular pressure of the patient is not adequately HOW SUPPLIED:
controlled on this regimen , concomitant therapy with pilocarpine Campylobacter coli Klebsiella Salmonella typhi
In 15ml sterile DROPTAINER bottles. pneumophila
, other miotics ,epinephrine or systemically administered carbonic
STORAGE: Campylobacter Lehionella Shigella sonneil
anhydrase inhibitors can be instituted.
Store at 8 to 27C. jujuni pneumophila
When a patient is transferred from several concomitantly
administered anti glaucoma agents ,individualization is required. Citrobacter diversus Moraxella Shigella exnari
Adjustment should involve one agent at a time made at intervals of CILOXAN 0.3% Ophthalmic Solution (Branhamella)
not less than one week. Catarrhalis
STORAGE: Citrobacter freundii Morganella morganii Vibrio cholerae
(Ciprooxacin HCl) Edwarsiella tarda Neisseria gonorrhoeae Vibrio
Store at room temperature
Keep out of reach of children. DESCRIPTION: parahaemolyticus
Discard one month after opening. CILOXAN(Ciprooxacin HCl) Ophthalmic Solutions is Enterobacter Neisseria Vibrio vulnicus
HOW SUPPLIED: synthetic, sterile, multiple dose, antimicrobial for topical aerogenes meningitidis
ophthalmic use. Ciprooxacin is a uoroquinolone antibacterial Enterobacter Pateurella multicoda Yersinia
In 5 ml white opaque plastic ophthalmic DROPTAINER
active against a broad spectrum of gram-positive and gram-negative cloacae enterocolitica
Dispensers.
ocular pathogens. It is available as the monohydrochloride salt of
1-cyclopropyl-6-ouro-1, 4-dihydro-4-oxo-7-(1 piperazinyl)-3- Other organisms: Chlamydia trachomatic (only moderately
BSS lrrigating Solution quinoline-carboxylic acid. It is a faint to light yellow crystalline susceptible) and Mycobacterium tuberculosis (only moderately
powder with a molecular weight of 385.8. Its empirical formula is susceptible).
OTC Most strains of Pseudomonas cepacia and some strains of
C17H18FN3O3HclH2O and its chemical structure is as follows:
Pseudomonas maltophilia are resistant to ciprooxacin as are most
(Sodium Chloride, Potassium Chloride, anaerobic bacteria, including Bacteroides fragilis and Clostridium
Calcium Chloride Dihydrate, Magnesium difcile.
Chloride Hexahydrate, Sodium Acetate The minmal bactericidal concentration (MBC) generally does not
exceed the minimal inhibitory concentration (MIC) by more than
Trihydrate, Sodium Citrate Dihydrate) a factor of 2. Resistance to ciprooxacin in vitro usually develops
slowly (multiple-step mutation).
BALANCED SALT SOLUTION:
Ciprooxacin does not cross-react with ither microbial agents such
DESCRIPTION:
as beta-lactams or aminoglycosides; therefore, organisms resistant
BSS Sterile lrrigating Solution is a sterile physiological balanced to these drugs may be susceptible to ciprooxacin.
salt solution, each ml containing:
Clinical Studies: Following therapy with CELOXAN
Sodium Chloride (NaCl) 0.64%. Potassium Chloride (KCI) Ciprooxacin differs from other quinolones in that it has a uorine Ophthalmis Solution 76% of the patients with corneal ulcers and
0.075%. Calcium Chloride Dihydrate (CaCI2. 2H2O) 0.048%, atom at the 6-position, a piperazine moiety at the 7-position, and a positive bacterial cultures were clinically cured and complete
Magnesium Chloride Hexahydrate (MgCI) 6H20) 0.03% Sodium cyclopropyl ring at the 1-position. re-epithealization occurred in about 92% of the ulcers. In 3
Acetate Trihydrate (C2H3NaO2. 3H20) 0.39% Sodium Citrate and 7 days multicenter clinical trials, 54% of the patients with
Each ml of CILOXAN Ophthalmic Solution contains:
Dihydrate (C6H5Na3O7 2H2O) 0.17% Sodium Hydroxide and/or conjunctivitis and positive conjucntival cultures were clinically
Hydrochloric Acid (to adjust pH), and Water for Injection. Active: Ciprooxacin HCI 3.5 mg equivalent to 3 mg base. cured and 70-80% had all causative pathogens eradicated by the
BSS Sterile irrigating Solution is isotonic to the tissues of the Preservative: Benzalkonium Chloride 0.006%. end of treatment.
eyes. Inactives: Sodium Acetate, Acetic Acid, Mannitol 4.6%, Edetate INDICATIONS AND USAGE:
It is a lint-free solution containing essential ions for normal cell Disodium 0.05%, Hydrochloric Acid and/or Sodium Hydroxide CILOXAN Ophthalmic Solution is indicated for the treatment
metabolism (to adjust pH) and Puried Water. The pH is approximately 4.5 of infections caused by susceptible strains of the designated
and the osmolality is approximately 300 mOsm. microorganisms in the conditions listed below:
CLINICAL PHARMACOLOGY:
CLINICAL PHARMACOLOGY: Corneal Ulcers: Pseudomonas aeruginosa
A physiologic irrigating solution. Serratia marcescens
Systematic Absorption: A systematic absorption study was
INDICATIONS AND USAGE: Staphylococcus aureus
performed in which CILOXAN Ophthalmic Solution was
For irrigation during various surgical procedures of the eyes, ears, administered in each eye every two hours while awake for two days Staphylococcus epidermidis
nose, and/or throat followed by every four hours while awake for an additional 5 days. Streptococcus pneumoniae
WARNINGS: The maximum reported plasma concentration of ciprooxacin was Streptococcus (Viridans Group)
If blister or paper backing is damaged or broken, sterility of the less than 5 ng/ml. The mean concentration was usually less than Conjuntictivitis: Staphylococcus aureus
enclosed bottle cannot be assured. Open under aseptic conditions 2.5 ng/ml. Staphylococcus epidermidis
only. Microbiology: Ciprooxacin has in vitro activity against a wide Streptococcus pneumoniae
13
Book_01.indd 13 6/4/2008 2:18:54 PM

ALCON
SPDI
Efcacy for this organism was studied in fewer than 10 revealed no evidence of impaired fertility or harm to the fetus Chemical Name:
infections. due to ciprooxacin. In rabbits, as with most antimicrobial 2-(Dimethylamino)ethyl1-hydroxy--phenylcyclopentaneascetate
CONTRAINDICATIONS: agents, ciprooxacin (30 and 100 mg/kg orally) produced gastro hydrochloride
A history of hypersensitivity to ciprooxacin or any other intestinal disturbances resulting in maternal weight loss and an Each ml contains:
component of the medication is a contraindication to its use. increased incidence of abortion. No teratogenicity was observed
at either dose. After intravenous administration at doses up to 20 Active: Cyclopentolate Hydrochloride 0.5% (N.R.) or 1%
A history of hypersensitivity to other quinolones may also
mg/kg, no maternal toxicity was produced and no embryotoxicity Preservative: Benzalkonium Chloride 0.01%.
contraindicate the use of ciprooxacin.
or teratogenicity was observed. There are no adequate and well \Inactive: Boric Acid, Edetate Disodium, Potassium Chloride,
WARNINGS: controlled studies in pregnant women. Sodium carbonate Monohydrate and/or concentrated Hydrochloric
FOR TOPICAL USE ONLY NOT FOR INJECTION INTO CILOXAN Ophthalmic Solution should be used during Acid (to adjust pH), Puried Water.
THE EYE. pregnancy only if the potential benets justies the potential rist CLINICAL PHARMACOLOGY:
Serious and occasionally fatal hypersensitivity (anaphylactic) to the fetus.
This anticholnergic preparations blocked the responses of the
reactions, some following the rst dose, have been reported
NURSING MOTHER: sphincter muscle of the iris and the accommodative muscle of
in patients receiving systematic quinolone therapy. Some
It is not known whether topically applied ciprooxacin is excreted the ciliary body to cholinergic stimulation, producing papillary
reactions were accompanied by cardiovascular collapse, loss of
in human milk, however, it is known that orally administered dilation (mydriasis) and paralysis of accommodation (cycloplegia).
consciousness, tingling, pharyngeal or facial edema, dyspnea,
ciprooxacin is excreted in the milk of lactating rats, and oral It acts rapidly, but has a shorter duration than atropine. Maximal
urticaria, and itching. Only a few patients had a history of
ciprooxacin has been reported in human breast milk after a single cycloplegia occurs within 25 to 75 minutes after instillation.
hypersensitivity reactions. Serious anaphylactic reactions require
500 mg dose. Caution should be exercised when CILOXAN Complete recovery of accommodation usually takes 6 to 24 hours.
immediate emergency treatment with epinephrine and other
Ophthalmic Solution is administered to a nursing mother. Complete recovery from mydriasis in some individuals may
resuscitation measures, including oxygen, intravenous uids,
require several days. Heavily pigmented irides may require more
intravenous antihistamines, corticosteroids, pressor amines and PEDIATRIC USE: doses than lightly pigmented irides.
airway management, as clinically indicated.
Safety and effectiveness in children below the age of 12 have not
Remove contact lenses before using. INDICATIONS AND USAGE:
been established. Although ciprooxacin and other quinolones
cause arthropathy in immature animals after oral administration, Cyclopentolate Hydrochloride is used to produced mydriasis and
PRECAUTIONS:
topical ocular administration of ciprooxacin to immature animals cycloplegia.
GENERAL:
did not cause any arthropathy, and there is no evidence that the CONTRAINDICATIONS:
As with other antibacterial preparations, prolonged use of ophthalmic dosage form has any effect on the weight bearing
ciprooxacin may result in overgrowth of non-susceptible Should not be used when untreated narrow-angle glaucoma, or
joints.
organisms, including fungi. If superinfection occurs, appropriate untreated anatornically narrow angles are present, or if the patient
therapy should be initiated. Whenever clinical judgement dictate, ADVERSE REACTIONS: is hypersensitive to any components of this preparation.
the patient should be examined with the aid of magnication, such The most frequently reported drug related adverse reaction was WARNINGS:
as slit jamp biomicroscopy and, where appropriate, ourescein local burning or discomfort. In corneal ulcer studies with frequent
staining. For topical ophthalmic use only. Not for Injection. This
administration of the drug, white crystalline precipitates were preparation may cause CNS disturbances. This is especially true
Ciprooxacin should be discontinued at the rst appearance of a seen in approximately 17% of patients (see PRECAUTIONS). in younger age groups, but may occur at any age, especially with
skin rash or any other sign of hypersensitivity reaction. Other reactions occurring in less than 10% of patients included lid the stronger solutions. Infants are especially prone to CNS and
In clinical studies of patients with bacterial corneal ulcer, a margin crusting, crystals/scales, foreign body sensation, itching, cardiopulmonary side effects from cyclopentolate. To minimize
white crystalline precipitate located in the supercial portion of conjunctival hyperemia and a bad taste following instillation. absorption, use only 1 drop of 0.5% CYCLOGYL solution
the corneal defect was observed in 35 (16.6%) of 210 patients. Additional events occurring in less than 1% of patients included per eye, followed by pressure applied over the nasolacrimal sac
The onset of the precipitate was within 24 hours to 7 days after corneal staining, keratopathy/keratitis, allergic reactions, lid for two to three minutes. Observe infants closely for at least 30
starting therapy. In one patient, the precipitate was immediately edema, tearing, photophobia, corneal inltrates, nausea and minutes following instillation.
irrigated out upon its appearance. In 17 patients resolution of the decreased vision.
Mydriatics may produce a transient elevation of intraocular
precipitate was seen in 1 to 8 days (seven within the rst 24-72
OVERDOSE: pressure.
hours); in ve patients, resolution was noted in 10-13 days. In
nine patients, exact resolution days were unavailable: however, A topical overdose of CILOXAN Ophthalmic Solution may be PRECAUTIONS:
at follow-up examinations, 18-44 days after onset of the event, ushed from the eye(s) with warm tap water.
GENERAL:
complete resolution of the precipitate was noted. In three patients, DOSAGE ADMINISTRATION: The lacrimal sac should be compressed by digital pressure for two
outcome information was unavailable. The precipitate did not
The recommended dosage regimen for the treatment or corneal to three minutes after instillation to reduce excessive systemic
preclude continued use of ciprooxacin, nor did it adversely affect
ulcer is: Two drops into the affected eye every 15 minutes for absorption. Caution should be observe when considering use of
the clinical course of the ulcer or visual outcome (see ADVERSE
the rst six hours and then two drops into the affected eye every this medication in the presence of Down syndrome and in those
REACTION).
30 minutes for the remainder of the rst day. On the second day, predisposed to angle-closure glaucoma.
Information for Patients: Do not touch dropper tip to any surface, instill two drops in the affected eye hourly. On the third through
as this may contaminate the solution. INFORMATION FOR PATIENTS:
the fourteenth day, place two drops in the affected eye every four
Do not touch the dropper tip to any surface, as this may
DRUG INTERACTIONS: hours. Treatment may be continued after 14 days if corneal re-
contaminate the solution. A transient varying sensation may occur
epithelialization has not occurred.
Specic drug interaction studies have not been conducted with upon instillation. Patients should be advised not to drive or engage
ophthalmic ciprooxacin. However, the systematic administration The recommended dosage regimen for the treatment of bacterial in other hazardous activities while pupils are dilated. Patients may
of some quinolones has been shown to elevate plasma conjunctivitis is: One or two drops instilled into the conjunctival experience sensitivity to light and should protect eyes in bright
concentrations of theophylline, interfere with the metabolism of sa(s) every two hours while awake fro two days and on or two illumination during dilation. Parents should be warned not to
caffeine, enhance the effects of the oral anticoagulant, warfarin, drops every four hours while awake for the next ve days. get this preparation in their child's mouth and to wash their own
and its derivatives and have been associated with transient HOW SUPPLIED hands and the child's hands following administration. Feeding
elevations in serum creatinine in patients receiving cyclosporine intolerance may follow ophthalmic use of this product in infants.
concomitantly. As a sterile opthalmic solution : 5 ml in plastic Droptainer
It is recommended that feeding be withheld for four (4) hours after
dispensers.
examination.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF
FERTILITY: STORAGE DRUG INTERACTION:
Eight in vitro mutagenicity test have been conducted with Store at 2 to 30 C. Protect from light. Keep out of reach of Cyclopentolate may interfere with the ocular anti-hypertensive
ciprooxacin and the test results are listed below: children. Discard one moth after opening. action of carbachol, pilocarpine, or ophthalmic cholinesterase
Salmonella Microsome Test (Negative) ANIMAL PHARMACOLOGY: inhibitors.
E. coli DNA Repair Assay (Negative) Ciprooxacin and related drugs have been shown to cause Carcinogenesis, Mutagenesis, and Impairment of Fertility: Studies
Mouse Lymphoma Cell Forward Mutation Assay arthropathy in immature animals of most species tested following in animals or humans have not been conducted to evaluate the
(Positive) oral administration. However, a one-month topical acular study carcinogenic potential of CYCLOGYL.
Chinese Hamster V79 Cell HGPRT Test (Negative) using immature Beagle dogs did not demonstrate any particular PREGNANCY CATEGORY C:
Syrian Hamster Embryo Cell Transformation Assay lesions. Animal reproduction studies have not been conducted with
(Negative) cyclopentolate. It is also not known whether cyclopentolate
Saccharomyces cerevisiae Point Mutation Assay CYCLOGYL Ophthalmic Solution can cause fatal harm when administered to a pregnant woman
(Negative) or can affect reproduction capacity. Cyclopentolate should be
administered to a pregnant woman only if clearly needed.
Saccharomyces cerevisiae Miotic Crossover and
Gene Conversion Assay (Negative) (Cyclopentolate Hydrochloride) NURSING MOTHERS:
Rat Hepatocyte DNA Repair Assay (Positive) it is not known whether this drug is excreted in human milk.
DESCRIPTION: Because many drugs are excreted in human milk caution should
Thus, two of the eight tests were positive, but the results of the
following three in vivo test systems gave negative results: CYCLOGYL is an anticholinergic prepared as a sterile, borate be exercised when cyclopentolate hydrochloride is administered
buffered, solution for topical ocular use. The active ingredient is to a nursing woman.
Rat Hepatocyte DNA Repair Assay
represented by the structural formula: PEDIATRIC USE:
Micronucleus Test (Mice)
Dominant Lethal Test (Mice) Use of cyclopentolate has been associated with psychotic reactions
Long term carcinogenicity studies in mice and rats have been and behavioral disturbances in pediatric patients. Increased
completed. After daily oral dosing for up to two years, there is no susceptibility to cyclopentolate has been reported in infants,
evidence that ciprooxacin had any carcinogenic or tumorigenic young children, and in children with spastic paralysis or brain
effects in these species. damage. These disturbances include ataxia, incoherent speech,
restlessness, hallucinations, hyperactivity, seizures, disorientation
USAGE DURING PREGNANCY: as to time and place and failure to recognize people. Feeding
Reproduction studies have been performed in rats and mice at Established name: intolerance may follow ophthalmic use of this product in infants.
doses up to six times the usual daily human oral dose and have Cyclopentolate Hydrochloride It is recommended that feeding be withheld for four (4) hours after
14
Book_01.indd 14 6/4/2008 2:18:55 PM

ALCON
SPDI
examination. Observe infants closely for at least 30 minutes (See ointment base that quickly melts and prevents the drying and An unpredictable decrease of IOP control in some patients and
WARNINGS). discomfort. No prescription is required. incidence of ocular allergic responses and systemic side effects
Directions for use: Apply a small amount in the eyes as needed or may limit the utility of IOPIDINE 0.5% Ophthalmic Solution.
ADVERSE REACTIONS:
as directed by a physician. However, patients on maximally tolerated medical therapy may
Ocular: still benet from the additional IOP reduction provided by the
If irritation persists, consult your physician.
Increased intraocular pressure, burning, photophobia, blurred short term use of IOPIDINE 0.5% Ophthalmic Solution.
vision, irritation, hyperemia, conjunctivitis, blepharoconjuctivities, HOW TO APPLY DURATEARS ? Topical use of IOPIDINE 0.5% Ophthalmic Solution leads to
punctale keratitis, synechiae have been reported. 1 Tilt vow head back. systemic absorption. Studies of IOPIDINE 0.5% Ophthalmic
Non-ocular: 2. Place a nger on your cheek just under your eye and gently Solution dosed one drop three times a day in both eyes for 10 days
Use of cyclopentolate has been associated with psychotic pull down until a " V" pocket is formed between your eyeball in normal volunteers yielded mean peak and trough concentrations
reactions and behavioral disturbances, usually in children and your lower lid. of 0.9 ng/ml and mean peak and trough concentrations of 0.9 ng/
(especially with 2% concentration). These disturbances 3. Apply small amount (about 1 cm)in the "V" pocket. D not let ml and 0.5 ng/ml, respectively. The half-life of IOPIDINE 0.5%
include ataxia, incoherent speech, restlessness, hallucinations, the tip of the tube touch the eye. (apracionidine ophthalmic solution) was calculated to be 8 hours.
hyperactivity, seizures, disorientation as to time and place and Keep out of reach of children. IOPIDINE 0.5% Ophthalmic Solution, because of its alpha
failure to recognize people. This drug produces reactions similar adrenergic activity is a vasoconstrictor. Single dose ocular blood
to those of other antichlolinergic drugs, but the central nervous ow studies in monkeys, using the microsphere technique,
IOPIDINE 0.5% Ophthalmic Solution
system manifestations as noted above are more common. Other demonstrated a reduced blood ow for the anterior segment;
toxic manifestation of anticholinergic drugs are skin rash, however, no reduction in blood ow was observed in the posterior
abdominal distention in infants, unusual drowsiness, tachycardia, segment of the eye after a topical dose of IOPIDINE 0.5%
hyperpyrexia, vasodilation, urinary retention, disminished
(Apraclonidine hydrochloride) Ophthalmic Solution. Ocular blood ow studies have not been
gastrointestinal mobility and decreased secretion in salivary conducted in humans.
and sweat glands pharynx, bronchii and nasal passages. Severe DESCRIPTION:
IOPIDINE 0.5% Ophthalmic solution contains apraclonidine INDICATIONS AND USAGE:
manifestations of toxicity include coma, medullary paralysis and
death. hydrochloride, an alpha adrenergic agonist, in a sterile Isotonic IOPIDINE 0.5% Ophthalmic Solution is indicative for
solution for topical application to the eye. Apraclonldine short-term adjunctive therapy in patients on maximally tolerated
OVERDOSAGE: hydrochloride is a white to off-white powder and is highly soluble medical therapy who require additional IOP reduction. Patients
Excessive dosage may produce behavioral distyurbances, in water. Its chemical name is 2-[(4-amlno-2,6 dichlorophenyl) on maximally tolerated medical therapy who are treated with
tachycardia, hyperpyrexa, hypertension, elevated intraocular lmino] imldazolidlne monohydrochloride with and empirical IOPIDINE 0.5% Ophthalmic Solution to delay surgery who
pressure, vasodilation, urinary retention, diminished gastrointestinal formula of C9H11CI3N4 and a molecular weight of 281.57. The have frequent follow up examinations and treatment should be
mobility and decreased secretion in salivary and sweat glands, chemical structure of apraclonidine hydrochloride is: discontinued if the intraocular pressure rises signicantly.
pharynx, bronchi and nasal passages. Patients exhibiting signs of H The addition of IOPIDINE 0.5% Ophthalmic Solution to
overdosage should receive supportive care and monitoring. CI N patients already using aqueous suppressing drugs (i.e., bet-blocker
plus carbonic anhydrase imhibitor) as part of their maximally
H2N N
N tolerated medical therapy may not provide additional benet.
Adults: Instill one or two drops of 0.5% or 1% solution in the eye This is because IOPIDINE 0.5% Ophthalmic Solution is an
H
which may repeated in ve to ten minutes if necessary. Complete aqueous suppressing drug and the addition of a third aqueous
recovery from mydriasis in some individuals may require several CI
suppressant may not signicantly reduce IOP.
days. Each ml of IOPIDINE 0.5% Ophthalmic Solution contains: The IOP lowering efcacy of IOPIDINE 0.5% Ophthalmic
Children: Instill one or two drops of 0.5% or 1% solution in the Active: apraclonidine hydrochloride 5.75mg equivalent to Solution diminishes over time in some patients. This loss of
eye which may be repeated ve to ten minutes later by a second apraclonidine base 5mg: Preservative: benzalkonlum chloride effect, or tachyphylaxis, appears to be an individual occurrence
application of 0.5% or 1% solution if necessary. 0.01% with a variable time of onset and should be closely monitored. The
Small Infants: A single instillation of one drop of 0.5% Inactives: sodium chloride, sodium acetate, sodium hydroxide benet for most patients is less than one month.
CYCLOGYL in the eye. To minimize absorption, apply and/or hydrochloric acid (pH4.4-7.8) and puried water.
pressure over nasolacrimal for two to three minutes. Observe CONTRAINDICATIONS:
infant closely for at least 30 minutes following instillation with CLINICAL PHARMACOLOGY: IOPIDINE 0.5 Ophthalmic Solution is contraindicated in
heavily pigmented irides may require higher strengths. Apraclonidine hydrochloride is a relatively selective alpha-2- patients with hypersensitivity to apraclonidine or any other
adrenergic agonist. When instilled in the eye, IOPIDINE 0.5% component of this medication as well as systemic clonidine. It
HOW SUPPLIED: is also contraindicated in patients receiving monoamine oxidase
Ophthalmic Solution, has the action of reducing elevated, as well
In 15 ml plastic DROP-TAINER dispensers. as normal, intraocular pressure (IOP), whether or not accompanied inhibitors (MAO inhibitors).
STORAGE: by glaucoma. Ophthalmic apraclonidine has minimal effect on WARNINGS:
cardiovascular parameters.
Store at room temperature (8 - 30 C). Not for injection or oral ingestion.
Elevated IOP presents a major risk factor in glaucomatous eld
loss. The higher the level of IOP, the greater the likelihood of For topical ophthalmic use only
DURATEARS Ocular Lubricant Ointment optic nerve damage and visual eld loss. IOPIDINE 0.5% PRECAUTIONS:
Ophthalmic Solution has the action of reducing IOP. The onset
OTC General: Glaucoma patients on maximally tolerated medical
of action of apraclonidine can usually be noted within one hour, therapy who are treated with IOPIDINE 0.5% Ophthalmic
(Mineral oil, Anhydrous liquid, Lanoline, and maximum IOP reduction occurs about three hours after Solution to delay surgery should have their visual elds monitored
instillation. Aqueous uorophotometry studies demonstrate that periodically.
Whit Petrolatum) apraclonidine's predominant mechanism of action is reduction of
Although the topical use of IOPIDINE 0.5% Ophthalmic
aqueous ow via stimulation of the alpha-adrenergic system.
DRY EYES: Solution has not been studied in renal failure patients, structurally
Repeated dose-response and comparative studies (0.125%-1.0% related clonidine undergoes a signicant increase in half-life
Dry eyes are caused by changes in the quality or the quantity of
apraclonidine ) demonstrate that 0.5% apraclonidine is at the top in patients with severe renal impairment. Close monitoring of
the natural tears that the tear glands produce. Because the tears are
of the dose/response IOP reduction curve. cardiovascular parameters in patients with impaired renal function
imperfect, they have the tendency to prematurely break up into dry
spots on the front surface of the eye instead of forming a smooth The clinical utility of IOPIDINE 0.5% Ophthalmic Solution is advised as the systemic dosage form of clonidine is partly
continous lubricating layer . These dry spots are very sensitive and is most apparent for those glaucoma patients on maximally metabolized in the liver.
uncomfortable. tolerated medical therapy. patients on maximally tolerated medical While the topical administration of IOPIDINE 0.5%
therapy with uncontrolled IOP and scheduled to undergo laser Ophthalmic Solution had minimal effect on heart rate or blood
There are several different causes of dry eyes. The most common
trabeculoplasty or trabeculectomy surgery were enrolled into a pressure in clinical studies evaluating glaucoma patients, the
is aging. As we get older, tear production naturally diminishes, so
double-masked, piacabo-controlled, multi-canter clinical trial to preclinical pharmacology of this drug suggests that caution
the eyes have an Increased tendency to become "dry" through lack
determine if IOPIDINE 0.5% Ophthalmic Solution, dosed should be observed in treating patient with severe, uncontrolled
of sufcient tears. Other causes, regardless of age, can include
three times daily (TID),could delay the need for surgery for up cardiovascular disease, including hypertension.
allergies, vitamin deciencies and hot, arid climatic conditions.
to three moths. IOPIDINE 0.5% Ophthalmic Solution should be used with
WHAT ARE THE SYMPTOMS OF DRY EYES? All patients enrolled into this trial had advanced glaucoma and were caution in patients with coronary insufciency recent myocardial
Because of the many causes of dry eyes, symptoms may vary undergoing maximally tolerated medical therapy, i,e., patients were infection, cerebrovascular disease , chronic renal failure, Raynaud's
However, the most common symptoms Include burning, itching, using combinations of a topical beta blocker, sympathomimetics, disease, or Thromboangiltis obliterans. Caution and monitoring
a sandy or gritty sensation, tiredness, and redness. In some cases, parasympathomimetics and oral carbonic anhydrase inhibitors. of depressed patients are advised since apraclonidine has been
discomfort may cause an overabundance of tears but, because Patients were considered to be treatment failures in this study if, infrequently association with depression.
they lack certain components, these excess tears cannot properly in the opinion of the investigators, their IOP was uncontrolled by Apraclonidine can cause dizziness and somnolence. Patients who
wet the eye, so they become an annoyance the masked study medication or there was evidence of further optic engage in hazardous activities requiring mental alertness should
nerve damage or visual eld loss, and surgery was indicated. Of be warned of the potential for a decrease in mental alertness while
RELIEF FOR DRY EYES:
171 patients receiving masked medication, 84 were treated with using apraclonidine. Topical ocular administration of two drops
The most satisfactory answer to the problem of dry eyes is the IOPIDINE 0.5% Ophthalmic Solution and 87 were treated of 0.5, 1.0 and 1.5% apraclonidine ophthalmic solution to New
use of articial tear solutions and, if necessary, special lubricating with placebo (apraclonidine vehicle). Zealand albino rabbits three times daily for one month resulted
ointments. ointments are usually used at night time to provide
Apracionidine treatment resulted in a signicantly greater in sporadic and transient instances of minimal corneal edema in
lubrication during sleep. Alcon Laboratories, the world's largest
percentage of treatment successes compared to patients treated the 1.5% group only; no hispathological changes were noted in
manufacturer of ophthalmic preparations; makes such a product.
with with placebo. In this placebo controlled maximum therapy those eyes.
DURATEARS OCULAR LUBRICANT OINTMENT: trial 14.3% Ophthalmic Solution were discontinued due to adverse Use of IOPIDINE 0.5% Ophthalmic Solution can lead to
DURATEARS ointment, because It was specially designed events, primarily allergic-like reactions (12.9%). an allergic-like reaction characterized wholly or in part by the
for the use in the eye, is ideal for keeping the eye lubricated and The IOP lowering efcacy of IOIDINE 0.5% Ophthalmic symptoms of hyperemia, puritus, discomfort, tearing, foreign
comfortable during the night time hours when it is impractical Solution diminishes over time in some patients. This loss of effect body sensation, and edema of the lids and conjunctiva. If ocular
to instill articial tear drops. There is no medication in or Tachyphylaxis, appears to be an individual occurrence with a allergic-like symptoms occur, IOPIDINE 0.5% (apraclonidine
DURATEARS ointment, only a smooth. comfortable variable time of onset and should be closely monitored. ophthalmic solution) therapy should be discontinued.
15
Book_01.indd 15 6/4/2008 2:18:55 PM

ALCON
SPDI
PATIENT INFORMATION: conjunctival edema, conjunctival follicles, corneal erosion, corneal
Do not touch dropper tip to any surface as this may contaminate inltrate, corneal staining, edema, Irritation, keratitis, keratopathy, ISOPTO FENICOL 0.5 %
the contents. lid disorder, lid erythema, lid margin crusting, lid retraction, lid Ophthalmic solution
scales, pain, photophobla.
DRUG INTERACTIONS:
Nonocular
Apraclonidine should not be used in patients receiving MAO (Chloramphenlcol)
Dry mouth occurred in approximately 20% of the patients.
inhibitors. (See CONTRAINDICATIONS). Although no
specic drug interactions with topical glaucoma drugs or systemic The following adverse reactions were reported in less than 3% of FENICOL OINTMENT 0.1%
medications were identied in clinical studies of IOPIDINE the patients: abnormal coordination, asthenia, anhythmia, asthma, Ophthalmic Ointment
0.5% Ophthalmic Solution, the possibility of an additive or chest pain, constipation, contact dermatitis, depression,dermatitis,
potentiating affect with CNS depressants (alcohol, barbiturates, dizziness, dry nose, dyspnea, facial edema, headache, Insomnla,
oplates, sedatives, anesthetics) should be considered. Tricyclic malalse, myalgla, nausea, nervousness, paresthesia. Parosmia, (Chloramphenicol)
antidepressants have been reported to blunt the hypotensive effect perlpheral edema, pharyngltis, rhinltis, somnolence, and taste
of systemic clonldlne. It is not known whether the concurrent use perversion. DESCRIPTION:
of these agents with aprecionldine can lead to a reduction in IOP Clinical Practice: A sterile ophthalmic solution
lowering effect. No data on the level of circulating catecholamines The following events have been identied during post-marketing Each ml contains :
after apraclonldine withdrawal are available. Caution, however, use of IOPIDINE 0.5% Ophthalmic Solution in clinical Active: Chloramphenicol 0.5% (5 mg/g)
is advised in patients taking tricyclic antidepressants which can practice. Because they are reported voluntarily from a population Preservative: Thimerosal 0.01%.
affect the metabolism and uptake of circulating amines. of unknown size, estimates of frequency cannot be mad. The
Vehicle: HydroxypropylMethylcellulose.
An additive hypotensive effect has been reported with the events, which have been chosen for inclusion due to either their
combination of systemic clonidine and neuroleptic therapy. seriousness, frequency of reporting, possible causal connection to Inaclives: Boric Acid, Sodium Borate (to adjust pH), Puried
IOPIDINE 0.5% Ophthalmic Solution, or a combination of Water.
Systemic colnldine any inhibit the production of catecholamines
in response to Insulin-induced hypoglycemia and mask the signs these factors, include: bradycardia. A sterile ophthalmic ointment
and symptoms of hypoglycemia. Each gram contains :
OVERDOSAGE:
Since apraclonldine may reduce pulse and blood pressure, caution Active: Chloramphenicol 0.1% (10mg/ g)
Ingestion of IOPIDINE 0.5% Ophthalmic Solution has been
in using drugs such as beta-blockers (ophthalmic and systemic), Inactives: Mineral oil, Anhydrous Liquid Lenolin. White
reported to cause bradycardfa, drowsiness, and hypothermia.
antihypertensives, and cardiac glycosides is advised Patients petroleum.
using cardiovascular drugs concurrently with IOPIDINE Accidental or intentional ingestion of oral clonidine has been
ACTIONS:
0.5% Ophthalmic Solution should have pulse and blood reported to cause apnea, arrhythmias, asthenia, bradycardia,
conduction defects, diminished or absent reexes, dryness of the Chloramphenicol is a broad spectrum antibiotic originally isolated
pressures frequently monitored. Caution should be exercised with
mouth, hypotension, hypothermia, hypoventilation, irritability, from streptomyces venezuelae. It is primarily bacteriostatic and
simultaneous use of clonidine and other similar pharmacologic
lethargy, miosis, pallor, respiratory depression, sedation or coma, acts by inhibition of protein synthesis by interfering with the
agents. transfer of activated amino acids from soluble RNA to ribosomes.
seizure, somnolence, transient hypertension, and vomiting.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Development of resistance to chloramphenicol can be regarded as
Treatment of an oral over dos includes supportive and symptomatic
No signicant change in tumor incidence or type was observed minimal for straphylococci and many other species of bacteria.
therapy; a patent airway should be maintained. Hemodialysis is
following two years of oral administration of apraclonidine HCL
of limited value since a maximum of 5% of circulating drug is INDICATION
to rats and mice at dosages of 1.0 and 0.6 mg/kg up to 20 and 12
removed. For the treatment of supercial ocular infections involving the
times, respectively, the maximum dose recommended for human
conjunctiva and / or cornea caused by chlorampheicol susceptible
topical ocular use. DOSAGE AND ADMNISTRATION:
studies should be performed to determine the causative organisms
Apraclonidine HCL was not mutagenic in a series of in vitro One to two drops of IOPIDINE 0.55 Ophthalmic Solution and their sensitivity to chloramphenicol.
mutagenicity tests, including the Ames test, a mouse lymphoma should be instilled In the affected eye(s) three times daily. Since
forward mutation assay, a chromosome aberration assay in cultured IOPIDINE 0.5% Ophthalmic Solution will be used with other CONTR4INDICATIONS.
Chinese hamster ovary (CHO) cells, a sister chromatid exchange ocular glaucoma therapies, an approximates 5 minute interval This product is contraindicated in those persons who have shown
assay in CHO cells, and a cell transformation assay. between instillation of each medication should be practiced to hypersensitivity to any of its components.
An in vivo mouse micronucleus assay conducted with apraclonidlne prevent washout of the previous dose NOT FOR INJECTION
WARNINGS
HCL also provided no evidence of mutagenlcity; INTO THE EYE FOR ORAL INGESTION.
Prolonged or frequent intermittent use of topical chloramphenicol
Reproduction and fertility studies in rats showed no adverse effect HOW SUPPLIED: should be avoided because of the possibility of hypersensitivity
on male or female fertility at a dose of 0.5 mg/kg (5 to 10 times the IOPIDINE 0.5% Ophthalmic Solution as base in a reactions , including bone marrow hypoplasia which may lead to
maximum recommended human dose). sterile, isotonic, aqueous solution containing apraclonidine aplastic anaemia.Ophthalmic ointment may retard corneal wound
PREGNANCY: hydrochloride. healing.
Pregnancy Category C: Apracionidlne HCL has been shown to Supplled in plastic ophthalmic DROP-TAINER dispenser as PRECAUTIONS
have an embryocidal effect in rabbits when given in an oral dose follows: Prolonged use of antibiotics may occasionally results in
of 3.0 mg/kg (60 times the maximum recommended human dose). 5 ml NDC0065-0665-05 ovrer growth of non susceptible organisms, including fungi.
Dose related maternal toxicity was observed in pregnant rats at 10 ml (N.R.) NDC 0065-0665-10 If new infections appear during treatment , the drug should be
0.3mg/kg (6 time the maximum recommended human dose). discontinued and appropriate measures should be supplemented
There are no adequate and well controlled studies in pregnant STORAGE Store between 2- 27C (36-80F), by appropriate systemic medication.
women. IOPIDINE 0.5% Ophthalmic Solution should be used Protect from freezing and light.
ADVERSE REACTIONS
during pregnancy only it the potential benet benet justies the
potential risk to the fetus. ISOPTO CARPINE Eye drop Blood dyscrasias may be associated with the systemic use of
chloramphenicol. One case of bone marrow hypoplasia followed
NURSING MOTHERS: the prolonged (23 months ) topical use of chloramphenicol
It is not known whether this drug is excreted in human milk. ophthalmic solution has been reported.
(Pilocarpine Hydrochloride)
Because many drugs are excreted in human milk, caution should DOSAGE AND ADMINISTRA1ION
be exercised when IOPIDINE 0.5% Ophthalmic Solution is ISOPTO CARPINE 0.25%(N.R):0.5%(N.R); 1 %;2%;3%(N. Solution: In sever disease ,instill two drops on the eye(s)
administered to a nursing woman. R);4%;5%(N.R);6%(N.R);8%(N.R); 10%(N.R). hourly until improvement, following which treatment should be
PEDIATRIC USE: Active: Pilocarpine Hydrochloride(0.25%; 0.5%; 1%; 2%; diminished prior to discontinuation. In mild disease , drops may
Safety and effectiveness in pediatric patients have not been 3%;4%;5%; 6%; 8% or l0%) be used four times daily.
established. Vehicle: Hydroxypropyl Methylcellulose (4,000 cps) 0.5%. Ointment: Apply a small amount to the lower conjunctival sac(s)
Geriatric Use: No overall differences in safety or effectiveness at bedtime as a supplement to the drops.
INDICATIONS
have been observed between elderly and younger patients. HOWSUPPLIED:
Pilocarnine Hvdrochloride is a miotic parasympathomimetic used
ADVERSE REACTIONS: to control intraocular pressure in chronic simple glaucoma. In acute Solution in 5 (N.R.) /15ml DROPTAINER Dispenser.
In clinical studies the overall discontinuation rate related to glaucoma it may be used alone prior to emergency surgery, or in Ointment in 35gram ophthalmic tube.
IOPIDINE 0.5% Ophthalmic Solution was 15%. The most combination with other miotics or carbonic anhydrase inhibitors.
Patients can be maintained on Pilocarpine Hyarochloride as long STORAGE:
commonly reported events leading to discontinuation Included
as lntraocular tension is controlled there is no visual deterioration Solution: Refrigerate until dispensed.
(in decreasing order of frequency) hyperemia, pruritus, tearing,
discomfort, lid edema dry mouth, and foreign body sensation. as indicated by changes in the visual eld. Ointment: Store at 15 to 25 C.
Keep out of reach of children
The following adverse reactions (incidences) were reported in PRECAUTIONS AND SIDE EFFECTS:
clinical studies of IOPIDINE 0.5%(apraclonidine Ophthalmic There are no known side effects except slight ciliary spasm
solution) as being possibly, probably, or denitely related to with resultant temporary reduction in visual acuity. Sensitivity
MAXITROL Ophthalmic Suspension
therapy. is infrequently observed. Contact allergy may develop after MAXITROL Ointment
Ocular prolonged use.
The following adverse reactions were reported in 5 to 15% of CONTRAINDICATIONS:
the patients: discomfort, hyperemia, and puritus. The following (Dexamethasone, Neomycin Sulfate, Polymyxin
Miotics are contraindicated where constriction is undesirable such
adverse reactions were reported in 1 to 5% of the patients:
as in acute irritis B Sulfate)
blanching, blurred vision, conjunctivitis, discharge, dry eye,
foreign body sensation, lid edema, and tearing. USUAL DOSAGE: DESCRIPTION:
The following adverse reactions were reported in less than 1% of Two drops topically in the eye(s) three times daily or as directed MAXITROL (Dexamethasone 0.1%, Neomycin Sulfate,
the patients: abnormal vision, blepharitis, blepharoconjunctivitls, by a physician. Polymyxin B Sulfate) is a multiple dose anti-effective steroid
16
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combination in sterile suspension and sterile ointment forms for infective ingredients are allergic sensitizations. The reaction due Each ml contains:
topical application. The ophthalmic preparation of MAXITROL to the steroid component in decreasing order of frequency are: Active: Naphazoline Hydrochloride 0.025%. Pheneramine
combines two antibiotics offering broad spectrum antibacterial elevation of intraocular pressure (IOP) with possible development Maleate 0.3%.
activity with the anti-inammatory activity of a new corticosteroid, of glaucoma and infrequent optic nerve damage, posterior
Preservative: Benzalkonium Chloride 0.01% inactives and
dexamethasone for combating certain microbial infections of the subcapsular cataract formation and delayed wound healing.
Puried Water.
anterior segment of the eye(s). The suspension is formulated in an Secondary infection: The development of secondary infection
isotonic menstrum containing hydroxypropyl methylcellulose for has occurred after use of combinations containing steroids and CLINICAL PHARMACOLOGY:
maximum effectiveness and comfort. antimicrobials. Fungi infections of the cornea are particular Naphcon-A combines the effects of the antihistamine, pheneramine
Each ml of solution contains: prone to develop coincidentally with long-term applications of maleate, and the decongestant naphazoline.
Active: Dexamethasone 0.1% Neomycin Sulfate 3,500 IU/ml, steroid. The possibility of fungi invasion must be considered in
any persistent corneal ulceration where steroid treatment has been INDICATIONS AND USAGE:
Polymyxin B Sulfate 6,000 IU/ml.
used. For relief of ocular irritation and/or congestion or for the treatment
Preservatives: Benzalkonlum Chloride 0.004% of allergic or inammatory ocular conditions.
Secondary bacterial ocular infection following suppression of host
Vehicle: Hydroxypropyl Methylcellulose 0.5%
responses also occurs. CONTRAINDICATIONS:
Inactives and puried water.
DOSAGE AND ADMINISTRATION: Hypersensitivity to one or more of the components of this
Each gram of ointment contains:
Keep out of reach of children. preparation
Active: Dexamethasone 0.1% Neomycin Sulfate 3,500 IU/ml,
Polymyxin B Sulfate 6,000 IU/ml. MAXITROL Suspension: One to two drops topically in the WARNINGS:
conjunctival sac(s). In severe disease, drops may be used hourly Do not use in the presence of narrow angle glaucoma. Patients
Preservatives: Methylparaben 0.05%, Propylparaben 0.01%
being tapered to discontinuation as the inammation subsides. In under MA0 lnhibitors may experience a severe hypertensive
Inactives: White Petrolatum, Anhydrous Liquid Lanolin. mild disease drops may be used up to four to six times daily. crisis if given a sympathomimetic drug
CLINICAL PHARMACOLOGY: MAXITROL Ointment: Apply a small amount into the Use in Infants and children may result In CNS depression leading
Corticoids suppress the inammatory response to a variety of conjunctival sac(s) up to three or four times daily or, may be used to coma and marked reduction in body temperature.
agents and they probably delay or slow healing. Since corticoids adjunctively with drops at bedtime.
AVAILABLE DOSAGE FROMS: PRECAUTIONS:
may inhibit the body's defense mechanism against infection, a
concomitant antimicrobial drug may be used when this inhibition MAXITROL supplied in 5 ml sterile Drop tainer dispensers. This preparation should be used with caution in elderly patients
is considered to be clinically signicant in a particular case. w ill severe cardiovascular disease including cardiac arrthytmias;
MAXITROL Ointment in 3.5 g ophthalmic tube.
patients with poorly controlled hypertension, patients with diabetes,
The anti-infective component in the combination is included
especially those with a tendency toward diabetic ketoacidosis. To
to provide action against specic organisms susceptible to it.
Neomycin Sulfate is considered active against the following
MYDRIACYL 0.5%(N.R), 1.0% prevent contaminating the dropper tip and solution, care should be
Ophthalmic solution taken not to touch the eyelids or surrounding area with the dropper
microorganisms: Staphyiococcus aureus, Corynebacterium
tip of the bottle.
diphterae, Streptococcus viridans, Escherichia coli, Kiebsiella
pneumonia, Proteus vulgaris, Aerobacter aerogenes, and ADVERSE REACTIONS:
Haemophilus inuenzae. (Tropicamide) The following adverse reactions may occur: Pupillary dilation,
Polymyxin B Sulfate is considered active against the following increase in intraocular pressure, systemic effects due to absorption
microorganisms: Pseudomonas aeruginosa, Aerobacter aerogebes, DESCRIPTION
(i.e.. hypertension, cardiac irregularities, hyperglycemia).
Escherichia coli, Klebsiella pneumoniae and Koch-Weeks Tropicamide is pharmacologically related to the parasympatholytic
bacillus. (anticholinergic ) group. It is a white crystalline solid melting DOSAGE AND ADMINISTRATION:
When a decision to administer both a corticoid and an antimicrobial at 96 to 96.5C.It is slightly soluble in water. Tropicamide is a One or two drops instilled in each eye every 3to4 hours or less
is made the administration of such drugs in combination has the synthetic compound described chemically as Tropic acid N- frequently, as required10 relieve symptoms.
ethyl-N(-piconyl) amide
advantage of greater patient compliance and convenience, with STORAGE:
the added assurance that the appropriate dosage of both drugs is ACTIONS: Store at room temperature. Keep bottle tightly closed when not in
administered, plus assured compatibility of ingredients when both A mydriatic-cycloplegic. Its action is remarkable in that maximum use. Protect from light and excessive heat.
types of drugs are in the same formulation and particularly, that the mydriasis and cyclopiegia are obtained within 20 to 25 minutes
correct volume of drug is delivered and retained. Keep out of reach of children. Discard one month after opening.
following instillation in the eye. Complete recovery occurs within
The relative potency of corticosteroids depends on the molecular 5 to 6 hours without the use of a miotic. HOW SUPPLIED:
structure, concentration and release from the vehicle. In 15 ml plastic DROP-TAINER Dispenser.
INDICATIONS:
INDICATIONS AND USAGE: For mydriasis and cycloplegia for diagnostic purposes. The 0.5%
MAXITROL is indicated in ocular inammation when concurrent is recommended where mydriasis only is desired. For cycloplegic PATANOL 0.1% Eye Drops, Solution
use of an antimicrobial is judged necessary. effect in refractions, the 1.0% solution is necessary.
CONTRAINDICATIONS: CONTRAINDICATIONS:
(Olopatadine Hydrochloride)
Epithelial herpes simplex keratitis (dentrillo keratitis, vaccinia, Contraindicated in narrow angle glaucoma.
varicella, and many other viral diseases of the cornea and DESCRIPTION
WARNINGS:
conjunctiva. Mycobacterial infection of the eye. Fungal diseases
For topical use only - NOT FOR INJECTION PATANOL Eye Drops, Solution, are supplied as a sterile
of ocular structures.
aqueous solution containing olopatadine, a relatively selective
Hypersensitivity to a component of the medication. PRECAUTIONS: H,-receptor antaaonist and inhibitor of histamine release from the
(Hypersensititvity to the antibiotic component occurs at a higher As with any mydriatic, caution should be used when intraocuiar mast cell for topical administration 'to the eyes.
rate than for other components). pressure is high or unknown or when anterior chamber is shallow.
CONTAINS
The use of this combinations is always contraindicated after In refractions where prolongation of cycloplegia is desirable, one
uncomplicated removal of a corneal foreign body. additional drop only is recommended. Each ml of PATANOL Eye Drops, Solution contains:
WARNINGS: Active: 1 .11 mg olopatidlne hydrochloride equivalent to 1 mg
ADVERSE REACTIONS:
olopatadine
Prolonged use may result in glaucoma, with damage to the optic Transient stinging may occur when drops are instilled.
nerve, defects in visual acuity and elds of vision, and posterior Preservative: benzalkonium chloride 0.01%
subcapsular cataract formation, Prolonged use may suppress the DOSAGE AND ADMINISTRATION: Inactives: disodium phosphate, dodecahydrate; sodium chloride;
host response and thus increase the hazard of secondary ocular For refraction. 1 or 2 drops of 1 0% solution in eye(s) repeated in 5 concentrated hydrochloric acid/ sodium hydroxide (adjust pH);
infections. In those diseases causing thinning of the cornea or minutes if patient is not seen with in 20 to 30 minutes an additional and puried water.
sclera, perforations have been known to occur with the use of drop may be instilled to Prolong mydriatic effect. For examination
CLINICAL PHARMACOLOGY
topical steroids. In acute purulen conditions of the eye, steroids of fundus,1 or 2 drop of 0.5% solution .15 or 20 minutes prior to
may mask infection or enhance existing infection. If these products examination. Olopatadlne is a multiple action molecule : an inhibitor of the
are used for 10 days or longer, intraocular pressure should be release of the release of histamine from the mast cell and a
HOW SUPPLIED: relatively selectlve hlstamine H1-antagonist that inhibits the in
routinely monitored even though it may be difcult in children
and uncooperative patients. 0.5% (N.R.) and 1.0% in 5ml (N.R.) and 15 ml plastic DROP- vivo and and in vitro type 1 hypersensitivity reaction including
TAINER dispenser. inhibition of histamine induced effects on human conjunctival
Employment of steroid medication in the treatment of herpes
epithelial cells and an inhibitor of cytokine secretion. Olopatadine
simplex requires great caution. STORAGE:
is devoid of effects on alphaadrenergic, dopamine, muscarinic
PRECAUTIONS: Store at room temperature. Do not refrigerate or store at high Type 1 and 2, and serotonin receptors.
temperatures. Keep container tightly closed.
The initial prescription and renewal of the medication order beyond Following topical ocular administration in man, oiopatadine
20 ml or 8 g should be made by a physician only after examination Keep out of reach of children. Discard one month after opening. was shown to have low systemic exposure. Two studies in
of the patient with the aid of magnication, such as slit lamp normal volunteers (totalling 24 subjects) dosed bilaterally with
biomicroscopy and where appropriate uorescent staining. NAPHACON-A Ophthalmic Solution olopatadine 0.15% eve drops solution once every 12 hours for 2
The possibility of persistent fungal infections of the cornea should weeks demonstrated plasma concentrations to be generally below
be considered after prolonged steroid dosing. OTC the quantitation limit of the assay (<0.5 ng/ ml). Samples in which
olopatadine was quantiable were typically found within 2 hours
ADVERSE REACTIONS: (Naphazoline Hydrochloride and Phenira- of dosing and ranged from 0.5 to 1.3 ng/ ml. The half life in plasma
Adverse reaction have occurred with steroid/anti-infective mine Maleate) was approximately 3 hours , and elimination was predominantly
combination drugs which can be attributed to the steroid through renal excretion, Approximately 6 0 - 70% of the dose
component, the anti-infective component or the combination. DESCRIPTION : was recovered in the urine as parent drug. Two metabolites , the
Exact incidence gures are not available since no denominator of NAPHCONB-A (Naphazoline Hydrochloride Pheneramine mono desmethyl and N-oxide were detected at low concentrations
treated patients is available. Maleate) is a combination of an antihistamine and a decongestant in the urine.
Reactions occurring more often from the presence of the anti- prepared as a sterile topical ophthalmic solution Results from conjunctival antigen challenge studies demonstrated
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that PATANOL when subjects were challenged with antigen Each ml of solution contains: DIRECTIONS FOR USE:
both initially and up to 8 hours after dosing, was signicantly more Active: lnstill one or two drops as frequently as required to relieve eye
etfective than its vehicle in preventing ocular itching associated Neomycin sulphate 3500 I.U polymyxin B sulphate 16,250 I.U irritation symptoms or as directed by your doctor.
allergic conjunctivitis. Results from an environmental study THE FOLLOWING ATTRlBUTES OF TEARS NATURALE
Preservative: Benzalkonium chloride 0.004%
demonstrated that PATANOL was effective i n the treatment HAVE BEEN DEMONSTRATED:
of the signs and symptoms of allergic conjunctivitis when dosed Vehicle: Hydroxy propyl methyl cellulose 0.5%
Inactives and puried water. Synergistically utilizes existing tear components to provide a
twice daily for up to 6 weks.
hydrophilic surface on the comea through normal pre corneal
Each gram of ointment contains: tear lm - corneal surface adsorptive processes.
INDICATIONS AND USAGE
Active: Enhances pre corneal tear lm stability and promotes corneal
PATANOL (olopatadine hydrochloride 0.1 %) Eye Drops,
Solution is indicated for the treatment of the signs and symptoms Neomycin sulphate 3500 I.U polymyxin B sulphate 6,000 I.U wetting through physiological blending with the pre corneal
of allergic conjunctivitis. Preservative : Methylparaben 0.05 %, Propyl paraben 0.01 % tear lm.
Inactives : White petrolatum, Anhydrous Liquid lanolin. Extends retention time without increased viscosity.
Increases corneal wetting as judged by a greatly reduced contact
The recommended dose is one drop in each affected eye two times ACTION angle on the clean surface (18-21C) (Normal saline=4852).
per day. An Antibiotic drug in a sterile ophthalmic preparation for use in Increases pre corneal tear lm stability as evidenced by tear lm
the treatment of certain eye disorders when administered topically breakup time studies.
ADVERSE REACTIONS
and for the prophylaxis of bacterial infection of the eye due to Statistically shown in double blind studies more comfortable
Headaches have been reported at an incidence of 7%. The susceptible organisms. Polymyxin B sulphate is effective against
following adverse experiences have been reported in less than than any other tear substitutes reported to possess prolonged
gram negative bacilli including virtually all strains of pseudomonas retention time as well as mucomimetic activity.
5% of patients: asthenia, blurred vision, burning or stinging, aeruginosa. Polymyxin is acknowledged to be the most effective
cold syndrome, dry eye, foreign body sensation, hyperemia, Mimics the action of conjunctival mucus.
agent known for the treatment and prophylaxis of pseudomonas
hypersensitivity, keratitis, lid edema, nausea, pharyngitis, pruritus, infections. The frequent invasion of the mucous membranes Keep out of reach of children.
rhinitis, sinusitis, and taste perversion. Some of these events were of the eye by gram negative bacilli, especially Ps .aeruginosa Discard one month after opening
similar to the underlying disease being studied. and H. Inuenzae (Koch weeks bacillus) , make this preparation
important in these infections. TRAVATAN 40 mcg/ml
CONTRAINDICATIONS
Neomycin is a broad spectrum antibiotic , effective against many
Hypersensitivity to any component of this product.
strains of both gram negative and gram positive organisms,
Eye Drops, Solution
WARNINGS including many strains of Proteus valgaris. One of the most
Patients should be instructed not to instill PATANOL common etiological organism in bacterial conjunctivitis is
(olopatadine hydrochloride 0.1 %) Eye Drops, Solution while Staphylococcus aureus , and Neomycin is considered by many (Travoprost)
wearing contact lenses. For topical use only. Not for injection. authorities to be one of the most effective antibiotics against this
organism. DESCRIPTION
PRECAUTIONS Barr, et al (1) reported that the combination of polymyxin and Travoprost is a highly selective, potent agonist for the FP prostanoid
Do not use if tamoer evident seal is damaged or broken at time neomycin had a denite synergestic action when tested against receptor. Its chemical name is isopropyl (Z)-7-[1R,2R,3R,5S)-3,5-
of purchase. Micrococcus pyrogens var, aureus (Sytaphylococcus aureus) dihydroxy-2-[(1E,3R)-3-hydroxy-4-[(,,-triuoro-m-toly)oxy]-
Store at 4C to 30C. Bacillus subtills, Escharichia coli, streptococcus faecalis, proteus 1-butenyl] cyclopentyl]-5- heptenoate. Its molecular formula is
vulgaris, streptococcus agalactiae, and Pseudomonas aeruginosa, C26H35F3O6 .
To prevent contaminating the dropper tip and solution, care should
The chemical structure of TRAVATAN is shown below:
be taken not to touch the Eye lids or surrounding areas with the INDICATIONS
dropper tip of the bottle. In bacterial infections of the external eye such as acute ,chronic
Keep bottle tightly closed when not in use. or catarrhal conjunctivitis, melbomitis, blepharoconjunctivitis and
Keep out of the reach and sight of children. keratoconjunctivitis when due o susceptible organisms.
Discard four weeks after rst opening. CONTRAINDICATIONS
Carcinogenesis, Mutagenesis, Impairment of Fertility: This product is contraindicated in those persons who have shown
Olopatadine administered carcinogenic in mice and rats in doses hypersensitivity to any of its components.
up to 500 mg/kg/day and 200 mg/kg/day. respectively.
PRECAUTION Ravoprost is a clear, colortess to pale yellow oil, which is very
Based on a 40 l drop size, these doses were 78,125 and 31,250 soluble in acetonitrlle, methanol, oclanol, and chloroform. It is
No adverse effect on ocular tissues has been observed. The
times higher than the maximum recommended ocular human practically insoluble in water.
incidence of sensitivity to the component antibiotics is very low
dose (MROHD). No mutagenic potential was observed when
and bacteria rarely develop resistance to them. If sensitivities TRAVATAN 40 micrograms/ml eye drops, solution is supplied
olopatadine was tested in an in vitro bacterial reverse mutation occure , the use of the solution should be discontinued. As as a sterile, buffered aqueous solution of travoprost with a pH
(Ames) test, an in vitro mammalian chromosome aberration assay with other antibiotic preparations ,prolonged use may result in of approximately 6.0 and an osmolality of approximately 290
or an in vivo mouse micronucleus test. Olopatadine administered overgrowth of non susceptible organisms, particularly Monilia. If m0smol/kg.
to male and female rats at oral doses of 62.500 times MROHD super infection develops , appropriate therapy should be instituted.
level resulted in a slight decrease in the fertility decrease index Each ml of TRAVATAN 40 micrograms/ml eye drops, solution
Use with caution in narrow angle glauma. contains 40 g travoprost.
and educed implantation rate; no effective in reproductive function
were observed at doses of 7800 times the maximum recommended DOSAGE AND ADMINISTRATION Preservative: benzalkonium chloride.
ocular human use level. Solution: Instill one or two drops in the lower conjunctival sac(s) Inactive ingredients : hydrogenated castor oil 40 (HCO-40),
Pregnancy: Pregnancy Category C. Olopatadine was found not three or more times daily as required. trometamol, disodium edentate, boric acid, mannitol, sodium
to be teratogenic in rats and rabbits. However, rats treated at 600 Ointment: Instill about a half inch ribbon into the conjunctival hydroxide and/or hydrochloric acid (to adjust pH) and puried
mg/kg/day, or 93,750 times the MROHD and rabbits treated at 400 sac(s) at when used adjunctively with the solution. water.
mg/kg-/day., or 62.500 times the MROHD, during organogenesis Not more than 20 ml or 8 g should be prescribed initially and the CLINICAL PHARMACOLOGY
showed a decrease in live fetuses. There are-.. however. no adequate prescription should not be relled without further evaluation as
Mechanism of Action
and well controlled studies in pregnant women. Because animal outlined in Precautions above.
studies are not always predictive of human responses, this drug Travoprost free acid is a highly selective, potent agonist for the FP
HOW SUPPLIED prostanoid receptor. FP receptor agonists are reported to reduce
should be used in pregnant women only if the potential benet to
the mother justies the potential risk to the embryo fetus. Solution: In 5 ml plastic DROPTAINER dispenser. Discard one intraocular pressure by increasing oveoscleral outow.
month after opening.
Nursing Mothers: Olopatadine has been identied in the milk of PHARMACOKINETICS/PHARMACODYNAMICS
nursing rats following oral administration. it is not known whether Ointment: In 3.5 g ophthalmic tube.
Absorption: Trvoprost is absorbed through the cornea. Studies in
topical ocular administration could result in sufcient systemic STORAGE rebbits have shown peak concentrations in aqueous humor were
absorption to produce detectable quantities in the human breast reached one to two hours following topical administration. In
Should be stored at room temperature, protect from freezing.
milk. Nevertheless, caution should be exercised when PATANOL humans, peak plasma concentrations of travoprost free acid were
(olopatadine hydrochloride 0.1 %) Eye Drops, Solution Keep out of reach of children.
low (25pg/ml or less) and occurred within 30 minutes following
is administered to a nursing mother. topical administration.
Pediatric Use: Safety and effectiveness in pediatric patients below
TEARS NATURALE Articial Tears Elimination from plasma was rapid resulting in concentrations
the age of 3 years have not been established. OTC below the limit of quantitation (< 10 pg/ml) by one hour.
(Duasorb) Metabolism: travoprost, and isopropyl ester prodrug, is rapidly
HOW SUPPLIED
hydrolyzed by esterases in the cornea to the biologically active fee
PATANOL is supplied as follows : 5 rnl in plastic acid. Systemically, travoprost free acid is rapidly and extensively
DROPTAINER dispensers. TEARS NATURALE articial Tears is a product of Alcon
Laboratories - the world's leading manufacturer of prescription metabolized to inactive metabolites.
products made especially for the eye. Bio transformations include beta-oxidation of the a (carboxylic
STATROL TEARS NATURALE is formulated for relief of various ocular
acid) chain to give the 1,2-dinor and 1,2,3,4-tetranor analogs,
Opthalmic Soluton and Ointment oxidation of the 15-hydroxyl moiety,as well as reduction of the
irritation syndromes (dry eye). This unique solution contains
13, 14 double bond.
DUASORB, water soluble polymeric system which combines
with the existing tears of the eye to promote corneal wetting. Excretion: In rats, 95% of a subcutaneous radiolabeled dose was
eliminated within 24 hours, the major route of elimination was via
(Neomycln Sulfate, Polymyxin B Sulfate) TEARSNATURALE provides extended retention time in the eye
the bite (61%) with the remainder excreted by the kidneys.
even though it is not a highly viscous(thick) solution. TEARS
DESCRIPTION: NATURALE also reduces the discomfort normally associated INDICATIONS AND USAGE
STATROL (Neomycin sulphate, Poly myxin B sulphate) is with dry eye conditions. TRAVATAN 40 micrograms/ml eye drops, solution is indicated
a sterile ophthalmic drug combining two antibacterials in both Statistical studies have shown it to be more comfortable than other for the reduction of intraocular pressure in patients with open-
solution and ointment forms. tear substitutes. angle glaucoma or ocular hypertension.
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CLINICAL STUDIES because this could cause the tip to become contaminated by treatment related pharmacotoxic signs were present in the animals
TRAVATAN 40 micrograms/ml eye drops, solution dosed once- common bacteria known to cause ocular infections. Serious receiving Travoprost.
daily inpatients with open-angle glaucoma or ocular hypertension damage to the eye and subsequent loss of vision may result from If overdosage with TRAVATAN occurs, treatment should be
produced signicant reductions in intraocular pressure (IOP) when using contaminated solutions. symptomatic.
used either as primary therapy of adjunctively to TIMOPTIC Patients also should be advised that if they develop an intercurrent
(timolol maleate ophthalmic solution) 0.5% BID. ocular condition (e.g., trauma, or infections) or have ocular
surgery, they should immediately seek their physicians advice The recommended dosage is one drop in the affected eye(s)
As primary therapy, TRAVATAN, dosed QD, reduced IOP 7 to
concerning the continued use of the multi dose container. once-daily in the evening. The dosage of TRAVATAN should
9 mmHg (TRAVATAN 40 micrograms/ml eye drops, solution).
not exceed once-daily since it has been shown that more frequent
Stable diurnal IOP reductions were achieved as early as 2 weeks Patients should also be advised that TRAVATAN contains
administration may decrease the intraocular pressure lowering
after initiation of therapy and were maintained over the 6 to 12 benzalkonium chloride which may be absorbed by contact effect.
month treatment periods in three (3) well-controlled studies. lenses. contact lenses should be removed prior to administration
Reduction of intraocular pressure starts approximately 2 hours
The IOP reductions with TRAVATAN 40 micrograms/ml eye of the solution. Lenses may be reinserted 15 minutes following
administration of TRAVATAN. after administration and the maximum effect is reached after 12
drops, solution were superior to those obtained with XALATAN
hours.
(latanoprost ophthalmic solution) 0.005% QD TRAVATAN If more than one topical ophthalmic drug is being used, the drugs
40 micrograms/ml eye drop, solution demonstrated an earlier TRAVATAN may be used concomitantly with other topical
should be administered at least ve (5) minutes apart.
stabilization of IOP in black patients. ophthalmic drug products to lower intraocular pressure. If more
Carcinogenesis, Mutagenesis, Impairment of Fertility than one topical ophthalmic drug is being used, the drugs should
A responder analysis (IOP reduction 30% or mean IOP 17 Travoprost was not mutagenic in bacteria, in one mouse lymphoma be administered at least ve (5) minutes apart.
mmHg) demonstrated that TRAVATAN 40 micrograms/ml eye assay, in the mouse micronuclaus tests nor in the rat chromosome
drops, solution had a signicantly higher responder rate (56%) aberration assay. In another mouse lymphoma assay, higher HOW SUPPLIED
compared to XALATAN 0.005% (50%) and which were both concentrations of travoprost were slightly mutagenic only in the TRAVATAN 40 micrograms/ml eye drops solution is a sterile,
signicantly greater then TIMOPTIC (40%). presence of activation enzymes. In life and early post-mortem isotonic, buffered, preserved, aqueous solution supplied in Alcons
In a 6-month will- controlled study, TRAVATAN 40 micrograms/ evaluations of carcinogenicity studies in rats and mice suggest no oval DROP-TAINER package system inside a sealed foil pouch.
ml eye drops, solution dosed QD adjunctively to TICOPTIC evidence of a carcinogenic potential. This package system is comprised of a plastic oval bottle with
0.5% BID provided additional clinically signicant IOP reductions dispensing plug and screw cap.
Travoprost did not affect mating or fertility indices in male or
(6 to 7 mmKg). female rats and mice at subcutaneous doses up to 10 g/kg/day The following pack sizes are available:
CONTRAINDICATIONS (250 times the recommended human dose). Cartons containing 1 or 3 bottles of 2.5 ml. Not all pack sizes may
The men number of corpora lutea was slightly reduced at that be marketed.
Known hypersensitivity to travoprost, benzalkonlum chloride or
any other ingredients in this product TRAVATAN may interfere dose, and the post-implantation losses were increased, but was SHELF LIFE:
with the maintenance of pregnancy and should not be used by not affected at 3g/kg/day (75 times the maximum recommended
2 years
women during pregnancy or by women attempting to become human dose).
Discard 4 weeks after rst opening
pregnant. PREGNANCY: TERATOGENIC EFFECTS
STORAGE
WARNINGS Pregnancy Category: C
Store at 2 to 25 C (36 to 77 F)
TRAVATAN may gradually change eye color, increasing In reproduction studies conducted in pregnant rats and mice,
the amount of brown pigmentation in the iris by increasing the travoprost reduced fatal viability when administered during Keep out of the reach and sight of children.
number of melanosomes (pigment granules) in melanocytes. The gestation at doses as low as 1.0 g/kg/day (25 times the maximum TIMOPTIC is a registered trademark of Merck & Co. Inc.
long term effects on the meanocytes and any consequences thereof recommended human dose) with the lowest no effect level at 0.3 XALATAN is a registered trademark of Pharmacia Corp.
are currently unknown. The change in iris color occurs slowly and g/kg/day (7.5 times the maximum recommended human dose).
may not be noticeable for months to years. These changes may The incidence of skeletal malformations was increased in fetuses
be permanent. of rat dams reselving travoprost by subcutaneous injection at 10 ALLERGAN
Periorbital and/or eyelid skin darkening has been reported in g/kg/day (250 times the maximum recommended human dose), P.O BOX: 5022, RIYADH-11533
association with the use of TRAVATAN but not at 3 g/kg/day (75 times the maximum recommended SAUDI ARABIA
human dose). No fetal abnormalities were observed in mice at 1.0
TRAVATAN may gradually change eyelashes in the treated eye; TEL: 14626764, FAX: 14653709
g/kg/day (25 times the maximum recommended human dose).
these changes include increased length, thickness, pigmentation,
No adequate and well-controlled studies have been performed
and/or number of lashes.
in pregnant women. TRAVATAN may interfere with the ACULAR 0.5%
Patients who receive treatment in only one eye may experience maintenance of pregnancy and should not be used by women
increased brown pigmentation of the iris, periorbital and/or eyelid during pregnancy or by women attempting to become pregnant.
Sterile Ophthalmic Solution
tissue, and eyelashes in the treated eye. They may also experience
disparity between the eyes in length, thickness, and/or number of NURSING MOTHERS
eyelashes. These changes in pigmentation and lash growth may A study in lactating rats demonstrated that radiolabeled travoprost
(Ketorolac tromethamine)
be permanent. and/or its metabolites were excreted in milk. It is not known
DESCRIPTION :
whetherthis drug or its metabolites are excreted in human milk.
PRECUTIONS Each mL contains: ketorolac tromethamine 5 mg with:
Because many drugs are excreted in human milk, caution should
General benzalkonium chloride 0.1 mg, edetate disodium 1mg, octoxynol
be exercised when TRAVATAN is administered to a nursing
40, sodium chloride, and puried water.
There have been reports of bacterial keratitis associated with the women.
use of multiple dose containers of topical ophthalmic products. ANIMAL PHARMACOLOGY
These containers had been inadvertenltly contaminated by patients PEDIATRIC USE
Ketorolac tromethamine prevented the development of increased
who in most cases, had a concurrent corneal disease or a disruption Safety and effectiveness in pediatric patients have not been
intraocular pressure induced in rabbits with topically applied
of the epithelial surface (see Information for Patients). established. arachidonic acid. Ketorolac did not inhibit rabbit lens aldose
Patients may slowly develop increased brown pigmentation of GERIATRIC USE reductase in vitro.
the iris. This change may not be noticeable for months to years No overall differences in safety or effectiveness have been Ketorolac tromethamine ophthalmic solution did not enhance
(see warnings) . this change in eye color has predominantly been observed between elderly and other adult patients. the spread of ocular infections induced in rabbits with Candida
seen in patients with mixed colored irides, i.e., blue-brown, grey- ADVERSE REACTIONS (see Warnings and Precautions) albicans, herpes simplex virus type one, or Pseudomonas
brown, yellow-brown and green-brown; however, it has also been aeruginosa.
The most common ocular adverse event observer in controlled
observed in patients with brown eyes. Based upon information from
clinical studies with TRAVATAN 40 micrograms/ml eye drops, CLINICAL PHARMACOLOGY
the literature, the color change is believed to be due to increased
solution was ocular hyperemia which was reported in 35 to 50% of Ketorolac tromethamine is a nonsteroidal anti-inammatory
melanin content in the stromal melanocytes of the iris. Typically
patients. 95% of the ocular hyperemia observed with TRAVATAN drug which, when administered systemically, has demonstrated
the brown pigmentation around the pupil spreads concentrically
40 micrograms/ml eye drops. Solution was mild in intensity and analgesic, anti-inammatory and anti-pyretic activity. The
towards the periphery in affected eyes, but the entire iris or parts subsided over time without treatment Approximately 3% of
of it may become more brownish. mechanism of its action is thought to be due, in part, to its ability to
patients discontinued therapy due to conjunctival hyperemia. inhibit prostaglandin biosynthesis. Ketorolac tromethamine given
No further increase in brown iris pigment has been observed after Ocular adverse events reported at anincidence of 5 to 10% systemically does not cause pupil constriction.
discontinuation of treatment, but the resultant color change may included, decreased visual acuity eye discomfort, foreign body
be permanent. Two drops (0.1 mL) of 0.5% ACULAR ophthalmic solution
sensation, pain, and pruritus. instilled into the eyes of patients 12 hours and 1 hour prior to
TRAVATAN should be used with caution inpatients with active Ocular adverse events reported at an incidence of 1 to 4 % cataract extraction achieved measurable levels in 8 of 9 patients
intraocular inammation (iritis/uveitis). included, abnormal vision, blepharitis, blurred vision, cataract, eyes (mean ketorolac concentration 95 ng/mL aqueous humor,
Macular edema, including cystoid macular edema, has been cells, conjunctivitis, dry eye disorder, are, iris discoloration, range 40 to 170 ng/mL). Ocular administration of ketorolac
reported during treatment with prostaglandin F2 analogues. These dermatitis, lid margin crusting, photophobia, subconjunctival tromethamine reduces prostaglandin E2 (PGE2) levels in aqueous
reports have mainly occurred in aphakic patients, pseudophakic hemorrhage, and tearing. humor. The mean concentration of PGE2 was 80 pg/mL in the
patients with a tom posterior lens capsule, or in patients with Nonocular adverse events reported at a rate of 1 to 5% were aqueous humor of eyes receiving vehicle and 28 pg/mL in the
known risk factors for macular edema. accidental injury, angina pectoris, anxiety, arthritis, back eyes receiving ACULAR 0.5% ophthalmic solution. One drop
TRAVATAN 40 micrograms/ml eye drops, solution should be pain, bradycardia, bronchitis, chest pain, cold syndrome, (0.05 mL) of 0.5% ACULAR ophthalmic solution was instilled
used with caution in these patients. depression, dyspepsia, gastrointestinal disorder, headache, into one eye and one drop of vehicle into the other eye tid in 26
hypercholesterolemia, hypertension, hypotension, infection, pain, normal subjects. Only 5 of 26 subjects had a detectable amount
Patients should remove contact lenses prior to administration
prostate disorder, sinusitis, urinary incontinence, and urinary tract of ketorolac in their plasma (range 10.7 to 22.5 ng/mL) at Day 10
of the solution. Lenses may be reinserted 15 minutes following
during topical ocular treatment. When ketorolac tromethamine 10
administration of TRAVATAN. infection.
mg is administered systemically every 6 hours, peak plasma levels
Information for Patients OVERDOSE at steady state are around 960 ng/mL.
Patients should be advised concerning all the information A single-dose intravenous study in rats was conducted to elucidate Two controlled clinical studies showed that ACULAR
contained in the warnings and Precautions sections. maximal acute hazard. The dose employed was 250,000-times the ophthalmic solution was signicantly more effective than its
Patients should also be instructed to avoid allowing the tip of the proposed daily clinical exposure and over 5000-times the possible vehicle in relieving ocular itching caused by seasonal allergic
dispensing container to contact the eye or surrounding structures exposure from the entire contents of one product container. No conjunctivitis.
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Results from clinical studies indicate that ACULAR has caused by pupil constriction. The onset of action with one drop
no signicant effect upon intraocular pressure. ACULAR ALBALON 0.1% of BETAGAN can be detected within one hour after treatment,
ophthalmic solution has been safely administered in conjunction Liquilm with maximum effect seen between 2 and 6 hours. A signicant
with other ophthalmic medications such as antibiotics, beta decrease can be maintained for up to 24 hours following a single
blockers, carbonic anhydrase inhibitors, cycloplegics, and
Sterile ophthalmic solution dose.
mydriatics. OTC INDICATIONS
INDICATIONS AND USAGE (Naphazoline HCl) BETAGAN is indicated for the control of intraocular pressure in
ACULAR ophthalmic solution is indicated for the temporary chronic open angle glaucoma and ocular hypertension.
DESCRIPTION
relief of ocular itching due to seasonal allergic conjunctivitis.
Contains: CONTRAINDICATIONS
ACULAR is also indicated for the treatment of postoperative
inammation in patients who have undergone cataract extraction. naphazoline HCl ...............................................................0,1% BETAGAN is contraindicated in patients with severe chronic
obstructive pulmonary disease, bron-chospasm, including
CONTRAINDICATIONS Liquilm (polyvinyl alcohol) ...........................................1,4%
bronchial asthma, and uncontrolled congestive heart failure.
ACULAR ophthalmic solution is contraindicated in patients with with benzalkonium chloride 0,004%, edetate disodium, Citric BETAGAN is also contraindicated in those individuals who are
acid, sodium citrate, sodium chloride, and puried water. hypersensitive to any constituent of this product.
previously demonstrated hypersensitivity to any of the ingredients
in the formulation. ACTIONS WARNINGS
WARNINGS Constricts the vascular system of the conjunctiva. It is presumed As with other topically applied ophthalmic drugs, BETAGAN
this effect is due to direct action of the drug upon the alpha may be absorbed systemically. This ophthalmic product contains
There is the potential for cross-sensitivity to acetylsalicylic
(excitatory) receptors of the vascular smooth muscle. Benzalkonium Chloride as a preservative which may be deposited
acid, phenylacetic acid derivatives, and other nonsteroidal anti-
inammatory agents. Therefore, caution should be used when INDICATIONS in soft contact lenses, therefore this product should not be used
treating individuals who have previously exhibited sensitivities to while wearing these lenses. These lenses should be removed
For use as a topical ocular vasoconstrictor.
these drugs. before application of this product & not re-inserted earlier than
CONTRAINDICATIONS 15 minutes after use.
With some nonsteroidal anti-inammatory drugs, there exists
the potential for increased bleeding time due to interference with Hypersensitivity to a component of this medication; narrow-angle PRECAUTIONS
thrombocyte aggregation. There have been reports that ocularly glaucoma; infants and children.
General: BETAGANshould be used with caution in patients
applied nonsteroidal anti-inammatory drugs may cause increased WARNINGS with known contraindications to systemic use of beta-adrenoceptor
bleeding of ocular tissues (including hyphemas) in conjunction blocking agents. These include abnormally low heart rate and
A severe hypertensive crisis may ensue in patients under MAO
with ocular surgery. heart block more severe than rst degree. Congestive heart failure
inhibitor medication from use of a sympathomimetic drug.
PRECAUTIONS CNSdepression leading to coma and marked reduction in body should be adequately controlled before beginning therapy with
temperature may occur in children, especially infants. betagan . In patients with a history of signicant cardiac disease,
General: It is recommended that ACULAR ophthalmic solution
pulse rates should be monitored.
be used with caution in patients with known bleeding tendencies or PRECAUTIONS
who are receiving other medications which may prolong bleeding BETAGAN should be used with caution in patients with known
Use only with caution in the presence of hypertension, cardiac hypersensitivity to other betaadren-oceptor blocking agents.
time. irregularities, hyperglycemia (diabetes), hyperthyroidism, and
Information for Patients: ACULAR should not be administered Use with caution in patients with known diminished pulmonary
when other medications are being used.
while wearing contact lenses. function.
ADVERSE REACTIONS Drug Interactions: BETAGAN may have additive effects in
Carcinogenesis, Mutagenesis, and Impairment of Fertility: An
18-month study in mice at oral doses of ketorolac tromethamine Pupillary dilation with increase in intraocular pressure, systemic patients taking systemic antihypertensive drugs. These possible
equal to the parenteral MRHD (Maximum Recommended Human effects due to absorption (hypertension, cardiac irregularities, additive effects may include hypotension, including orthostatic
Dose) and a 24-month study in rats at oral doses 2.5 times the hyperglycemia). Drowsiness may be experienced in some patients. hypotension, bradycardia, dizziness,and/or syncope. Conversely,
parenteral MRHD, showed no evidence of tumorigenicity. Coma may occur in young children. systemic beta-adrenoceptor blocking agents may potentiate the
ocular hypotensive effect of BETAGAN.
Ketorolac tromethamine was not mutagenic in Ames test, DOSAGE AND ADMINISTRATION
unscheduled DNA synthesis and repair, and in forward mutation Pregnancy:There are no adequate and well controlled studies in
One to two drops every three to four hours.
assays. Ketorolac did not cause chromosome breakage in the in pregnant women. Levobunolol should be used during pregnancy
HOW SUPPLIED only if the potential benet justies the potential risk to the fetus.
vivo mouse micronucleus assay. At 1590 mg/mL (approximately
As a sterile solution in 15 ml plastic dropper bottles. Nursing Mothers : lt is not known whether this drug is excreted
1000 times the average human plasma levels) and at higher
concentrations, ketorolac tromethamine increased the incidence Note: in human milk. Systemic beta blockers and topical timolol maleate
of chromosomal aberrations in Chinese hamster ovarian cells. are known to be excreted in human milk. Because similar drugs
Store between 15-30C. On prescription only. Keep out of the
Impairment of fertility did not occur in male or female rats at are excreted in human milk, caution should be exercised when
reach of children.
oral doses of 9 mg/kg and 16 mg/kg, respectively. Pregnancy: BETAGAN is administered to a nursing woman.
Teratogenic Effects: Pregnancy Category C. Reproduction Pediatric Use: Safety and effectiveness in children have not been
studies have been performed in rabbits, using daily oral doses at BETAGAN 0.5% established.
3.6 mg/kg and in rats at 10 mg/kg during organogenesis. Results Liquilm ADVERSE REACTIONS
of these studies did not reveal evidence of teratogenicity to the Sterile ophthalmic suspension
fetus. Oral doses of ketorolac tromethamine at 1.5 mg/kg, which Blepharconjunctivitis, transient ocular burning , stinging.and
was half of the human oral exposure, administered after gestation decreases in heart rate and blood pressure have been reported
day 17 caused dystocia and higher pup mortality in rats. There occasionally with the use of BETAGAN. Urticaria has been
(Levobunolol HCl) reported rarely with use of BETAGAN. The following adverse
are no adequate and well-controlled studies in pregnant women.
Ketorolac tromethamine should be used during pregnancy only effects have been reported rarely and a denite relationship with
if the potential benet justies the potential risk to the fetus. DESCRIPTION the use of BETAGAN has not been established:change in heart
Nursing Mothers: Caution should be exercised when ACULAR Contains: rhythm, iridocyclitis browache, headache, elevated liver enzymes,
is administered to a nursing woman. Pediatric Use: Safety and eructation, transient ataxia, lethargy, dizziness, and itching.
levobunolol HCl...............................................................0,5%
efcacy in pediatric patients below the age of 12 have not been with : Liquilm (polyvinyl alcohol 1,4%), benzalkonium DOSAGE AND ADMINISTRATION
established. chloride 0,004%, edetate disodium, sodium metabisulte, sodium The usual dose is one drop in the affected eye(s) once or twice
ADVERSE REACTIONS phosphate dibasic, potassium phosphate monobasic, sodium a day.
In controlled clinical studies, the most frequent adverse events chloride and puried water.
HOW SUPPLIED
reported with the use of ACULAR ophthalmic solution have ACTIONS As a sterile ophthalmic solution in 5 ml.
been transient stinging and burning on instillation. These events Levobunolol is a noncardioselective beta-adrenoceptor blocking 10 ml(N.R) sizes in plastic dropper bottles. Store between 15-
were reported by approximately 40% of patients treated with agent, equipotent at both betal and beta 2 receptors. Levobunolol 25C; Protect from light .On prescription only. Keep out of reach
ACULAR ophthalmic solution. In all development studies is greater than 60-times more potent than its dextro isomer in its of children.
conducted, other adverse events occurring less than 5% of the beta-blocking activity, yet equipotent in its potential for direct
time during treatment with ACULAR included ocular irritation, myocardial depression.Accordingly, the levo isomer, Levobunolol
allergic reactions, supercial ocular infections and supercial is used. Levobunolol does not have signicant local anesthetic BOTOX Puried Neurotoxin Complex
keratitis. (membrane-stabilizing) or intrinsic sympathomimetic activity. Injection
DOSAGE AND ADMINISTRATION BETAGAN (levobunolol HCI 0,5%) has been shown to be as
The recommended dose of ACULAR ophthalmic solution is one effective as timolol in lowering intraocular pressure.
drop (0.25mg) four times a day for relief of ocular itching due to BETAGAN when instilled in the eye will lower elevated (Botulinum Toxin Type A)
seasonal allergic conjunctivitis. intraocular pressure as well as normal intraocular pressure,
For the treatment of postoperative inammation in patients who whether or not accompanied by glaucoma. Elevated intraocular DESCRIPTION:
have undergone cataract extraction, one drop of ACULAR pressure presents a major risk factor in the pathogenesis of BOTOX (Botulinum Toxin Type A) Puried Neurotoxin
ophthalmic solution should be applied to the affected eye(s) glaucomatous eld loss. The higher the level of intraocular Complex is a sterile vacuum-dried form of puried botulinum
four times daily beginning 24 hours after cataract surgery and pressure, the greater the likelihood of optic nerve damage and toxin type A, produced from a culture of the Hall strain of
continuing through the rst 2 weeks of the postoperative period. visual eld loss. The primary mechanism of the ocular hypotensive Clostridium botulinum grown in a medium containing N-Z amine
action of levobunolol HCI in reducing IOP is most likely a and yeast extract. It is puried from the culture solution by a series
HOW SUPPLIED decrease in aqueous humor production. BETAGAN reduces of acid precipitations to a crystalline complex consisting of the
ACULAR (ketorolac tromethamine ophthalmic solution) is intraocular pressure with little or no effect on pupil size in contrast active high molecular weight toxin protein and an associated
available for topical ophthalmic administration as a 0.5% sterile to the miosis which cholinergic agents are known to produce. The hemagglutinin protein. The crystalline complex is re-dissolved in
solution, and is supplied in a white opaque plastic bottle. Note: blurred vision and night blindness often associated with miotics a solution containing saline and albumin and sterile ltered (0.2
Store between 15 - 25C protect from light. On prescription would not be expected with the use of BETAGAN. Patients microns) prior to vacuum-drying. BOTOX is to be reconstituted
only. with cataracts avoid the inability to see around lenticular opacities with sterile, non-preserved saline prior to intramuscular injection.
20
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Each vial of BOTOX Puried Neurotoxin Complex contains 100 inc. at (800) 433-8871 from 8:00 a.m. to 4:00 p.m. Pacic Time, or rates of adverse reactions per treated eye are listed below:
units (U) of Clostridium botulinum toxin type A, 0.5 milligrams at (714)246-5954 for arecorded message at other times. Ptosis 11.0%
of albumin (human), and 0.9 milligrams of sodium chloride in The effect of botulinum toxin may be potentiated by Irritation/Tearing 10.0%
a sterile, vacuum-dried form without a preservative. One unit aminoglycoside antibiotics or any other drugs that interferes with
(U)corresponds to the calculated median lethal intraperitoneal (includes dry eye, lagophthalmos, and photophobia)
neuromuscular transmission. Caution should be exercised when
dose (LD/50) in mice of the reconstituted BOTOX injected. BOTOX Puried neurotoxin complex is used in patients taking Ectropion, keratitis, diplopia and entropion were reported rarely
any of these drugs.6 (incidence less than 1%)
CLINICAL PHARMACOLOGY:
Precautions: General:The safe and effective use of BOTOX Ecchymosis occurs easily in the soft eyelid tissues. This can be
BOTOX (Botulinum Toxin Type A) Puried Neurotoxin prevented by applying pressure at the injection site immediately
Complex blocks neuromuscular conduction by binding to (Botulinum Toxin Type A) Puried Neurotoxin Complex depends
upon proper storage of the product, Selection of the correct after the injection.
receptor sites on motor nerve terminals, entering the nerve
dose, and proper reconstitution and administration techniques. In two cases of VII nerve disorder (one case of an aphakic eye)
terminals, and inhibiting the release of acetylcholine. When
Physicians administering BOTOX must understand the reduced blinking from BOTOX Puried Neurotoxin Complex
injected intramuscularly at therapeutic doses, BOTOX produces
relevant neuromuscular and orbital anatomy and any alterations injection of the orbicularis muscle led to serious corneal exposure,
a localized chemical denervation muscle paralysis. When the
to the anatomy due to prior surgical procedures, and standard persistent epithelial defect and corneal ulceration. Perforation
muscle is chemically denervated, it atrophies and may develop
electromyographic techniques, requiring corneal grafting occurred in one case, an aphakic eye.
extrajunctional acetylcholine; receptors. There is evidence that the
As with all biologic products, epinephrine and other precautions Avoidance of injection into the lower lid area to avoid ectropion
nerve can sprout and reinnervate the muscle, with the weakness
as necessary should be available should an anaphylactic reaction may reduce this hazard. Vigorous treatment of any corneal
thus being reversible.
occur. epithelial defect should be employed. This may require protective
The paralytic effect on muscles injected with BOTOX Puried drops, ointment, therapeutic soft contact lenses, or closure of the
Neurotoxin Complex is useful in reducing the excessive, abnormal During the administration of BOTOX Puried Neurotoxin
eye by patching or other means.
contractions associated with blepharospasm. When used for the Complex for the treatment of strabismus, retrobulbolar
maemorrhage sufcient to compromise retinal circulation Two patients previously incapacitated by Blepharospasm
treatment of strabismus, it is postulated that the administration of
BOTOX affects muscle pairs by inducing an atrophic lengthening have occurred from needle It is recommended that appropriate experienced cardiac collapse attributed to over-exertion within
of the injected muscle and a corresponding shortening of the instruments to decompress the orbitbe accessible.Ocular {globe) three weeks following BOTOX Puried Neurotoxin Complex
muscles antagonist. Following peri-ocular injection of BOTOX, penetrations by needles have also occurred. An ophthalmoscope therapy. Sedentary patients should be cautioned to resume activity
distant muscles show electrophysiologic changes but no clinical to should be available, slowly and carefully following the administration of BOTOX.
weakness or other clinical change for a period of several Weeks or Reduced blinking from BOTOX Puried Neurotoxin Complex Overdosage: In the event of overdosage may be obtained by
months, parallel to the duration of local clinical paralysis.1 injection of the orbicularis muscle can lead to corneal exposure, contacting Allergan, nc. at (800) 433-8871 from 8:00 a.m. to 4:00
In one study, botulinum toxin was evaluated in 27 patients with persistent epithelial defect and corneal ulceration, especially in p|.m. Pacic Time, or at (714) 246-5954 for a recorded, message
essential blepharospasm. Twenty-six of the patients had previously patients One case of corneal perforation in an aphakic eye requiring at other times.
undergone drug treatment utilizing benztropine mesylate, corneal grafting has occurred because of this effect. Careful testing Dosage and Administration: Strabismus BOTOX (Botulinum
clonazepam and/or baclofen without adequate clinical results. of corneal sensation in eyes previously operated upon, avoidance Toxin Type A) Puried neurotoxin Complex is intended for
Three of these patients then underwent muscle stripping surgery of injection into the lower lid area to avoid ectropion, and vigorous injection into ext aocular muscles utilizing the electrical activity
still without an adequate outcome. One patient of the 27 was treatment of any epithelial defect should be employed. This may recorded from the tip of the injection needle as a guide to placement
previously untreated, Upon using botulinum toxin, 25 of the 27 require protective drops, ointment, therapeutic soft contact lenses, within the target muscle. Injection without surgical exposure or
patients reported improvement within 48 hours. One of the other or closure of the eye by patching or other means. electromyographic guidance should not be attempted. Physicians
patients was later controlled with a higher dosage. The remaining Information for Patients: Patients with blepharospasm may have should be familiar with electromyographic technique.
patient reported only mild improvement but remained functionally been extremely sedentary for a Long time. Sedentary patients An injection of BOTOX Puried Neurotoxin Complex is
impaired.2 should be cautioned to resume activity slowly and carefully prepared by drawing into a sterile 1.0 mL tuberculin syringe an
In another study, 12 patients with blepharospasm were evaluated following the administration of BOTOX Puried Neurotoxin amount of the properly diluted toxin (see Dilution Table) slightly
in a double-blind, placebo-controlled study. All patients receiving Complex, greater than the intended dose. Air bubbles in the syringe barrel
botulinum toxin (n=8) were improved compared with no Drug Interactions: The effect of botulinum toxin may be are expelled and the syringe is attached to the electromyographic
improvements in the placebo group (n=4). The mean dystonia potentiated by aminoglycoside antibiotics or any other drugs that injection needle, preferably a 1.5 inch, 27 gauge needle. Injection
score improved by 72%, the self-assessment score rating improved interfere with neuromuscular transmission. Caution should be volume in excess of the intended dose is expelled through the
by 61%, and a videotape evaluation rating improved by 39%. The exercised when BOTOX Puried Neurotoxin Complex is used needle into an appropriate waste container to assure patency of the
effects of the treatment lasted a mean of 12.5 weeks.3 in patients taking any of these drugs.6 (See Warnings), needle and to conrm that there is no syringe-needle leakage. A
One thousand six hundred eighty clinical improvement lasting an Pregnancy: Pregnancy Category C: Animal reproduction studies new sterile, needle and syringe should be used to enter the vial on
average four Patient with blepharospasm evaluated in an open trial have not been conducted with BOTOX Puried Neurotoxin each occasion for dilution or removal of BOTOX,
showed of 12.5 weeks prior to the need for re-treatment.4 Complex. It is also not known whether BOTOX can cause To prepare the eye for BOTOX Puried NeurotoxinComplex
Six hundred seventy-seven patients with strabismus treated with fetal harm when administered to a pregnant woman or can affect injection, it is recommended that several drops of a local
one or more injections of BOTOX Puried Neurotoxin Complex reproduction capacity. BOTOX should be Administered to anesthetic and an ocular decongestant be given several minutes
were evaluated in an open trial. Fifty-ve percent of these patients pregnant women only if needed. prior to injection.
were improved to an alignment of 10 prism diopters or less when Carcinogenesis, Mutagenesis, Impairment of fertility: long Note: The volume of BOTOX Puried Neurotoxin Complex
evaluated six months or more following injection.5 These results term studies in animals have not been performed to evaluate injected for treatment of strabismus should be between 0.05 mLto
are consistent with results from additional open label trials which carcinogenic potential of Botox puried Neurotoxin Complex, 0.15 mL per muscle.
were conducted for this indication.4 Nursing mothers: It is not known whether this drug is excreted Strabismus dosage: The initial listed doses of the diluted
Indications and Usage: BOTOX (Botulinum Toxin Type A) in human milk, Because many drugs are excreted in human milk BOTOX Puried Neurotoxin Complex (see Dilution Table
Puried Neurotoxin Complex is indicated for the treatment of .caution should be exercised when BOTOX Puried Neurotoxin below) typically create paralysis of injected muscles beginning
strabismus and blepharospasm associated with dystonia, including Complex is administered to a nursing woman, one to two days after injection and increasing in intensity during
benign essential blepharospasm or VII nerve disorders in patients Pediatric use: Safety and effectiveness in children below the age the rst week. The paralysis lasts for 2-6 weeks and gradually
12 years of age and above. of 12 have not been established resolves over a similar time period. Overcorrections lasting over
The efcacy of BOTOX Puried Neurotoxin Complex in six months have been rare, About one half of patients will require
Adverse Reactions: 4 There have been reports of seven cases of
deviations over 50 prism diopters, in restrictive strabismus, in subsequent doses because of inadequate paralytic response of the
diffuse skin rash and two cases of local swelling of the eyelid skin
Duanes syndrome with lateral rectus weakness, and in secondary muscle to the initial dose, or because of mechanical factors such as
lasting for several days following eyelid injection,
strabismus caused by prior surgical over-recession of the antagonist large deviations or restrictions, or because of the lack of binocular
Strabismus: Inducing paralysis in one or more extraocular motor fusion to stabilize the alignment.
is doubtful, or multiple injections over time may be required. muscles may produce spatial disorientation double vision, or past-
BOTOX is ineffective in chronic paralytic strabismus except to 1. Initial doses in units (abbreviated as U) use the lower listed
pointing. Covering the affected eye alleviate these symptoms.
reduce antagonist contracture in conjunctibn with surgical repair. doses for treatment of small deviations
Extraocular muscles adjacent to the injection site are often affected,
Presence of antibodies to botulinum toxin type A may reduce the causing ptosis or vertical deviation, especially with higher doses Use the larger doses only for large deviations
effectiveness of BOTOX Puried of BOTOX (Botulinum Toxin Type A) Puried Neurotoxin A. For vertical muscles, and for horizontal strabismus of less
Neurotoxin Complex therapy. In clinical studies, reduction in Complex. The incidence rates of these side effects in 2058 adults than 20 prism diopters: 1.25U to 2.5U in any one muscle, For
effectiveness due to antibody production has occurred in one who received 3650 injections tor horizontal strabismus are listed horizontal strabismus of 20 prism in any one diopters to 50
patient with blepharospasm receiving three doses of below: prism diopters: 2.5 U to 5.0
blepharospasm received multiple doses of BOTOX for Ptosis 15.7% In any one muscle For persistent VI nerve palsy of one month
strabismus and blephaospasm should be kept below 200 U in a Vertical deviation 16.9% or longer duration :1.25 U to 2.5 U in rectus muscle.
one month period. The incidence of ptosis was much less after inferior rectus injection 2. Subsequent doses for residual or recurrent strabismus
Contraindications: BOTOX (0.9%) and much greater after superior rectus injection (37.7%) A. It is recommended that patients be re-examined 7-14 days
(Botulinum Toxin Type A) Puried Neurotoxin Complex is The incidence rates of these side effects persisting for over six after each effect of that dose,
contraindicated. In individual with known hypersensitivity to any months in an enlarged series of 5587 injections of horizontal B. Patients experiencing adequate paralysis of the target muscle
ingredient in the formulation, muscles in 3104 patients are listed below: that require subsequent injections should receive a dose
Ptosis lasting over 180 days 0.3% comparable to the initial dose injection to assess the effect of
WARNINGS:
that dose
The recommended dosages and frequencies of administration Vertical deviation greater than 2 prism diopters lasting over 180
days 2.1% C. Subsequent doses for patients experiencing incomplete
for BOTOX (Botulinum Toxin Type A) Puried Neurotoxin
paralysis of the target muscle may be increased up to twice
Complex should not be exceeded. There have not been any reported In these patients, the injection procedure itself caused nine scleral
the size of the previously administered dose.
instances of systemic toxicity resulting from accidental injection perforations. A vitreous hemorrhage occurred and later cleared in
or oral ingestion of BOTOX, Should accidental injection or oral one case. No retinal detachment or visual loss occurred in any case, D. Subsequent injections should not be administered until the
ingestion occur, the person should be medically supervised for Sixteen retrobulbar hemorrhages occurred. Decompression of the effects of the previous dose have dissipated as evidenced by
several days on an ofce or outpatient basis for signs or symptoms orbit after ve minutes was done to restore retinal circulation in substantial function in the injected and adjacent muscles,
of systemic weakness or muscle paralysis. The entire contents of one case. No eye lost vtstorrfron retrobulbar hemorrhage. Five E. The maximum recommended dose as a single injection for
a vial is below the estimated dose for systemic toxicity in humans eyes had pupillary change consistent with ciliary ganglion any one muscle is 25 U,
weighing 6 kg. or greater, damage (Adies pupil). Blepharospasm: For blepharospasm, diluted BOTOX Puried
In the event of overdose or injection into the wrong muscle, Blepharospasm: In 1684 patients who received 4258 treatments Neurotoxin Complex (see Dilution Table) is injected using a
additional information may be obtained byt contacting Allergan (involving multiple injections) for blepharospasm, the incidence sterile, 27 - 30 gauge needle without electromyographic guidance.
21
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1.25 U to 2.5 U (0.05 mL to 0.1 ml volume at each site) injected ACTIONS a lower propensity to increase intraocular pressure than did
into the medic I and lateral pre-tarsal orbicularis oculi of the upper Inhibition of the inammatory response to inciting agents of dexamethasone.
lid and into the lateral pre-tarsal orbicularis oculi of the lower lid mechanical, chemical or immunological nature. No generally Neomycin is a broad spectrum bactericidal antibiotic effective
is the initial recommended dose. In general, the initial effect of accepted explanation of this steroid property has been against a variety of gram-positive and gram-negative organisms,
the injections is seen within three days and reaches a peak at one advanced. Adrenocortico-steroids and their derivatives are such as Staphylococcus aureus, Escherichia coli, Haemophilus
to two weeks post-treatment. Each treatment lasts approximately capable of producing a rise in intraocular pressure. In clinical inuenzae, Klebsiella/Enterobacter species, Neisseria species,
three months, following which the procedure can be repeated studies on patients eyes treated with both dexamethasone and Proteus and Corynebacterium. Pus, exudates, and bacteria growth
indenitely. At repeat treatment sessions, the dose may be products do not inactivate the antibiotic.
uorometholone, uorometholone demonstrated a lower propensity
increased up to two-fold if the response from the initial treatment
to increase intraocular pressure than did dexamethasone.
is considered insufcient-usually dened as an effect that does INDICATIONS
not last longer than two months. However there appears to be INDICATIONS 1. FML-NEO is effective in the treatment of infectious
little benet obtainable from injecting more than 5.0 U per site. For steroid responsive inammation of the palpebral and bulbar conjunctivitis due to organisms sensitive to neomycin.
Some tolerance may be found when BOTOX is used in treating conjunctiva, cornea and anterior segment of the globe. 2. FML-NEO may be used for the treatment of anterior segment
blepharospasm if treatments are given any more frequently than
every three months, and is rare to have the effect be permanent. CONTRAINDICATIONS inammatory disorders which may be threatened with or
complicated by bacteria sensitive to neomycin.
The cumulative dose of BOTOX. Puried Neurotoxin Complex Acute supercial herpes simplex keratitis. Fungal diseases of
in a 30-day period should not exceed 200 U. ocular structures. 3. FML-NEO is effective following removal of foreign bodies
as well as before and after surgery where the possibility of
Dilution Technique: To reconstitute vacuum-dried BOTOX Vaccinia, varicella and most other viral diseases of the cornea infection with susceptible organisms exists.
(Botulinum Toxin Type A) Puried Neurotoxin Complex, use and conjunctiva. Tuberculosis of the eye. Hypersensitivity to the
sterile normal saline without a preservative; 0.9% Sodium constituents of this medication. CONTRAINDICATIONS
Chloride Injection is the recommended diluent. Draw up the Acute untreated purulent ocular infections caused by
proper amount of diluent in the appropriate size syringe. Since WARNINGS
microorganisms not sensitive to neomycin. Acute supercial
BOTOX is denatured by bubbling or similar violent agitation, Steroid medication in the treatment of herpes simplex keratitis herpes simplex (dendritic keratitis), vaccinia, varicella, and
inject the diluent into the vial gently. Discard the vial if a vacuum (involving the stroma) requires great caution; frequent slit-lamp most other viral diseases of the conjunctiva and cornea. Ocular
does not pull the diluent into the vial. Report the date and time microscopy is mandatory. Prolonged use may result in glaucoma, tuberculosis. Fungal diseases of the eye. Hypersensitivity to any
of reconstitution on the space on the label. BOTOX should be damage to the optic nerve, defects in visual acuity and elds of of the components of the drug.
administered within four hours after reconstitution. vision, posterior subcapsular cataract formation, or may aid in the
During this time period, reconstituted BOTOX Puried establishment of secondary ocular infections from fungi or viruses WARNINGS
Neurotoxin Complex should be stored in a refrigerator (2 to liberated from ocular tissue. 1. In diseases due to microorganisms resistant to neomycin,
8C Reconstituted BOTOX should be clear, colorless) and In those diseases causing thinning of the cornea or sclera, infection may be masked, enhanced or activated by the steroid.
free of particulate matter. Parenteral drug products should be perforation has been known to occur with use of topical steroids. Prolonged use may result in overgrowth of non-susceptible
inspected visually for particuIate matter and discoloration prior organisms.
Acute purulent untreated infection of the eye may be masked or
to administration and whenever the solution and the container 2. Articles in current medical literature indicate an increase in the
activity enhanced by presence of steroid medication.
permit.the use of one vial for more contain a than one patient prevalence of persons sensitive to neomycin. The possibility of
is not recommended because the product and diluent do not Safety and effectiveness have not been demonstrated in children of
the age group 2 years or below. such a reaction should be borne in mind.
preservative,
Use in Pregnancy: Safety of the use of topical steroids during 3. If sensitivity or other untoward reactions occur, discontinue the
Dilution Table
pregnancy has not been established. medication.
Diluent Added (0.9% sodium) Resulting dose
4. As fungal infections of the cornea have been reported
Dhloride Injection Units per 0.1 ml PRECAUTIONS coincidentally with long-term local steroid applications, fungal
1.0 ml 10.0 U As fungal infections of the cornea are particularly prone to develop invasion may be suspected in any persistent corneal ulceration
2.0 ml 5.0U coincidentally with long-term local steroid applications, fungus where a steroid has been used, or is in use, over a prolonged
4.0 ml 2.5 U invasion must be suspected in any persistent corneal ulceration period of time.
8.0 ml 1.25 U where a steroid has been used or is in use. Intraocular pressure 5. Various ocular diseases and long-term use of topical
should be checked frequently. corticosteroids have been known to cause corneal and scleral
Note: These dilutions are calculated for an injection volume of 0.1
ADVERSE REACTIONS thinning. Use of topical corticosteroids in the presence of thin
mL. A decrease or increase in the BOTOX Puried Neurotoxin
corneal or scleral tissue may lead to perforation.
Complex dose is also possible by administering a smaller or larger Glaucoma with optic nerve damage, visual acuity or eld defects,
injection volume - from 0.05 ml (50% decrease in dose) to 0.15 posterior subcapsular cataract formation, secondary ocular 6. Acute purulent untreated infections of the eye may be masked,
mL (50% increase in dose) infection from pathogens liberated from ocular tissues, perforation enhanced, or activated by the presence of steroid medication.
of the globe. Secondary ocular infection may occur from pathogens liberated
HOW SUPPLIED: Each vial contains 100 U of vacuum-dried
from ocular tissues.
Clostridium botulinium toxin type A DOSAGE AND ADMINISTRATION 7. Use of steroid medication in the treatment of patients with a
CAUTION: Federal (U.S.A.) law prohibits dispensing without a 1 to 2 drops instilled into the conjunctival sac two to four times history of herpes simplex requires great caution, frequent slit-
prescription, daily. During the initial 24 to 48 hours the dosage may be safely lamp microscopy is required.
STORAGE: Store the vacuum-dried product either at 2C - 8C increased to 2 drops every hour. Care should be taken not to 8. Reports in the literature indicate that posterior subcapsular
(in a refrigerate r), or in a freezer at or below -5C. Administer discontinue therapy prematurely. lenticular opacities have occurred after heavy or protracted use
BOTOX (Botulinum Toxin Type A) Puried Neurotoxin HOW SUPPLIED of topical ophthalmic corticosteroids.
Complexwith in four hours after the vial is reconstituted. During
As a sterile suspension in 5 mL . 9. Prolonged use of topical steroids may increase intraocular
these four hours, Reconstituted BOTOX should be stored in a
refrigerator (2 to 8C). Reconstituted BOTOX should be clear, 10 mL(N.R) plastic dropper bottles. pressure. Although currently available data indicate that
colorless and free of particulate matter. Note: Store between 15- 25C; protect from freezing. On intraocular pressure rise is generally not a problem with patients
prescription only. Keep out of the reach of children. Shake well being treated with uorometholone 0.1%, their intraocular
All vials, including expired vials, or equipment used with the drug pressure should be checked periodically.
should he disposed of carefully as is done with all medical waste before use.
USE IN PREGNANCY Safety of intensive or protracted use of
1. Sanders D, Massey W, Buckley E. Botulinum toxin for topical steroids during pregnancy has not been substantiated.
blepharospasm: Single-ber EMG studies. FML - NEO
PRECAUTIONS Use of topical steroids may increase intraocular
Neurology 1986;36:545-547. Liquilm pressure. With prolonged use of FML-NEO the intraocular
2. Arthurs B, Flanders M, Codere F, Gauthier S, Dresner S, Stone Sterile ophthalmic suspension pressure and lens should be examined periodically.
L. Treatment of blepharospasm with medication, surgery and DOSAGE AND ADMINISTRATION 1 to 2 drops in the
type A botulinum toxin. Can J Ophthalmol 1987;22:24-28. conjuctival sac two to four times daily. During the initial 24-48
3. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical (Fluorometholone-neomycin sulfate) hours, the dosage may be safely increased to 1 drop every hour.
dystonia: A double-blind, placebocontrolled Care should be taken not to discontinue treatment prematurely.
DESCRIPTION
study. Neurology 1987;37:616-623. HOW SUPPLIED
4. Data on le, Allergan, Inc. Each ml contains:
FML-NEO is available as a sterile suspension in 5 ml and
5. Scott AB. Botulinum toxin treatment of strabismus. American uorometholone................................................................... 0,1%
10 ml(N.R) plastic dropper bottles.
Academy of Ophthalmology, Focal Points 1989:Clinical neomycin sulfate (equivalent to 0,35% neomycin base)..... 0,5%
Note: Store between 15-30C; protect from freezing. On
Modules for Ophthalmologists Vol VII Module 12. Liquilm (polyvinyl alcohol) ............................................. 1,4% prescription only. Keep out of the reach of children.
6. Wang YC, Burr DH, Korthals GJ, Sugiyama H. Acute toxicity of with: benzalkonium chloride 0,004%; edetate disodium; Shake well before use.
aminoglycoside antibiotics as an aid in detecting botulism. Appl sodium phosphate dibasic; sodium chloride; sodium thiosulfate;
Environ Microbiol 1984;48:951-955. polysorbate 80; and puried water.
LUMIGAN 0.3 mg/ml
ACTIONS
FML 0.1% Eye drops, solution
Corticosteroids, such as uorometholone, inhibit the inammatory
Liquilm response to a variety of inciting agents. They inhibit the edema,
Sterile ophthalmic suspension brin deposition, capillary dilation, leukocyte migration,
phagocytic activity, capillary proliferation, broblast proliferation, (Bimatoprost)
deposition of collagen, and scar formation associated with
(Fluorometholone) inammation. Corticosteroids inhibit the synthesis of histamine LUMIGAN 0.3 mg/ml eye drops, solution Bimatoprost
within mast cells by blocking the action of histidine decarboxylase. The active substance is bimatoprost 0.3 mg/ml.
Each mL contains: Corticosteroids also decrease prostaglandin synthesis and retard The other ingredients are benzalkonium chloride (preservative),
Fluorometholone 1 mg with: Liquilm (polyvinyl alcohol) 14 epithelial regeneration. Corticosteroids and their derivatives are sodium chloride, sodium phosphate dibasic heptahydrate,
mg , benzalkonium chloride 0,04 mg, edetate disodium, sodium capable of producing a rise in intraocular pressure. In clinical citric acid monohydrate and puried water. Small amounts of
chloride, sodium phosphate monobasic, sodium phosphate dibasic, studies on patients eyes treated with both dexamethasone 0.1% hydrochloric acid or sodium hydroxide may be added to keep
polysorbate 80, and puried water. and uorometholone 0.1%, uorometholone demonstrated the level of acid (pH levels) normal
22
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ALLERGAN
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1. WHAT LUMIGAN eye drops IS AND WHAT IT IS USED If you forget to take LUMIGAN eye drops, use a single drop SIDE EFFECTS
FOR as soon as you remember, and then go back to your regular Transient ocular irritation (burning, stinging, redness, itching or
LUMIGAN eye drops is a colourless, clear eye drop solution routine. Do not take two doses to make up for the one that you photophobia) was reported in clinical trials in 22 patients out of
in a plastic bottle with a screw cap. Each bottle is just under half missed. 1373 (1.6%). One report of dizziness with numbness and nausea,
full and contains three millilitres of solution. This is enough for 4. POSSIBLE SIDE EFFECTS one report of dizziness alone, one report of headache, and one
4 weeks usage. report of haemorrhagic conjunctivitis with palpebral edema
Like all medicines, LUMIGAN eye drops can have side due to an allergic reaction were received from the same patient
LUMIGAN eye drops is an antiglaucoma preparation. It effects. Most of the side effects are not serious.
belongs to a group of medicines called prostamides. population.
Very common side effects Since a small amount of ooxacin is systemically absorbed after
LUMIGAN eye drops are used to reduce high pressure in the
These may affect more than one person in every 10 people topical administration, side effects reported with systemic use
eye. This high pressure can lead to a disease called glaucoma
If the high pressure is not reduced, it could eventually damage Affecting the eye could possibly occur.
your sight. Longer eyelashes (up to 45% of people) Slight redness (up DOSAGE
Your eye contains a clear, watery liquid that feeds the inside (Itching to 14% of people) to 44% of people) Three or four times daily in the affected eye(s). Dosage should
of the eye. Liquid is constantly being drained out of the eye Common side effects not normally be continued for more than 10 days without an
and new liquid is made to replace this. If the liquid cannot These may affect up to nine people in every 100 people ophthalmic review.
drain out quickly enough, the pressure inside the eye builds
Affecting the eye HOW SUPPLIED
up. LUMIGAN eye drops works by increasing the amount of
liquid that is drained. This reduces the pressure inside the eye. An allergic reaction in the eye OFLOX (ooxacin 0,3%) solution is supplied in 5 mL.
LUMIGAN eye drops may be used on its own or with other Sensitivity to light 10 mL(N.R) plastic dropper bottles.
drops called beta-blockers which also reduce pressure. Darker eyelashes Note: Store between 15 - 25C. On prescription only. Keep out
A feeling that something is in your eye of the reach of children.
2. BEFORE YOU USE LUMIGAN eye drops
Irritation
Do not use LUMIGAN eye drops if you are allergic to
bimatoprost or any of the other ingredients.
Inamed, red and itchy eyelids PRED FORTE 1%
Dryness
Take special care with LUMIGAN eye drops if any of the Tired eyes
Sterile ophthalmic suspension
following apply. Darker skin colour around eye
You wear contact lenses. Dont use the drops when you Pain (Prednisolone acetate)
are wearing your lenses. Wait 15 minutes after using the Sticky eyes
drops before you put your lenses back in. A preservative in Difculty in seeing clearly DESCRIPTION
LUMIGAN eye drops called benzalkonium chloride may Burning Each mL contains: prednisolone acetate 10 mg with:
cause eye irritation and can discolour soft contact lenses
Tears benzalkonium chloride 0,04 mg, polysorbate 80, boric acid,
Talk to your doctor, if: Cataract sodium citrate, sodium metabisulte, sodium chloride, edetate
You have any breathing problems. Swelling of the see-through layer which covers the surface of disodium. hydroxypropyl methylcellulose and puried water.
You have liver or kidney problems. the eye
ACTIONS
LUMIGAN eye drops may cause your eyelashes to darken Small breaks in the surface of the eye, with or without
Prednisolone acetate is a glucocorticoid that, on the basis of weight,
and grow, and cause the skin around the eyelid to darken too. inammation
has 3 to 5 times the anti-inammatory potency of hydrocortisone.
The colour of your iris may also go darker over time These Affecting the body Glucocorticoids inhibit the edema, brin deposition, capillary
changes may be permanent. Headaches Increased blood pressure dilatation and phagocytic migration of the acute inammatory
The change may be more noticeable if you are treating one An increase in blood test results that show how your liver is response as well as capillary proliferation, deposition of collagen
eye. working. and scar formation
People under 18 must not use LUMIGAN eyedrops. If you notice any side effects not mentioned in this leaet, INDICATIONS
Pregnancy please inform your doctor or pharmacist. For steroid responsive inammation of the palpebral and bulbar
Ask your doctor or pharmacist for advice before taking any conjunctiva cornea and anterior segment of the globe
5. STORING LUMIGAN eye drops
medicine.
Store between 15C and 25C.You must throw away the bottle CONTRAINDICATIONS
Breast-feeding
four weeks after you rst opened it, even if there are still some Acute untreated purulent ocular infections, acute supercial herpes
LUMIGAN eye drops may get into breast milk so you should drops left. This will prevent infections. To help you remember, simplex (dendritic keratitis), vaccinia, varicella and most other
not breast-feed while you are taking LUMIGAN eye drops. write down the date you opened it in the space on the box. viral diseases of the cornea and conjunctiva, ocular tuberculosis,
Driving and using machines: Keep out of the reach and sight of children. and fungal diseases of the eye, and sensitivity to any components
Your sight may become blurred for a short time just after using Keep the container tightly closed to prevent contamination. Do of the formulation
LUMIGAN eye drops. You should not drive or use machines not use LUMIGAN eye drops after the expiry date (marked WARNINGS
until your sight is clear again. EXP:) on the bottle label and box. 1. In those diseases causing thinning of the cornea, perforation has
Using other medicines: been reported with the use of topical steroids. Various ocular
Please tell your doctor or pharmacist if you are taking, or have OFLOX 0.3% diseases and long-term use of topical corticosteroids have
recently taken, any other medicines, even those not prescribed. been known to cause corneal or scleral thinning. Use of topical
Sterile ophthalmic solution corticosteroids in the presence of thin corneal or scleral tissue
3. HOW TO USE LUMIGAN eye drops may lead to perforation
LUMIGAN eye drops should only be applied to the eye. 2. Since PRED FORTE contains no antimicrobial, if infection
Normally, you should put one drop of LUMIGAN eye (Ooxacin)
is present appropriate measures must be taken to counteract the
drops in each eye that needs treatment, once every day, in the organisms involved.
evening following the instructions for use below. Always use DESCRIPTION
Each mL contains: ooxacin 3 mg with: benzalkonium chloride 3. Acute purulent infections of the eye may be masked or enhanced
LUMIGAN eye drops exactly as your doctor has instructed
0.05 mg, sodium chloride and puried water. by the use of topical steroids. Prolonged use may suppress the
you. If you use LUMIGAN eye drops with another eye drop,
host immune response in ocular tissues and thus increase the
leave at least ve minutes between putting in LUMIGAN eye INDICATIONS possibility of secondary ocular infections
drops and then the other drops. OFLOX is indicated for the treatment of external ocular infections 4 Use of steroid medication in the treatment of patients with a
Instruction for use: in adults and children that are caused by ooxacin-sensitive history of herpes simplex requires caution and should be
You must not use the bottle if the tamper -proof seal on the organisms. followed by frequent mandatory slit-lamp microscopy.
bottle neck is broken before you rst use it
CONTRAINDICATIONS 5. As fungal infections of the cornea have been reported
1. 2. 3. 4. coincidentally with long-term local steroid applications fungal
OFLOX is contraindicated in patients sensitive to ooxacin or any
of its components. invasion may be suspected in any persistent corneal ulceration
where a steroid has been used, or is in use
WARNINGS
6. Use ot topical corticosteroids may cause increased intraocular
OFLOX is not for injection. pressure in certain individuals. This may result in glaucoma with
Let go of the
Wash your Turn the lower lid, and PRECAUTIONS damage to the optic nerve with defects in the visual elds. It is
hands.Tilt Gently pull bottle upside advisable that the intraocular pressure be checked frequently,
close your eye As with other antiinfectives, prolonged use may result in
your head down the down and particularly in patients with a history or presence of glaucoma.
for 30 seconds. overgrowth of nonsusceptible organisms. If superinfection occurs,
back and lower eyelid squeeze it to 7. Use in Pregnancy - Safety of intensive or protracted use of
until there or if clinical improvement is not noted within a reasonable period,
ook at the release one discontinue use and institute appropriate therapy. topical steroids during pregnancy has not been substantiated
ceiling. is a small drop into each 8 Nursing Mothers - It is not known whether topical
pocket. eye that needs Use OFLOX with caution in patients who have exhibited
sensitivities to other quinolone antibacterial agents. administration could result in sufcient systemic absorption to
treatment, produce detectable quantities in breast milk. Caution should be
Pregnancy: There were no adequate and well-controlled studies exercised when PRED FORTE is administered to a nursing
If a drop misses your eye, try again to help prevent infections, performed in pregnant women. Since systemic quinolones have
do not let the tip of the bottle touch your eye or anything else. woman taking into consideration the importance of the drug to
been shown to cause arthropathy in immature animals, it is the mother.
Put the cap back on and close the bottle straight after you have recommended that OFLOX not be used in pregnant women.
used it. 9 Use in Children - Safety and effectiveness of corticosteroids in
Nursing Mothers: Because ooxacin and other quinolones taken children below the age ot two years has not been established
If you use more LUMIGAN eye drops than you should, it is systemically are excreted in breast milk, and there is potential
unlikely to cause you any serious harm. for harm to nursing infants, a decision should be made whether PRECAUTIONS
Put your next dose in at the usual time. If you are worried, talk to temporarily discontinue nursing or not to administer the drug, Posterior subcapsular cataract formation has been reported after
to your doctor or pharmacist. taking into account the importance of the drug to the mother. heavy or protracted use of topical ophthalmic corticosteroids.
23
Book_01.indd 23 6/4/2008 2:19:01 PM

ALLERGAN
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ADVERSE REACTIONS Efcacy for this organism was-studied-in fewer than 10 ZYMAR solution should not be injected subconjunctivally, nor
Increased intraocular pressure, with optic nerve damage, defects infections. should it be introduced directly into the anterior chamber of the eye.
in the visual elds. Also posterior subcapsular cataract formation, The following in vitro data are available, but their clinical In patients receiving systemic quinolones, including gatioxacin,
secondary ocular infections from fungi or viruses liberated from signicance in ophthalmic infections is unknown. The safety serious and occasionally fatal hypersensitivity (anaphylactic)
ocular tissues, perforation of the globe when used in conditions and effectiveness of ZYMAR in treating ophthalmic infections reactions, some following the frst dose, have been reported. Some
where there is thinning of the cornea or sclera, and delayed wound due to the following organisms have not been established in reactions were accompanied by cardiovascular collapse, loss of
healing. Systemic side effects may occur with extensive use of adequate and well-controlled clinical trials. consciousness, angioedema (including laryngeal, pharyngeal or
steroids. The following organisms are considered susceptible when facial edema), airway obstruction, dyspnea, urticaria, and itching.
evaluated using systemic breakpoints. However, a correlation If an allergic reaction to gatioxacin occurs, discontinue the drug.
between the in vitro systemic breakpoint and ophthalmological Serious acute hypersensitivity reactions may require immediate
f to 2 drops instilled into the conjunctival sac two to four times emergency treatment. Oxygen and airway management should be
daily. During the initial 24 to 48 hours the dosage may be safely efcacy has not been established. The following list of organisms
is provided as guidance only in assessing the potential treatment administered as clinically indicated.
increased to 2 drops every hour. Care should be taken not to
of conjunctival infections. Gatioxacin exhibits in vitro minimal PRECAUTIONS
discontinue therapy prematurely.
inhibitory concentrations (MICs) of 2g/mL or less (systemic General: As with other anti-infectives, prolonged use may result
HOW SUPPLIED susceptible breakpoint) against most ( 90%) strains of the in overgrowth of nonsusceptible organisms, including fungi. If
As a sterile suspension in 5 mL. following ocular pathogens. superinfection occurs discontinue use and institute alternative
10 mL (N.R.) plastic dropper bottles. Aerobes, Gram-Positive: therapy. Whenever clinical judgment dictates, the patient should
Note: Store between 15 - 25C: protect from freezing. On Listeria monocytogenes be examined with the aid of magnication, such as slit lamp
prescription only. Keep out of the reach of children biomicroscopy and, where appropriate, uorescein staining.
Staphylococcus saprophytics
Patients should be advised not to wear contact lenses if they have
Shake well before use. Streptococcus agalactiae signs and symptoms of bacterial conjunctivitis.
Streptococcus pyogenes Information for Patients: Avoid contaminating the applicator tip
ZYMAR Streptococcus viridans Group with material from the eye, ngers or other source.
Ophthalmic solution 0.3% sterile Streptococcus Groups C, F, G Systemic quinolones, including gatioxacin, have been associated
Aerobes, Gram-Negative: with hypersensitivity reactions, even following a single dose.
Acinetobacter twof Discontinue use immediately and contact your physician at the
(Gatioxacin ) rst sign of a rash or allergic reaction.
Enterobacter aerogenes
DESCRIPTION Drug Interactions: Specic drug interaction studies have not
Enterobacter cloacae
been conducted with ZYMAR ophthalmic solution. However,
ZYMAR (gatioxacin ophthalmic solution) 0.3% is a sterile Escherichia coli the systemic administration of some quinolones has been shown
ophthalmic solution. It is an 8-methoxy uoroquinolone anti- Citrobacter freundii to elevate plasma concentrations of theophylline, interfere with
infective for topical ophthalmic use. the metabolism of cafeine, and enhance the effects of the oral
Citrobacter koseri
Chemical Name: ()-1-cyclopropyl-6-uoro-1,4- anticoagulant warfarin and its derivatives, and has been associated
Haemophilus parainuenzae
dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3- with transient elevations in serum creatinine in patients receiving
Klebsiella oxytoca
quinolinecarboxylic acid sesquihydrate Contains: Active: systemic cyclosporine concomitantly.
gatioxacin 0.3% (3 mg/mL). Klebsiella pneumoniae
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Preservative: benzalkonium chloride 0.005%. Inactives: edetate Moraxella catarrhalis
There was no increase in neoplasms among B6C3F1 mice given
disodium; puried water and sodium chloride. May contain Morganella morganii gatioxacin in the diet for 18 months at doses averaging 81 mg/
hydrochloric acid and/or sodium hydroxide to adjust pH to Neisseria gonorrhoeae kg/day in males and 90 mg/kg/day in females. These doses are
approximately 6. ZYMAR is a sterile, clear, pale yellow colored approximately 2000-fold higher than the maximum recommended
Neisseria meningitidis
isotonic unbuffered solution. It has an osmolality of 260-330 ophthalmic dose of 0.04 mg/kg/day in a 50 kg human.
mOsm/kg. Proteus mirabilis
Proteus vulgaris There was no increase in neoplasms among Fischer 344 rats given
Structure and Empirical Formula gatioxacin in the diet for 2 years at doses averaging 47 mg/kg/day
Serratia marcescens in males and 139 mg/kg/day in females
Vibrio cholerae (1000 and 3000-fold higher, respectively, than the maximum
Yersinia enterocolitica recommended ophthalmic dose). A statistically signicant increase
Other Microorganisms: in the incidence of large granular lymphocyte (LGL) leukemia
Chlamydia pneumoniae was seen in males treated with a high dose of approximately
2000-fold higher than the maximum recommended ophthalmic
Legionella pneumophila
dose. Fischer 344 rats have a high spontaneous background rate
Mycobacterium marinum of LGL leukemia and the incidence in high-dose males only
Mycobacterium fortuitum slightly exceeded the historical control range established for this
C19H22FN3O4 1 .5 H2O Mol Wt 402.42 Mycoplasma pneumoniae strain. In genetic toxicity tests, gatioxacin was positive in 1 of
Anaerobic Microorganisms: 5 strains used in bacterial reverse mutation assays; Salmonella
CLINICAL PHARMACOLOGY strain TA102. Gatioxacin was positive in in vitro mammalian
Pharmacokinetics: Gatioxacin ophthalmic solution 0.3% or 0.5% Bacteroides fragilis
cell mutation and chromosome aberration assays. Gatioxacin was
was administered to one eye of 6 healthy male subjects each in an Clostridium perfringens positive in in vitro unscheduled DNA synthesis in rat hepatocytes
escalated dosing regimen starting with a single 2 drop dose, then 2 Clinical Studies: In a randomized, double-masked, multicenter but not human leukocytes. Gatioxacin was negative in in vivo
drops 4 times daily for 7 days and nally 2 drops 8 times daily for clinical trial, where patients were dosed for 5 days, ZYMAR micronucleus tests in mice, cytogenetics test in rats, and DNA
3 days. At all time points, serum gatioxacin levels were below the solution was superior to its vehicle on day 5-7 in patients with repair test in rats. The ndings may be due to the inhibitory effects
lower limit of quantication (5 ng/mL) in all subjects. conjunctivitis and positive conjunctival cultures. Clinical outcomes of high concentrations on eukaryotic type II DNA topoisomerase.
Microbiology: Gatioxacin is an 8-methoxyuoroquinolone for the trial demonstrated clinical cure of 77% (40/52) for the There were no adverse effects on fertility or reproduction in
with a 3-methylpiperazinyl substituent at C7. The antibacterial gatioxacin treated group versus 58% (28/48) for the placebo rats given gatioxacin orally at doses up to 200 mg/kg/day
action of gatioxacin results from inhibition of DNA gyrase and treated group. Microbiological outcomes for the same clinical trial (approximately 4500-fold higher than the maximum recommended
topoisomerase IV. DNA gyrase is an essential enzyme that is demonstrated a statistically superior eradication rate for causative ophthalmic dose for ZYMAR).
involved in the [replication, transcription and repair of bacterial pathogens of 92% (48/52) for gatioxacin vs. 72% (34/48) for
DNA. Topoisomerase IV is an enzyme known to play a key role placebo. Please note that microbiological eradication does not Pregnancy: Teratogenic Effects. Pregnancy Category C:
in the partitioning of the chromosomal DNA during bacterial cell always correlate with clinical outcome in antiinfective trials. There were no teratogenic effects observed in rats or rabbits
division. following oral gatioxacin doses up to 50 mg/kg/day
INDICATIONS AND USAGE (approximately 1000-fold higher than the maximum recommended
The mechanism of action of uoroquinolones including
gatioxacin is different from that of aminoglycoside, macrolide, ZYMARsolution is indicated for the treatment of bacterial ophthalmic dose). However, skeletal/craniofacial malformations
and tetracycline antibiotics. Therefore, gatioxacin may be active conjunctivitis caused by susceptible strains of the following or delayed ossication, atrial enlargement, and reduced fetal
against pathogens that are resistant to these antibiotics and these organisms: weight were observed in fetuses from rats given 150 mg/kg/day
antibiotics may be active against pathogens that are resistant to Aerobic Gram-Positive Bacteria: (approximately 3000-fold higher than the maximum recommended
gatioxacin. There is no cross-resistance between gatioxacin Corynebacterium propinquum* ophthalmic dose). In a perinatal/postnatal study, increased late
and the aforementioned classes of antibiotics. Cross resistance post-implantation loss and neonatal/perinatal mortalities were
Staphylococcus aureus
has been observed between systemic gatioxacin and some other observed at 200 mg/kg/day (approximately 4500 times the
Staphylococcus epidermidis maximum recommended ophthalmic dose). Because there are
uoroquinolones.
Resistance to gatioxacin in vitro develops via multiple-step Streptococcus mitis* no adequate and well-controlled studies in pregnant women,
mutations. Resistance to gatioxacin in vitro occurs at a general Streptococcus pneumoniae ZYMAR solution should be used during pregnancy only if the
frequency of between 1 x 10-7 to 10-10. Aerobic Gram-Negative Bacteria: potential benet justies the potential risk to the fetus.
Gatioxacin has been shown to be active against most strains Haemophilus infuenzae Nursing Mothers: Gatioxacin is excreted in the breast milk
of the following organisms both in vitro and clinically, in of rats. It is not known whether this drug is excreted in human
*Efcacy for this organism was studied in fewer than 10
conjunctival infections as described in the INDICATIONS AND milk. Because many drugs are excreted in human milk, caution
infections.
USAGE section. should be exercised when gatioxacin is administered to a nursing
CONTRAINDICATIONS woman. Pediatric Use: Safety and effectiveness in infants below
Aerobes, Gram-Positive:
ZYMAR solution is contraindicated in patients with a history of the age of one year have not been established.
Corynebacterium propinquum* Staphylococcus aureus Staphy-
lococcus epidermidis Streptococcus mitis* [Streptococcus pneu- hypersensitivity to gatioxacin, to other quinolones, or to any of Geriatric Use: No overall differences in safety or effectiveness
moniae the components in this medication. have been observed between elderly and younger patients.
Aerobes, Gram-Negative: WARNINGS ADVERSE REACTIONS
Haemophilus inuenzae NOT FOR INJECTION. Ophthalmic Use: The most frequently reported adverse events
24
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ALPHARMA
SPDI
in the overall study population were conjunctival irritation, 8.3 In breast feeding women
increased lacrimation, keratitis, and papillary conjunctivitis. As progesterone is a natural hormone, it is not expected to DUMOZOL 250 and 500 mg Tablets
These events occurred in approximately 5-10% of patients. Other have adverse effects, however, no evidence is available to DUMOZOL 25 mg/ml Suspension.
reported reactions occurring in 1-4% of patients were chemosis, this effect.
conjunctival hemorrhage, dry eye, eye discharge, eye irritation, 8.4 In the elderly
eye pain, eyelid edema, headache, red eye, reduced visual acuity
Not applicable. (Metronidazole)
and taste disturbance.
8.5 Persons with specic pathological conditions
DOSAGE AND ADMINISTRATION 1. IDENTIFICATION
Progesterone is metabolized in the liver and should be used
The recommended dosage regimen for the treatment of with caution in patients with hepatic dysfunction. 1.1 Trade name: DUMOZOL
bacterial conjunctivitis is: Days 1 and 2: Instill one drop every 8.6 Potential effects on the ability to drive and use 1.2 Generic name: Metronidazole.
two hours in the affected eye(s) while awake, up to 8 times daily. machines 2./3. FORM AND STRENGTHS:
Days 3 through 7: Instill one drop up to four times daily while None known. Tablets 250mg and 500mg.
awake.
8.7 Details of excipients Suspension 25mg/ml
HOW SUPPLIED None.
4. PHARMACO-THERAPEUTIC GROUP:
ZYMAR(gatioxacin ophthalmic solution) 0.3% is supplied 9. INSTRUCTIONS FOR PROPER USE
sterile in a white, low density polyethylene (LDPE) bottle with a Metronidazole is active against Trichomonas vaginalis, Giardia
9.1 Dosage lamblia, and Entamoeba histolytica. Metronidazole is also active
controlled dropper tip and a tan, high impact polystyrene (HIPS)
cap in the following size: Adults: 200mg daily to 400mg twice a day, by vaginal or against a wide range of obligate anaerobic bacteria, including
rectal insertion. For premenstrual syndrome commence Bacteroides spp., Fusobacterium spp,, and Clostridium spp.,
5 mL bottle
treatment on day 14 of menstrual cycle and continue various anaerobic cocci, and Gardnerella vaginalis. Its action is
10 mL (N.R) bottle treatment until onset of menstruation. If symptoms are trichomonacidal, amoebacidal, and bactericidal.
Note: Store at 15-25C (59-77F). Protect from freezing. present at ovulation commence treatment on day 12.
5. THERAPEUTIC INDICATIONS
ANIMAL PHARMACOLOGY 9.2 The method and route of administration
Prevention and treatment of infections caused by micro-
Quinolone antibacterials have been shown to cause bone or For rectal or vaginal insertion. organisms susceptible to metronidazole, such as trichomoniasis,
cartilage changes in immature animals. There was no evidence 9.3 Duration of treatment bacterial vaginosis, amoebiasis, giardiasis, anaerobic infections,
of bone cartilage changes following ocular administration of Individually, see point 10.1 above. Crohns disease, and ulcerative gingivitis.
gatioxacin in rabbits or dogs. 9.4 Overdose 6. ACTIVE AND INACTIVE INGREDIENTS AND THEIR
There is a wide margin of safety with CYCLOGEST QUANTITIES
pessaries, but overdosage may produce euphoria or
ALPHARMA dysmenorrhoea.
Tablets:
P.O.BOX 215, RIYADH 11411 Active ingredients: Metronidazole 250mg and 500mg, Inactive
9.5 Action to be taken when one or more doses have not ingredients: Sodium carboxymethylcellulose, cross linked,
SAUDI ARABIA been taken lactose monohydrate, povidone, magnesium stearate, maize
TEL :01-4769669, 014785199, FAX:014785199 The patient should continue the treatment as prescribed. starch, microcrystalline cellulose.
9.6 Indication the risk of withdrawal effects Filmcoating: Opadry Y-I-7000 (hydroxypropylmethyl
CYCLOGEST 200 mg, 400mg Pessaries None. cellulose, titanium dioxide, polyethyleneglycol 400).
10. UNDESIRABLE EFFECTS Suspension:
Menstruation may occur earlier than expected, or, more Active ingredients: Metronidazole 25 mglml.
(Progesterone) rarely, menstruation may be delayed. Soreness, diarrhea and Inactive ingredients: Methyl parahydroxybenzoate, propyl
atulence may occur with rectal administration. As with other parahydroxybenzoate, Sunset Yellow (C.I.No. 15985, E-110),
1. IDENTIFICATION vaginal and rectal preparations, some leakage of the pessary Blood Orange 50.407 A, hypromellose, carmgeenan (E-407),
1.1 Trade name: CYCLOGEST base may occur. colloidal anhydrous silica, polysorbate 20, sorbitan trioleate,
1.2 Generic name: Progesterone. ethanol, antifoam M I0, potassium chloride, puried water.
11. REFERENCE TO THE EXPIRY DATE:
2./3. FORM AND STRENGTHS: 36 months from the date of manufacture. 7. A LIST OF INFORMATION
Pessaries each containing 200mg and 400mg progesterone. 7.1 Contra-indications
12. STORAGE CONDITIONS:
In the treatment of amoebiasis, giardiasis, and anaerobic
4. PHARMACO-THERAPEUTIC GROUP: Store below 25C in a dry place. infections where high doses are required: blood dyscrasias
Progesterone is a progestational steroid. 13. WARNING AGAINST VISIBLE SIGNS OF DETERIO- and active non-infectious disease in the central nervous
RATION: system.
5. THERAPEUTIC INDICATIONS
Do not use the medicine. 7.2 Precautions
1) Treatment of premenstrual syndrome, including premenstrual
tension and depression. - False negative syphilis serology has been observed in
DUMOZOL 1% Cream patients receiving metronidazole,
2) Treatment of puerperal depression.
- The dose should be reduced in the presence of severe liver
6. ACTIVE AND INACTIVE INGREDIENTS AND THEIR insufciency.
QUANTITIES (Metronidazole) - If abnormal neurological symptoms occur during oral
Each pessary contains as active ingredients 200mg and 400mg or intravenous metronidazole therapy, the patient should
progesterone. COMPOSITION be observed closely and the benet of continued therapy
Inactive ingredient: Vegetable fat. Each gram contain metronidazole 10 mg should be weighed against the risks.
PHARMACEUTICAL FORM - Metronidazole should be used with caution in patients
7. A LIST OF INFORMATION with evidence or a history of blood dyscrasias, and total
Cream
7.1 Contra-indications and differential leukocyte counts should be. Performed
Undiagnosed vaginal bleeding. PHARMACODYNAMICS before and after treatment with the drug, especially when
7.2 Precautions Metronidazole is active against protozoas and certain anaerobic repeated courses of therapy are necessary.
bacteria. Its precise mode of action against rosacea is unknown. - The use of oral or intravenous metronidazole may result
Use vaginally if patients suffer from colitis or faecal
The clinical effect is presumed to be a combined anti-inammatory in oral, vaginal, or intestinal candidiasis. If suprainfection
incontinence. Use rectally if patients suffer from vaginal and immunological response. or superinfecti0n occurs, appropriate therapy should be
infection (especially moniliasis) or recurrent cystitis. Use
DUMOZOL 1% cream does not appear to affect the normal ora instituted.
rectally in patients who have recently given birth. Use
of the skin. 7.3 Drug and food interactions
rectally if barrier methods of contraception are used.
Progesterone is metabolized in the live and should be used PHARMACOKINETICS - Concomitant use of metronidazole and phenobarbital
Precutaneous absorption of traces of metronidazole have been appears to decrease the serum half-life of metronidazole,
with caution in patients with hepatic dysfunction.
detected in a few patients, but in such small quantities that presumably by increasing metabolism of the anti-
CYCLOGEST contains the hormone progesterone which infective.
is present in signicant concentrations in women during the systemic effect can be excluded
- Initiation of short-term metronidazole therapy in patients
second half of the menstrual cycle and during pregnancy. INDICATIONS stabilised on a relatively high dosage of lithium has
This should be borne in mind when treating patients with Rosacea been reported to increase serum lithium concentrations,
conditions that may be hormone-sensitive. resulting in signs of lithium toxicity in several patients; in
PRECAUTIONS
7.3 Drug and food interactions some cases signs of renal damage were present.
Should not come into contact with eyes. Exposure to strong sunlight
None known. - The possibility that metronidazole may interact with
and sun lamps should be avoided for four hours after application of
the cream (UV irradiation may break down metronidazol) Terfenadine and Astemizole, resulting in serious adverse
8. SPECIAL WARNINGS
cardiovascular effects, should be considered,
8.1 In children PREGNANCY AND LACTATION - Cimetidine is an enzyme inhibitor that can decrease
Not applicable. DUMOZOL 1% cream is not contra-indicated . the hepatic metabolism of metronidazole. As a result,
8.2 In pregnant women elimination can be delayed and. serum metronidazole
SIDE EFFECTS
Due to the indications of the product, it is anticipated concentrations can increase, the sequelae of this
No serious effects have been observed. Dryness of skin, itching, interaction are unclear, although prolonged administration
that it will not be administered to pregnant women. As stinging and reddening are reported occasionally.
progesterone is a natural hormone, it is not expected to have of metronidazole has been associated with seizures.
adverse effects, however, no evidence is available to this DOSAGE If possible, cimetidine should not be used during
effect. Adults: 1-2 applications a day for 1-2 months metronidazole therapy.
25
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ALPHARMA
SPDI
- The potential of neurotoxicity can be increased 10. UNDESIRABLE EFFECTS DOSAGE AND ADMINISTRATION:
when metronidazole is used with other neurotoxic The variation in the reported frequency must be seen in relation According to the physicians prescription, or: 1 suppository every
medications.. to the different indications for which metronidazole is used and 8 hours for 3 days, then every 12 hours
- Metronidazole may potentiate the anticoagulant activity the considerable variation in the dosage pattern. Side effects are
of warfarin. PRECAUTIONS:
generally dose related.
- Metronidazole may induce a disulram-like reaction with - Patients should be advised not to drink alcohol during
Gastrointestinal effects; The most frequent adverse reaction
alcohol. treatment.
to oral metronidazole is nausea and anorexia. Other occasional
- Concomitant intake with disulram may cause acute adverse gastrointestinal effects include vomiting, diarrhea, - Prolonged courses of treatment should be avoided.
confusional states. Special warnings in children none. epigastric distress, abdominal discomfort, constipation, - Keep out of reach of children.
dyspepsia, and unpleasant metallic taste.
8. SPECIAL WARNINGS CONTRAINDICATIONS:
Nervous system effects: Peripheral neuropathy, characterized
8.1 In childen Although AMRIZOLE suppositories are well tolerated, yet
by numbness, tingling or paresthesia of an extremity,
None as with other drugs, they should not be taken during pregnancy
convulsive seizures, unconsciousness, and polyneuropathy
and lactation. Also they are contra indicated in known cases of
8.2 In pregnant women have been reported rarely with oral or intravenous,
metronidazole sensitivity
Metronidazole crosses the placenta. The drug should only metronidazole. Polyneuropathy, which is generally reversible,
be given in the rst trimester on compelling grounds. occurs most often with relatively high doses and a long period SIDE EFFECTS:
8.3 In breast feeding women of treatment. Mild side effects may appear such as headache, malaise,drowsiness
Metronidazole occurs in breast mill< in concentrations Peripheral neuropathy is usually reversible if metronetronidazole transient rashes, anorexia, nausea, gastro-intcstinal disturbances,
similar to those found in the maternal plasma. Breast-feeding is discontinued but may persist in patients who receive and darkening of the urine
mothers should preferably not be given metronidazole. prolonged therapy or higher than recommended dosage of the
DRUG-DRUG INTERACTION:
drug. Dizziness, vertigo, incoordination, ataxia, confusion,
8.4 In the elderly . Metronidazole enhances the activity of Warfarin; so in patients
irritability, depression, weakness, insomnia, headache,
None. syncope, tinnitus, and hearing loss have also occurred with receiving oral anticoagulants, the dose of the anticoagulant should
8.5 Persons with specic pathological conditions metronidazole. be recalibrated
The dose should be reduced in the presence of severe liver Blood: Less common: Leucopenia. Rare(<l/1000): PRESENTATION:
insufciency. Agranylocytosis. Box containing 5 suppositories.
Metronidazole should be used with caution in patients with Genitourinary effects. Darkening of the urine, urethral
evidence or a history of blood dyscrasias, and total and STORAGE:
burning or discomfort, dysuria, cystitis, polyuria, incontinence;
differential leukocyte counts should be performed before Protect from light and heat.
a sense of pelvic pressure, dryness of the vagina or vulva,
and after treatment with the drug, especially when repeated
dyspareunia and decreased libido have been reported with oral
courses of therapy are necessary. AMRIZOLE Vaginal suppositories
metronidazole.
8.6 Potential effects on the ability to drive and use
Sensitivity&reactions: Hypersensitivity reactions including
machines
urticaria, pruritus, erythematous rash, itching, ashing, nasal
No adverse effects are expected. congestion, and fever and eeting joint pains sometimes
(Metronidazole)
8.7 Details of.excipients resembling serum sickness have been reported in patients.
Antiprotozoal - Anaerobicidal
None. Receiving oral metronidazole.
Other adverse effects: Furry tongue, glossitis, and stomatitis COMPOSITION:
9. INSTRUCTIONS FOR PROPER USE
have been reported with oral metronidazole and may be due to Each Vaginal supp. contains:
9.1 Dosage overgrowth of Candida which may occur during metronidazole Metronidazole 500 mg
Protozoal infections Adults Children therapy. Thrombophlebitis has been reported after intravenous
infusion of metronidazole. PROPERTIES:
Oral administration
Metronidazole, is the active constituent in Amrizole vaginal
Trichomoniasis 2g in a single dose, 11. REFERENCE TO THE EXPIRY DATE:
suppositories. Metronidazole was proven to be an effective agent
or 250mg twice a day Tablets: 5 years. for the prophylaxis and treatment of Protozoal infections as
for 6 days Suspension: 3 years. Trichomonas vaginalis, and of anaerobic vaginal infections like
Bacterial vaginosis 500mg a day for 7 days, those with bacteroides, Clostridia, Fusobacteria... etc.
or 2g on the rst and 12. STORAGE CONDITIONS:
Store below 25C, away from light The local action of Amrizole vaginal suppositories has the
third day
advantage of reducing the anaerobic population of the female
Amoebiasis, acute 2g once a day for 3 days, 35- 50mg/-kg/day 13. WARNING AGAINST VISIBLE SIGNS OF DETERIO- genital tract without a signicant systemic effect.
Amoebic dysentery, or 750mg every 8 hours divided into 3 RATION:
Amoebic liver for 5 -10 days doses for 5 days INDICATIONS:
Do not use the medicine.
abscess - Prophylaxis and treatment of Trichomonas vaginalis.
Asymptomatic 750mg every 8 hours 25-40mg/kg/day - Prophylaxis and treatment of anaerobic vaginal infections
Intestinal amoebiasis for 10 days divided into 2 AMARIYA PHARMA INDUSTRIES including those with bacteroides, Clostridia, or Fusobacteria
Doses for 5-10
days
P.O BOX 42, JEDDAH- 21411, SAUDI ARABIA CONTRAINDICATIONS:
TEL: 02-6441111 EXT:750, FAX: 02-6441256 Known hypersensitivity to Metronidazole.
Giardiasis 2g once a day for 2-3 25-40mg/kg/day
days Or 250 mg every divided into 2 MOB: 0504199647
WARNING:
8 hours for 7 days doses for 7 days
The use of Amrizole vaginal suppositories during pregnancy and
Anaerobic infections Adults Children AMRIZOLE Suppositories lactation should be under strict medical supervision.
Oral administration
Treatment 500mg every 8 hours 30-50mg/kg/day SIDE EFFECTS:
(Metronidazole) Rarely, it may cause darkening of urine or transient rashes.
Divided into 3
doses Antimicrobial - Antiprotozoal - Anacrobicidal DOSAGE:
Prophylaxis 1g about 2 hours 25mg/kg 2 hours
COMPOSITION: One vaginal suppository daily for 10 days.
before surgery before surgery
Followed by 30- 50mg/kg/day Each suppository contains 1000 mcg metronidazole. N.B. Concomitant treatment of the sexual partner is strongly
500mg every 8 hours
postoperatively divided into 3 recommended (1 Amrizole tablet 250 mg three times daily for 10
PROPERTIES: days).
doses
AMRIZOLE rectal suppository is a very effective drug: product
PRESENTATION:
Ulcerative gingivitis for the prophylaxis and treatment of anaerobic infections in
patients undergoing abdominal and gynecological surgeries as it A box of 5 suppositories.
Adults: 250mg every 8 hours for 3 days.
Crohns disease is a very powerful bactericide. Recently, it has been reported that
Adults: 500mg twice a day.
rectally administered metronidazole was clinically as effective as CAFAMOL Tablets
an intravenous dosage form, it can pass the blood/ brain barrier
Children: 15mg/kg/day divided into 2 doses. and also rapidly reaches therapeutic concentrations in most other
9.2 The method and route of administration body uids. AMRIZOLE suppositories are also effective in (Paracetamol, Doxylamine succinate, Caffeine)
Tablets and suspension for oral administration. cases of urogenital trichomoniasis, amaebiasis, giardiasis, and
acute ulcerative gingivitis (Vincents infection) which is caused by For headache - Pain - fever - Common Cold - Flu - Catarrh
9.3 Duration of treatment
gram-negative anaerobic microorganisms.
Individually, see point I0. I above, COMPOSITION:
9.4 Overdose INDICATIONS:
Each tablet conlains
Symptoms: Ingestion of 12g metronidazole has. been - Treatment and prevention of anaerobic infections such as:
Paracetamol 450mg
reported, to cause vomiting and oliguria during the rst 12 septicaemia, puerperal sepsis, bacteraemia, brain abscess, pelvic
Dopamine succinate 3mg
hours, but otherwise no symptoms, cellulitis, peritonitis, acute necrotizing ulcerative gingivitis
Caffeine 30mg
(Vincents infection) and postoperative wound infection,
Treatment: Symptomatic.
specially those caused by anaerobic bacteria. PROPERTIES:
9.5 Action to be taken when one or more doses have not - Treatment of giardiasis and Vincents infection.
been taken * CAFAMOL is an excelled preparation for relieving headache
- Treatment of infections of trichomoniasis of the genito-urinary painr fever and catarrh and is particularly useful in the
The patient should continue the treatment as prescribed. tract in males and females management of common cold inuenza. The drug combination
9.6 Indication - the risk of withdrawal effects - Treatment of amoebic liver abscess. -Treatment of amoebic includes a non-aspirin analgesic-antipyretic, an antihistamine
None. dysentery. and a natural stimulant.
26
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AMGEN
SPDI
* Paracetamol has analgesic and antipyretic properties equivalent SIDE-EFFECTS:
to those of acetylsalicylic acid (aspirin) without undesirable KETOFAN Tablets No adverse effects attributable to SPASMOTALIN have been
sideeffects. reported after the use of the drug in therapeutic doses
* Doxylamine Succinate is one of the most active antihistamine
that gjves symptomatic relief of allergic manifestations, catarrh
(Ketoprofen) CONTRA INDICATIONS
and watery eyes Contraindications to the use of SPASMOTALIN are not known
Fast acting analgesic As atropine-like side-effects are absent. SPASMOTALIN
* Caffeine is benecial in relieving certain types of headache
through cerebral vascular constriction. The stimulant effect COMPOSITION: is not contra indicated in patients with glaucoma or prostatic
of cafene offsets the drowsiness which may occur with the Each tablet contains.: hypertrophy
antihistaminic component. Ketoprofen ..25mg PRECAUTIONS
INDICATIONS: PROPERTIES: Though experiments in rats and rabbits have shown that mebeverine
* Pains of mild to moderate intensity such as headache, neuralgia, hydrochloride is not teratogenic in these species administration of
Ketoprofen Is a powerful nonsteroidal analgesic. It has a very
arthralgia and toothaches rapid onset of action (within one hour); and higher peak effect SPASMOTALIN is to be discouraged during pregnancy
* Common cold, u. fever, allergic rhinitis, acute rhinitis and than other non-steroidal analgesic & antipyretic drugs. It is rapidly PRESENTATION:
rhinosinusitis absorbed from the gastrointestinal tract. It is preferred to be taken
Box containing 2 strips, 10 tablets each
DOSAGE: after meals.
Adults: 1-2 tablets three times daily. INDICATIONS:
Children (over 6 years). 1/2-1 tablet three times daily. KETOFAN can he used far rapid onset of analgesic effect for AMGEN
pain of various origins such as: P.O.BOX: 991, RIYADH: 11421
PRECAUTIONS:
Dental Pain and Dental surgery pain. SAUDI ARABIA
CAFAMOL should be used with care in patients suffering from
elevated blood pressure, coronary insufciency hyperthyroidism * Postpartum pain. TEL: 01-4027077, FAX: 01-4612695
or diabetes mellitus * Dysmenorrhea.
Post-operative, and post-fracture pain.
CONTRA- INDICATIONS; Orthopedic pain. ARANESP Injection
* Hypersensitivity to any of its components. Headache.
* Patients with impaired renal or hepatic function * Rheumatic pain, osteoarthritis, periarthritis, sciatica, lumbago,
neuralgia, Cramps, and inammatory rheumatism.
(Darbepoetin alfa)
PRESENTATION:
Box containing 20 tablets DOSAGE & ADMINISTRATION: DESCRIPTION:
For Acute Pain: Initial dose: 2 tablets to be followed by 1 tablet ARANESP is an erythropoiesis stimulating protein, closely
If necessary after meals. Total dose should not exceed 5-6 tablets related to erythropoietin, that is produced in Chinese hamster
DEPOVIT B12 1000 Injection / day. ovary (CHO) cells by recombinant DNA technology. ARANESP
For chronic pain; initial dose: 1 or 2 tablets to be followed by 1 is a 165-amino acid protein that differs from recombinant human
(Hydroxocobalamin acetate) tablet if necessary after meals. Total dose should not exceed 3-4 erythropoietin in containing 5 N-linked oligosaccharide chains,
tablets / day. whereas recombinant human erythropoietin contains 3 chains1.
Vitamin B12 Long Acting The two additional N-glycosylation sites result from amino acid
SIDE EFFECTS: substitutions in the erythropoietin peptide backbone.
(Hydroxocobalamin 1000 mg/ml)
Biological tolerance of Ketoprofen is excellent: no signicant The additional carbohydrate chains increase the approximate
PROPERTIES : change In the hemogram. Or In the hepatic and kidney function molecular weight of the glycoprotein from 30,000 to 37,000
DEPOVIT B12 is a vitamin B12 preparation with prolonged tests was observed . daltons. ARANESP is formulated as a sterile, colorless,
action. The only side effect reported during the use of Ketoprofen was preservative-free protein solution for intravenous (IV) or
Vitamin B12 is essential to growth, cell reproduction, mainly digestive disorders (gastric pain, nausea). Generally the subcutaneous (SC) administration.
hematopoiesis. nucleoprotein and myelin synthesis. side effects were mild and transient.
Single-dose vials (N.R.) are available containing 25, 40, 60, 100,
Vitamin B12 deciency brings about the fatal disease of PRECAUTIONS: 150, 200, 300, or 500 mcg of ARANESP.
megaloblastic anaemia and/or neurological symptoms. Single-dose prelled syringes are available containing 25(N.R),
- Ketoprofen is highly protein-bound and might necessitate
DEPOVIT B12 (Hydroxocobalamin) with prolonged action is dosage adjustment of concomitantly administered protein- 40, 60, 100, 150, 200(N.R), 300, or 500 mcg of ARANESP. To
the only practicable method of restoring body needs of vitamin bound drugs. reduce the risk of accidental
B12.
- Ketoprofen should be given with caution to pregnant and needlesticks to users, each prelled syringe is equipped with a
DEPOVIT B12 has the advantage of being painless and causes lactatlng women. needle guard that covers the needle during disposal. Single-dose
no local reactions. vials and prelled syringes are available in two formulations that
CONTRA-INDICATION:
INDICATIONS : contain excipients as follows:
Active peptic ulceration or history of recurrent peptic ulceration.
Pernicious anaemia, both uncomplicated and accompanied by - Polysorbate solution Each 1 mL contains 0.05 mg polysorbate
nervous system involvement. - Ketoprofen Is contra Indicated In bronchial asthma, and In 80, and is formulated at pH 6.2 0.2 with 2.12 mg sodium
cases of sensitivity to acetyl-salicylLc acid (aspirin) and other phosphate monobasic monohydrate, 0.66 mg sodium phosphate
Macrocytic anaemia or neuropathies caused by Inadequate non-steroidal anti-inammatory agents.
supply or absorption of vitamin B12 such as : dibasic anhydrous, and 8.18 mg sodium chloride in Water for
PRESENTATION: Injection, USP (to 1 mL).
- after resection of the stomach for gastric and duodenal ulcers,
after ileocaecal resection and proctotomy with ileostomy A box Containing 2 strips, 10 tablets each. - Albumin solution Each 1 mL contains 2.5 mg albumin
- inadequate nutrition, whether caused by undernourishment or (human), and is formulated at pH 6.0 0.3 with 2.23 mg sodium
phosphate monobasic monohydrate, 0.53 mg sodium phosphate
Inappropriate diet, applying especially to elderly people and SPASMOTALIN Tablets dibasic anhydrous, and 8.18 mg sodium chloride in Water for
vegetarians whose diet is wholly without animal protein.
- in tropical sprue, vitamin B12 deciency and subsequent
OTC Injection, USP (to 1 mL).
megaloblastic anaemia are common; even in patients treated for (Mebeverine Hydrochloride) CLINICAL PHARMACOLOGY
years with conventional doses of folic acid, the serum levels MECHANISM OF ACTION
of vitamin B12 are found to be low. It has been reported that Selective Spasmolytic
vitamin B12 is as therapeutically effective as folic acid in the ARANESP stimulates erythropoiesis by the same mechanism
COMPOSITION: as endogenous erythropoietin. A primary growth factor for
treatment and management of patients with tropical sprue.
Each tablet contains: erythroid development, erythropoietin is produced in the kidney
- In some cases pregnancy may cause a drop in vitamin B12
4-{Ethyl (4-methoxy- - methylphenethyl) amino} - butyl and released into the bloodstream in response to hypoxia. In
serum concentrations.
veratrate hydrochloride; responding to hypoxia, erythropoietin interacts with progenitor
Total gastrectomy. stem cells to increase red blood cell (RBC) production. Production
Mebeverine Hydrochloride..................... 100 mg
Neurologists and neurosurgeons use aqueous solutions of of endogenous erythropoietin is impaired in patients with chronic
vitamin B12 to a great extent in neurological disorders of PROPERTIES: renal failure (CRF), and erythropoietin deciency is the primary
various aetiologies, especially in painful conditions such as cause of their anemia. Increased hemoglobin levels are not
SPASMOTALIN tablets contain Mebeverine hydrochloride
neuritis, radiculitis, trigeminal neuralgia, and in herpes zoster. generally observed until 2 to 6 weeks after initiating treatment
which is a myotropic spasmolytic with a strong and selective
Vitamin B12 has also proved efcacious in male and female action on the smooth muscle spasms of the gastro-intestinal tract with ARANESP (see DOSAGE AND ADMINISTRATION:
Infertility caused by hypovitaminosls B12. particularly of the colon. It is not an anticholinergic drug Dose Adjustment). In patients with cancer receiving concomitant
CONTRAINDICATIONS: chemotherapy, the etiology of anemia is multifactorial.
INDICATIONS:
Not to be used for newborn babies. PHARMACOKINETICS
Spastic functional disturbances of the colon.
DOSAGE AND ADMINISTRATION : Adult Patients:
Irritable colon syndrome in its primary form.
- Usual dose : initially : 1 - 3 ampoules every week. The pharmacokinetics of ARANESP were studied in patients
Colonic irritation associated with organic lesions of the
maintenance treatment 1 ampoule every month, with CRF and cancer patients receiving chemotherapy.
gastrointestinal tract such as diveticulosis and diverticulitis of the
severe cases : 1 ampoule per day. Following intravenous (IV) administration in CRF patients,
colon, intestinal amoebiasis, regional enteritis, diseases of the gall-
- For anaemia : Initially : 1 ampoule every 6 weeks. ARANESP serum concentration-time proles were biphasic,
bladder and bile ducts (biliary dyskinesia), gastric and duodenal
maintenance treatment : 1 ampoule every 4-6 weeks. with a distribution half-life of approximately 1.4 hours and a
ulcers, dysentery {whether or not anamnestic) and aspecic or
mean terminal half-life of 21 hours. The terminal half-life of
- For Hypovitaminosis : 1 ampoule every week for 10 weeks. specic inammations of the digestive tract
ARANESP was approximately 3-fold longer than that of epoetin
DEPOVIT Bl2 ampoule should be given intramuscularly.
DOSAGE: alfa when administered intravenously.
PRESENTATION : One tablet 3 - 4 times daily, preferably 20 minutes before meals. Following subcutaneous (SC) administration, absorption is slow
2 ampoules of 1 ml each. In a folding box. When the desired effect has been obtained, the dosage may be and rate limiting. The observed half-life in CRF patients, which
Keep the medicine out ot reach of children. reduced gradually after few weeks reected the rate of absorption, was 49 hours (range: 27 to 89
27
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AMGEN
SPDI
hours). Peak concentrations occurred at 34 hours (range: 24 to 72 with ARANESP and 338 patients continued on Epoetin alfa. WARNINGS
hours). The bioavailability of ARANESP as measured in CRF Study N4 was an open-label study conducted in Europe and Cardiovascular Events, Hemoglobin, and Rate of Rise of
patients after SC administration was 37% (range: 30% to 50%). Australia in which 347 patients were randomized to treatment Hemoglobin ARANESP and other erythropoietic therapies
Following the rst SC dose of 6.75 mcg/kg (equivalent to 500 mcg with ARANESP and 175 patients were randomized to continue may increase the risk of cardiovascular events, including death.
for a 74-kg patient) in patients with cancer, the mean terminal half- on Epoetin alfa or Epoetin beta. Of the 347 patients randomized The higher risk of cardiovascular events may be associated with
life of 74 hours (range: 24 to 144 hours). to ARANESP, 92% were receiving hemodialysis and 8% were higher hemoglobin and/or higher rates of rise of hemoglobin. The
Peak concentrations were observed at 90 hours (range: 71 to 123 receiving peritoneal dialysis. hemoglobin level should be managed carefully to avoid exceeding
hours) after a dose of 2.25 mcg/kg, and 71 hours (range: 28 to In Study N3, a median weekly dose of 0.53 mcg/kg ARANESP a target level of 12 g/dL.
120 hours) after a dose of 6.75 mcg/kg. When administered on (25th, 75th percentiles: 0.30, 0.93 mcg/kg) was required to In a clinical trial of Epoetin alfa (rHuEPO) treatment in
a once - every - 3 - week (Q3W) schedule, 48-hour post - dose maintain hemoglobin in the study target range. hemodialysis patients with clinically evident cardiac disease,
ARANESP levels after the fourth dose were similar to those In Study N4, a median weekly dose of 0.41 mcg/kg ARANESP patients were randomized to a target hemoglobin of either 14
after the rst dose. Over the dose range of 0.45 to 4.5 mcg/kg (25th, 75th percentiles: 0.26, 0.65 mcg/kg) was required to 1 g/dL or 10 1 g/dL2. Higher mortality (35% vs 29%) was
ARANESP administered IV or SC on a once-weekly (QW) maintain hemoglobin in the study target range. observed in the 634 patients randomized to a target hemoglobin of
schedule and 4.5 to 15 mcg/kg administered SC on a once-every- 14 g/dL than in the 631 patients assigned a target hemoglobin of
Pediatric Patients
3-week (Q3W) schedule, systemic exposure was approximately 10 g/dL. The reason for the increased mortality observed in this
proportional to dose. No evidence of accumulation was observed Study N5 was an open-label, randomized study, conducted in the study is unknown; however, the incidence of nonfatal myocardial
beyond an expected < 2-fold increase in blood levels when United States in pediatric patients from 1 to 18 years of age with infarction, vascular access thrombosis, and other thrombotic events
compared to the initial dose. CRF receiving or not receiving dialysis. Patients that were stable was also higher in the group randomized to a target hemoglobin of
on Epoetin alfa were randomized to receive either darbepoetin 14 g/dL.
Pediatric Patients
alfa (n = 82) administered once weekly (SC or IV) or to continue In patients treated with ARANESP or other recombinant
ARANESP pharmacokinetics were studied in 12 pediatric CRF receiving Epoetin alfa (n=42) at the current dose, schedule, and
patients (age 3-16 years) receiving or not receiving dialysis. erythropoietins in ARANESP clinical trials, increases in
route of administration. A median weekly dose of 0.41 mcg/kg hemoglobin greater than approximately 1.0 g/dL during any
Following a single IV or SC ARANESP dose, Cmax and ARANESP (25th, 75th percentiles: 0.25, 0.82 mcg/kg) was 2-week period were associated with increased incidence of
half-life were similar to those obtained in adult CRF patients. required to maintain hemoglobin in the study target range. cardiac arrest, neurologic events (including seizures and stroke),
Following a single SC dose, the average bioavailability was 54% Cancer Patients Receiving Chemotherapy exacerbations of hypertension, congestive heart failure, vascular
(range: 32% to 70%), which was higher than that obtained in adult
Once-Weekly (QW) Dosing thrombosis/ischemia/infarction, acute myocardial infarction,
CRF patients.
The safety and effectiveness of ARANESP in reducing and uid overload/edema. It is recommended that the dose of
CLINICAL STUDIES: ARANESP be decreased if the hemoglobin increase exceeds
the requirement for RBC transfusions in patients undergoing
Throughout this section of the package insert, the ARANESP 1.0 g/dL in any 2-week period, because of the association of
chemotherapy was assessed in a randomized, placebo-controlled,
study numbers associated with the nephrology and cancer excessive rate of rise of hemoglobin with these events.
double-blind, multinational study (C1). This study was conducted
clinical programs are designated with the letters N and C, in anemic (Hgb 11 g/dL) patients with advanced, small cell or Hypertension
respectively. non-small cell lung cancer, who received a platinum-containing Patients with uncontrolled hypertension should not be treated with
Chronic Renal Failure Patients chemotherapy regimen. Patients were randomized to receive ARANESP; blood pressure should be controlled adequately
The safety and effectiveness of ARANESP have been assessed ARANESP 2.25 mcg/kg (n = 156) or placebo (n = 158) before initiation of therapy. Blood pressure may rise during
in a number of multicenter studies. Two studies evaluated the administered as a single weekly SC injection for up to 12 weeks. treatment of anemia with ARANESP or Epoetin alfa. In
safety and efcacy of ARANESP for the correction of anemia The dose was escalated to 4.5 mcg/kg/week at week six, in subjects ARANESP clinical trials, approximately 40% of patients with
in adult patients with CRF, and three studies (2 in adults and 1 in with an inadequate response to treatment, dened as less than 1 CRF required initiation or intensication of antihypertensive
pediatric patients) assessed the ability of ARANESP to maintain g/dL hemoglobin increase. There were 67 patients in the Aranesp therapy during the early phase of treatment when the hemoglobin
hemoglobin concentrations in patients with CRF who had been was increasing.
arm who had their dose increased from 2.25 to 4.5 mcg/kg/week,
receiving other recombinant erythropoietins. at any time during the treatment period. Hypertensive encephalopathy and seizures have been observed in
De Novo Use of ARANESP patients with CRF treated with ARANESP or Epoetin alfa.
Efcacy was determined by a reduction in the proportion of
In two open-label studies, ARANESP or Epoetin alfa was patients who were transfused over the 12 week treatment period. Special care should be taken to closely monitor and control
administered for the correction of anemia in CRF patients who had blood pressure in patients treated with ARANESP.
A signicantly lower proportion of patients in the ARANESP
not been receiving prior treatment with exogenous erythropoietin. During ARANESP therapy, patients should be advised of the
arm, 26% (95% CI: 20%, 33%) required transfusion compared
Study N1 evaluated CRF patients receiving dialysis; Study N2 importance of compliance with antihypertensive therapy and
to 60% (95% CI: 52%, 68%) in the placebo arm (Kaplan-Meier
evaluated patients not requiring dialysis (predialysis patients). dietary restrictions. If blood pressure is difcult to control by
estimate of proportion; p < 0.001 by Cochran - Mantel - Haenszel pharmacologic or dietary measures, the dose of Aranesp should be
In both studies, the starting dose of ARANESP was 0.45 mcg/kg test). Of the 67 patients who received a dose increase, 28% had a reduced or withheld (see DOSAGE AND ADMINISTRATION:
administered once weekly. The starting dose of Epoetin alfa was 2 g/dL increase in hemoglobin over baseline, generally occurring Dose Adjustment).
50 U/kg 3 times weekly in Study N1 and 50 U/kg twice weekly in between weeks 8 to 13. Of the 89 patients who did not receive
Study N2. When necessary, dosage adjustments were instituted to A clinically signicant decrease in hemoglobin may not be
a dose increase, 69% had a 2g/dL increase in hemoglobin over
maintain hemoglobin in the study target range of 11 to 13 g/dL. observed for several weeks.
baseline, generally occurring between weeks 6 to 13.
(Note: The recommended hemoglobin target is lower than Seizures
Once-Every-3-Week (Q3W) Dosing
the target range of these studies. See DOSAGE AND Seizures have occurred in patients with CRF participating in
The safety and effectiveness of Q3W ARANESP therapy in
ADMINISTRATION: General for recommended clinical clinical trials of ARANESP and Epoetin alfa. During the rst
reducing the requirement for red blood cell (RBC) transfusions in
hemoglobin target.) The primary efcacy endpoint was the several months of therapy, blood pressure and the presence of
patients undergoing chemotherapy was assessed in a randomized,
proportion of patients who experienced at least a 1.0 g/dL increase premonitory neurologic symptoms should be monitored closely.
double-blind, multinational study (C2). This study was conducted
in hemoglobin concentration to a level of at least 11.0 g/dL by While the relationship between seizures and the rate of rise
in anemic (hgb < 11 g/dL) patients with non-myeloid malignancies of hemoglobin is uncertain, it is recommended that the dose of
20 weeks (Study N1) or 24 weeks (Study N2). The studies were
receiving multicycle chemotherapy. ARANESP be decreased if the hemoglobin increase exceeds 1.0
designed to assess the safety and effectiveness of Aranesp but
not to support conclusions regarding comparisons between the two Patients were randomized to receive ARANESP at 500 mcg g/dL in any 2-week period.
products. Q3W (n = 353) or 2.25 mcg/kg (n = 352) administered weekly as Thrombotic Events And Increased Mortality
a SC injection for up to 15 weeks. In both groups, the dose was
In Study N1, the hemoglobin target was achieved by 72% (95% An increased incidence of thrombotic events has been observed in
reduced by 40% of the previous dose (e.g., for rst dose reduction,
CI: 62%, 81%) of the 90 patients treated with Aranesp and 84% patients treated with erythropoietic agents. In patients with cancer
to 300 mcg in the Q3W group and 1.35 mcg/kg in the QW group)
(95% CI: 66%, 95%) of the 31 patients treated with Epoetin alfa. who received ARANESP, pulmonary emboli, thrombophlebitis
if hemoglobin increased by more than 1 g/dL in a 14-day period.
The mean increase in hemoglobin over the initial 4 weeks of and thrombosis occurred more frequently than in placebo controls
ARANESP treatment was 1.10 g/dL (95% CI: 0.82 g/dL, 1.37 Study drug was withheld if hemoglobin exceeded 13 g/dL. In the
(see ADVERSE REACTIONS:
g/dL). Q3W group, 254 patients (72%) required dose reductions (median
time to rst reduction at 6 weeks). In the QW group, 263 patients Cancer Patients Receiving Chemotherapy, Table 4).
In Study N2, the primary efcacy endpoint was achieved by 93% In a randomized controlled study with another erythropoietic
(75%) required dose reductions (median time to rst reduction at
(95% CI: 87%, 97%) of the 129 patients treated with ARANESP product in 939 women with metastatic breast cancer receiving
5 weeks).
and 92% (95% CI: 78%, 98%) of the 37 patients treated with chemotherapy, patients received either weekly Epoetin alfa
Epoetin alfa. The mean increase in hemoglobin from baseline Efcacy was determined by a comparison of the Kaplan-Meier
or placebo for up to a year. This study was designed to prevent
through the initial 4 weeks of ARANESP treatment was 1.38 estimates of the proportion of patients who received at least one
anmia (maintain hemoglobin levels between 12 and 14 g/dL or
g/dL (95% CI: 1.21 g/dL, 1.55 g/dL). RBC transfusion between day 29 and the end of treatment. Three
hematocrit between 36 and 42%).
hundred thirty ve patients in the Q3W group and 337 patients in
Conversion From Other Recombinant Erythropoietins Treatment with Epoetin alfa was associated with a higher rate of
the QW group remained on study through or beyond day 29 and
Two adult studies (N3 and N4) and one pediatric study (N5) were were evaluated for efcacy. Twenty seven percent (95% CI: 22%, fatal thrombotic events (1.1% Epoetin alfa vs 0.2% placebo) in the
conducted in patients with CRF who had been receiving other 32%) of patients in the Q3W group and 34% (95% CI: 29%, 39%) rst 4 months of the study. Based on Kaplan-Meier estimates, the
recombinant erythropoietins. The studies compared the abilities in the weekly group required a RBC transfusion. The observed proportion of subjects surviving at 12 months after randomization
of ARANESP and other erythropoietins to maintain hemoglobin difference in the transfusion rates (QW-Q3W) was 6.7% (95% was lower in the Epoetin alfa group than in the placebo group
concentrations within a study target range of 9 to 13 g/dL in adults CI: -13.8%, 0.4%). (70% vs 76%), p = 0.012, log rank.
and 10 to 12.5 g/dL in pediatric patients. (Note: The recommended However, due to insufcient monitoring and data collection,
hemoglobin target is lower than the target range of these studies. INDICATIONS AND USAGE reliable comparisons cannot be made concerning the effect of
See DOSAGE AND ADMINISTRATION: ARANESP is indicated for the treatment of anemia associated Epoetin alfa on overall time to disease progression, progression-
General for recommended clinical hemoglobin target.) CRF with chronic renal failure, including patients on dialysis and free survival, and overall survival. Until further information is
patients who had been receiving stable doses of other recombinant patients not on dialysis, and for the treatment of anemia in patients available, the recommended target hemoglobin should not exceed
erythropoietins were randomized to ARANESP, or to continue with non-myeloid malignancies where anemia is due to the effect 12 g/dL in men or women.
with their prior erythropoietin at the previous dose and schedule. of concomitantly administered chemotherapy. Pure Red Cell Aplasia
For patients randomized to ARANESP, the initial weekly dose
CONTRAINDICATIONS Cases of pure red cell aplasia (PRCA) and of severe anemia,
was determined on the basis of the previous total weekly dose of
with or without other cytopenias, associated with neutralizing
recombinant erythropoietin. ARANESP is contraindicated in patients with:
antibodies to erythropoietin have been reported in patients
Adult Patients uncontrolled hypertension treated with ARANESP. This has been reported predominantly
Study N3 was a double-blind study conducted in North America, known hypersensitivity to the active substance or any of the in patients with CRF receiving ARANESP by subcutaneous
in which 169 hemodialysis patients were randomized to treatment excipients administration. Any patient who develops a sudden loss of
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Book_01.indd 28 6/4/2008 2:19:05 PM

AMGEN
SPDI
response to ARANESP, accompanied by severe anemia and erythropoietic products (ie, Epoetin alfa and Epoetin beta) with rabbits during gestation, no evidence of a direct embryotoxic,
low reticulocyte count, should be evaluated for the etiology of higher hemoglobin targets. The rst study was a randomized fetotoxic, or teratogenic outcome was observed at doses up to
loss of effect, including the presence of neutralizing antibodies to controlled study in 939 women with metastatic breast cancer 20 mcg/kg/day. The only adverse effect observed was a slight
erythropoietin (see PRECAUTIONS: Lack or Loss of Response to receiving chemotherapy where patients received either weekly reduction in fetal weight, which occurred at doses causing
ARANESP). If anti-erythropoietin antibody-associated anemia Epoetin alfa or placebo for up to a year. This study was designed exaggerated pharmacological effects in the dams (1 mcg/kg/day and
is suspected, withhold Aranesp and other erythropoietic proteins. to prevent anemia (maintain hemoglobin levels between 12 and higher). No deleterious effects on uterine implantation were seen
Contact Amgen (1-800-77AMGEN) to perform assays for binding 14 g/dL or hematocrit between 36 and 42%). particularly myeloid in either species. No signicant placental transfer of ARANESP
and neutralizing antibodies. ARANESP should be permanently malig Mortality at 12 months was signicantly higher in the was observed in rats. An increase in post implantation fetal loss
discontinued in patients with antibody-mediated anemia. Epoetin alfa arm (see WARNINGS: Thrombotic Events and was observed in studies assessing fertility (see PRECAUTIONS:
Patients should not be switched to other erythropoietic proteins Increased Mortality). Carcinogenesis, Mutagenesis, and Impairment of Fertility:
as antibodies may cross-react. (see ADVERSE REACTIONS: This difference was observed primarily in the rst 4 months of the Impairment of Fertility).
Immunogenicity). study with more deaths attributed to breast cancer progression in Intravenous injection of ARANESP to female rats every other
Albumin (Human) the Epoetin alfa group (6% Epoetin alfa vs 3% placebo). Due to day from day 6 of gestation through day 23 of lactation at dose of
ARANESP is supplied in two formulations with different insufcient monitoring and data collection, reliable comparisons 2.5 mcg/kg/dose and higher resulted in offspring (F1generation)
excipients, one containing polysorbate 80 and another cannot be made concerning the effect of Epoetin alfa on overall with decreased body weights, which correlated with a low
containing albumin (human), a derivative of human blood time to disease progression, progression-free survival, and overall incidence of deaths, as well as delayed eye opening and delayed
(see DESCRIPTION). Based on effective donor screening and survival. The second study was a randomized controlled study in preputial separation. No adverse effects were seen in the F2
product manufacturing processes, ARANESP formulated with 351 head and neck cancer patients where Epoetin beta or placebo offspring. There are no adequate and well-controlled studies in
albumin carries an extremely remote risk for transmission of viral was administered to achieve target hemoglobins of 14 and 15 g/dL pregnant women. ARANESP should be used during pregnancy
diseases. A theoretical risk for transmission of Creutzfeldt-Jakob for women and men, respectively. Locoregional progression-free only if the potential benet justies the potential risk to the fetus.
disease (CJD) also is considered extremely remote. No cases of survival was signicantly shorter (median of 406 days Epoetin Nursing Mothers:
transmission of viral diseases or CJD have ever been identied beta vs 745 days placebo, p = 0.04) in patients receiving Epoetin
It is not known whether ARANESP is excreted in human milk.
for albumin. beta.
Because many drugs are excreted in human milk, caution should
PRECAUTIONS There is insufcient information to establish whether use of be exercised when ARANESP is administered to a nursing
Epoetin products, including ARANESP, have an adverse effect woman.
General
on time to tumor progression or progression-free survival.
The safety and efcacy of ARANESP therapy have not been Pediatric Use
These studies permitted or required dosing to achieve a hemoglobin
established in patients with underlying hematologic diseases (e.g., Pediatric CRF Patients
level greater than 12 g/dL. Until further information is available,
hemolytic anemia, sickle cell anemia, thalassemia, porphyria). A study of the conversion from Epoetin alfa to ARANESP among
the recommended target hemoglobin should not exceed 12 g/dL
Lack or Loss of Response to ARANESP. in men or women. pediatric CRF patients over 1 year of age showed similar safety
A lack of response or failure to maintain a hemoglobin response and efcacy to the ndings from adult conversion studies (see
Laboratory Tests
with ARANESP doses within the recommended dosing range CLINICAL PHARMACOLOGY and CLINICAL STUDIES).
After initiation of Aranesp therapy, the hemoglobin should be Safety and efcacy in the initial treatment of anemic pediatric
should prompt a search for causative factors. Deciencies of folic
determined weekly until it has stabilized and the maintenance dose CRF patients or in the conversion from another erythropoietin to
acid, iron or vitamin B12 should be excluded or corrected.
has been established. (see DOSAGE AND ADMINISTRATION). ARANESP in pediatric CRF patients less than 1 year of age
Depending on the clinical setting, intercurrent infections, After a dose adjustment, the hemoglobin should be determined have not been established.
inammatory or malignant processes, osteobrosis cystica, occult weekly for at least 4 weeks, until it has been determined that the
blood loss, hemolysis, severe aluminum toxicity, and bone marrow Pediatric Cancer Patients
hemoglobin has stabilized in response to the dose change. The
brosis may compromise an erythropoietic response. hemoglobin should then be monitored at regular intervals. The safety and efcacy of ARANESP in pediatric cancer patients
In the absence of another etiology, the patient should be evaluated have not been established.
In order to ensure effective erythropoiesis, iron status should
for evidence of PRCA and sera should be tested for the presence be evaluated for all patients before and during treatment, as the Geriatric Use
of antibodies to erythropoietin (see WARNINGS: Pure Red Cell majority of patients will eventually require supplemental iron Of the 1598 CRF patients in clinical studies of ARANESP,
Aplasia). therapy. Supplemental iron therapy is recommended for all 42% were age 65 and over, while 15% were 75 and over. Of the
Hematology patients whose serum ferritin is below 100 mcg/L or whose serum 873 cancer patients in clinical studies receiving ARANESP and
Sufcient time should be allowed to determine a patients transferrin saturation is below 20%. concomitant chemotherapy, 45% were age 65 and over, while 14%
responsiveness to a dosage of ARANESP before adjusting the Information for Patients were 75 and over. No overall differences in safety or efcacy were
dose. Because of the time required for erythropoiesis and the observed between older and younger patients.
Patients should be informed of the possible side effects of
RBC half-life, an interval of 2 to 6 weeks may occur between ARANESP and be instructed to report them to the prescribing ADVERSE REACTIONS
the time of a dose adjustment (initiation, increase, decrease, or
physician. Patients should be informed of the signs and symptoms General
discontinuation) and a signicant change in hemoglobin.
of allergic drug reactions and be advised of appropriate actions. Because clinical trials are conducted under widely varying
In order to prevent the hemoglobin from exceeding the Patients should be counseled on the importance of compliance with
recommended target (12 g/dL) or rising too rapidly (greater than conditions, adverse reaction rates observed in the clinical trials of
their ARANESP treatment, dietary and dialysis prescriptions, ARANESP cannot be directly compared to rates in the clinical
1.0 g/dL in 2 weeks), the guidelines for dose and frequency of dose and the importance of judicious monitoring of blood pressure and
adjustments should be followed (see WARNINGS and DOSAGE trials of other drugs and may not reect the rates observed in
hemoglobin concentration should be stressed. practice.
AND ADMINISTRATION: Dose Adjustment)
It is recommended that ARANESP should be administered by a Immunogenicity
Allergic Reactions healthcare professional. In those rare cases where it is determined
There have been rare reports of potentially serious allergic that a patient can safely and effectively administer ARANESP at As with all therapeutic proteins, there is a potential for
reactions, including skin rash and urticaria, associated with home, appropriate instruction on the proper use of ARANESP immunogenicity. Neutralizing antibodies to erythropoietin, in
ARANESP. Symptoms have recurred with rechallenge, should be provided for patients and their caregivers, including association with PRCA or severe anemia (with or without other
suggesting a causal relationship exists in some instances. If a careful review of the accompanying Information for Patients cytopenias), have been reported in patients receiving ARANESP
serious allergic or anaphylactic reaction occurs, ARANESP insert. Patients and caregivers should also be cautioned against (see WARNINGS: Pure Red Cell Aplasia) during post-marketing
should be immediately and permanently discontinued and the reuse of needles, syringes, or drug product, and be thoroughly experience.
appropriate therapy should be administered. instructed in their proper disposal. A puncture-resistant container In clinical studies, the percentage of patients with antibodies to
Patients With CRF Not Requiring Dialysis for the disposal of used syringes and needles should be made ARANESP was examined using the BIAcore assay. Sera from
available to the patient. 1501 CRF patients and 1159 cancer patients were tested.
Patients with CRF not yet requiring dialysis may require lower
maintenance doses of ARANESP than patients receiving Drug Interactions At baseline, prior to ARANESP treatment, binding antibodies
dialysis. Though predialysis patients generally receive less No formal drug interaction studies of ARANESP have been were detected in 59 (4%) of CRF patients and 36 (3%) of cancer
frequent monitoring of blood pressure and laboratory parameters performed. patients. While receiving ARANESP therapy (range 22-177
than dialysis patients, predialysis patients may be more responsive weeks), a follow-up sample was taken. One additional CRF patient
Carcinogenesis, Mutagenesis, and Impairment of Fertility and eight additional cancer patients developed antibodies capable
to the effects of ARANESP, and require judicious monitoring Carcinogenicity:
of blood pressure and hemoglobin. Renal function and uid and of binding ARANESP. None of the patients had antibodies
electrolyte balance should also be closely monitored. The carcinogenic potential of ARANESP has not been evaluated capable of neutralizing the activity of ARANESP or endogenous
in long-term animal studies. ARANESP did not alter the erythropoietin at baseline or at end of study. No clinical sequelae
Dialysis Management
proliferative response of non-hematological cells in vitro or in consistent with PRCA were associated with the presence of these
Therapy with ARANESP results in an increase in RBCs and a vivo. In toxicity studies of approximately 6 months duration in antibodies.
decrease in plasma volume, which could reduce dialysis efciency; rats and dogs, no tumorigenic or unexpected mitogenic responses
patients who are marginally dialyzed may require adjustments in The incidence of antibody formation is highly dependent on the
were observed in any tissue type. Using a panel of human tissues, sensitivity and specicity of the assay. Additionally, the observed
their dialysis prescription. the in vitro tissue binding prole of ARANESP was identical to incidence of antibody (including neutralizing antibody) positivity
Tumor Growth Factor Potential Epoetin alfa. Neither molecule bound to human tissues other than in an assay may be inuenced by several factors including assay
ARANESP is a growth factor that primarily stimulates RBC those expressing the erythropoietin receptor. methodology, sample handling, timing of sample collection,
production. Erythropoietin receptors are also found on the urfaces Mutagenicity: concomitant medications, and underlying disease. For these
of normal, non-hematopoietic tissues and some malignant cell ARANESP was negative in the in vitro bacterial and CHO reasons, comparison of the incidence of antibodies across products
lines and tumor biopsy specimens. However, it is not known if cell assays to detect mutagenicity and in the in vivo mouse within this class (erythropoietic proteins) may be misleading.
these receptors are functional. The possibility that ARANESP micronucleus assay to detect clastogenicity. Chronic Renal Failure Patients
can act as a growth factor for any tumor type, nancies, has not
Impairment of Fertility: Adult Patients
been evaluated. In a randomized, placebo-controlled study in
314 anemic subjects with advanced lung cancer randomized to When administered intravenously to male and female rats prior to In all studies, the most frequently reported serious adverse
either ARANESP or placebo, statistically signicant differences and during mating, reproductive performance, fertility, and sperm reactions with ARANESP were vascular access thrombosis,
in time-to-progression (TTP) or overall survival (OS) were assessment parameters were not affected at any doses evaluated congestive heart failure, sepsis, and cardiac arrhythmia. The
not observed; however, the study was not designed to detect or (up to 10 mcg/kg/dose, administered 3 times weekly). An increase most commonly reported adverse reactions were infection,
exclude clinically meaningful differences in either TTP or OS (see in post implantation fetal loss was seen at doses equal to or greater hypertension, hypotension, myalgia, headache, and diarrhea, (see
CLINICAL STUDIES). than 0.5 mcg/kg/dose, administered 3 times weekly. WARNINGS: Cardiovascular Events, Hemoglobin, and Rate
Two additional studies explored the effect on survival and/or Pregnancy Category C: of Rise of Hemoglobin, and Hypertension).
disease progression following administrations of two other When ARANESP was administered intravenously to rats and The most frequently reported adverse reactions resulting in clinical
29
Book_01.indd 29 6/4/2008 2:19:06 PM

AMGEN
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intervention (e.g., discontinuation of ARANESP, adjustment in The incidence rates for other clinically signicant events are Table 4. Incidence of Other Clinically Signicant Adverse
dosage, or the need for concomitant medication to treat an adverse shown in Table 2. Events in Patients Receiving Chemotherapy
reaction symptom) were hypotension, hypertension, fever, myalgia, Table 2. Percent Incidence of Other Clinically Signicant All ARANESP Placebo
nausea, and chest pain. The data described below reect exposure Events in CRF Patients Event
(n = 873) (n = 221)
to ARANESP in 1598 CRF patients, including 675 exposed for Hypertension 3.7% 3.2%
Event Patients Treated With
at least 6 months, of whom 185 were exposed for greater than 1 Seizures/Convulsionsa
ARANESP (n = 1598) 0.6% 0.5%
year. ARANESP was evaluated in active-controlled (n = 823)
Thrombotic Events 6.2% 4.1%
and uncontrolled studies (n = 775). Acute Myocardial Infarction 2%
Pulmonary Embolism 1.3% 0.0%
The rates of adverse events and association with ARANESP are Seizure 1%
Thrombosisb 5.6% 4.1%
best assessed in the results from studies in which ARANESP
Stroke 1% a Seizures/Convulsions include the preferred terms:
was used to stimulate erythropoiesis in patients anemic at study
baseline (n = 348), and, in particular, the subset of these patients Transient Ischemic Attack 1% Convulsions, Convulsions Grand Mal, and Convulsions Local.
in randomized controlled trials (n = 276). Because there were no b Thrombosis includes: Thrombophlebitis, Thrombophlebitis
Pediatric Patients Deep, Thrombosis Venous, Thrombosis Venous Deep,
substantive differences in the rates of adverse reactions between
these subpopulations, or between these subpopulations and the In Study N5, ARANESP was administered to 81 pediatric Thromboembolism, and Thrombosis.
entire population of patients treated with ARANESP, data from CRF patients who had stable hemoglobin concentrations while
previously receiving Epoetin alfa (see CLINICAL STUDIES). In a randomized controlled trial of ARANESP 500 mcg Q3W
all 1598 patients were pooled.
In this study, the most frequently reported serious adverse reactions (n = 353) and ARANESP 2.25 mcg/kg QW (n = 352), the
The population encompassed an age range from 18 to 91 years. incidences of all adverse events and of serious adverse events were
Fifty-seven percent of the patients were male. The percentages with ARANESP were fever and dialysis access infection. The
most commonly reported adverse reactions were fever, headache, similar between the two arms.
of Caucasian, Black, Asian, and Hispanic patients were 83%,
upper respiratory infection, hypertension, hypotension, injection Thrombotic and Cardiovascular Events
11%, 3%, and 1%, respectively. The median weekly dose of
site pain and cough. ARANESP administration was discontinued Overall, the incidence of thrombotic events was 6.2% for
ARANESP was 0.45 mcg/kg (25th, 75th percentiles: 0.29,
because of injection site pain in two patients and moderate ARANESP and 4.1% for placebo. However, the following
0.66 mcg/kg). Some of the adverse events reported are typically
hypertension in a third patient. Studies have not evaluated the events were reported more frequently in ARANESP treated
associated with CRF, or recognized complications of dialysis, and
effects of ARANESP when administered to pediatric patients as patients than in placebo controls: pulmonary embolism,
may not necessarily be attributable to ARANESP therapy.
the initial treatment for the anemia associated with CRF. thromboembolism, thrombosis, and thrombophlebitis (deep and/or
No important differences in adverse event rates between treatment
Thrombotic Events supercial). In addition, edema of any type was more frequently
groups were observed in controlled studies in which patients
received ARANESP or other recombinant erythropoietins. The Vascular access thrombosis in hemodialysis patients occurred in reported in ARANESP treated (21%) patients than in patients
data in Table 1 reect those adverse events occurring in at least 5% clinical trials at an annualized rate of 0.22 events per patient year of who received placebo (10%).
of patients treated with ARANESP. ARANESP therapy. Rates of thrombotic events (e.g., vascular
OVERDOSAGE
access thrombosis, venous thrombosis, and pulmonary emboli)
Table 1. Adverse Events Occurring in 5% of CRF Patients with ARANESP therapy were similar to those observed with The maximum amount of ARANESP that can be safely
Event Patients Treated With other recombinant erythropoietins in these trials; the median administered in single or multiple doses has not been determined.
ARANESP (n = 1598) duration of exposure was 12 weeks. Doses over 3.0 mcg/kg/week for up to 28 weeks have been
APPLICATION SITE Cancer Patients Receiving Chemotherapy administered to CRF patients. Doses up to 8.0 mcg/kg every
week and 15.0 mcg/kg every 3 weeks have been administered
Injection-site Pain 7% The incidence data described below reect the exposure to
to cancer patients for up to 12-16 weeks. Excessive rise and
BODY AS A WHOLE ARANESP in 873 cancer patients including patients exposed to
rate of rise in hemoglobin concentration, however, have been
ARANESP QW (547, 63%), Q2W (128, 16%), and Q3W (198,
Peripheral Edema 11% associated with adverse events (see WARNINGS and DOSAGE
23%). ARANESP was evaluated in seven studies that were
Fatigue 9% AND ADMINISTRATION: Dose Adjustment). In the event of
active-controlled and/or placebo-controlled studies of up to 6 polycythemia, ARANESP should be temporarily withheld (see
Fever 9% months duration. The ARANESP treated patient demographics
DOSAGE AND ADMINISTRATION: Dose Adjustment).
Death 7% were as follows: median age of 63 years (range of 20 to 91 years);
40% male; 88% Caucasian, 5% Hispanic, 4% Black, and 3% If clinically indicated, phlebotomy may be performed.
Chest Pain, Unspecied 6%
Asian. Over 90% of patients had locally advanced or metastatic DOSAGE AND ADMINISTRATION
Fluid Overload 6% cancer, with the remainder having early stage disease. Patients
General
Access Infection 6% with solid tumors (e.g., lung, breast, colon, ovarian cancers),
and lymphoproliferative malignancies (e.g., lymphoma, multiple IMPORTANT: ARANESP dosing regimens are different for
Inuenza-like Symptoms 6% each of the indications described in this section of the package
myeloma) were enrolled in the clinical studies. All of the 873
Access Hemorrhage 6% ARANESP treated subjects also received concomitant cyclic insert. ARANESP should be administered under the supervision
Asthenia 5% chemotherapy. of a healthcare professional.
CARDIOVASCULAR The most frequently reported serious adverse events included ARANESP is supplied in either vials or in prelled syringes
death (10%), fever (4%), pneumonia (3%), dehydration (3%), with UltraSafe Needle Guards*.
Hypertension 23%
vomiting (2%), and dyspnea (2%). The most commonly reported Following administration of ARANESP from the prelled
Hypotension 22% adverse events were fatigue, edema, nausea, vomiting, diarrhea, syringe, the UltraSafe Needle Guard should be activated to
Cardiac Arrhythmias/ fever and dyspnea (see Table 3). prevent accidental needle sticks.
Cardiac Arrest 10% Except for those events listed in Tables 3 and 4, the incidence Chronic Renal Failure Patients
of adverse events in clinical studies occurred at a similar
Angina Pectoris/ ARANESP is administered either IV or SC as a single
rate compared with patients who received placebo and were
Cardiac Chest Pain 8% weekly injection. In patients on hemodialysis, the IV route is
generally consistent with the underlying disease and its treatment
with chemotherapy. The most frequently reported reasons for recommended. The dose should be started and slowly adjusted
Thrombosis Vascular Access 8%
discontinuation of ARANESP were progressive disease, as described below based on hemoglobin levels. If a patient fails
Congestive Heart Failure 6% to respond or maintain a response, this should be evaluated (see
death, discontinuation of the chemotherapy, asthenia, dyspnea,
CNS/PNS pneumonia, and gastrointestinal hemorrhage. No important WARNINGS)
Headache 16% differences in adverse event rates between treatment groups Pure Red Cell Aplasia, PRECAUTIONS: Lack or Loss of
Dizziness 8% were observed in controlled studies in which patients received Response to ARANESP and PRECAUTIONS: Laboratory
ARANESP or other recombinant erythropoietins. Tests). When ARANESP therapy is initiated or adjusted, the
GASTROINTESTINAL
Table 3. Adverse Events Occurring in 5% of Patients hemoglobin should be followed weekly until stabilized and
Diarrhea 16% Receiving Chemotherapy monitored at least monthly thereafter.
Vomiting 15% For patients who respond to ARANESP with a rapid increase
ARANESP Placebo
Nausea 14% Event in hemoglobin (e.g., more than 1.0 g/dL in any 2-week period),
(n = 873) (n = 221)
Abdominal Pain 12% the dose of ARANESP should be reduced (see DOSAGE
BODY AS A WHOLE AND ADMINISTRATION: Dose Adjustment) because of the
Constipation 5% association of excessive rate of rise of hemoglobin with adverse
Fatigue 33% 30%
MUSCULO-SKELETAL events (see WARNINGS: Cardiovascular Events, Hemoglobin,
Edema 21% 10% and Rate of Rise of Hemoglobin). The dose should be adjusted
Myalgia 21%
Fever 19% 16% for each patient to achieve and maintain a target hemoglobin level
Arthralgia 11%
CNS/PNS not to exceed 12 g/dL.
Limb Pain 10%
Dizziness 14% 8% Starting Dose
Back Pain 8%
Headache 12% 9% Correction of Anemia
RESISTANCE MECHANISM
The recommended starting dose of ARANESP for the correction
GASTROINTESTINAL
Infectiona 27% of anemia in adult CRF patients is 0.45 mcg/kg body weight,
Diarrhea 22% 12% administered as a single IV or SC injection once weekly. Because
RESPIRATORY
Constipation 18% 17% of individual variability, doses should be titrated to not exceed a
Upper Respiratory Infection 14%
METABOLIC/NUTRITION target hemoglobin concentration of 12 g/dL (see DOSAGE AND
Dyspnea 12%
ADMINISTRATION: Dose Adjustment).
Dehydration 5% 3%
Cough 10% For many patients, the appropriate maintenance dose will be lower
MUSCULO-SKELETAL
Bronchitis 6% than this starting dose. Predialysis patients, in particular, may
Arthralgia 13% 6% require lower maintenance doses. Also, some patients have been
SKIN AND APPENDAGES
Myalgia 8% 5% treated successfully with a SC dose of ARANESP administered
Pruritus 8%
SKIN AND APPENDAGES once every 2 weeks. The use of ARANESP in pediatric CRF
a Infection includes sepsis, bacteremia, pneumonia, patients as the initial treatment to correct anemia has not been
Rash 7% 3%
peritonitis, and abscess. studied.
30
Book_01.indd 30 6/4/2008 2:19:06 PM

APOTEX
SPDI
Conversion From Epoetin alfa to ARANESP Do not pool unused portions from the vials or prelled syringes. STORAGE
The starting weekly dose of ARANESP for adults and pediatric Do not use the vial or prelled syringe more than one time. Store at 2 to 8 C (36 to 46 F). Do not freeze or shake. Protect from
patients should be estimated on the basis of the weekly Epoetin Following administration of ARANESP from the prelled light.
alfa dose at the time of substitution (see Table 5). For pediatric syringe, activate the UltraSafe Needle Guard. Place your hands
patients receiving a weekly Epoetin alfa dose of <1500 units/week, behind the needle, grasp the guard with one hand, and slide the
the available data are insufcient to determine an ARANESP guard forward until the needle is completely covered and the guard APOTEX
conversion dose. P.O. BOX : 523, RIYADH: 11421
clicks into place.
Because of individual variability, doses should be titrated to SAUDI ARABIA
maintain the target hemoglobin. Due to the longer serum half-life, NOTE:
ARANESP should be administered less frequently than Epoetin
TEL: 01-4454545, FAX: 01-4978800
If an audible click is not heard, the needle guard may not be
alfa. ARANESP should be administered once a week if a patient completely activated. The prelled syringe should be disposed of
was receiving Epoetin alfa 2 to 3 times weekly. ARANESP by placing the entire prelled syringe with guard activated into
should be administered once every 2 weeks if a patient was APO-DICLO 25 mg Tablet
an approved puncture-proof container. See the accompanying
receiving Epoetin alfa once per week. The route of administration OTC
Information for Patients leaet for complete instructions on
(IV or SC) should be maintained.
the preparation and administration of ARANESP for patients. (Diclofenac Sodium)
Table 5. Estimated ARANESP Starting Doses (mcg/week) for
Patients Based on Previous Epoetin alfa Dose (Units/week) HOW SUPPLIED
ARANESP is available in single-dose vials (N.R.) in two APO-DICLO 50 mg Tablet
Previous Weekly Epoetin Weekly Dose
ARANESP (mcg/week) solutions, an albumin solution and a polysorbate solution. The APO-DICLO
alfa Dose (Units/week) words Albumin Free appear on the polysorbate container
Adult Pediatric labels and the package main panels as well as other panels as SR 75 mg (N.R.) and 100 mg Tablet
< 1,500 6.25 See text* space permits. ARANESP albumin solution is also available in
single-dose prelled syringes supplied with a 27 gauge, inch
1,500 to 2,499 6.25 6.25
needle. To reduce the risk of accidental needlesticks to users, each (Diclofenac Sodium)
2,500 to 4,999 12.5 10 prelled syringe is equipped with an UltraSafe Needle Guard
5,000 to 10,999 25 20 that covers the needle during disposal. ARANESP is available THERAPEUTIC CLASSIFICATION
11,000 to 17,999 40 40 in the following packages: Anti-inammatory, Analgesic Agent
18,000 to 33,999 60 60 Single-dose Vial, Polysorbate Solution (N.R) ACTIONS AND CLINICAL PHARMACOLOGY
34,000 to 89,999 100 100 1 Vial/Pack, 4 Vials/Pack, Diclofenac sodium has demonstrated anti-inammatory, analgesic,
4Vials/ Pack,
90,000 200 200 4 Packs/Case 4 Packs/Case 10 Packs/Case and antipyretic properties in classical animal test systems. Its exact
mode of action is not known. However, since it exhibits an anti-
* For pediatric patients receiving a weekly Epoetin alfa dose 200 mcg/1 mL 200 mcg/1 mL 25 mcg/1 mL inammatory effect even in adrenalectomized animals, its action
of <1,500 units/week, the available data are insufcient to (NDC 55513-006-01) (NDC 55513-006-04) (NDC 55513-002-04)
is not mediated through the pituitary-adrenal axis. Diclofenac
determine an ARANESP conversion dose. 300 mcg/1 mL 300 mcg/1 mL 40 mcg/1 mL sodium inhibits prostaglandin biosynthesis in vitro and in vivo
Dose Adjustment (NDC 55513-110-01) (NDC 55513-110-04) (NDC 55513-003-04) by interfering with the action of prostaglandin synthetase. This
The dose should be adjusted for each patient to achieve and 500 mcg/1 mL 60 mcg/1 mL inhibitory effect may be involved in its anti-inammatory actions.
maintain a target hemoglobin not to exceed 12 g/dL.Increases in (NDC 55513-008-01) (NDC 55513-004-04)
Diclofenac sodium has been found to relieve pain, reduce fever,
dose should not be made more frequently than once a month. 100 mcg/1 mL swelling and tenderness, and increase mobility in patients with
If the hemoglobin is increasing and approaching 12 g/dL, the dose (NDC 55513-005-04) rheumatic disorders of the types listed. Although diclofenac
should be reduced by approximately 25%. 150 mcg/0.75 mL sodium affords relief of symptoms, it does not alter the course
If the hemoglobin continues to increase, doses should be (NDC 55513-053-04) of the underlying disease. From a clinical efcacy standpoint,
temporarily withheld until the hemoglobin begins to decrease, at diclofenac sodium 75 mg is similar to 3.6 g of acetylsalicylic
Single-dose Vial, Albumin Solution (N.R)
which point therapy should be reinitiated at a dose approximately acid.
25% below the previous dose. If the hemoglobin increases 1 Vial/Pack, 4 Vials/Pack, 4Vials/ Pack, Diclofenac sodium is similar in activity to equivalent dosages of
by more than 1.0 g/dL in a 2-week period, the dose should be 4 Packs/Case 4 Packs/Case 10 Packs/Case indomethacin (75-1 50 mg daily), and causes less central nervous
decreased by approximately 25%. If the increase in hemoglobin is
200 mcg/1 mL (NDC 200 mcg/1 mL (NDC 25 mcg/1 mL (NDC system side effects at these doses.
less than 1.0 g/dL over 4 weeks and iron stores are adequate (see
55513-014-01) 55513-014-04) 55513-010-04) Diclofenac 150 mg daily induces minimal gastrointestinal blood
PRECAUTIONS: Laboratory Tests), the dose of ARANESP
may be increased by approximately 25% of the previous dose. 300 mcg/1 mL (NDC 300 mcg/1 mL (NDC 40 mcg/1 mL (NDC loss, signicantly less so than acetylsalicylic acid 3 g daily or
Further increases may be made at 4-week intervals until the 55513-015-01) 55513-015-04) 55513-011-04) naproxen 750 mg daily.
specied hemoglobin is obtained. 500 mcg/1 mL (NDC 60 mcg/1 mL (NDC Although APO-DICLO (diclofenac sodium) does not alter the
Maintenance Dose 55513-016-01) 55513-012-04) course of the underlying disease, it has been found to relieve pain,
ARANESP dosage should be adjusted to maintain a target 100 mcg/1 mL (NDC reduce fever, swelling and tenderness, and increase mobility in
hemoglobin not to exceed 12 g/dL. If the hemoglobin exceeds 12 55513-013-04) patients with rheumatic disorders of the types listed.
g/dL, the dose may be adjusted as described above. Doses must 150 mcg/0.75 mL Comparative B ioavailability
be individualized to ensure that hemoglobin is maintained at an (NDC 55513-054-04)
A bioavailability study was performed using normal human
appropriate level for each patient.
Single-dose Prelled Syringe (SingleJect) With a 27 gauge, volunteers. The rate and extent of absorption after a single 50
Cancer Patients Receiving Chemotherapy mg oral dose of APO-DICLO (diclofenac sodium) 25 mg and
inch Needle With an UltraSafe Needle Guard, Polysorbate
For pediatric patients, see PRECAUTIONS: Pediatric Use. VOLTAREN 25 mg enteric coated tablets was measured and
Solution
The recommended starting dose for ARANESP administered compared. The results are summarized as follows:
weekly is 2.25 mcg/kg as a SC injection. The recommended 1 Syringe/Pack, 4 Syringe/Pack, 4 Syringe/ Pack,
4 Packs/Case
VOLTAREN APO-DICLO %
starting dose for ARANESP administered once every 3 weeks 4 Packs/Case 10 Packs/Case
25 mg 25 mg diffr.
(Q3W) is 500 mcg as a SC injection. For both dosing schedules, 200 mcg/0.4 mL (N.R.) 200 mcg/0.4 mL(N.R.) 25 mcg/0.42 mL(N.R.) AUC0-12 (ng.hr/ml) 1357.87 1338.55 -1.4
the dose should be adjusted for each patient to maintain a target (NDC 55513-028-01) (NDC 55513-028-04) (NDC 55513-057-04) Cmax(ng/ml) 1220.29 1236.58 +1.3
hemoglobin not to exceed 12 g/dL. If the hemoglobin exceeds 13 Tmax(hr) 1.16 1.34 +15.5
300 mcg/0.6 mL (NDC 300 mcg/0.6 mL(N.R.) 40 mcg/0.4 mL (NDC
g/dL, doses should be temporarily withheld until the hemoglobin t1/2(hr) 1.1 1.0 -9.1
55513-111-01) (NDC 55513-111-04) 55513-021-04)
falls to 12 g/dL. At this point, therapy should be reinitiated at
a dose 40% below the previous dose. If the rate of hemoglobin 500 mcg/1 mL (NDC 60 mcg/0.3 mL (NDC Two additional bioavailability studies were performed using
increase is more than 1.0 g/dL per 2-week period or when the 55513-032-01) 55513-023-04)
slow-release tablets, one with food and one without food. The rate
hemoglobin exceeds 11 g/dL, the dose should be reduced by 40% 100 mcg/0.5 mL and extent of absorption of diclofenac after a single 100 mg oral
of the previous dose. For patients receiving weekly administration, (NDC 55513-025-04) dose of APO-DICLO SR 100 mg and VOLTAREN SR 100 mg
if there is less than a 1.0 g/dL increase in hemoglobin after 6 weeks 150 mcg/0.3 mL slow release tablets was measured and compared. The results are
of therapy, the dose of ARANESP should be increased up to (NDC 55513-027-04) summarized as follows:
4.5 mcg/kg.
Single-dose Prelled Syringe (SingleJect) With a 27 gauge, Study 1 (without food)
Preparation and Administration of Aranesp
inch Needle With an UltraSafe Needle Guard, Albumin Geometric Mean
Do not shake ARANESP or leave vials or syringes exposed
Solution Arithmetic Mean(CV)
to bright light. After removing the vials or prelled syringes
from the cartons, keep them covered to protect from room light 1 Syringe/Pack, 4 Syringe/Pack, 4 Syringe/ Pack, Voltaren SR Apo-Diclo SR Ratio of
until administration. Vigorous shaking or exposure to light may 4 Packs/Case 4 Packs/Case 10 Packs/Case 100 mg 100 mg Means (%)
denature ARANESP causing it to become biologically inactive.
200 mcg/0.4 mL (N.R.) 200 mcg/0.4 mL(N.R.) 25 mcg/0.42 mL (N.R.) AUCT 2361 2500 105.9
Always store vials or prelled syringes of Aranesp in their carton (NDC 55513-044-01) (NDC 55513-044-04) (NDC 55513-058-04) (ng.hr/mL) 2435(25) 2584(25)
until use. Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration. Do not 300 mcg/0.6 mL (NDC 300 mcg/0.6 mL(N.R.) 40 mcg/0.4 mL (NDC
AUC1 2417 2561 105.9
55513-046-01) (NDC 55513-046-04) 55513-037-04)
use any vials or prelled syringes exhibiting particulate matter or (ng.hr/ml) 2489(25) 2643 (24)
discoloration. 500 mcg/1 mL (NDC 60 mcg/0.3 mL (NDC
55513-048-01) 55513-039-04) Cmax 537 529 98.4
Do not dilute ARANESP.
100 mcg/0.5 mL (ng/mL) 585(42) 558(27)
Do not administer Aranesp in conjunction with other drug
(NDC 55513-041-04) Tmax *(hr) 4.07(1.98) 3.79 (2.46) -
solutions.
ARANESP is packaged in single-dose vials and prelled syringes 150 mcg/0.3 mL t1/2 3.43(1.40) 3.42(1.59) -
(NDC 55513-043-04)
and contains no preservative. Discard any unused portion.
31
Book_01.indd 31 6/4/2008 2:19:07 PM

APOTEX
SPDI
Study 2 (with food) INDICATIONS AND CLINICAL USE women are unknown. However, as with other nonsteroidal anti-
Geometric Mean APO-DICLO (diclofenac sodium) is indicated for the symptomatic inammatory drugs, it is possible that APO-DICLO (diclofenac
treatment of rheumatoid arthritis and osteoarthritis, including sodium) may inhibit uterine contraction. Reproduction studies
Arithmetic Mean(CV)
degenerative joint disease of the hip. performed in rats, rabbits and mice showed prolonged pregnancy
Voltaren SR Apo-Diclo SR Ratio of and protracted labour when diclofenac sodium was administered
100 mg 100 mg Means (%) CONTRAINDICATION before or after the delivery process had begun.
AUCT 2561 2704 105.7 APO-DICLO (diclofenac sodium) should not be used in patients Use in Children
(ng.hr/mL) 2724(36) 2847(36) with active, or recent history of inammatory diseases of the
APO-DICLO (diclofenac sodium) is not recommended in children
gastrointestinal tract such as peptic ulcer, gastritis, regional
AUC1 3024 2944 100.8 under 16 years of age. Safety and dosages for the pediatric age
enteritis, or ulcerative colitis.
group have not been established.
(ng.hr/ml) 3142(25) 3094 (34) Diclofenac sodium is contraindicated in patients with known or
Nursing Mothers
Cmax 381 351 92.6 suspected hypersensitivity to the drug or other non-steroidal anti-
inammatory drugs. Since cross-sensitivity has been demonstrated, Diclofenac has been found in the milk of nursing mothers. As with
(ng/mL) 457(59) 379(44) other drugs that are excreted in milk, APO-DlCLO (diclofenac
APO-DICLO should not be given to patients with the complete
Tmax *(hr) 8.79(4.69) 6.58 (2.57) - or partial syndrome of nasal polyps or in whom acetylsalicylic sodium) is not recommended for use in nursing women.
t1/2 4.84(2.69) 4.81(3.15) - acid or other nonsteroidal anti-inammatory agents have induced The highest diclofenac level observed in the breast milk of patients
asthma, rhinitis, urticaria, or other allergic-type reactions because receiving diclofenac in an oral dose of 150 mg day 1, followed by
severe, rarely fatal, anaphylactic like reactions to diclofenac have 100 mg day 2, was smaller than 5 nglg. By extrapolation, an infant
* For the Tmax and t, parameters, these are the arithmetic means been reported in such patients. Individuals with the above medical of 3 kg, consuming 500 glday (with a maximum concentration
(standard deviations). problems are at risk of a severe reaction even if they have taken of 5 nglg) of breast milk, would receive less than 0.83 pglkglday
PHARMACOKINETICS NSAIDS in the past without any adverse effects. of diclofenac. On the other hand, in one patient on long-term
As well, patients with signicant hepatic impairment or active treatment with diclofenac sodium 150 mg daily, a level of 100
In man, orally administered diclofenac sodium is rapidly and
liver disease. ngImL (1 00 nglg) was measured in breast milk. By extrapolation,
almost completely absorbed and distributed to blood, liver and
an infant of 3 kg, consuming 500 glday of breast milk, would
kidneys. The plasma concentrations show a linear relationship to Severely impaired or deteriorating renal function (creatinine
receive less than 17 pglkglday of diclofenac.
the amount of drug administered. clearance c30 mumin (0.5 mUs)). Individuals with lesser degrees
of renal impairment are at risk of deterioration of their renal When administering diclofenac sodium to the elderly, special care
No accumulation occurs provided the recommended dosage
function when prescribed NSAlDs and must be monitored. is indicated. The dosage should be reduced to the lowest level that
intervals are observed. Absorption occurs more rapidly when the
will provide control of symptoms.
drug is administered on an empty stomach (T,, 2.5 hours), than APO-DICLO is not recommended for use with other NSAlDs
with meals (T,, 6 hours). The bioavailability remains the same because of the absence of any evidence demonstrating synergistic CROSS-SENSITIVITY
under both conditions. The mean peak: plasma concentration of benets and the potential for additive side effects. Patients sensitive to any one of the nonsteroidal anti-inammatory
1.5 pglm (5 pmollL) is attained, on average, 2 hours after ingestion drugs may be sensitive to any of the other NSAlDs also.
WARNINGS
of one 50 mg enteric-coated tablet.
Serious GI toxicity such as peptic ulceration, perforation and Aseptic Meningitis
The mean terminal drug half-life in plasma was 1.8 hr after oral
gastrointestinal bleeding, sometimes severe and occasionally In occasional cases, with some NSAIDs, the symptoms of aseptic
doses. Diclofenac is extensively bound (99%) to serum albumin. In
fatal have been reported and can occur at any time during therapy meningitis (stiff neck, severe headaches, nausea and vomiting,
single-dose studies (p.0. or i.m.) in patients with active rheumatoid
with nonsteroidal anti-inammatory drugs (NSAIDs) including fever or clouding of consciousness) have been observed.
disease and joint effusions, diclofenac sodium concentrations were
diclofenac. Patients with autoimmune disorders (systemic lupus erythematosus,
found to be higher in synovial uid than in plasma within 4 to 6
hours of administration and remained higher for up to 12 hours. APO-DICLO (diclofenac sodium) should be given under close mixed connective tissues diseases, etc.) seem to be pre-disposed.
Maximum synovial uid concentrations were measured 2 to 4 medical supervision to patients prone to gastrointestinal tract Therefore, in such patients, the physician must be vigilant to the
hours after the peak plasma values were obtained. The elimination irritation particularly those with a history of peptic ulcer, development of this complication.
half-life from synovial uid was at least 3 times greater than that diverticulosis or other inammatory disease of the gastrointestinal PRECAUTIONS
from plasma. tract (such as ulcerative colitis or Crohns disease). In these
cases the physician must weigh the benets of treatment against Diclofenac sodium should not be used concomitantly with
Following administration of slow-release diclofenac sodiu m,C,, diclofenac potassium since both exist in plasma as the same active
is reached at approximately 4 hours or later, and a signicant the possible hazards (see CONTRAINDICATIONS AND
ADVERSE REACTIONS). organic ion.
concentration of drug prevails in plasma when the drug levels Gastrointestinal Svstem
Patients taking any NSAlD including this drug should be instructed
following the conventional form have dropped almost to baseline If peptic ulceration is suspected or conrmed, or if gastrointestinal
to contact a physician immediately if they experience symptoms or
values. bleeding or perforation occurs, APO-DICLO (diclofenac sodium)
signs suggestive of peptic ulceration or gastrointestinal bleeding.
Mean plasma concentrations of 13 ng/mL (40 nmol1L) were These reactions can occur without warning symptoms or signs and should be discontinued, an appropriate treatment instituted and the
produced 24 hours after diclofenac sodium SR 100 mg, or 16 at any time during the treatment. patient closely monitored.
hours after diclofenac sodium SR 75 mg (single dose). Trough There is no denitive evidence that the concomitant administration
Because serious GI tract ulceration and bleeding can occur without
levels are approximately 22-25 ng/mL (70-80 nmol/L) during of histamine H2-receptor antagonists and/or antacids will either
warning symptoms, physicians should follow chronically treated
treatment with diclofenac sodium SR 100 once daily or diclofenac prevent the occurrence of gastrointestinal side effects or allow
patients by checking their hemoglobin periodically and by being
sodium SR 75 twice daily. In pharmacokinetic studies no continuation of diclofenac therapy when and if these adverse
vigilant for the signs and symptoms of ulceration and bleeding and
accumulation of diclofenac sodium was found following repeated reactions appear.
should inform the patients of the importance of this follow-up.
once daily administration of diclofenac sodium SR 100 mg tablets
No studies, to date, have identied any group of patients at risk of Peptic ulceration and gastrointestinal bleeding have been reported
or repeated twice daily administration of diclofenac sodium SR
developing ulceration and bleeding. A prior history of serious GI in patients receiving diclofenac. Physicians and patients should
75 mg tablets.
events and other factors such as excess alcohol intake, smoking, therefore remain alert for ulceration and bleeding in patients
The ability of elderly subjects to absorb, metabolize and excrete treated chronically with diclofenac sodium, even in the absence
age, female gender and concomitant oral steroid and anti-coagulant
diclofenac sodium does not appear to differ signicantly from of previous G.I. tract symptoms. It is recommended that patients
use have been associated with increased risk. Studies to date show
those of young subjects. be maintained on the lowest dose of diciofenac sodium possible
that all NSAIDs can cause GI tract adverse events. Although
Metabolism: existing data does not clearly identity differences in risk between consistent with achieving a satisfactory therapeutic response.
Diclofenac undergoes single and multiple hydroxylation and various NSAIDs, this may be shown in the xture. Risk of G.I. Ulcerations. Bleeding and Perforation with NSAlD
methoxylation, producing 3-, 4-, 5-hydroxy, 4- 5-hydroxy and APO-DICLO is not recommended for routine use with other Therapy
3-hydroxy-4-methoxy derivatives of diclofenac. These phenolic NSAIDs because of the potential for additive side effects (see Serious gastrointestinal toxicity such as bleeding, ulceration,
metabolites are largely inactive, and (along with the parent DRUG INTERACTIONS). and perforation can occur at any time, with or without warning
compound) are mostly converted to glucuronide conjugates. Elderly, frail and debilitated patients (older than 65 years of age), symptoms, in patients treated chronically with NSAlD therapy.
Elimination: appear to be at higher risk from a variety of adverse reactions from Although minor upper gastrointestinal problems such as dyspepsia
Plasma clearance of diclofenac is 263 + 56 mumin. The mean nonsteroidal anti-inammatory drugs (NSAIDs). For such are common, usually developing early in therapy, physicians
terminal drug half-life in plasma is 1.8 hour after oral doses. patients, consideration should be given to a starting dose lower than should remain alert for ulceration and bleeding in patients treated
In man about 40-60% of the drug and its metabolites are eliminated usual, with individual adjustment when necessary and under close chronically with NSAlDs even in the absence of previous G.I. tract
in the urine and the balance in the feces. supervision. The incidence of these adverse reactions increases symptoms.
More than 90% of an oral dose is accounted for in elimination with dose and duration of treatment. In addition, these patients In patients observed in clinical trials of several months to 2
products within 72 hours. Free diclofenac accounts for less than 1 are less tolerant to ulceration and bleeding. Most reports of fatal years duration, symptomatic upper G.I. ulcers, gross bleeding,
% of the dose excreted in the urine. Conjugates of diclofenac itself GI events are in this population. Older patients are also at risk of or perforation appear to occur in approximately 1% of patients
account for 5 to 10% of the dose recovered in the urine. lower esophageal ulceration and bleeding. See PRECAUTIONS treated for 3-6 months and in about 2-4% of patients treated for
for further advice. 1 year. Physicians should inform patients about the signs and/or
Renal Clearance:
Preanancv symptoms of serious G.I. toxicity and what steps to take if they
A single dose pharmacokinetic study in patients with varying occur.
degrees of renal dysfunction (creatinine clearance rates ranging Safety in pregnancy has not been established. As inhibition
of prostaglandins may cause premature closure of the ductus Studies to date have not identied any subset of patients not at risk
from 3 mumin. to 42 mumin.) suggests that moderate renal
arteriosus of the fetal cardiovascular system, APO-DICLO of developing peptic ulcer and bleeding. Except for a prior history
impairment does not affect the elimination rate of unchanged
(diclofenac sodium) is not recommended for use in pregnant of serious G.I. events and other risk factors known to be associated
diclofenac from plasma but that it may reduce the elimination
women. with peptic ulcer disease, such as alcoholism, smoking, etc., no
rate of the metabolites of the drug. In one patient with a creatinine
Diclofenac sodium readily crosses the placental barrier. It risk factors (e.g., age, sex) have been associated with increased
clearance of <I0 mumin, the theoretical steady-state plasma levels
should only be used during pregnancy for the most compelling risk. Elderly or debilitated patients seem to tolerate ulceration or
of metabolites (normally devoid of pharmacological activity)
reasons, and then only at the lowest effective dose. As with other bleeding less well than other individuals and most spontaneous
were about 4 times higher than those in normal subjects, with
prostaglandin inhibitors, this applies particularly to the last 3 reports of fatal G.I. events are in this population.
metabolites cleared through the bile. Although no accumulation
of pharmacologically active substance seems to occur, caution is months of pregnancy, because of the possibility of uterine inertia The incidence of these complications increases with increasing
advised while administering and/or premature closing of the ductus arteriosus. dose.
APO-DICLO (diclofenac sodium) to patients with impaired Labor and Delivery Renal Function
kidney function. The effects of diclofenac sodium on labor and delivery in pregnant As a class, nonsteroidal anti-inammatory drugs have been
32
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APOTEX
SPDI
associated with renal papillary necrosis and other abnormal renal Hematoloay Diclofenac does not alter glucose metabolism in normal subjects
pathology in long-term administration to animals. In humans, there Diclofenac sodium increases platelet aggregation time but does nor are the effects of oral hypoglycemic agents altered (i.e.
have been reports of acute interstitial nephritis with hematuria, not affect bleeding time, plasma thrombin clotting time, plasma potentation) by the concomitant administration of APO-DICLO.
proteinuria, and occasionally nephrotic syndrome. brinogen, or factors V and VII to XII. Statistically signicant There are rare reports, however, of changes in effects of insulin
A second form of renal toxicity generally associated with changes in prothrombin and partial thromboplastin times have been or oral hypoglycemic agents in the presence of diclofenac which
nonsteroidal anti-inammatory drugs is seen in patients with reported in normal volunteers. The mean changes were observed to necessitated changes in the doses of such agents. Both hypoand
conditions leading to a reduction in renal blood ow or blood be less than 1 second in both instances, however, and are unlikely hyperglycemic effects have been reported. A direct causal
volume, where renal prostaglandins have a supportive role in the to be clinically important. Diclofenac is a prostaglandin synthetase relationship has not been established, but physicians should
maintenance of renal perfusion. In these patients, administration of inhibitor and all drugs that inhibit prostaglandin synthesis interfere consider the possibility that diclofenac may alter a diabetic
a nonsteroidal anti-inammatory drug results in a dose-dependent with platelet function to some degree; therefore patients who patients response to insulin or oral hypoglycemic agents.
decrease in prostaglandin synthesis and, secondarily, in a reduction may be adversely affected by such an action should be carefully
Nonsteroidal anti-inammatory agents have been reported to
of renal blood ow, which may precipitate overt renal failure. observed.
inhibit the activity of diuretics. Concomitant treatment with
Patients at greatest risk of this reaction are those with impaired Patients on long-term treatment with diclofenac sodium should potassium-sparing diuretics may be associated with increased
renal function, heart failure, liver dysfunction, those taking have a periodic evaluation of their hemopoietic system performed serum potassium levels.
diuretics, and the elderly. Discontinuation of NSAID therapy is because abnormalities of bone marrow function have rarely
Concomitant administration of glucocorticoids, though sometimes
typically followed by recovery to the pretreatment state. occurred but could be with severe consequences. Periodic
necessary for therapeutic reasons, may aggravate gastrointestinal
Since diclofenac sodium metabolites are eliminated primarily by hemoglobin estimations are advised as anemia secondary to
side effects such as ulceration and bleeding. Concurrent oral
the kidneys, patients with signicantly impaired renal function gastrointestinal tract toxicity can occur.
treatment with two or more nonsteroidal antirheumatic drugs may
should be more closely monitored than subjects with normal renal Blood dyscrasias associated with the use of nonsteroidal promote the occurrence of side effects. This is especially the case
function. In these cases lower doses of APO-DICLO (diclofenac anti-inammatory drugs are rare, but could be with severe in older (>65 years of age) individuals.
sodium) should be anticipated and patients carefully monitored. consequences.
In vitro, diclofenac interferes minimally or not at all with the
During long-term therapy, kidney function should be monitored Infection protein binding of salicylic acid (20% decrease in binding),
periodically. The anti-inammatory, antipyretic, and analgesic effects of tolbutamide, prednisolone (10% decrease in binding), or warfarin.
Genitourinarv Tract diclofenac sodium may mask the usual signs of infection and Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycy-
Some NSAlDs are known to cause persistent urinary symptoms the physician should be alert to the development of infection in cline, cephalothin, erythromycin, and sulfamethoxazole have no
(bladder pain, dysuria, urinary frequency), hematuria or cystitis. patients receiving the drug. inuence in vitro on the protein binding of diclofenac in human
The onset of these symptoms may occur at any time after the Allergic Reactions serum.
initiation of therapy with an NSAID. Some cases have become As with other nonsteroidal anti-inammatory drugs, allergic Diclofenac sodium, when administered concomitantly with
severe on continued treatment Should urinary symptoms occur, reactions including anaphylaxis, have been reported with lithium will increase the lithium plasma concentration through
treatment with APO-DICLO (diclofenac sodium) must be diclofenac. Specic allergic manifestations consisting of an effect on lithium renal clearance; dosage adjustment of lithium
Stopped immediately to obtain recovery. This should be done swelling of eyelids, lips, pharynx and larynx, urticaria, asthma, may be required.
before any urological investigations or treatments are carried out. and bronchospasm, sometimes with a concomitant fall in blood There may be an increased risk of gastrointestinal side effects,
Hepatic effects pressure (severe at times) have been observed in clinical trials and/ including ulceration or\ hemorrhage, when alcohol is administered
As with other nonsteroidal anti-inammatory drugs, borderline or the foreign marketing experience with diclofenac. concomitantly with NSAIDs. There may be an increased risk
elevations of one or more liver tests may occur during APO- Anaphylaxis has been reported rarely from foreign sources; in of adverse renal effects when acetaminophen is administered
DICLO (diclofenac sodium) therapy in up to 15% of patients. U.S. clinical trials with diclofenac in over 6000 patients, 1 case concomitantly with NSAIDs.
These abnormalities may progress, may remain unchanged or may of anaphylaxis was reported. In controlled clinical trials, allergic There have been isolated reports of convulsions which may have
be transient with continued therapy. reactions have been observed at an incidence of 0.5%. These been due to concomitant use of quinolones and NSAIDs.
To minimize the possibility that patients with enzyme elevations reactions can occur without prior exposure to the drug. Therefore, Probenicid may decrease the excretion and increase serum
will go on to experience clinically signicant hepatic disease, it is careful questioning of patients for a history of asthma, nasal concentrations of NSAlDs possibly enhancing effectiveness and/
recommended that physicians inform patients of the risks of polyps, urticaria, and hypotension associated with NSAlDs before or increasing potential for toxicity. Concurrent therapy of NSAIDs
starting therapy is important. with probenicid requires close monitoring to be certain that no
hepatotoxic reactions, the warning signs and symptoms (e.g.,
nausea, fatigue, lethargy, pruritus, jaundice, upper-right quadrant Ophthalmology change in dosage is necessary.
tenderness and u-like symptoms), and the appropriate action to Blurred and/or diminished vision has been reported with the use Like other NSAIDs, diclofenac can reduce the antihypertensive
take should these signs and symptoms appear. Because severe of diclofenac and other nonsteroidal anti-inammatory drugs. If effects of propranolol and other P-blockers, as well as other
hepatotoxicity may develop without a prodrome of distinguishing such symptoms develop this drug should be discontinued and an antihypertensive agents.
symptoms, it is recommended that physicians also consider ophthalmologic examination performed; ophthalmic examination ADVERSE REACTIONS
periodic evaluation of transaminases in those patients for whom should be carried out at periodic intervals in any patient receiving
this drug for an extended period of time. Gastrointestinal, dermatological and central nervous system
long-term therapy with APO-DlCLO is planned. adverse reactions are most commonly seen. The most severe
Severe hepatic reactions including jaundice and cases of Central Nervous Svstem adverse reactions observed were gastric ulcer and gastrointestinal
fatal hepatitis have been reported with this drug as with other Headache, dizziness, vertigo, insomnia, depression, and mental bleeding while the most severe dermatological reactions observed
nonsteroidal anti-inammatory drugs. confusion have been reported following therapy with diclofenac were erythema multiforme (Stevens-Johnson Syndrome and Lyell
As with other NSAIDs, if abnormal liver tests persist or worsen, if sodium. Patients experiencing these symptoms should be cautioned Syndrome). Fatalities have occurred on occasion, particularly in
clinical signs and symptoms consistent with liver disease develop, against operating machinery or motor vehicles. the elderly.
or if systemic manifestations occur (e.g. eosinophilia, rash etc.) Use in Children Adverse reactions reported in clinical trials and spontaneous
APO-DICLO should be discontinued. Diclofenac sodium is not recommended in children under 16 years reports are summarized below. Frequency estimate: Frequent
In the largest U.S. trial which involved about 3000 patients of age because safety and dosage ranges have not been established >lo%, Occasional >1-1096, Rare >0.001-I%, Isolated cases
monitored for the rst time at 8 weeks, almost all marked in the pediatric age group. <0.001%.
transaminase elevations were detected before patients became Drug Interactions Gastrointestinal Svstem: 15.2%
symptomatic. Concurrent oral treatment with two or more NSAIDs, including Occasional: epigastric, gastric, or abdominal pain (6%), abdominal
There was only one instance of jaundice and all abnormalities those over the counter ones (such as ASA and Ibuprofen) is not cramps (5%), nausea (2%), dyspepsia, anorexia (1 %), diarrhea (1
were reversible. recommended due to the possibility of additive side effects. The %), vomiting (1 %), atulence (1 %).
Patients manifesting abnormal liver function test results, or signs bioavailability of ASA is reduced by the presence of diclofenac. Rare: gastrointestinal bleeding (bloody diarrhea, melena,
or symptoms that suggest liver dysfunction, should be evaluated Digoxin and methotrexate serum levels may be elevated as well as hematemesis) gastric and intestinal ulcerations with or without
for evidence of progression to a more severe hepatic reaction, cyclosporines nephrotoxicity. bleeding or perforation.
while on therapy with APO-DICLO. Patients receiving these drugs who are started on, or are given Isolated: lower gut disorders (e.g., non-specic hemorrhagic
Porohyria increased doses of, APO-DICLO (diclofenac sodium) or any colitis and exacerbation of ulcerative colitis or Crohns disease),
The use of diclofenac in patients with hepatic porphyria should be other NSAID, and particularly those patients with altered renal diaphragm-like intestinal strictures, hyperacidity, stomatitis,
avoided. To date 1 patient has been described in whom diclofenac function, should be observed for the development of the specic glossitis, coated tongue, esophageal lesions, constipation,
probably triggered a clinical attack of porphyria. The postulated toxicities of these drugs. In the case of digoxin, serum levels pancreatitis.
mechanism for causing such attacks by diclofenac, as well as some should be monitored. Caution should be exercised when NSAlDs Central Nervous Svstem: 9%
other NSAlDs is through stimulation of the porphyrin precursor are administered less than 24 hours before or after treatment with Occasional: dizziness (5%), headache (3%), vertigo.
delta-amino levulinic acid (AM, demonstrated in rats). methotrexate.
Rare (1 %): drowsiness, malaise, impaired concentration,
Fluid and Electrolyte Balance Although clinical investigations would appear to indicate that tiredness.
diclofenac has no inuence on the effect of anticoagulants, there
Fluid retention and edema have been observed in patients treated Isolated: sensory disturbances including paresthesia, memory
are isolated reports of an increased risk of hemorrhage with the
with diclofenac. Therefore, as with many other nonsteroidal anti- combined use of diclofenac and acenocoumarol anticoagulant disturbance, disorientation, insomnia, irritability, convulsions,
inammatory drugs, the possibility of precipitating congestive therapy. Numerous studies haveshown that the concurrent use depression, anxiety, nightmares, tremor, psychotic reactions,
heart failure in elderly patients or those with compromised cardiac aseptic meningitis.
of NSAlDs and anticoagulants increases the risk of GI adverse
function should be borne in mind. APO-DICLO (diclofenac events such as ulceration and bleeding. Special caution is therefore Dermatologic Svstem: 4%
sodium) should be used with caution in patients with cardiac recommended and frequent laboratory tests should be performed Occasional: rash (2%), pruritus (1.5%).
decompensation, hypertension and renal diseases and in those in order to check that the desired response to the anticoagulant is
recovering from surgical operations under general anesthesia and Rare: urticaria.
being maintained. Although diclofenac, as with other nonsteroidal
other conditions predisposing to uid retention. Isolated: bullous eruption, erythema, eczema, erythema
antiinammatory agents, is an inhibitor of induced platelet
multiforme, Stevens-Johnson Syndrome, Lyell Syndrome (toxic
There is a risk of potential hyperkalemia with NSAID treatment. aggregation in vitro or in vivo, at usual therapeutic dosages it has
epidermal necrolysis), erythroderma (exfoliative dermatitis),
Patients most at risk are: the elderly, those having conditions such little effect on spontaneous platelet aggregation.
loss of hair, photosensitivity reactions, purpura including allergic
as diabetes mellitus or renal failure, or those receiving concomitant However, because prostaglandins play an important role in purpura.
therapy with P-adrenergic blockers, angiotensin converting hemostasis, and NSAlDs affect platelet function, concurrent
enzyme inhibitors or some diuretics. Serum electrolytes should be Cardiovascular Svstem: 4.5%
therapy of APO-DICLO with anticoagulants requires close
monitored periodically during long-term therapy, monitoring to be certain that no change in anticoagulant dosage Rare: palpitation (2.5%), angina (2.0%), arrhythmias (2.0%).
especially in those patients who are at risk. is necessary. Isolated: exacerbation of cardiac failure, hypertension.
33
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APOTEX
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Special Senses Structural Formula: In adult patients with urethritis, cervicitis and vaginitis with
Isolated: vision disturbances blurred vision, diplopia), impaired O a positive test for Chlamydia trachomatis and/or Ureaplasma
hearing, tinnitus, taste alteration disorders. urealyticurn, clinical resolution and absence of detectable
NaOCCH2 organisms have been observed at completion of therapy with
Hematoloaic Svstem H Cl
doxycycline. Relapses or reinfection can occur.In these cases,
Isolated: thrombocytopenia, leukopenia, agranulocytosis, limited data suggest that some patients may derive clinical benet
hemolytic anemia, aplastic anemia, anemia secondary to N
from the administration of doxycycline or an alternative therapy.
gastrointestinal bleeding. The effect on long term morbidity has not been established.
Renal Svstem: 2.5% Skin and Soft Tissue Infections:
Rare: edema (facial (2%), general (0.5%), peripheral). Impetigo, furunculosis, cellulitis, abscess, wound sepsis, paro-
Isolated: acute renal failure, nephrotic syndrome, urinary nychia caused by susceptible strains of Staphylococcus aureaus
Cl
abnormalities (e.g., hematuria and proteinuria), interstitial and albus Streptococcus, E. coli, and the Klebsiella-Aerobacter
nephritis, papillary necrosis. Molecular Formula: Cl4H10CI2NNaO2 group.
Hepatic Molecular Weight: 31 8.1 3 Gastro-intestinal infections:
Occasional: elevations (23 times the upper normal limit) of serum Description: Diclofenac sodium is a white to off-white powder Caused by susceptible strains of shigella, salmonella and E.coli.
aminotransferase enzymes with a salty bitter taste. At 25 diclofenac sodium is 2% soluble in CONTRAINDICATION
(SGOT or AST, SGPT or ALT). water (pH 7.7). It is almost insoluble in aqueous acidic solution.
APO-DOXY is contra indicated in individuals who have shown
Rare: liver function disorders including hepatitis with or - without Composition hypersensitivity to tetracyclines.
jaundice. Enteric-Coated Tablets: In addition to diclofenac sodium, each
enteric coated tablet contains the non-medicinal ingredients WARNINGS
Isolated: fulminant hepatitis.
dextrates, methylcellulose, stearic acid, magnesium stearate, As with other tetracyclines, APO-DOXY (doxycycline) may form
Hyper Sensivity
colloidal silicon dioxide, hydroxypropyl methylcellulose, a stable calcium complex in any bone-forming tissue, though in
Rare: hypersensitivity reactions such as asthma in patients polyethylene glycol, titanium dioxide, yellow ferric oxide, Sunset vitro it binds calcium less strongly than do other tetracyclines.
sensitive to ASA e.g., bronchospasm; anaphylactic/anaphylactoid Yellow Aluminum lake 40% polyvinylacetate phthalate, triethyl Though not observed in clinical studies to date, it should be
systemic reactions including hypotension. citrate and methanol. Each 25 mg tablet also contains the non- anticipated that the use of doxycycline, 1ike other tetracyclines,
Isolated: vasculitis, pseumonitis. medicinal ingredient D&C yellow #I 0. during tooth development (last trimester of pregnancy, during
Other Slow Release Tablets: In addition to diclofenac sodium, each slow lactation, neonatal period and early childhood) may cause
Administration of the suppositories may occasionally give rise release tablet contains the non-medicinal ingredients dextrates, discoloration of the teeth. Though more commonly associated with
microcrystalline cellulose, hydroxyethyl cellulose, magnesium long-term use of tetracyclines, this effect has also been known to
to local irritation, rarely local bleeding and exacerbation of
stearate, hydroxypropyl methylcellulose, polyethylene glycol, occur after short courses.
hemorrhoids.
titanium dioxide and red ferric oxide, carnauba wax (lubricant PRECAUTIONS
Respiratory system
only).
Asthma in patients sensitive to ASA. In clinical studies to date doxycycline administration did not lead
Stabilitv and Storage Recommendations to increased serum levels nor to an increase in the serum ha1 f-1 i
SYMPTOMS AND TREATMENT OF OVERDOSAGE Store at room temperature (1 5-30C) and protect from high fe of doxycycline in patients with impaired renal function. APO-
Worldwide reports on overdosage with diclofenac cover 27 cases. humidity. DOXY (doxycycline) in normal dosage may be used to treat these
In 10 of these 27 cases, diclofenac was the only drug taken; all AVAILABILITY OF DOSAGE FORMS patients.
of these patients recovered. The highest dose of diclofenac was Although no evidence of increased toxicity has been observed in
2.5 g in a 20-year-old male who suffered acute renal failure as APO-DICLO (diclofenac sodium) Tablets 25 mg: round,
biconvex, mustard yellow, entericcoated tablets, engraved 25 on such patients, the potential for increased hepatic or other toxicity
a consequence, and who was treated with three dialysis sessions should be considered until further data on the metabolic fate of
one side.
and recovered in 2 days. The next highest dose was 2.35 g in a 17- doxycycline under these conditions becomes available. Liver
year-old girl who experienced vomiting and drowsiness. A dose of APO-DICLO (diclofenac sodium) Tablets 50 mg: round,
function tests should be carried out at regular intervals on patients
2.0 g of diclofenac was taken by a woman of unspecied age who biconvex, light (mocha) brown, entericcoated tablets, engraved
receiving high doses for prolonged periods of time. Concurrent
remained asymptomatic. 50 on one side.
administration of doxycycline and agents known to be hepatotoxic
There is no specic antidote for diclofenac sodium. In cases of APO-DICLO SR (diclofenac sodium) Slow-Release Tablets should be avoided if possible.
overdosage, absorption should be prevented as soon as possible by 75 mg: triangular, light pink, biconvex with bevelled edge, lm-
The use of antibiotics may occasionally result in over-growth
means of induction of vomiting, gastric lavage or treatment with coated tablets, engraved PO over 75 on one side, other side
of non-susceptible organisms; thus, observation of the patient is
activated charcoal. Supportive and symptomatic treatment should plain.
essential. There is evidence to suggest that doxycycline may have
be given for complications such as hypotension, renal failure, APO-DICLO SR Slow-Release Tablets 100 mg: round, pink, less effect on the gut ora than other tetracyclines (see under
convulsions, gastrointestinal irritation and respiratory biconvex with bevelled edge, lm-coated tablets, engraved APO Microbiology).
over 1 00 on one side, other side plain.
depression. Measures to accelerate elimination (forced diuresis, Doxycycline should not be administered to pregnant and lactating
hemoperfusion, dialysis) may be considered, but may be of APO-DICLO and APO-DICLO SR tablets are packaged in women or neonates until its safety in such cases has been
limited use because of the high protein-binding and extensive bottles of 100,500 and 1000. established beyond all reasonable doubt, unless in the judgment
metabolism. of the physician the potential benet to the patient outweighs the
APO- DOXY CAPSULES risk to the fetus or child.
[APO- DOXY TABS(N.R)] Certain hypersensitive individuals may develop a photodynamic
APO-DICLO 25 mg and 50 ma (enteric-coated tablets1
reaction to sun1 ight during treatment with doxycycline. If this
In rheumatoid arthritic patients, APO-DICLO (diclofenac sodium) or any other allergic reaction should occur, medication should be
treatment should be initiated with 75 mg to 150 mg per day in 3 or (Doxycycline hyclate) discontinued.
4 divided doses, depending on the severity of the condition. Increased intracranial pressure with bulging fontanelles has been
For maintenance, the dose should be reduced to the minimum Antibiotic observed in infants receiving therapeutic doses of tetracyclines.
amount that will provide control of symptoms, usually 75 mg to Although the mechanism of this phenomenon is unknown, the
NAME OF DRUG
100 mg daily in 3 divided doses. In osteoarthritic patients, the signs and symptoms have disappeared rapidly upon cessation of
starting and maintenance dose is usually 75 mg/day in 3 divided APO-DOXY (DOXYCYCLINE HYCLATE) CAPSULES
treatment without sequelae.
doses. The dose should be adjusted individually to the minimum [APO-DOXY-TABS (DOXYCYCLINE HYCLATE) TAB- Esophageal injury consisting of esophagitis and esophageal
dose that will provide control of symptoms. LETS (N.R)] ulceration have rarely been reported in patients receiving
The maximum recommended daily dose is 150 mg. APO-DICLO THERAPEUTIC OR PHARMACOLOGICAL CLASSIFI- doxycycline orally. If this should occur, doxycycline should be
should be taken with food and the tablets should be swallowed CATION discontinued until heal ing occurs.
whole. Administration of antacids and/or cimetidine has provided relief in
Broad-spectrum antibiotic
APO-DICLO SR 75 mg and 100 mg (slow-release the treatment of such cases. To reduce the risk of esophageal injury,
tablets)Treatment should be initiated and individual titration ACTIONS patients should be advised to take APO-DOXY CAPSULES
carried out using diclofenac enteric coated tablets. Patients with APO-DOXY (doxycycline) i s a broad-spectrum antibiotic and is or APO-DOXY-TABS with an adequate amount of uid while
rheumatoid arthritis or osteoarthritis on a maintenance dose of active against a wide range of Gram-negative and Gram-positive standing or sitting upright.
75 mg per day may be changed to a once daily dose of APO- organisms. Doxycycline exerts it Is antimicrobial effect by inhibit
ADVERSE REACTIONS
DICLO SR 75 mg, administered morning or evening. Patients on of protein synthesis.
on a maintenance dose of 100 mg per day may be changed to a As with other broad-spectrum antibiotics, gastrointestinal
INDICATIONS AND CLINICAL USE disturbances such as nausea, vomiting and diarrhea, as well
once-daily dose of APO-DICLO SR 100 mg tablets, administered
morning or evening. Patients on a maintenance dose of 150 mg per APO-DOXY (doxycycline) is indicated for the treatment of :- as glossitis, stomatitis and protitis, may occur during APO-
day may be changed to a twice daily dose of one APO-DICLO SR Pneumonia: DOXY (doxycycline) therapy , but have rarel y been sufciently
75 mg tablet administered morning and evening. troublesome to warrant discontinuation of therapy. Rare
Single and multilobe pneumonia and broncho-pneumonia is
instances of esophagit s and esophageal ulcerations in patients
The maximum daily dose of diclofenac should not exceed 150 due to susceptibles trains of Pneumococcus, Streptococcus,
receiving the capsule form of doxycyline have been reported
mg. Staphylococcus, H. inuenzae, and Klebsiella pneumoniae.
(See PRECAUTIONS and DOSAGE AND ADMINISTRATION
APO-DICLO SR tablets should be swallowed whole with liquid, Other Respiratory Tract Infections: sections).
preferably at mealtime. Pharyngitis, tonsillitis , sinusitis , otitis media, bronchitis caused by As with other tetracyclines, elevation o f SGOT, or SGPT values,
susceptible strains of B-hemolytic Streptococcus, Staphylococcus, anemia, neutropenia, eosinophil ia, leukopenia or elevated BUN
PHARMACEUTICAL INFORMATION
Pneumococcus and H. inuenzae. have been reported, the signicance of which is not known.
Drug Substance
Genitourinary Tract Infections: SYMPTOMS AND TREATMENT OF OVERDOSAGE
ProperICommon Name: diclofenac sodium
Pyelonephritis, cystitis, urethritis, gonococcal urethritis caused Gastric lavage if necessary.
Trade Name: Apo-Diclo by susceptible strains of the Klebsiella-Aerobacter group, E.
Chemical Name: sodium-(o-((2,6-dichlorophenyl)-amino)-phenyl) coli, Enterococcus, Staphylococcus, Streptococcus, and Neisseria DOSAGE AND ADMINISTRATION
-acetate gonorrhoeae. The recommended oral dosage of APO-DOXY (doxycycline)
34
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APOTEX
SPDI
in adults for the majority of susceptible infectionsisa single Listeria rnonocytogenes Shigel la exneri Monkeys which received doxycycline at dosages of 25 and 50 mg/
loading dose of 200 mg on the rst day of treatment followed by Corynebacterium diphtheriae Pseudomonas aeruginosa kg/day for 1 to 2 months showed mild yellow ultra - violet
a maintenance dosage of 100 mg once daily at the same time each Bacillus anthracis Haemophilus inuenzae uorescence of liver, kidney and bone, and the presence of small
day thereafter. Bacillus subtilis Serratia spp. amounts of intracytoplasmic granular material i n the thyroid
The recommended dosage schedule for children above 8 years gland.
Neisseria qonorrhoeae Brucella spp.
weighing up to 100 pounds is a single loading dose of 2 mg/lb of Neisseria catarrhalis Proteus spp. c) Chronic Toxicity
bodyweight on the rst day, followed by a maintenance dosage of In an 18-month chronic tox icity study, rats were fed diets
Escherichia coli Pasteurella spp.
1 mg/lb once daily a t the same time each day thereafter. containing doxycycline at leve is to provide daily drug intake of
Aerobacter aerogenes Mycoplasma pneumoniae
As absorption is not signicantly affected by food or milk APO- 500, 250, 50 and 0 mg/kg. Slight depression of weight gains in
Chlamydia trachomatis Ureaplasmaurealyticum
DOXY should be given with or aftera meal, thus minimizing the some rats receiving the 500 mg/kg/day dose occurred during the
possibility of gastric upset. Antacids and iron preparations impair In vivo studies in mice with doxycycline administered in a single middle third of the study. The usual yellow ultraviolet uorescence
absorption and should not be given concomitantly to patients oral doseshow the PD5o to be 4.8, 6.5, and 1.38 for S. aureus, P. of bone, teeth and/or kidneys was seen in rat s receiving all levels
taking oral doxycyline. multocida, and, respectively (Smith, 1966). of doxycycline for 6, 12 or 18 months.
APO-DOXY CAPSULES and APO-DOXY-TABS should be There is evidence to suggest that doxycycline, because of its rapid Dark to light brown discoloration of the thyroid gland was also
given to patients with adequate amounts ofuid while standing or and almost complete absorption, may have less effect on the gut noted in rats receiving doxycycline for 12 months at levels of
sitting upright to reduce the risk of esophageal injury . ora than other tetracyclines. Hinton (1968) has reported that the 500 and 250 mg/kg/day, and at 18 months at all levels. The only
normal dosage regimen of tetracycline HCL administered to 17 other change noted was depletion of hepatic glycogen in four rats
In severe infections in adults, such as lung abscesses or
volunteers was associated with important effects on the intestinal receiving the highest dose level for 12 months
osteomyelitis,and in chronic urinary tractinfections, a single
ora in terms of both changes in total population and the emergence
daily dose of 200 mg may be used throughout. For more severe Beagle dogs received doxycycline at levels of 10 and 100 mg/kg,
of resistant strains. Large doses of oral doxycycl ine (double the
infections in children, up to 2 mg/lb of bodyweight may be given. six days per week. Moderate to marked elevations of alkaline
maximum recommended dosage) had to be administered to
Therapy should be continued after symptoms and fever have produce an equivalent effect. phosphatase and SGPT (occasionally SGOT) were observed
subsided. It should be noted, however, that effectiveanti bacteri a1 in animals receiving doxycycline, 100 mg/kg/day . One of two
Excellent oral absorption of doxycycline and protracted half-
levels are usually present 24 to 36 hours following discontinuance dogs receiving doxycycine, 100 mg/kg/day, displayed mild bile
life permit signicantly lower dosage to achieve blood levels
of APO-DOXY therapy. ductular proliferation and hepatocellular inclusion bodies of
comparable to those obtained with tetracycline. This raises the
When used in steptococcal infections, therapy should be continued 5 months (biopsy sample) and 12 months (necropsy sample).
possibility that doxycyline may induce fewer changes in the
for 10 days to prevent development of rheumatic fever or Administration of doxycycline for 5 and 12 months at a dose
intestinal ora. Bartlett et al. (1975), however, noted that in 30
glomerulonephritis. level of 100 mg/kg/day and for 12 months at a dose level of 10
volunteers treated for 8 to 10 days, there were no signicant
mg/kg/day caused black and brownish discoloration of the thyroid
For treatment of acute gonococcal infections, the recommended changes in total populations of anaerobic and aerobic bacteria in
gland, respectively, with intracytoplasmic granules. Other changes
dosage is 200 mg stat. and 100 mg at bedtime, the rst day, the gut with either tetracycline or doxycycline at the recommended
included vasodilation and focal areas of necrosis o f the mucosa
followed by 100 mg b.i .d. for 3 days. daily dosage of each antibiotic.However the increase in relative
of the pyloric and fundic stomach of dogs, and yellow ultra violet
For treatment of uncomplicated urethral, endocervical, or vaginal proportions of resistant strains of E.coli was signicantly greatr
uorescence of teeth and bones of animals at 100 mg/kg/day dose
infections in adults associated with Chl amvdia trachomatis and with tetracycline than with doxycycline and this difference is
1eve1 sof doxycycline.
Ureaplasma urealvticum: 100 mg, by mouth, twice a day for at ascribed to reduced intestinal concentrations of bioactive drug
with recommended oral dosage of doxycycline. Additional groups of 4 beagles each received doxycycline in
least 10 days.
dosages of 5, 1 and 0 mg/kg/day for 6 months. The only abnormal
No a1teration in recommended dosage schedule need be made PHARMACOLOGY ndings weres light elevations of SGPT values in 3 dogs at the 5
when treating patients with impaired renal function. Doxycycline differs from other tetracyclines in that serum mg/kg level at 180 days.
PHARMACEUTICAL INFORMATION levels after oral administration follow a pattern similar to those In a one year chronic toxicity study, groups of four rhesus
obtained with equivalent dosages of intravenous doxycycl ine. monkeys each received doxycycl ine in oral doses of 0, 5, 25 and
(i) Drug Substance
As expected, peak serum levels are slightly higher and occur 50 mg/kg/day, respectively. Oral dosage of 100 mg/kg produced
Proper name(s) earlier with intravenous doxycycline than with oral doxycycl ine. severe gastrointestinal symptoms, e.g., vomiting and diarrhea. In
doxycycline hyclate (doxycycline hydrochloride hemiethanolate Hernodialysis does not alter serum half -1ife. one out of 4 monkeys receiving the 50 mg/kg/day dose, occasional
hemihydrate) Doxycycline is rapidly and almost completely absorbed following anorexia and diarrhea were observed during the rst six months.
Chemical Name: -6-deoxy-5-oxytetracycline oral administration and shows a prolonged duration of in vivo Signicant pathologic changes noted in monkeys sacriced
Structural Formul a : antibacterial activity. The absorption of doxycycl ine is not after receiving doxycycline for 1 year at dose levels of 50 mg/
CH3 OH N(CH3)2 signicantly inf tuenced by ingestion of food or milk, which kg/day were: 1) grossly, very light brown discoloration of the
H impair the absorption of other tetracyclines. Doxycycline can thus
OH thyroid gland in one of the four monkeys, and 2) microscopically,
. HCI be administered with or after meals, It is about 93% protein bound.
OH brownish intracytoplasmic inclusions in the acinar cell so f thyroid
. H2O As its serum half-life is longer than that of the other tetracyclines, follicles of three out of four monkeys. Bone and dentin exhibited
CONH2 . C2H5OH doxycycline in therapeutic dosage given once a day will produce slight to moderate ultra - v iolet uorescence.
OH O OH O serum concentrations above 0.6 ug/mL for 24 hours.
Two monkeys, in another study, receiving the 25 mg/kg/day
Doxycycline Hyclate The serum half-life of doxycycline is not increased, nor do serum dosage, were sacriced after 6 and 8 months on test , respectively
levels accumulate, in patients with impaired renal function. . Signicant gross and histopathologic ndings were slight yellow
Molecular Weiqht: 512.9
TOXICOLOGY ultraviolet uorescence of the endosteum and periosteum of
Mot ecul ar Forrnul a: C22H2408N2. Hcl0.5H20.0. 5C2H5OH
bone, and microscopic appearance of small amounts o f granular
Description: Doxvcvcline Hvclate
intracytoplasmic material in the acinar cells of thyroidfollicles .
doxycycline hyclate is a 1ight ye11ow, crystal1 ine powder a) Acute Toxicity
The highlights of the chronic toxicity studies can be summa-
essentially free of solvent odour. It is soluble in water; pH (1% The acute oral and parenteral toxicity of doxycycline hyclate in rized as follows:
H20) is between 2.0 and 3.0. It decomposes without melting at mice, rats and dogs are as follows:
Repeated daily oral administration o f doxycycline i n appropriate
201c. LD50 (95% Condence Limits) dosage, may result in two characteristic effects commonly seen in
(ii) Composition: ORAL I. V. animals receiving many other tetracycline antibiotics :
APO-DOXY CAPSULES contain doxycycline hyclate equivalent mg/kg mg/kg 1) Discoloration of the thyroid gland, with deposition of
to 100 mg of doxycycline base. Mice 1,900 (1696-2128) 241 (230-253) intracytoplasmic granules in the acinar cells of the follicle. Thyroid
APO-DOXY-TABS contain doxycycline hyclate equivalent to Rats >2,000 228 (202-258) function, however, did not seem to be affected. This phenomenon
100 mg of doxycycline base.(N.R) Dogs >500 >lo0 appears to be a result of the interaction of the antibiotic with the
(iii) Stability and Storage Recommendations: active iodinating system of the gland.
The intraperitoneal LD50s of doxycycline in weanling and
Storage: newborn rats are 262 (222-309) and 300 (275-327) mg/kg, 2) Yellow staining of bones and teeth, which is thought to be due to
respectively. formation of a tetracycline-calcium-phosphate complex.
APO-DOXY CAPSULES (doxycycl i ne) 100 mg, APO-DOXY
-TABS (doxycycl ine) 100 mg: Protect from light. Dispense in a Otherwise doxycycline is well tolerated by the rat and monkey
b) Subacute Toxicity at doses up to and including 500 and 50 mg/kg/day for 18 and 12
light-resistant container.
One to 2 - month subacute toxicity studies were conducted in rats, months, respectively.
AVAILABILITY hamsters, dogs and monkeys. Like other tetracycline antibiotics, In dogs, however, repeated daily oral administration of large
DOSAGE FORMS doxycycline induced a yellow uorescence (under ultraviolet light) doses of doxycycline may result in certain hepatic functional
of bone, teeth, kidney and/or liver , inall animal species tested. In and histopathologic changes which are reversible after drug
APO-DOXY CAPSULES (doxycycl ine) 100 mg are available
rats, doxycycline produced no toxic effectsin doses of up to 500
asi blue hard gelatin capsules containing doxycycline hyclate withdrawal. It is to be noted that no adverse hepatic effects were
mg/kg/day for 30 days. In hamsters, doxycycline in dosages of 500
equivalent to 100 mg of doxycycline, supplied in bottles of noted in the hamster (1 month), rats (18 months) or monkeys (12
or 250 mg/kg/dayproduced weight loss and early death, but the 50
10,100(N.R), 500(N.R) and 1000. months) of doses up to and including 500, 500 and 50 mg/kg/day,
mg/kg level (for 30 days) was non-toxic. In dogs, doxycycl ine in
APO-DOXY-TABS (doxycycline) 100 mg are avai1able as round, respectively. In view of this and in view of the lack of notable
dosages of 250 mg/kg/day for one month produced discoloration
1ight orange, lm-coated tablets, engraved APO-DOXY 100 on toxicity so far reported in humans, this is likely a species specic
of the thyroid gland with the presence of intracytoplasmic granules
one side, containing doxycycline hyclate equivalent to 100 mg of phenomenon for the dog only.
in follicula racini and occasional amorphous body formation w ith
doxycycline, supplied in bottles of 100, 500 and 1000.(N.R) in follicular colloid . d) Reproduction and Teratogenic Studies
MICROBIOLOGY Certain biochemical, functional and histological changes of Doxycycline has no teratologic effects in rats, rabbits or monkeys.
the liver occurred in the dogs (but not in the rats, hamsters, or Breeding rats received doxycycline by gavage in doses of 50 and
APO-DOXY (doxycycline) is a broad-spectrum antibiotic and 250 mg/kg/day prior to and throughout two consecutive litters.
has been shown to be active in vitro against the following Gram- monkeys) receiving doxycycline for 30 days at dosage levels
of 250 and 50 mg/kg/day, but not at the 25 mg/kg/day level. The There was no evidence that doxycycline interfered with the
negative and Gram-positive and other microorganisms: reproductive process in rats.
biochemical changes in the blood were elevations of alkaline
Staphylococcus pyoqenes Klebsiella pneumoniae phosphatase, SGPT and/or BSP retention. Histologic changes Pregnant female white New Zealand rabbits received doxycycline
Streptococcus pyogenes Salmonella typhi were conned to bile ducter proliferation and hepatocellular orally in doses of 8 and 40 mg/kg/day, respectively, from day 8 to
Streptococcus faecalis Salmonella typhimurium intracyto plasmic inclusion bodies and Kupffer cells swollen with day 16 of pregnancy. Spina bida and partial anencephaly in one
Streptococcus pneurnoniae Salmonella enteriditis PAS-positive granular material . These changes in the dog were pup each in the control and the 8 mg/kg group, respectively, are
Streptococcus viridans Shigel la sonnei reversible upon drug withdrawal . be1ieved to be spontaneous and drug-induced.
35
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APOTEX
SPDI
In teratogenic studies using a limited number of monkeys, PREGNANCY AND LACTATION antidiabetic preparation, or when the tablets have not been taken
doxycycline, in doses ranging from 1 to 50 mg/kg/day, did not During pregnancy, no oral anti-diabetic drugs should be given. regularly, alertness and reaction time may be altered to such an
produce any teratologic effects. extent that the patient cannot safely cope with road trafc or
Due to the possible excretion in human milk, the patient should
operate machinery.
discontinue nursing or discontinue taking the drug depending
APO-GLYBURIDE Tablets on the importance of the drug to the mother. If glyburide is ADVERSE REACTIONS
discontinued, the patient should be transferred to insulin therapy. Hypoglycemia (See PRECAUTIONS)
WARNINGS Severe hypoglycemia, which may be prolonged and has
(Glyburide) occasionally been life-threatening, may occur and mimics acute
The use of APO-GLYBURIDE (glyburide) will not prevent the
development of complications peculiar to diabetes mellitus. CNS disorders (see SYMPTOMS AND TREATMENT OF
Glyburide tablets Apotex standard
OVERDOSAGE). Hepatic and/or renal disease, malnutrition
2.5(N.R) and 5 mg The use of glyburide must be considered as treatment in addition
and/or irregular meals, exercise without adequate caloric
to a proper dietary regime and not as a substitute for diet.
THERAPEUTIC CLASSIFICATION supplementation, debility, advanced age, patient non-compliance,
Over a period of time, patients may become progressively less alcoholism, certain disorders of thyroid function, adrenal or
Oral hypoglycemic agent responsive to therapy with oral hypoglycemic agents because of pituitary insufciency, excessive glyburide dosage, treatment
ACTIONS AND CLINICAL PHARMACOLOGY deterioration of their diabetic state. If a loss of adequate blood with glyburide in the absence of indication or concurrent use with
glucose lowering response to APO-GLYBURIDE is detected, the other agents may be predisposing factors.
The principal action of glyburide results in an increased insulin drug should be discontinued.
release from the beta cells of the pancreas. Other mechanisms Gastrointestinal Reactions
leading to a reduction of blood glucose are also believed to be PRECAUTIONS Nausea, epigastric fullness and heartburn are common reactions.
inuenced by glyburide. The insertion of an alkylene chain on the Patient Selection and Follow-Up Vomiting, diarrhea and abdominal pain have also been reported.
benzene nucleus results in a product of very high potency. Careful selection of patients is important. It is imperative that These tend to be dose related and may disappear when dosage is
Schulz and Schmidt indicated that the presence of a sulfonamide reduced.
there be rigid attention to diet, adherence to regular exercise,
(sulphaphenazoIe) decreased the distribution volume of glyburide reduction of body weight in obese patients, careful adjustment of Dermatologic and Sensitivity Reactions
without inuence on the half-life of the oral hypoglycemic agent. dosage, instruction of the patient on hypoglycemic reactions and Allergic and pseudoallergic skin reactions such as pruritus,
As a result, insulin and serum concentrations of glyburide were their control as well as regular thorough follow-up examinations. erythema, urticaria, morbilliform or maculopapular eruptions
higher and hypoglycemic attacks could he expected. Since the effects of oral hypoglycemic agents on the vascular have been reported in a number of patients. These may subside
Hirn and Konigstein have observed hypoglycemia when changes and other long-term sequelae of diabetes mellitus are on continued use of glyburide, but if they persist the drug should
phenylbutazone and oxyphenbutazone were added to glyburide. not fully known, patients receiving such drugs must be closely be discontinued. Mild reactions such as urticaria may very rarely
observed for both short and long-term complications. develop into serious and life-threatening reactions including
Schulz and Schmidt conrmed that phenylbutazone has an
dyspnea, hypotension or shock. Porphyria cutanea tarda and
enhancing effect on the blood-sugar-Iowering effect of glyburide Periodic assessment of cardiovascular, ophthalmic, hematologic,
photosensitivity reactions have been associated with the use of oral
and found higher insulin levels. The plasma haIf-life of glyburide renal and hepatic status is advisable.
hypoglycemic drugs. Allergic vasculitis have been observed very
did not change with phenylbutazone administration. However, a In patients stabilized on APO-GLYBURIDE (glyburide), loss rarely in patients receiving glyburide and in some circumstances
signicant decrease in the renal excretion of the main metabolite of blood sugar control may occur in cases of acute intercurrent may be life-threatening.
of glyburide was observed, suggesting that the elimination in the disease or in stressful situations such as trauma or surgery. Under
Cross-sensitivity to sulfonamides or their derivatives may occur in
bile may compensate for the amount not excreted in the urine. these conditions, discontinuation of APO-GLYBURIDE and patients treated with oral sulfonylurea hypoglycemic agents.
Glyburide is highly bound to plasma proteins after absorption administration of insulin should be considered.
Hematologic Reactions
from the gastrointestinal tract. It is completely metabolized Oral hypoglycemic agents should be administered with caution to
by hydroxylation of the cyclohexyl ring into 3 cis and 4 trans patients with Addisons disease. Rare cases of mild to severe thrombocytopenia which can manifest
derivatives in the liver and the kidneys play only a minor role itself as purpura have been reported. Leukopenia, agranulocytosis,
The use of APO-GLYBURIDE is not recommended for women pancytopenia (which may be due to myelosuppression),
in their biotransformation and elimination from plasma. The planning a pregnancy (see CONTRAINDICATIONS); these erythrocytopenia, granulocytopenia, hemolytic anemia and aplastic
metabolites have no essential hypoglycemic effect and they are patients should be changed over to insulin therapy. anemia have been observed very rarely with glyburide therapy.
not stored in the body, but they are eliminated via the bile, and
Hypoglycemic Reactions These reactions may be reversible following discontinuation of
in approximately the same amounts in the urine conjugated to
Severe hypoglycemia can be induced by all sulfonylurea drugs. the sulfonylurea antidiabetic agent.
glucoronic acid and in the feces.
Particularly susceptible are elderly subjects, patients with Metabolic Reactions
Maximal plasma levels of insulin, after an oral dose of 5 mg impaired hepatic and renal function, those who are debilitated
of glyburide in normal subjects were reached 90 minutes after Hepatic porphyria and disulram-like reactions have been
or malnourished, and patients with primary or secondary adrenal observed in patients treated with oral hypoglycemic drugs.
dosing. insufciency. Hypoglycemia is more likely to occur when the Elevation of liver enzyme levels has been reported very rarely in
Minimal blood levels of glucose, after an oral dose of 5 mg of caloric intake is inadequate or after strenuous or prolonged patients treated with glyburide. In isolated cases, impairment of
glyburide in normal subjects were reached 120 minutes after exercise. liver function (e.g., cholestasis and jaundice) and hepatitis have
dosing corresponding to a reduction of about 35%. Drug Interactions been observed which can regress after withdrawal of the drug or
Comparative Bioavailability Patients who receive or discontinue certain medications while may lead to life-threatening liver failure.
The relative bioavailability of Apo-Glyburide (10 mg) tablets of undergoing treatment with glyburide may experience changes in Endocrine Reactions
Apotex Inc. and DiaBeta (10 mg) of Hoechst Canada Inc. were blood glucose control. Reduced radioactive iodine uptake by the thyroid gland has been
compared. The study was a single oral dose (2 x 5 mg of each Hypoglycemia may be potentiated when a sulfonylurea reported with oral hypoglycemic therapy.
brand) administered to each of 20 fasted healthy volunteers in is used concurrently with agents such as: insulin and Other Adverse Reactions
a balanced randomized crossover design with a 7 day washout other oral antidiabetics, anabolic steroids and androgens, Transient visual disturbances may occur at the commencement of
period. Glyburide was assayed in the human plasma using azapropazone, chloramphenicol, clobrate, coumarin derivatives, treatment due to uctuations in blood glucose levels.
a validated HPLC method. The results of this biostudy are cyclophosphamide, disopyramide, fenuramine, brates,
summarized in the following table: In isolated cases, reduction of serum sodium concentrations has
uoxetine, ifosfamide, miconazole, monoamine oxidase inhibitors,
been observed in patients receiving glyburide.
Parameter DiaBeta Apo-Glyburide Percentage of oxyphenbutazone, para-aminosalicylic acid, phenylbutazone,
DiaBeta probenecid, propranolol, quinolones, salicylates, sulnpyrazone, SYMPTOMS AND TREATMENT OF OVERDOSAGE
AUCT* sulfonamides, sympatholytic agents (e.g., beta-blockers, Overdosage with sulfonylureas may result in hypoglycemia, but
1446 (45) 1336 (44) - 7.6 guanethidine), tetracyclines, tuberculostatics.
(nghrs/mL) it should be noted that the dosage which causes hypoglycemia
Certain drugs tend to produce hyperglycemia and may lead varies widely, and may be within the accepted therapeutic range
AUCI*
1525 (44) 1425 (46) -6.6 to loss of blood sugar control; these include: acetazolamide, in sensitive individuals.
(nghrs/mL)
barbiturates, corticosteroids, diazoxide, diuretics (thiazides, The manifestations of hypoglycemia include: ushing or pallor,
Cmax* furosemide), glucagon, laxatives (after protracted use), nicotinic
317 (36) 329 (38) +3.8 chilliness, excessive hunger, trembling, headache, dizziness,
(ng/mL) acid (in pharmacologic doses), oral contraceptives (estrogen nausea, vomiting, restlessness, aggressiveness, depression, speech
Tmax (hrs)** 2.6 (0.9) 2.1 (0.7) - plus progestogen), phenothiazines, phenytoin, rifampin, disorders, sensory and/or visual disturbances, helplessness,
t (hrs)** 4.5 (3.3) 4.6 (4.4) - sympathomimetic agents (e.g., epinephrine) and thyroid lassitude, shallow respiration or bradycardia. In more severe
* Geometric mean (CV) hormones. cases, the clinical symptoms of a stroke or coma appear.
** Arithmetic mean (SD) Under the inuence of sympatholytic drugs such as beta-blockers, However, symptoms of hypoglycemia are not necessarily
clonidine, guanethidine, and reserpine, the signs of adrenergic as typical as described above and sulfonylureas may cause
Complete details on the comparative bioavailability study are
counter-regulation to hypoglycemia may be reduced or absent. insidious development of symptoms mimicking cerebrovascular
available from Apotex Inc. upon request.
Concurrent use of H2 receptor antagonists, clonidine or reserpine insufciency. (e.g., disordered sleep, somnolence, impaired
INDICATIONS AND CLINICAL USE with glyburide may lead to either a potentiation or an attenuation alertness and reactions, confusion, delirium, cerebral convulsions,
To control hyperglycemia in glyburide-responsive diabetes of the blood-glucose-lowering effect. paralytic symptoms or loss of consciousness).
mellitus of stable, mild, non-ketosis-prone, maturity-onset or adult Both acute and chronic alcohol intake may potentiate or weaken Signs of adrenergic counter-regulation to hypoglycemia include:
type which cannot be controlled by proper dietary management, the blood-glucose-lowering action of glyburide in an unpredictable sweating, damp skin, anxiety, tachycardia, hypertension,
exercise and weight reduction, or when insulin therapy is not fashion. Intolerance to alcohol (disulram-like reaction: ushing, palpitations, angina pectoris and cardiac arrhythmias. However,
appropriate. sensation of warmth, giddiness, nausea, and occasionally these symptoms may be milder or absent in patients who develop
tachycardia) may occur in patients treated with oral hypoglycemic hypoglycemia gradually, patients with autonomic neuropathy, or
CONTRAINDICATIONS patients who receive concurrent treatment with sympatholytic
drugs. These reactions can be prevented by avoiding the use of
APO-GLYBURIDE (glyburide) should not be given to patients alcohol. agents (e.g., beta-blockers, clonidine, reserpine, guanethidine).
with known hypersensitivity or allergy to the active ingredient or Discontinue medication and treat hypoglycemia by giving dextrose
Barbiturates should be used cautiously in patients receiving an oral
any other component of the formulation. Glyburide should not be promptly and in sufcient quantity.
hypoglycemic agent, since their action may be prolonged.
given to patients with: unstable and/or insulin-dependent diabetes The symptoms of hypoglycemia nearly always subside when blood
mellitus; ketoacidosis; diabetic precoma; coma; in the presence Glyburide may potentiate or weaken the effects of coumarin
glucose control is attained. However, some sulfonylurea-induced
derivatives.
of pre-existing complications peculiar to diabetes; during stress hypoglycemias may be refractory to treatment and susceptible to
conditions such as severe infections, trauma or surgery; in the Impairment of Alertness and Reaction Time relapse, especially in elderly or malnourished patients. Continuous
presence of liver disease or renal impairment; or frank jaundice. Until optimal control has been achieved, when changing the dextrose infusions for hours to days have been necessary.
36
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APOTEX
SPDI
DOSAGE AND ADMINISTRATION APO 5 on the other, contains 5 mg of glyburide. Available in more than 8 hours, and after 12 hours the plasma concentrations
In diabetic subjects there is no xed dosage regimen for bottles of 100 and 500, and in unit dose packages of 30 and 100. were sufciently high to have a signicant inhibitory effect upon
management of blood glucose levels. Individual determination of gastric acid secretion. In patients with duodenal ulcer, 150 mg
PHARMACOLOGY
the minimum dose that will lower the blood glucose adequately oral ranitidine every 12 hours signicantly reduced mean 24 hour
Animal hydrogen ion activity by 69% and nocturnal gastric acid output by
should be made.
In the isolated, perfused rat pancreas, glyburide produced a sustained 90%. Furthermore, 300 mg oral ranitidine at night is as effective
If the maximal recommended dose fails to lower blood glucose
rise in insulin output. In the presence of 0.5 mcg/mL of glyburide, in reducing 24hour intragastric acidity as 150 mg ranitidine given
adequately in patients on initial trial, APO-GLYBURIDE
isolated rat pancreatic islets released insulin continuously. When twice daily.
(glyburide) should be discontinued. During the course of therapy
isolated pieces of rat pancreas were repeatedly exposed to glucose In respect of both 24 hour acidity and nocturnal acid output,
a loss of effectiveness may occur. It is advisable to ascertain
or glyburide for brief periods of time at intervals of 30 minutes, ranitidine 150 mg twice daily was superior to cimetidine 200 mg
the contribution of the drug in the control of blood glucose by
they consistently released insulin. In the presence of 300 mg% three times daily and 400 mg at night (p < 0.001 and p < 0.05
discontinuing the medication semi-annually or at least annually
with careful monitoring of the patient. If the need for the drug of glucose, glyburide (2.5 mcg/min.) increased effectively insulin respectively).
is not evident, the drug should not be resumed. In some diabetic output from isolated rat pancreas.
Treatment of volunteers with an oral dose of ranitidine 150 mg
subjects short-term administration of the drug may be sufcient Sirek et al. found that the beta adrenergic blocker, propranolol, twice daily for 7 days did not cause bacterial overgrowth in the
during periods of transient loss of blood sugar control. inhibits sulphonylurea-stimulated insulin secretion in the dog and stomach.
Adjustment of glyburide dosage should be considered whenever that the hypoglycemia produced by glyburide in the presence of
Volunteers treated with oral ranitidine have reported no
factors predisposing the patient to the development of hypo- or propranolol could be the result of extrapancreatic effects. signicant gastrointestinal or central nervous system side effects;
hyperglycemia such as weight or lifestyle changes, are present TOXICOLOGY moreover pulse rate, blood pressure, electrocardiogram and
(see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS The LD50 for white mice, rats and guinea pigs was found to be electroencephalogram were not signicantly affected in man
and ADVERSE REACTIONS). more than 15 g/kg body weight and for rabbits and beagles, more following ranitidine administration.
Newly-Diagnosed Diabetics than 10 g/kg body weight when glyburide is given orally. The In healthy human volunteers and patients, oral ranitidine did not
The initial dose is 5 mg daily (2.5 mg in patients over 60 years of LD50 in rats following intraperitoneal injection is 6.3 to 8.4 g/kg inuence plasma levels of the following hormones - cortisol,
age) and it should be continued for 5 to 7 days. Depending on the body weight. testosterone, oestrogens, growth hormone, follicle stimulating
response, the dosage should then be either increased or decreased Long-term feeding experiments were carried out in rats and dogs hormone, luteinizing hormone, thyroid stimulating hormone,
by steps of 2.5 mg. The maximum daily dose of glyburide is 20 over the course of one year. Rats were given glyburide in their aldosterone or gastrin - although like cimetidine, ranitidine
mg (because higher doses normally have no additional effect on food in doses of approximately 0.2, 1.0 and 5.0 mg/kg body weight reduced vasopressin output. Treatment for up to 6 weeks with
control of metabolic state). Occasionally, control is maintained daily. The highest dose is equivalent to 350 times the minimal ranitidine 150 mg twice daily by mouth did not affect the human
with 2.5 mg daily. The majority of cases can be controlled by hypoglycemic dose in man. Organ function tests were carried out hypothalamicpituitary testicular, ovarian or adrenal axes.
5 to 10 mg (1 to 2 tablets) daily given as a single dose during continuously. Hematological examination, blood sugar tests and Comparative Bioavailability
or immediately after breakfast. Patients who eat only a light urinary analyses were performed every three months. None of Bioavailability studies were performed using healthy human
breakfast should defer the rst dose of the day until lunchtime. If the rats showed any abnormal ndings in the function tests or the volunteers. The rate and extent of absorption after a single oral
more than 10 mg (2 tablets) daily is required, the excess should be blood and urine studies. Subsequent post-mortem examination 150 mg dose of Zantac 150 mg and ApoRanitidine 150 mg was
taken with the evening meal. revealed no macroscopic or histological changes attributable to a measured and compared. The results are summarized as follows:
Changeover From Other Oral Hypoglycemic Agents toxic effect of glyburide. Dogs were given glyburide by mouth Zantac ApoRanitidine %
There is no exact dosage relationship between glyburide and other at dose levels of 0.4, 2.0 and 10.0 mg/kg body weight daily. The
150 mg 150 mg Diffr
oral antidiabetic agents. Discontinue previous oral medication and highest dose is equivalent to 650 times the minimal effective
start APO-GLYBURIDE 5 mg daily (2.5 mg in patients over 60 hypoglycemic dose in man. Regular checks of blood cell counts, AUC0-12 hrs (ng-hr/mL) 2041 2186 +7.1
years of age). This also applies to patients changed over from the blood glucose, urine, electrolytes, electrophoresis, BUN and serum AUC 0-Inf. (ng-hr/mL) 2107 2243 + 6.5
maximum dose of other oral antidiabetic medication. Determine enzyme levels (GPT, GOT, LDH, AP) showed no abnormalities.
Cmax (ng/mL) 466 478 + 2.6
maintenance dosage as in newly-diagnosed diabetics. All the animals behaved normally during the period of the
experiment. There was no vomiting or diarrhea, and their weights Tmax (hr) 2.8 2.8 0.0
Consideration must be given to the potency and duration of action
remained unchanged. Subsequent post-mortem examination and t1/2 (hr) 2.6 2.5 - 3.8
of the previous antidiabetic agent. A break from medication may
histological investigations showed no abnormality.
be required to avoid any summation of effects entailing a risk of Peak plasma concentrations were observed in 1 to 4 hours.
hypoglycemia. Teratological tests were carried out in rats and rabbits. Rats were
given 0.2, 20 and 2,000 mg/kg body weight of glyburide from day INDICATIONS AND CLINICAL USE
Changeover From Insulin
7 to 16 of gestation. For rabbits the doses were 0.035, 3.5 and 350 APORANITIDINE (ranitidine) is indicated for the treatment
If a change from insulin to glyburide is contemplated in a patient mg/kg given from day 7 to 17 of gestation in a starch suspension of duodenal ulcer, benign gastric ulcer, reux esophagitis, post
with stable, mild, maturity-onset diabetes, treatment with insulin by gastric tube. Examination of the intact fetuses, followed by operative peptic ulcer, ZollingerEllison syndrome, and other
should be discontinued for a period of two or three days to examination of transverse sections of the stained skeleton, showed conditions where reduction of gastric secretion and acid output is
determine whether any therapy other than dietary regulation and no evidence of teratogenic action. desirable. These include the following:
exercise is needed. During this insulin-free interval, the patients
urine should be tested at least three times daily for glucose the treatment of nonsteroidal antiinammatory (NSAID)in-
and ketone-bodies, and the results monitored carefully by a APO-RANITIDINE duced lesions, both ulcers and erosions, and their gastrointesti-
nal (GI) symptoms and the prevention of their recurrence;
physician. The appearance of signicant ketonuria accompanied 150 mg and 300 mg Tablet
by glucosuria within 12-24 hours after the withdrawal of insulin the prophylaxis of GI hemorrhage from stress ulceration in
strongly suggests that the patient is ketosis-prone and precludes seriously ill patients;
the change from insulin to APO-GLYBURIDE. the prophylaxis of recurrent hemorrhage from bleeding ulcers;
(Ranitidine)
the prevention of Acid Aspiration Syndrome from general
PHARMACEUTICAL INFORMATION anaesthesia in patients considered to be at risk for this, including
THERAPEUTIC CLASSIFICATION
Drug Substance obstetrical patients in labour, and obese patients.
Histamine H2Receptor Antagonist
Chemical Name: N-4-(2-(5-chloro-2-methoxybenzamido)- In addition, APORANITIDINE is indicated for the prophylaxis
ethyl)-phenyl-sulfonyl-N-cyclohexylurea ACTIONS AND CLINICAL PHARMACOLOGY and maintenance treatment of duodenal or benign gastric ulcer in
Structural Formula: Ranitidine is an antagonist of histamine at gastric H2receptor patients with a history of recurrent ulceration.
sites. Thus, ranitidine inhibits both basal gastric secretions and CONTRAINDICATIONS
Cl gastric acid secretion induced by histamine, pentagastrin and other
secretagogues. On a weight basis, ranitidine is between 4 and APORANITIDINE (ranitidine) is contraindicated in patients
CONHCH2CH2 9 times more potent than cimetidine. Inhibition of gastric acid known to have hypersensitivity to the drug.
SO2NHCONH
secretion has been observed following intravenous, intraduodenal, WARNINGS
OCH3 and oral administration of ranitidine. This response is dose Gastric Ulcer
related, a maximum response being achieved at an oral dose of
Molecular Formula: C23H28ClN3O5S Treatment with a histamine H2antagonist may mask symptoms
300 mg/day.
Molecular Weight: 494 associated with carcinoma of the stomach and therefore may delay
Pepsin secretion is also inhibited but secretion of gastric mucus is diagnosis of that condition. Accordingly, where gastric ulcer is
Description not affected. Ranitidine does not alter the secretion of bicarbonate suspected, the possibility of malignancy should be excluded before
White, crystalline, tasteless, odourless powder practically insoluble or enzymes from the pancreas in response to secretin and therapy with APORANITIDINE (ranitidine) is instituted.
in water and dilute acids, very sparingly soluble in ethanol and pancreozymin.
chloroform, sparingly soluble with salt formation in alkali and Concomitant NSAID Use
Ranitidine is rapidly absorbed after oral administration, peak
readily soluble in dimethylformamide with a melting range of plasma concentrations being achieved within 2 to 3 hours. Plasma Regular supervision of patients who are taking nonsteroidal anti
172-174EC. The pKa is 5.3. concentrations are not signicantly inuenced by the presence inammatory drugs concomitantly with APORANITIDINE is
Composition of food in the stomach at the time of oral administration, nor by recommended especially in the elderly and in those with a history
regular doses of antacids. of peptic ulcer. Baseline endoscopy and histological evaluation is
In addition to the active ingredient glyburide, each tablet contains
necessary to rule out gastric carcinoma.
the non-medicinal ingredients lactose, microcrystalline cellulose, Bioavailability of oral ranitidine is approximately 50%. Serum
croscarmellose sodium and magnesium stearate. protein binding of ranitidine in man is in the range of 10 to Use in Patients with a History of Acute Porphyria
Stability and Storage Recommendations 19%. The elimination half-life is approximately 3 hours. The Rare clinical reports suggest that ranitidine may precipitate acute
principal route of excretion is the urine (40% recovery of free and porphyric attacks. Therefore, ranitidine should be avoided in
Store at controlled room temperature 15E-30EC (59E-86EF).
metabolized drug in 24 hours). patients with a history of acute porphyria.
AVAILABILITY OF DOSAGE FORMS There is a signicant linear correlation between the dose Use in Pregnancy and Nursing Mothers
APO-GLYBURIDE 2.5 mg: Each white, round, at-faced, administered and the inhibitory effect upon gastric acid secretion The safety of APORANITIDINE in the treatment of conditions
bevelled-edge tablet, scored and engraved APO over 2.5 on for oral doses up to 300 mg. A plasma ranitidine concentration where a controlled reduction of gastric secretion is required
one side, contains 2.5 mg of glyburide. Available in bottles of 100 of 50 ng/mL has an inhibitory effect upon stimulated gastric during pregnancy has not been established. Reproduction
and 500, and in unit dose packages of 30 and 100. acid secretion of approximately 50%. Estimates of IC50 range studies performed in rats and rabbits have revealed no evidence
APO-GLYBURIDE 5 mg: Each white, capsule-shaped, at- from 36 to 94 ng/mL. Following the administration of 150 mg of impaired fertility or harm to the foetus due to ranitidine. If
faced, bevelled-edge tablet, scored on one side and engraved ranitidine orally, plasma concentrations in excess of this lasted for the administration of ranitidine is considered to be necessary, its
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use requires that the potential benets be weighed against possible angioneurotic edema, hypotension) and small increases in serum Description: Ranitidine hydrochloride is a white to pale yellow,
hazards to the patient and to the foetus. creatinine have occasionally occurred after a single dose. Acute crystalline, practically odorless powder. It is sensitive to light
Ranitidine is secreted in breast milk in lactating mothers but the pancreatitis has been reported rarely. and moisture, and melts at about 140, with decomposition. It is
clinical signicance of this has not been fully evaluated. very soluble in water, moderately soluble in alcohol, and sparingly
SYMPTOMS AND TREATMENT OF OVERDOSAGE
soluble in chloroform.
Children There is no experience to date with deliberate overdosage.
Composition
Experience with ranitidine in children is limited. It has, however, The usual measures to remove unabsorbed drug from the
been used successfully in children aged 8 - 18 years in oral doses gastrointestinal tract (including activated charcoal or syrup of In addition to ranitidine hydrochloride, each lmcoated tablet
up to 150 mg twice daily. ipecac), clinical monitoring and supportive therapy should be contains the nonmedicinal ingredients: microcrystalline
employed. Also, if need be, the drug can be removed from the cellulose, croscarmellose sodium, magnesium stearate, colloidal
PRECAUTIONS silicon dioxide, hydroxypropyl methylcellulose, polydextrose,
plasma by haemodialysis.
Use in Impaired Renal Function polyethylene glycol, titanium dioxide, vanillin and carnauba wax.
Ranitidine is excreted via the kidney and, in the presence of severe DOSAGE AND ADMINISTRATION Stability and Storage Recommendations
renal impairment, plasma levels of ranitidine are increased and Duodenal Ulcer or Benign Gastric Ulcer: 300 mg once daily Store at room temperature 15-30 C. Protect from light.
prolonged. Accordingly, it is recommended in such patients, to at bedtime or 150 mg twice daily taken in the morning and before
decrease the dosage by onehalf. Accumulation of ranitidine with retiring. It is not necessary to time the dose in relation to meals. In AVAILABILITY OF DOSAGE FORMS
resulting elevated plasma concentrations will occur in patients with most cases, healing will occur in four weeks. In the small number APORANITIDINE 150 mg: Each round, white, lmcoated
severe renal impairment (plasma creatinine concentration greater of patients whose ulcers may not have fully healed, these are tablet engraved APO over 150 on one side contains 150 mg of
than 300 mol/L); a recommended daily dose of oral ranitidine in likely to respond to a further four week course of therapy. In the ranitidine (as the hydrochloride). Available in bottles of 60, 100
such patients should be 150 mg. In patients undergoing chronic treatment of duodenal ulcers, 300 mg twice daily for 4 weeks may and 500 tablets and in unit dose packages of 60 and 100.
ambulatory peritoneal dialysis or chronic hemodialysis, a single be of benet when more rapid healing is desired. APORANITIDINE 300 mg: Each capsuleshaped, white, lm
oral dose of 150 mg ranitidine should be taken immediately after Maintenance Therapy: duodenal ulcers: benign gastric ulcers: coated tablet engraved APO-300 on one side contains 300 mg of
dialysis. Patients who have responded to shortterm therapy, particularly ranitidine (as the hydrochloride). Available in bottles of 30, 100
Interactions With Other Drugs those with a history of recurrent ulcer, may benet from chronic and 500 tablets and in unit dose packages of 30 and 100.
Although ranitidine has been reported to bind weakly to maintenance therapy at a reduced oral dosage of 150 mg once
daily at bedtime. PHARMACOLOGY
cytochrome P450 in vitro, recommended doses of the drug do
In the management of duodenal ulcers, smoking is associated with Animal Pharmacology
not inhibit the action of the hepatic cytochrome P450linked
oxygenase enzymes. However, there have been isolated reports a higher rate of ulcer relapse (up to 9.2 times higher in one trial), Ranitidine is a potent, competitive, reversible, selective antagonist
of drug interactions which suggest that ranitidine may affect and such patients should be advised to stop smoking. In those of histamine at H2-receptors in vitro and in vivo. Thus, ranitidine
the bioavailability of certain drugs (eg. ketoconazole) by some patients who fail to comply with such advice, 300 mg nightly antagonised the actions of histamine at H2-receptors in the rat
mechanism as yet unidentied (eg. a pH dependent effect on provides additional therapeutic benet over the 150 mg once daily isolated uterus and in the guinea-pig isolated atrium. Ranitidine
absorption or a change in volume of distribution). dosage regimen. is not an anticholinergic agent. On a molar basis it is 4 to 5
Reux Esophagitis: Acute treatment: 300 mg once daily at times more active than cimetidine with a pA2 value of 7.2. In
As well, sporadic cases of drug interactions have been reported
bedtime or alternatively, 150 mg twice daily, taken in the morning concentrations 1000 times greater than those required to block
in elderly patients involving both hypoglycemic drugs and
and before retiring for up to eight weeks. In patients with H2receptors it failed to block either H1-receptors or muscarinic
theophylline. The signicance of these reports cannot be
moderate to severe esophagitis, the dosage of ranitidine may be receptors in the guineapig isolated ileum. The beta-adrenoceptor
determined at present, as controlled clinical trials with theophylline
and ranitidine have not shown interaction. increased to 150 mg four times daily for up to 12 weeks. Long responses of the rat uterus and guinea-pig atrium to isoprenaline
term management: the recommended adult oral dose is 150 mg were also unaffected by ranitidine.
If high doses (2 grams) of sucralfate are coadministered with
ranitidine, the absorption of ranitidine may be reduced. This effect twice daily. Blockade of histamine H2-receptors in the stomach in vivo is
is not seen if sucralfate is taken at least two hours after ranitidine Postoperative Peptic Ulcer: 150 mg twice daily, taken in the the pharmacological action of ranitidine with greatest immediate
administration. morning and before retiring. clinical relevance. Ranitidine inhibits gastric secretion induced by
various secretagogues in both the rat and dog.
Use in the Elderly Pathological Hypersecretory Conditions (such as Zollinger-
Ellison syndrome): 150 mg three times daily may be administered In the conscious dog with a Heidenhain pouch, ranitidine given
Since malignancy is more common in the elderly, particular orally or intravenously antagonised gastric acid secretion
consideration must be given to this before therapy with ranitidine initially. In some patients, it may be necessary to administer 150
mg doses more frequently. Doses should be adjusted to individual induced by histamine, pentagastrin and bethanechol. It was 5 to
is instituted. Elderly patients receiving nonsteroidal anti 10 times more active than cimetidine. However, both ranitidine
inammatory drugs concomitantly with ranitidine should be patient needs. Doses up to 6 g/day have been well tolerated.
and cimetidine has similar time curves of action. Ranitidine also
closely supervised. Treatment of NSAIDinduced lesions (both ulcers and erosions)
inhibited the gastric secretory response to food in the conscious
As with all medication in the elderly, when prescribing APO and their gastrointestinal symptoms and prevention of their
stulated dog.
RANITIDINE, consideration should be given to the patients recurrence: In ulcers following nonsteroidal antiinammatory
drug therapy or associated with continued nonsteroidal anti Ranitidine inhibited acid secretion in the perfused stomach of the
concurrent drug therapy. Sporadic cases of drug interactions have anaesthetised rat and aspirininduced gastric lesion formation
been reported in elderly patients involving both hypoglycemic inammatory drugs, 150 mg twice daily for 812 weeks may be
necessary. For the prevention of nonsteroidal antiinammatory in the conscious rat, both in the presence and absence of excess
drugs and theophylline. The signicance of these reports cannot be hydrochloric acid. Measurements of the ratio of mucosal blood
determined at present, as controlled clinical trials with theophylline drug associated ulcer recurrence, 150 mg twice daily may be
given concomitantly with nonsteroidal antiinammatory drug ow to acid secretion show that the inhibitory action of ranitidine
and ranitidine have not shown interaction. Elderly patients may be upon gastric acid secretion cannot be attributed to changes in
at increased risk for confusional states and depression. therapy.
blood ow.
Prophylaxis of Acid Aspiration Syndrome (AAS): 150 mg the
ADVERSE REACTIONS evening prior to anaesthesia induction is recommended, however, There were no behavioural effects in the mouse and rat after
The following adverse reactions have been reported as events in 150 mg two hours before anaesthesia induction is also effective. oral administration of 800 mg/kg ranitidine. Cats and dogs
clinical trials or in the routine management of patients treated For the prevention of AAS in prepartum patients who elect for dosed with ranitidine 80 mg/kg orally, exhibited no behavioural
with ranitidine. A cause and effect relationship to ranitidine is not anaesthesia, 150 mg every six hours may be employed, but if effects indicative of an action on the central nervous system,
always established. general anaesthesia is warranted, a nonparticulate oral antacid although at this high dose level in the dog there was an indication
Central Nervous System: headache, sometimes severe; malaise; (for example, sodium citrate) could supplement ranitidine therapy. of peripheral vasodilation and skin irritation due to released
dizziness; somnolence; insomnia; vertigo; and reversible blurred In an emergency situation, the use of alkalis, antacids, and histamine. Ranitidine, when coadministered with the following
vision suggestive of a change in accommodation. Isolated cases of meticulous anaesthetic technique is still necessary as ranitidine CNS modulating preparations; codeine, hexobarbitone, ethyl
reversible mental confusion, agitation, depression, hallucinations does not affect the pH and volume of the existing gastric content. alcohol, chlordiazepoxide, chlorpromazine, imipramine, alpha-
have been reported, predominantly in severely ill elderly patients. Prophylaxis of hemorrhage from stress ulceration in seriously methyldopa, reserpine, apomorphine or pentylenetetrazol, did not
ill patients or prophylaxis of recurrent hemorrhage in patients alter the pharmacological effects of either preparation.
Cardiovascular: isolated reports of tachycardia, bradycardia,
premature ventricular beats, and AV block have been noted. bleeding from peptic ulceration who are currently managed by At a dose level 45 times the antisecretory ED50, intravenous
Asystole has been reported in very few individuals with and intravenous ranitidine: an oral dose of 150 mg twice daily may infusion of ranitidine had no effect on the heart rate, blood pressure
without predisposing conditions following i.v. administration and be substituted for the injection once oral feeding commences. or electrocardiogram of the anaesthetized dog. The respiratory
has not been reported following oral administration of ranitidine. Dosage For the Elderly system was unaffected by ranitidine after oral doses in the mouse,
rat, rabbit, cat and dog and after intravenous doses in the dog.
Gastrointestinal: constipation, diarrhea, nausea/vomiting, and For all conditions listed above, the drug dosage for the elderly who
abdominal discomfort/pain. are seriously ill should start at the lowest recommended dose and In the conscious dog, ranitidine had no appreciable effect on
be adjusted as necessary with close supervision. blood pressure or heart rate when administered orally at 10 mg/
Hepatic: with oral administration, there have been occasional
kg. There were shortlived falls in diastolic blood pressure after
reports of hepatitis, hepatocellular or hepatocanalicular or mixed, PHARMACEUTICAL INFORMATION an intravenous dose of 10 mg/kg, 370 times the antisecretory
with or without jaundice. In such circumstances, ranitidine should
Drug Substance dose level. There was no evidence of arrhythmia nor of any
be discontinued immediately. These are usually reversible, but in
Proper Name: ranitidine hydrochloride electrocardiographic abnormality.
exceedingly rare circumstances, death has occurred.
Chemical Name: N-(2-(((5-((Dimethylamino) Long-term toxicity studies have shown that ranitidine does
Musculoskeletal: rare reports of arthralgia and myalgia.
methyl)-2-furanyl)methyl)thio)ethyl)- not possess antiandrogenic activity nor does it displace
Hematologic: blood count changes (leukopenia, thrombocytopenia) dihydrotestosterone from the androgen binding sites.
N-methyl-2-nitro-1,1-ethenediamine,
have occurred in a few patients. These are usually reversible. Rare
hydrochloride. Metoclopramide, atropine and aspirin in the rat produced no
cases of agranulocytosis or pancytopenia, sometimes with marrow
change in the antisecretory activity of ranitidine.
hypoplasia or aplasia have been reported.
Structural Formula: The effect of ranitidine on antiinammatory drugs was
Endocrine: no clinically signicant interference with endocrine CHNO2 varied. There was no effect on the antiinammatory action of
or gonadal function has been reported. There have been a few
prednisolone, but the antiinammatory effect of indomethacin
reports of breast symptoms in men taking ranitidine. (CH3)2NCH2 O CH2SCH2DH2NHCNHCH3 HCl was enhanced. Administration of ranitidine reduced the frequency
Dermatologic: rash, including cases suggestive of mild erythema of aspirin and indomethacin induced gastric erosions. The
multiforme. antinociceptive action of aspirin was reduced after ranitidine
Other: treatment.
Rare cases of hypersensitivity reactions (including chest pain, Molecular Formula: C13H22N4O3S HCl Ranitidine, unlike cimetidine, does not inhibit the mixed function
bronchospasm, fever, rash, eosinophilia, anaphylaxis, urticaria, Molecular Weight: 350.87 (as hydrochloride salt) oxygenase system. Spectral interaction studies have shown that
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whilst cimetidine binds strongly to cytochrome P450, ranitidine Ranitidine has been subjected to exhaustive toxicological testing The mean serum glutamic pyruvic transaminase values for
has only weak afnity for the enzyme. Cimetidine is known which has demonstrated the lack of any specic target organ or any dogs treated at 450 mg/kg/day were signicantly greater, albeit
to impair the metabolism of pentobarbitone and warfarin. In special risk associated with its clinical use. marginally, than the control values. These enzyme increases were
doses of up to 166 mg/kg in the rat, ranitidine had no effect on Acute Toxicity Studies not accompanied by any histological changes.
the pentobarbitone sleeping time or the pharmacokinetics and Species Sex Oral LD50 (mg/kg body weight) Studies in which ranitidine was administered parenterally were
pharmacodynamics of warfarin. performed. No sign of specic local irritation attributable
Mice* F 1430.0 (1213.3-1685.4)
Metabolism, Distribution and Excretion to ranitidine was detected. In the rat, no biochemical or
M 1350.0 (1225.2-1487.5) histopathological changes were observed at intravenous dose
The metabolism of ranitidine has been studied in four species of
laboratory animal (mouse, rat, rabbit and dog) using radio-labelled Combined 1430.0 (1273.1-1606.2) levels as high as 20 mg/kg. Specically, no signicant changes
drug. The drug was rapidly absorbed after oral administration. Rats** F 7000 (4506-10875) were found in the veins or subcutis. Mild lesions in some muscle
In the mouse, rat and rabbit between 30% and 60% of the M 5850 (5372-6371) samples were observed: usually, the cells were basophilic and
administered radioactivity was excreted in the urine, the remainder smaller than normal; and the nuclei were swollen, more numerous,
Combined 6700 (5690-7889)
being recovered in the faeces. and sometimes had migrated to the centre of the cell.
* 16 groups, each with 5 animals/sex were treated with the test
In the mouse, 47% was excreted in the urine within 24 hours. In the rabbit, slight inltration of the pannicular muscle by
article (ranitidine HCl) at logarithmically spaced doses.
In the rat, Ndemethylation of ranitidine was the major route of mononuclear cells were noted. This minor subcutaneous reaction
** 6 groups each with 5 animals/sex were treated with the test was uncommon and showed no group related distribution.
metabolism. 30% of the administered dose was excreted in the
article (ranitidine HCl) at logarithmically spaced doses. There was no apparent difference in irritance between ranitidine
urine as unchanged drug, up to 14% as desmethylranitidine, 3-
6% as the Noxide and 4% as the Soxide. In rat bile, the major Mortality generally occurred over a 4 hour period postdosing for injection and placebo injection. In the rat, intravenous ranitidine
radioactive components were ranitidine and an unidentied both species. at dose levels of 5.0 and 10.0 mg/kg daily for 15 days and 28 days
metabolite known as FastRunning Metabolite (FRM) which produced no treatment related changes of biological importance in
Signs of systemic toxicity consisted of a slight decrease in motor
is thought to be a charge transfer complex of ranitidine with bile the haematopoietic system.
activity 0-4 hours postdosing returning to normal within 24 hours
pigments. of treatment for mice and protruding eyeballs and reduced motor In Beagle dogs, intravenous ranitidine injection in doses up to 10
In the rabbit, sulphoxidation of ranitidine was the major route of activity during the rst 4 hours postdosing in rats. mg/kg/day for 28 and 42 days, produced no drugrelated change in
metabolism, 18% of the administered dose being excreted in the circulating erythrocytes or leukocytes and had no adverse effects
Necropsy of these animals generally revealed no abnormality in
urine as unmetabolised ranitidine, 8% as S-oxide, 2-4% as the N- on the haematopoietic system. No dose related changes were seen
mice and darkening of the liver and/or kidneys, pale spleen with
oxide, and 2-4% as desmethylranitidine. in electrocardiograms of Beagle dogs receiving up to 10 mg/kg
distention of the GI tract and reddening of the gastric and intestinal
ranitidine by intravenous injection. At dosage levels of up to 30
In the dog, up to 70% of the administered dose was excreted in the mucosae in rats. Animals killed routinely at the conclusion of the
mg/kg, administered twice daily to Beagle dogs for 14 to 15 days,
rst 24 hours. About 40% of the drug was excreted in the urine as 14day study generally revealed no abnormality at necropsy for
intravenous ranitidine injection produced no changes of biological
unchanged ranitidine and up to 30% as the Noxide, Noxidation both species.
signicance in haematology, clinical chemistry or urinalysis.
being the main route of metabolism of ranitidine in the dog. The In dogs, the oral minimum lethal dose is 450 mg/kg/day. High
Noxide was also the major radioactive component present in No changes were observed in the eyes of dogs (specically the
single doses of ranitidine (up to 80 mg/kg orally) show only
dog bile together with small amounts of unchanged ranitidine and tapetum lucidum) receiving ranitidine in doses up to 30 mg/kg
minimal and reversible signs of toxicity some of which are related
FRM. twice daily for 15 days. At intravenous doses above 1.25 mg/kg,
to transitory histamine release.
ranitidine injection produced immediate and transient reactions in
In the rat, rabbit and dog, less than 10.1% of ranitidine in plasma is Long Term Toxicity Studies the Beagle dog. The following reactions were typically produced
protein bound. Within one to seven days of administration of radio
In long term toxicity and carcinogenicity studies, very high doses by the administration of 1.25 mg/kg: bloodshot eyes, closing and
labelled drug in the rat and dog, over 99% of the radioactivity was
of ranitidine were given daily to mice (up to 2000 mg/kg/day) watering of eyes, defecation, diarrhea, erythema, atus, licking
cleared from the body. In common with many drugs, radioactivity
throughout their normal life span, and to dogs (up to 450 mg/kg/ of lips, running nose, salivation, subdued behaviour, swallowing,
persisted in the uveal tract of these two species, the halflife in
day) for periods of up to one year. tachycardia, and trembling. The range and severity of the effects
the dog uveal tract being of the order of 6 months. Ranitidine and
These doses produced massive plasma ranitidine concentrations was aggravated by increased dosage.
its Soxide have greater afnity for melanin than the desmethyl
metabolite; the Noxide is bound only to a small extent. far in excess of those found in human patients receiving ranitidine Reproduction Studies (Impairment of Fertility)
at the recommended therapeutic dose. For example in dogs, peak Reproduction studies were carried out in the rat and rabbit.
The placental transfer of radioactive ranitidine and its metabolites
plasma concentrations were in excess of 115 mcg/mL, and in
has been studied in the pregnant rat and rabbit. Whole body Rats were exposed to ranitidine before and during mating,
mice, basal plasma levels were in the ranges of 4-9 mcg/mL. In
autoradiography of rat and rabbit foetuses showed that small throughout pregnancy, lactation and during the weaning period.
man, after oral administration of 150 mg ranitidine, the mean peak
amounts of radioactivity were present in the uveal tract of the No effects on the reproductive process were seen and there was no
plasma concentration (Cmax) was between 360 and 650 ng/mL.
foetal eye in both species, in the gall bladder and intestine of the evidence of an antiandrogenic effect.
rabbit foetus and in the bladder of the rat foetus. Radioactivity was In the rat, doses as high as 2000 mg/kg/day were well tolerated. The
A total of 2297 foetuses from rats treated with ranitidine were
also detected in the salivary and mammary glands of the maternal only morphological change seen was in the increased incidence of
examined. There was no evidence that ranitidine is a rat
rat and at very low concentrations in the milk. accumulations of foamy alveolar macrophages in the lungs. The
teratogen. Cleft palates occurred in foetuses from both treatment
accumulations of these cells is a natural phenomena in aging rats
Human Pharmacokinetics groups, however, there were signicantly more in the control rat
and chronic administration of a wide variety of drugs has been
Serum concentrations necessary to inhibit 50% of stimulated gastric population.
known to contribute to this process. Therefore, it is unlikely that
acid secretion are estimated to be 36 to 94 ng/mL. Following a the pharmacologic concentrations of ranitidine administered to A total of 944 foetuses from rabbits treated with ranitidine were
single dose of 150 mg, serum concentrations of ranitidine are in these rats contributed to this natural process. examined; no drugrelated adverse events or abnormalities in the
this range for up to 12 hours. There is a relationship between foetuses were observed.
In the sixweek and sixmonth oral studies in dogs (100 mg/kg/
plasma concentrations of ranitidine and suppression of gastric acid Rabbits receiving a bolus injection of 10 mg/kg ranitidine once
day), loose faeces were occasionally detected, while in the six
production but wide interindividual variability exists. daily on gestation days 7-16 exhibited a reduction in weight
month study, loose stools were accompanied on eight occasions
Ranitidine is 50% absorbed after oral administration compared by mucuslike material and sometimes by blood, mostly from one gain. Their foetuses weighed signicantly less than foetuses of
to an i.v. injection with mean peak levels of 440 to 545 ng/mL dog. Loose faeces, salivation and vomiting were observed in the untreated controls. In addition, 12.4% of ranitidineexposed
occurring two to three hours after a 150 mg dose. The elimination 54week dog study. foetuses had cleft palates. Reanalysis of this and a companion
half life is 1.5 to 3 hours. study performed to assess reproducibility demonstrated a lack of
In isolated cases, dogs passed redstained faeces which
Ranitidine is absorbed very rapidly after an intramuscular data reproducibility. Therefore, the effects observed in the rst
occasionally tested positive for occult blood. When the dose
injection. Mean peak levels of 576 ng/mL occur within 15 minutes trial are aberrant, and should not form a basis for maternal or foetal
level was increased from 100 mg/kg/day to 225 - 450 mg/kg/
or less following a 50 mg intramuscular dose. Absorption from toxicity.
day, no further redstained faeces were seen, suggesting that any
intramuscular sites is virtually complete, with a bioavailability of relationship to ranitidine is unlikely. Post mortem examination of In the subsequent study, no evidence of maternal or foetal toxicity
90% to 100% compared with intravenous administration. the dogs revealed no ranitidineinduced changes in the alimentary was observed in rabbits dosed with 100 mg/kg ranitidine orally
The principal route of excretion is the urine, with approximately tract. during days 2-29 of pregnancy. The peak plasma levels of
30% of the orallyadministered dose collected in the urine as ranitidine after a 100 mg/kg oral dose are similar to those obtained
One dog had marginally raised levels of plasma alanine
unchanged drug in 24 hours. Renal clearance is about 530 mL/ 1 minute after a 10 mg/kg dose administered intravenously (20-25
aminotransferase and alkaline phosphatase during the sixweek
min, indicating active tubular excretion, with a total clearance of g/mL). Therefore, no teratogenic effects of ranitidine have been
study. This same dog also showed some necrotic foci in the liver.
760 mL/min. The volume of distribution is 1.4 L/kg. demonstrated at doses of 10 mg/kg (i.v.) and 100 mg/kg (tablets)
Small lesions of focal necrosis and brosis were also seen in one
in rabbits.
Studies in patients with hepatic dysfunction (compensated piece of liver from one female dog treated with 100 mg/kg for six
cirrhosis) indicate that there are minor, but clinically insignicant months. No other differences were detected by light and electron Carcinogenicity Studies
alterations in ranitidine half life, distribution, clearance and microscopic examination of the treated and control livers. Since There is no evidence that ranitidine is a carcinogen. Long term
bioavailability. the focal lesions were seen in only one dog and were restricted toxicity and carcinogenicity studies have involved the treatment of
Serum protein binding averages 15%. to one piece of liver, it suggests that they were not caused by 600 mice and 636 rats at doses up to 2,000 mg/kg for two years and
ranitidine. 129 weeks respectively and 42 dogs at doses up to 450 mg/kg/day
The gastric antisecretory activity of ranitidine metabolites has for periods up to one year. These dose levels are far in excess of
been examined. In man, both the principal metabolite in the urine, Muscular tremors, an inability to stand, and rapid respiration were
seen on occasion in dogs treated with 225 mg/kg in the 54week those to be used therapeutically in man. None of these animals had
Noxide (4% of the dose) and Soxide (1%) possess weak H2 any intestinal metaplasia. There was no evidence of a tumorigenic
receptor blocking activity but desmethylranitidine (1%) is only 4 study. The prevalence of these observations was increased when
the dose was increased to a toxic level of 450 mg/kg. One dog effect of ranitidine in any other tissue.
times less potent than ranitidine in the rat and half as potent as
died but no specic pathological changes or reason for the death Mutagenicity
ranitidine in the dog.
was discovered. Ranitidine was not mutagenic at doses as great as 30 mg/plate in
Clinical Trials
Changes in the colour or granularity of the tapetum lucidum of the Ames Assay utilizing S. typhimurium (TA 1538, TA 98, TA 100
In 6 clinical trials examining the healing of duodenal ulcers in and TA 1537) and in doses of 9 mg/plate utilizing E. coli (WP2 and
the eye were detected in three dogs receiving the highest dose of
1500 patients, a dose of 300 mg daily for 4 weeks was found to WP2 uvrA) with or without activation.
ranitidine (450 mg/kg/day) during the 54week study. In one dog,
have an 83% healing rate; however, increasing the dose to 300
this change was considered to be related to treatment. The change, Ranitidine at concentrations of 20-30 mg/plate had a weak direct
mg twice daily gave signicantly better results (92% healed at 4
a pallor of the tapetum, was reversible. No changes were seen with mutagenic action in S. typhimurium (TA 1535) and at 9 mg/plate in
weeks; p <0.001).
light or electron microscopic examination of the eye. The changes E. coli (WP67). Ranitidine was not mutagenic at a concentration
TOXICOLOGY in the tapetum are of no clinical signicance in humans since (i) of 2 mg/mL in E. coli or S. typhimurium in the more sensitive
Toxicology, Impairment of Fertility, Carcinogenesis, and humans do not have a tapetum lucidum and (ii) the changes were oral solution microtitre uctuation assay method. This weak direct
Mutagenesis only seen at toxic pharmacological concentrations of ranitidine. mutagenic effect is of no clinical signicance; the magnitudes of
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ranitidine concentrations used in these assays are thousands of PRE-CLINICAL SAFETY DATA an infection, deferiprone therapy should be interrupted and the
times greater than that attained therapeutically in human plasma. The most common effects of deferiprone in non-clinical studies neutrophil count monitored more frequently. Patients should be
The principal metabolites of ranitidine in man were not were haematological effects (most notably bone marrow advised to report immediately to their physician any symptoms
signicantly mutagenic. This conclusion is supported by the hypocellularity and decreased white and red blood cell count) indicative of infection such as: fever, sore throat and u-like
following experiment. A test solution obtained by interacting and atrophy of lymphoid tissues. These changes were observed at symptoms.
ranitidine (10 mM) and sodium nitrite (40 mM) was mutagenic in animal systemic exposures to deferiprone (based on AUC or body Suggested management for cases of neutropenia is outlined below.
S. typhimurium (TA 1535) but not in S. typhimurium (TA 1537) or surface area) similar to, or below those observed in humans at the It is recommended that such a management protocol be in place
in E. coli (WP67 or WP2 uvrA). This positive result is attributable recommended clinical dose. prior to initiating any patient on deferiprone treatment.
to the presence of a nitrosonitrolic acid derivative AH 23729,
CLINICAL TRIALS Treatment with deferiprone should not be initiated if the patient
which was mutagenic. When the sodium nitrite concentration was
is neutropenic.
reduced to 15 mM or less, the solution was not mutagenic in any Deferiprone has been investigated in 356 patients participating
of the test microorganisms. The formation of AH 23729 requires in Apotex sponsored clinical trials and a compassionate use In the event of neutropenia:
concentrations of nitrous acid far in excess of those encountered programme between 1993 and 2002. Serum ferritin was a common Instruct the patient to immediately discontinue deferiprone and
in any probable physiological conditions. The other nitrosation efcacy criterion in the studies. all other medications with a potential to cause medicinal product-
products were not mutagenic in any of the microorganisms tested. associated neutropenia. The patient should be advised to limit
A multicentre prospective iron chelation study (LA-02) was
There is no reason therefore for supposing that ranitidine is likely contact with other individuals in order to reduce the risk of potential
performed on 187 transfusion-dependent thalassaemia patients
to be mutagenic in animals or man as a consequence of nitrosation infection. Obtain a complete blood cell count, white blood cell
over a year. The results indicated that FERRIPROX at 25 mg/kg
in the stomach. count, neutrophil count, and a platelet count immediately upon
three times per day can prevent the progression of body iron load as
There is no evidence from long term toxicology, carcinogenicity assessed by serum ferritin, in transfusion-dependent thalassaemia diagnosing the event and then repeat daily. It is recommended
and mutagenicity studies in animals to suggest that ranitidine is patients previously regularly chelated with desferrioxamine. In that following recovery of the neutrophil count, weekly complete
likely to have any deleterious effects in man when administered at this study, a high level of compliance (mean compliance = 94%) blood cell count, white blood cell count, neutrophil and platelet
therapeutic dose levels. counts continue to be obtained for three consecutive weeks, to
with the oral iron chelator was observed in this cohort of patients.
ensure that the patient recovers fully. Should any evidence of
On completion of this study, some patients with transfusion-
FERRIPROX 500 mg Tablet dependent thalassemia continued treatment and intensive
infection develop concurrent with the neutropenia, the appropriate
cultures and diagnostic procedures should be performed and an
monitoring of their body iron load under another study protocol
appropriate antibiotic regimen instituted.
(LA-06). Eighty-four patients continued to be monitored weekly
(Deferiprone ) for four years after their enrolment and had not received any In the event of severe neutropenia or agranulocytosis:
iron chelator other than deferiprone during this period of time. Follow the guidelines above and administer appropriate therapy
NAME OF THE DRUG Results from this study demonstrate that under regular monitoring such as granulocyte colony stimulating factor, beginning the
Deferiprone conditions, FERRIPROX has a favourable benet/risk ratio same day that the event is identied; administer daily until the
in the treatment of iron overload in patients with transfusion- neutrophil count recovers. Provide protective isolation and if
DESCRIPTION
dependent thalassemia. No new adverse reactions were observed. clinically indicated, admit patient to hospital.
Deferiprone is an orally active synthetic iron chelator. Chemically,
Nausea and/or vomiting were the next most common adverse Limited data are available regarding rechallenge. Therefore in
deferiprone is designated as 3-hydroxy-1,2-dimethyl-4(1H)-
pyridone. Deferiprone is a white to off-white crystalline powder reactions, reported in 15% and 13% of patients respectively. the event of neutropenia rechallenge is not recommended. In the
with a molecular formula of C7H9NO2 and a molecular weight of Neutropenia, dened as a conrmed absolute neutrophil count event of agranulocytosis a rechallenge is contra-indicated.
139.15. It has a melting range of 272C to 278C. Deferiprone of between 0.5 and 1.5 x 109/L, was observed in 6% of patients. Renal or hepatic impairment and liver brosis
does not show stereoisomerism. The CAS Registry Number for Resolution occurred within 2 weeks to 2 months. Agranulocytosis, Renal impairment
deferiprone is 30652-11-0. dened as a conrmed absolute neutrophil count of less than 0.5 x
Currently there is no available data in patients with renal
Deferiprone is sparingly soluble in water, very slightly soluble in 109/L, was observed in three (0.8%) patients.
impairment. Since deferiprone and its metabolites are excreted
acetone and slightly soluble in methanol. The safety and efcacy of FERRIPROX (25 mg/kg three times by the kidney, there may be an increased risk of complications in
FERRIPROX is formulated as a white, capsule-shaped, lm per day) and desferrioxamine (50 mg/kg/day, 4 to 7 times/week) in patients with impaired renal function. Caution must be used when
coated tablet, imprinted APO bisect 500 on one side, plain on the treatment of iron overload in patients with thalassaemia major treating patients with renal impairment.
the other. The tablets are scored and breakable in half. were compared in a randomised study for about two years. At the
Hepatic impairment
Each tablet contains 500 mg deferiprone as active substance and completion of the second year of the study, no signicant change
from baseline was observed in the serum ferritin values or in the There are limited data on the safety and efcacy of deferiprone in
the following excipients: microcrystalline cellulose, magnesium patients with hepatic impairment. Deferiprone is metabolized by
stearate, silicon dioxide, hypromellose, macrogol 3350 and hepatic iron concentration of patients treated with either therapy.
The power to detect a 20% difference in serum ferritin or hepatic the liver and therefore caution should be exercised in such patients
titanium dioxide. and hepatic function should be monitored.
iron concentration between groups was less than 80% due to the
PHARMACOLOGY variability of the data and a relatively small sample size. In thalassaemia patients there is an association between liver
PHARMACODYNAMIC PROPERTIES A hepatic histology study was commissioned by the Deferiprone brosis and hepatitis C. Special care must be taken to ensure that
Deferiprone is a bidentate ligand which binds to iron in a 3:1 molar International Safety Monitoring Committee to ensure the safety of iron chelation in patients with hepatitis C is optimal. In these
ratio and therefore removes excess of iron from the body. the patients participating in the clinical trials for the development patients careful monitoring of liver histology is recommended.
Clinical studies have demonstrated that deferiprone is effective in of deferiprone. The major question addressed was whether chronic Deferiprone has been associated with hepatotoxicity (increased
promoting iron excretion and can lower serum ferritin levels and treatment with deferiprone was associated with any evidence for ALT) in some patients. If there is a persistent increase in serum
tissue iron stores in transfusion-dependent thalassaemia patients. hepatotoxicity or worsening of liver brosis. Three pathologists ALT, interruption of deferiprone therapy should be considered.
The precise mechanism by which deferiprone is effective in performed a blinded assessment of the largest collection of liver Cardiac function
promoting iron excretion and preventing the progression of iron biopsies reported to date in patients receiving deferiprone. The Studies on cardiac iron concentrations suggest that deferiprone
accumulation is unknown. The magnitude of the response is in histopathological ndings conrm the results of several other may protect the heart against the toxicity of iron overload.
general directly dependent on the patients initial body iron load smaller studies and demonstrate that there is no evidence of
and their ongoing transfusional requirements. Patient Monitoring
progressive brosis in patients with thalassaemia while on long-
term deferiprone therapy. Serum ferritin concentrations/ plasma Zn2+
PHARMACOKINETIC PROPERTIES
It is recommended that serum ferritin concentrations be monitored
Absorption INDICATION
regularly (every two to three months) to assess the long-term
Deferiprone is rapidly absorbed from the upper part of the gastro- FERRIPROX is indicated for the treatment of iron overload in effectiveness of the chelation regimen in controlling the body
intestinal tract. patients with thalassaemia major iron load. Interruption of therapy with deferiprone should be
Peak serum concentration is reported to occur 45 to 60 minutes - who are unable to take desferrioxamine therapy; or considered if serum ferritin measurements fall below 500 g/L.
following a single dose in fasted patients. This may be extended - in whom desferrioxamine therapy has proven ineffective. A monitoring of plasma Zn2+, as well as supplementation in case
to 2 hours in fed patients. of a deciency is recommended.
CONTRAINDICATIONS
Following a dose of 25 mg/kg, lower peak serum concentrations HIV positive or other immune compromised patients
have been detected in patients in the fed state (85 mol/L) than in FERRIPROX is contraindicated in patients who:
the fasting state (126 mol/L), although there was no decrease in - have demonstrated hypersensitivity to the active substance No data are available on the use of deferiprone in HIV positive or
the amount of substance absorbed when given with food. or any of the excipients in other immune compromised patients. Given that deferiprone
- have a history of recurrent episodes of neutropenia is associated with neutropenia and agranulocytosis, therapy in
Distribution
immune compromised patients should not be initiated unless
The protein binding of deferiprone is low (<10%). Following oral - have a history of agranulocytosis
potential benets outweigh potential risks.
administration of deferiprone, the volume of distribution is at least - are pregnant or breast-feeding.
Discoloration of urine
1.6 L/kg in thalassemia patients. Needs weekly monitoring of Absolute Neutrophil Count (ANC).
Patients should be informed that a reddish/brown discoloration
Metabolism The patient may need a colony stimulating factor/lgrastim to
reverse severe neutropenia or agranulocytosis if occurred. of the urine is commonly associated with deferiprone use which
Deferiprone is cleared from plasma by metabolism, predominantly is reported to be due to the excretion of the iron-deferiprone
to a glucuronide metabolite. The rate of clearance has not been PRECAUTIONS complex, which is a chromophore.
determined. The glucuronide metabolite lacks iron binding
Deferiprone may be associated with signicant toxicity and Carcinogenicity/mutagenicity/fertility
capacity because of inactivation of the 3-hydroxy group of
data available on the efcacy and safety of the drug are limited.
deferiprone. Peak concentrations of the glucuronide metabolite The genotoxic potential of deferiprone was evaluated in a set of in
Therefore, deferiprone should only be used in patients who cannot
occur 2 to 3 hours after administration of deferiprone. vitro and in vivo tests (non iron-loaded models). Deferiprone was
tolerate desferrioxamine therapy or in whom desferrioxamine
Elimination non-mutagenic in the bacterial reverse mutation assay, however,
therapy has proven ineffective.
In humans, deferiprone is eliminated mainly via the kidneys with it did display genotoxic characteristics in non-iron loaded in vitro
Neutropenia/Agranulocytosis and in vivo systems. No data on the carcinogenic properties
reports of 75% to 90% of the ingested dose being recovered in the
urine in the rst 24 hours, mainly in the form of the glucuronide Deferiprone has been shown to cause neutropenia, including are available. However, in view of the genotoxicity results, a
metabolite and the iron-deferiprone complex. Only 5% of an agranulocytosis. It is recommended that a patients neutrophil carcinogenic potential of deferiprone cannot be excluded.
administered dose of deferiprone is excreted unchanged in the count be monitored every week. A comparative study on the assessment of lymphocyte clastogenicity
urine. A variable amount of elimination into the faeces has been In clinical trials this has been effective in identifying cases of in patients with thalassaemia treated with deferiprone or with
reported. The elimination half-life in most patients is 2 to 3 neutropenia and agranulocytosis. Neutropenia and agranulocytosis desferrioxamine indicated that deferiprone is not associated with
hours. resolved once therapy was withdrawn. If the patient develops greater frequency of chromosomal aberrations than that observed
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ASTELLAS EUROPE B.V
SPDI
during therapy with desferrioxamine. This study showed that of treatment). The observed incidence of the less severe form of MODE OF ACTION
deferiprone had no greater clastogenicity activity than that of neutropenia (neutrophils <1.5 x 109/L) is 6% (2.5 cases per 100 By the inuence of gastric acid a precipitate containing bismuth is
desferrioxamine, in humans. patient years). This rate should be considered in context of the formed from DE-NOL, which adheres mainly to the ulcer.
Atrophy of the testis was reported at oral doses of 400 mg/kg/ underlying elevated incidence of neutropenia in thalassaemia De-Nol has an antibacterial action against Helicobacter pylori,
day (corresponding to a systemic exposure, based on body surface patients, particularly in those with hypersplenism. which causes gastritis.
area, about 3 times the human exposure at the recommended Other common effects include: nausea, vomiting, abdominal
clinical dose) in non iron-loaded dogs. PHYSIOLOGICAL EFFECT
pain and increased appetite. These effects are more frequent at
No animal studies to evaluate the potential effects of deferiprone the beginning of therapy with deferiprone and in most patients In a high percentage of patients with gastric or duodenal ulcers
are resolved within a few weeks without the discontinuation of DE-NOL exerts a curative effect, while the percentage of recur-
on fertility have been conducted.
treatment. In some patients it may be benecial to reduce the dose rences for duodenal ulcers is comparatively low.
USE IN PREGNANCY
of deferiprone and then scale it back up to the total 25 mg/kg three INDICATIONS
Reproductive studies in non iron-loaded rats and rabbits have times per day. Gastric and duodenal ulcers.
indicated that deferiprone is teratogenic and embryotoxic at
Arthropathies have also been reported in patients treated with
doses giving systemic exposures (on a body surface area basis) CONTRA-INDICATIONS
deferiprone. These events ranged from mild pain in one or more
considerably below those observed in patients at the recommended Severe renal dysfunction.
joints to severe arthritis. Most patients recover despite continuing
dose.
therapy. PRECAUTIONS
Women of childbearing potential should be advised to avoid
Increased ALT values have been reported in some patients taking Antacids and milk should not be taken within half an hour before
pregnancy due to the potential mutagenic, clastogenic and
teratogenic properties identied in pre-clinical studies with
deferiprone. In the majority of these patients this increase was to half an hour after taking DE-NOL, because gastric acid is nec-
asymptomatic and transient, and their ALT values returned essary for the formation of the protective layer.
deferiprone. Women should be counselled to take contraceptive
measures and should be advised to immediately stop taking to baseline without discontinuation or decreasing the dose of The absorption of tetracyclines may be reduced when DE-NOL
deferiprone should they become pregnant or plan to become deferiprone. is taken concomitantly.
pregnant. Some patients experienced progression of liver brosis associated Do not use other bismuth containing drugs concomitantly.
with an increase in iron overload or hepatitis C. If pregnant consult your doctor before using DE-NOL.
USE IN LACTATION
Low plasma zinc levels have been associated with deferiprone,
There is no relevant data on the use of deferiprone in nursing in a minority of patients. The levels normalised with oral zinc SIDE-EFFECTS
mothers. No perinatal/post-natal reproductive studies have been supplementation. Blackening of the stools is possible due to the formation of bis-
conducted in animals. Deferiprone should not be used in nursing muth sulphide. This discolouration may easily be distinguished
mothers. DOSAGE AND ADMINISTRATION from melena.
USE IN CHILDREN Therapy with FERRIPROX should be initiated and maintained Nausea and vomiting may also occur. These effects are not dan-
by a physician experienced in the treatment of patients with gerous and disappear upon completion of therapy.
Limited data are available on the use of deferiprone in children
thalassaemia.
between 2-10 years of age. The effects of deferiprone on growth DOSAGE AND ADMINISTRATION
are unknown. FERRIPROX is given as 25 mg/kg body weight, orally, three
Twice daily on an empty stomach, two tablets half an hour before
times a day for a total daily dose of 75 mg/kg body weight. The
INTERACTION WITH OTHER MEDICINAL PRODUCTS breakfast and two at bedtime, or one tablet 4 x daily, half an hour
dose was not developed through a formal dose nding study, but
AND OTHER FORMS OF INTERACTION before the 3 main meals and at bedtime.
rather through literature evaluation and assessment of an effective
Interactions between deferiprone and other medicinal products dose to produce iron excretion equivalent to the transfusional DURATION OF TREATMENT
have not been reported. However, since this compound binds input. Dosage per kilogram body weight should be calculated to DE-NOL should be taken for 4-8 weeks, hereafter DE-NOL or
to some metallic cations, the potential exists for interactions the nearest half tablet. See Dosage Table below. other bismuth containing drugs should not be taken for 8 weeks.
between deferiprone and trivalent cation-dependent medicinal Due to the nature of the serious adverse events, which can occur Then again a treatment course may be prescribed for 4-8 weeks,
products such as aluminium-based antacids. Therefore, it is not with the use of deferiprone, special monitoring is required for all if necessary.
recommended to concomitantly ingest aluminium-based antacids patients. Treatment with deferiprone should not be initiated if the
with deferiprone. PACKAGE QUANTITIES
baseline absolute neutrophil count (ANC) is low. Caution must
Due to the unknown mechanism of deferiprone-induced be used when treating patients with renal insufciency or hepatic Box with 40 tablets in 5 strips of 8 tablets.
neutropenia, patients should not take medicinal products known dysfunction (See PRECAUTIONS). Box with 120 tablets in 15 strips of 8 tablets (N.R).
to be associated with neutropenia or those that can cause Dosage Table
agranulocytosis.
Body Weight Dose Number of Tablets Total Daily Dose FLEMOXIN
The safety of concurrent use of deferiprone and vitamin C has not
been formally studied. Based on the reported adverse interaction (kg) (mg/three (three times/day) (mg)
that can occur between desferrioxamine and vitamin C, caution times/day) (Amoxicillin)
should be used when administering concurrent deferiprone and 20 500 1.0 1500
vitamin C. COMPOSITION
30 750 1.5 2250
Studies in vitro and in animals suggest that deferiprone does Capsules of 250 mg (N.R.) and 500 mg amoxicillin
40 1000 2.0 3000
not increase the risk of opportunistic Yersinia infections in iron Suspension of 125 mg/5ml amoxicillin (100 ml bottle with dosage
overload conditions. 50 1250 2.5 3750 spoon) (N.R.)
Effect on ability to drive and use machines 60 1500 3.0 4500 Suspension of 250 mg/5ml amoxicillin (100 ml bottle with dosage
There is no evidence that deferiprone affects the ability of patients 70 1750 3.5 5250 spoon) (N.R.)
to drive or use machinery. 80 2000 4.0 6000 Drops of 100 mg/ml amoxicillin (20 ml bottle with dropper)
90 2250 4.5 6750 MODE OF ACTION
ADVERSE REACTIONS
The very common (greater than or equal to 10%) and common Amoxicillin is a bactericidal broadspectrum antibiotic which can
OVERDOSE
(1% to < 10%) adverse reactions to deferiprone were: be classied as an ampicillin derivative with a better absorption.
Acute Toxicity and Symptoms
Body as a Whole: PHYSIOLOGICAL EFFECT
There have been no reports of acute overdose with deferiprone.
Very Common: abdominal pain (11%) Following oral administration, amoxicillin is rapidly and virtually
Management and Treatment
Common: headache (2%), asthenia (1%), back completely absorbed (85-90%). The absorption is not signicantly
pain (2%), pain (3%), u syndrome In case of overdosage, close clinical supervision of the patient is inuenced by food intake. Half-life is approx. 60-90 minutes.
(1%) required. Probenecid delays renal excretion. FLEMOXIN preparations
PRESENTATION contain no sugar and can be prescribed for diabetic patients.
Digestive System:
Very common: nausea (15%), vomiting (13%) FERRIPROX tablets are white, capsule-shaped, lm coated and INDICATIONS
Common: increased appetite (3%), dyspepsia imprinted APO bisect 500 on one side, plain on the other. The Infections caused by amoxicillin-sensitive micro-organisms, e.g.
(3%), diarrhea (2%), liver tenderness tablets are scored and breakable in half. respiratory, urogenital, gastro-intestinal infections and infections
(1%), anorexia (1%) FERRIPROX tablets are available in HDPE containers of 100 of the skin and soft tissues.
Hemic & Lymphatic System: tablets with child resistant closures. CONTRA-INDICATIONS
Common: neutropenia (neutrophils <1.5x109/L) Storage Condition Hypersensitivity to penicillins.
(6.0%), agranulocytosis (1%), Store below 30C.
PRECAUTIONS
thrombocytopenia (1%)
In patients with infectious mononucleosis and lymphatic leukemia,
Metabolic and Nutritional:
ASTELLAS EUROPE B.V a high incidence of exanthema is to be expected. Cross-allergy and
Common: increased ALT values (6%), cross-resistance may exist between penicillins and cephalosporins.
peripheral edema (1%)
P.O. BOX: 991, RIYADH 11421
As with other broadspectrum antibiotics, susperinfections caused
Musculoskeletal System:
SAUDI ARABIA by non-susceptible micro-organisms (e.g. Candida albicans, Ps.
Common: arthralgia (12%), arthrosis (3%),
TEL: 01-4631890, FAX: 01-4631890 aeruginosa) may occur, particularly in Patients with chronic
disorders and/or disturbed natural resistance.
arthritis (1%), bone pain (1%)
Nervous: DE-NOL Tablet SIDE-EFFECTS
Common: dizziness (1%), somnolence (1%) OTC Macular or maculopapular rashes may occur. Typical allergic
reactions, such as urticaria and purpura are less common. An
Skin: (Bismuth subcitrate) anaphylactic reaction following oral administration of penicillin
Common: pruritus (1%), urticaria (1%) or one of its derivatives has only very occasionally been reported,
The most serious undesirable effect of therapy reported in clinical COMPOSITION Gastro-intestinal side-effects, such as nausea, vomiting and diar-
trials with deferiprone is agranulocytosis (neutrophils <0.5 x Each tablet contains bismuth subcitrate, corresponding to 120 mg rhoea are sometimes observed, but are generally not serious and
109/L) with an incidence of 0.8% (0.4 cases per 100 patient years bismuth (III) oxide. of a transient nature.
41
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ASTELLAS EUROPE B.V
SPDI
DOSAGE AND ADMINISTRATION In chronic, relapsing and severe infections, the above-men- PRECAUTIONS
In non-severe to moderately severe infections the following tioned dosage may be increased to 3 x 750-1000 mg daily. In Contact with the eye should be avoided.
dosage scheme may be used: children, up to 100 mg/kg daily in 3 doses.
SIDE-EFFECTS
Adults and children over 10 years: Gonorrhoea (acute, non-complicated): 3 g in a single dose
(preferably with 1 g probenecid). In the treatment of females A slight exacerbation of the lesion may appear initially.
3 x 500 mg daily
repeated doses are recommended. DOSAGE AND ADMINISTRATION
Children 5-10 years* 3 x 250 mg daily
Children 2-5 years* 3 x 125 mg daily DURATION OF TREATMENT For adults and children, to be applied to the affected parts two to
Children 0-2 years* 3 x 100 mg daily About 1 week. Generally therapy should continue 3-4 days after four times a day, or as directed by the physician.
* Generally 25-50 mg/kg daily in 3 divided doses is the symptoms have disappeared. DURATION OF TREATMENT
recommended. PACKAGE QUANTITIES 2-4 weeks or longer.
In chronic, relapsing and severe infections, the above-men- 20 x 250 mg. PACKAGE QUANTITIES
tioned dosage may be increased to 3 x 750-1000 mg daily. In 20 x 500 mg.
children, up to 100 mg/kg daily in 3 doses. Cream: tubes of 30 g
Ointment: tubes of 30 g
Gonorrhoea (acute, non-complicated): 3 g in a single dose LOCOID
(preferably with 1 g probenecid). In the treatment of females
repeated doses are recommended.
ASTRAZENECA
DURATION OF TREATMENT (Hydrocortisone 17-butyrate) P.O.BOX.N0:17601, RIYADH: 11494
5 Days or longer depending on the severity of the infection. SAUDI ARABIA
COMPOSITION
PACKAGE QUANTITIES LOCOID cream, lipocream, ointment and lotion contain 0.1% TEL: 01-4190055, FAX: 01-4190638
Capsules : 20 x 250 mg (N.R) hydrocortisone 17-butyrate.
20 x 500 mg
MODE OF ACTION ACCOLATE Tablets
Suspension (N.R) : 125 mg/5 ml/100 ml,
LOCOID is a non-uorinated topical steroid with anti-inam-
250 mg/5 ml/100 ml
matory, anti-eczematous, anti-allergic and anti-pruritic properties. (Zarlukast)
Drops : 100 mg/ml/20 ml
PHYSIOLOGICAL EFFECT
PRESENTATION
LOCOID is more potent than hydrocortisone and is as effective
FLEMOXIN SOLUTAB as the potent uorinated steroids although there is a low incidence Tablets containing 20 mg zarlukast
of reported clinical side-effects. THERAPEUTIC INDICATION
(Amoxicillin) INDICATIONS ACCOLATE is indicated for the treatment of asthma.
Skin disorders responsive to topical corticosteroids, e.g. eczema, POSOLOGY AND METHOD OF ADMINISTRATION
COMPOSITION dermatitis and psoriasis.
ACCOLATE should be taken continuously.
FLEMOXIN SOLUTAB contains 250 or 500 mg amoxicillin.
CONTRA-INDICATIONS Adults and children aged 12 years and over:
MODE OF ACTION Hypersensitivity to any of the components of the preparation. The dosage is one 20 mg tablet twice daily. This dosage should not
Amoxicillin is a bactericidal broadspectrum antibiotic which can Viral or fungal infections, tubercular or syphilitic lesions, and be exceeded. Higher doses may be associated with elevations of
be classied as an ampicillin derivative with a better absorption. bacterial infections unless used in conjunction with appropriate one or more liver enzymes consistent with hepatotoxicity.
chemotherapy. As food may reduce the bioavailability of zarlukast, ACCOLATE
PHYSIOLOGICAL EFFECT
PRECAUTIONS should not be taken with meals.
Following oral administration amoxicillin is rapidly and virtually
completely absorbed (85-90%). The absorption is not signicantly Contact with the eye should be avoided. Topical steroids should Elderly:
inuenced by food intake. The mean maximum serum levels of not be used extensively in pregnancy, i.e. in large amounts or for The clearance of zarlukast is signicantly reduced in elderly
amoxicillin are reached about half an hour sooner with Flemoxin long periods. In infants, long-term continuous topical therapy patients (over 65 years old), and Cmax and AUC are approximately
Solutab than with amoxicillin capsules and are signicantly high- should be avoided. Adrenal suppression can occur, even without double those of younger adults. However, accumulation of
er. Half-life is approx. 60-90 minutes. Probenecid delays renal occlusion. zarlukast is no greater than that seen in multiple-dose trials
excretion. FLEMOXIN SOLUTAB contains no sugar and can conducted in adult subjects with asthma, and the consequences of
SIDE-EFFECTS the altered kinetics in the elderly are unknown.
be prescribed for diabetic patients.
Burning, itching, irritation and dryness have been observed. In- Clinical experience with ACCOLATE in the elderly (over
INDICATIONS tolerance to the occlusive dressing has occasionally been reported 65 years) is limited and caution is recommended until further
Infections caused by amoxicillin-sensitive micro-organisms e.g. (military eruptions, folliculitis). In long-term treatment of exten- information is available.
respiratory, urogenital, gastro-intestinal infections and infections sive skin areas with occlusive dressing inhibition of adrenal func-
Children:
of the skin and soft tissues. tion may occur.
There is no clinical experience of the use of ACCOLATE in
CONTRA-INDICATION DOSAGE AND ADMINISTRATION children under 12 years of age. Until safety information is
Hypersensitivity to penicillins. For adults and children, to be applied to the affected parts 1-3 times available, the use of Accolate in children is contraindicated.
per day, unless your doctor prescribes otherwise. When necessary, Renal Impairment:
PRECAUTIONS application may be made under an occlusive dressing.
No dosage adjustment is necessary in patients with mild renal
In patients with infectious mononucleosis and lymphatic leukemia, Duration of treatment impairment. However, experience is limited in patients with
a high incidence of exanthema is to be expected. Cross-allergy 2-4 weeks or longer. moderate to severe renal impairment (See Pharmacokinetic
and cross-resistance may exist between penicillins and cephalo- Properties) so clear dose recommendations cannot be given;
PACKAGE QUANTITIES
sporins. As with other broadspectrum antibiotics susperinfections ACCOLATE should be used with caution in this patient group.
caused by non-susceptible micro-organisms (e.g. Candida albicans Cream: tubes of 30 g
Ps. aeruginosa) may occur, particularly in patients with chronic Lipocream: tubes of 30 g CONTRAINDICATIONS
disorders and/or disturbed natural resistance. Ointment: tubes of 30 g ACCOLATE should not be given to patients who have previously
Lotion: bottle of 30 ml experienced hypersensitivity to the product or any of its
SIDE-EFFECTS ingredients.
Macular or maculopapular rashes may occur. Typical allergic PIMAFUCORT ACCOLATE is contraindicated in patients with hepatic
reactions such as urticaria and purpura are less common. An impairment or cirrhosis; it has not been studied in patients with
anaphylactic reaction following oral administration of penicillin OTC
hepatitis or in long term studies of patients with cirrhosis.
or one of its derivatives has only very occasionally been reported, (Hydrocortisone, Natamycin and Neomycin) ACCOLATE is contraindicated in children under 12 years of age
Gastro-intestinal side-effects, such as nausea, vomiting and
until safety information is available.
diarrhoea are sometimes observed, but are generally not serious
and of a transient nature. COMPOSITION SPECIAL WARNING AND PRECAUTIONS FOR USE
PIMAFUCORT cream and ointment contain 10 mg hydrocor- ACCOLATE should be taken regularly to achieve benet, even
DOSAGE AND ADMINISTRATION tisone, 10 mg natamycin and 3.5 mg neomycin base per g. during symptom free periods. ACCOLATE therapy should
FLEMOXIN SOLUTAB may be either directly swallowed with normally be continued during acute exacerbations of asthma.
some water or rst stirred well in half a glass of water and then MODE OF ACTION
PIMAFUCORT contains a combination of an antibacterial and a ACCOLATE does not allow a reduction in existing steroid
swallowed.
broadspectrum antifungal antibiotic with a topical corticosteroid. treatment.
In non-severe to moderately severe infections the following
As with inhaled steroids and cromones (disodium cromoglycate,
dosage scheme may be used: PHYSIOLOGICAL EFFECT nedocromil sodium), ACCOLATE is not indicated for use in the
Adults and children over 10 years: Hydrocortisone has an anti-inammatory and antipruriginous reversal of bronchospasm in acute asthma attacks.
3 x 1 FLEMOXIN SOLUTAB of 500 mg daily properties, neomycine is active against a number of bacteria and ACCOLATE has not been evaluated in the treatment of labile
Children 5-10 years: natamycin is active against fungi, particularly Candida albicans. (brittle) or unstable asthma.
3 x 1 FLEMOXIN SOLUTAB of 250 mg daily INDICATIONS Cases of eosinophilic conditions, including Churg-Strauss
Children 2-5 years: Suspected or ascertained impetiginized and/or mycotically in- Syndrome and eosinophilic pneumonia have been reported in
fected dermatoses. association with ACCOLATE usage. Presentations may involve
3 x FLEMOXIN SOLUTAB of 250 mg daily various body systems including vasculitic rash, worsening
FLEMOXIN drops (100 mg/ml) are available for children up to CONTRA-INDICATIONS pulmonary symptoms, cardiac complications or neuropathy. A
2 years*, dosage 3 x 100 mg daily. Tuberculosis of the skin or viral infections. Moreover in cases of causal relationship has neither been conrmed nor refuted. If
* Generally 25-50 mg/kg daily in 3 divided doses is resistance of the micro-organism or hypersensitivity of the patient a patient develops an eosinophilic condition or a Churg-Strauss
recommended. to any of its components. Syndrome type illness ACCOLATE should be stopped, a re-
42
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ASTRAZENECA
SPDI
challenge test should not be performed and treatment should not Musculoskeletal: arthraligia (rare), myalgia (rare) rash 80 mg bd), accumulation of zarlukast in plasma was low (not
be restarted. Skin: rash (including blistering), Pruritus, detectable - 2.9 times rst dose values; mean 1.45; median
Elevations in serum transaminases can occur during treatment hypersensitivity reactions including 1.27). The terminal half-life of zarlukast is approximately 10
with ACCOLATE. These are usually asymptomatic and transient urticaria and angioedema (rare) and hours. Steady-state plasma concentrations of zarlukast were
but could represent early evidence of hepatotoxicity, and have oedema(uncommon) proportional to the dose and predictable from sing`le-dose
very rarely been associated with more severe hepatocellular Neurological: Insomnia, headache (common) pharmacokinetic data.
injury, fulminant hepatitis and liver failure. In extremely rare post- Haematologic: bruising (rare), bleeding disorders, Zarlukast is extensively metabolised. Following a radiolabelled
marketing cases, no prior clinical symptoms or signs suggestive of including menorrhagia (rare), dose the urinary excretion accounts for approximately 10% dose
liver dysfunction preceded the severe hepatic injury. thrombocytopenia (rare) and and faecal excretion for 89%. Zarlukast is not detected in urine.
If clinical symptoms or signs suggestive of liver dysfunction agranulocytosis (very rare) The metabolites identied in human plasma were found to be at
occur (e.g. anorexia, nausea, vomiting, right upper quadrant pain, The above events have usually resolved following cessation of least 90-fold less potent than zarlukast in a standard in-vitro test
fatigue, lethargy, u-like symptoms, enlarged liver, pruritus and therapy. Headache and gastrointestinal disturbance are usually of activity.
jaundice), ACCOLATE should be discontinued. The serum mild and do not necessitate withdrawal from therapy. Zarlukast is approximately 99% protein bound to human plasma
transaminases, in particular serum ALT, should be measured In placebo-controlled clinical trials, an increased incidence of proteins, predominantly albumin, over the concentration range
immediately and the patient managed accordingly. Physicians may infection has been observed in elderly patients given Accolate 0.25 to 4.0 microgram/ml.
consider the value of routine liver function testing. Periodic serum (7.8% vs 1.4%). Infections were usually mild, predominantly Pharmacokinetic studies in special populations have been
transaminase testing has not proven to prevent serious injury but affecting the respiratory tract. performed in a relatively small number of subjects, and the clinical
is generally believed that early detection of drug-induced hepatic signicance of the following kinetic data is not established.
injury along with immediate withdrawal of the suspect drug may OVERDOSE
Pharmacokinetics of zarlukast in adolescents and adults with
enhance the likelihood of recovery. If liver function testing shows Limited information exists with regard to the effects of overdosage asthma were similar to those of healthy adult males. When
evidence of hepatotoxity ACCOLATE should be discontinued of Accolate in humans. adjusted for body weight, the pharmacokinetics of zarlukast are
immediately and the patient managed accordingly. Patients in Management should be supportive. Removal of excess medication not signicantly different between men and women.
whom ACCOLATE was withdrawn because of hepatotoxicity by gastric lavage may be helpful. Elderly subjects and subjects with stable alcoholic cirrhosis
with no other attributable cause should not be re-exposed to
PHARMACODYNAMIC PROPERTIES demonstrated an approximately two-fold increase in Cmax and
ACCOLATE.
AUC compared to normal subjects given the same doses of
ACCOLATE is not recommended for patients with hepatic ATC Code: R03D C01.
ACCOLATE.
impairment including hepatic cirrhosis. Pharmacotherapeutic Group: Leukotriene receptor antagonists.
There are no signicant differences in the pharmacokinetics of
INTERACTIONS The cysteinyl leukotrienes (LTC4, LTD4 and LTE4) are potent zarlukast in patients with mild renal impairment and in normal
inammatory eicosanoids released from various cells including subjects. However, there are no conclusive data available in
ACCOLATE may be administered with other therapies mast cells and eosinophils. These important pro-asthmatic
routinely used in the management of asthma and allergy. Inhaled patients with moderate or severe renal impairment, hence the
mediators bind to cysteinyl leukotriene receptors found in the recommendation for caution is used in this patient population.
steroids, inhaled and oral bronchodilator therapy, antibiotics human airway.
and antihistamines are examples of agents which have been co- PRE-CLINICAL SAFETY DATA
Leukotriene production and receptor occupation has been
administered with Accolate without adverse interaction.
implicated in the pathophysiology of asthma. Effects include After multiple doses of greater than 40 mg/kg/day for up to 12
ACCOLATE may be administered with oral contraceptives smooth muscle contraction, airway oedema and altered cell months, liver enlargement associated with degenerative/fatty
without adverse interaction. activity associated with the inammatory process, including change or glycogen deposition was seen in rats, mice and dogs.
Co-administration with warfarin results in an increase in eosinophil inux to the lung. Histiocytic aggregates were seen in a number of tissues of dogs.
maximum prothrombin time by approximately 35%. It is therefore ACCOLATE is a competitive highly selective and potent Male mice given 300 mg/kg zarlukast daily had an increased
recommended that if ACCOLATE is co-administered with oral peptide leukotriene antagonist of LTC4, LTD4 and LTE4 incidence of hepatocellular adenomas compared to control
warfarin, prothrombin time should be closely monitored. The components of slow reacting substance of anaphylaxis. In vitro animals. Rats given 2000 mg/kg zarlukast daily had an increased
interaction is probably due to an inhibition by zarlukast of the studies have shown that ACCOLATE antagonises the contractile incidence of urinary bladder papilloma compared to control
cytochrome P450 2C9 isoenzyme system. activity of all three peptide leukotrienes (leukotriene C4, D4, animals. Zarlukast was not mutagenic in a range of tests. The
In clinical trials co-administration with theophylline resulted in and E4) in human conducting airway smooth muscle to the same clinical signicance of these ndings during the long term use of
decreased plasma levels of zarlukast, by approximately 30%, but extent. Animal studies have shown ACCOLATE to be effective ACCOLATE in man is uncertain.
with no effect on plasma theophylline levels. However, during in preventing peptide leukotriene-induced increases in vascular There were no other notable ndings from the pre-clinical testing.
post-marketing surveillance, there have been rare cases of patients permeability, which give rise to oedema in the airways, and to
experiencing increased theophylline levels when co-administered inhibit peptide leukotriene-induced inux of eosinophils into SPECIAL PRECAUTIONS FOR STORAGE
ACCOLATE. airways. Do not store above 30C.
Co-administration with terfenadine resulted in a 54% decrease The specicity of ACCOLATE has been shown by its action SHELF-LIFE
in AUC for zarlukast, but with no effect on plasma terfenadine on leukotriene receptors and not prostaglandin, thromboxane,
Please refer to expiry date on the blister strip or outer carton.
levels. cholinergic and histamine receptors.
Co-administration with acetylsalicylic acid ("aspirin", 650 mg four In a placebo-controlled study where segmental bronchoprovocation PACK SIZE
times a day) may result in increased plasma levels of zarlukast, with allergen was followed by bronchoalveolar lavage 48 hours Please refer to the outer carton for pack size.
by approximately 45%. later, zarlukast decreased the rise in basophils, lymphocytes and ACCOLATE is a trademark of the AstraZeneca group of
Co-administration with erythromycin will result in decreased histamine, and reduced the stimulated production of superoxide companies.
plasma levels of zarlukast, by approximately 40%. by alveolar macrophages. ACCOLATE attenuated the increase
AstraZeneca 2005
in bronchial hyperresponsiveness that follows inhaled allergen
The clearance of zarlukast in smokers may be increased by
challenge. Further, methacholine sensitivity was diminished by
approximately 20%. ARIMIDEX 1 mg Film-coated Tablets
long-term dosing with ACCOLATE 20 mg twice daily.
At concentrations of 10 microgram/ml and above, zarlukast
Further, in clinical trials evaluating chronic therapy with
causes increases in the assay value for bilirubin in animal plasma.
ACCOLATE, the lung function measured when plasma levels
However, zarlukast has not been shown to interfere with the 2,5-
were at trough showed sustained improvements over baseline.
dichlorophenyl diazonium salt method of bilirubin analysis of (Anastrozole)
human plasma. ACCOLATE shows a dose dependent inhibition of
bronchoconstriction induced by inhaled LTD4. Asthmatic patients
PREGNANCY AND LACTATION are approximately 10-fold more sensitive to the bronchoconstricting COMPOSITION
Pregnancy activity of inhaled LTD4. A single oral dose of ACCOLATE can Each tablet contains 1 mg anastrozole.
The safety of ACCOLATE in human pregnancy has not been enable an asthmatic patient to inhale 100 times more LTD4 and For excipients see List of excipients.
established. In animal studies, zarlukast did not have any shows signicant protection at 12 and 24 hours.
apparent effect on fertility and did not appear to have any ACCOLATE inhibits the bronchoconstriction caused by several PHARMACEUTICAL FORM
teratogenic or selective toxic effect on the foetus. The potential kinds of challenge, such as the response to sulphur dioxide, Film-coated tablet
risks should be weighed against the benets of continuing therapy exercise and cold air. ACCOLATE attenuates the early and late White, round, biconvex tablet with logo on one side and strength
during pregnancy and ACCOLATE should be used during phase inammatory reaction caused by various antigens such as on the other.
pregnancy only if clearly needed. grass, cat dander, ragweed and mixed antigens.
In asthmatic patients not adequately controlled by beta-agonist THERAPEUTIC INDICATIONS
Lactation
therapy (given as required) ACCOLATE improves symptoms Adjuvant treatment of post-menopausal women with hormone
Zarlukast is excreted in human breast milk. Accolate should not
(reducing daytime and nocturnal asthmatic symptoms), improves receptor positive early invasive breast cancer.
be administered to mothers who are breast-feeding.
lung function, reduces the need for concomitant beta-agonist Adjuvant treatment of early breast cancer in hormone receptor
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES medication and reduces incidence of exacerbations. Similar positive post-menopausal women who have received 2 to 3 years
There is no evidence that ACCOLATE affects the ability to drive benets have been seen in patients with more severe asthma of adjuvant tamoxifen.
and use machinery. receiving high dose inhaled steroids. Treatment of advanced breast cancer in post-menopausal women.
In clinical studies, there was a signicant rst-dose effect on Efcacy has not been demonstrated in oestrogen receptor negative
UNDESIRABLE EFFECTS
baseline bronchomotor tone observed within 2 hours of dosing, patients unless they had a previous positive clinical response to
The following have been reported in association with the when peak plasma concentrations had not yet been achieved. Initial tamoxifen.
administration of Accolate. improvements in asthma symptoms occurred within the rst week,
Gastrointestinal: nausea, vomiting, abdominal pain and often the rst few days, of treatment with ACCOLATE. POSOLOGY AND METHOD OF ADMINISTRATION
(common) Adults including the elderly : One 1mg tablet to be taken
PHARMACOKINETIC PROPERTIES orally once a day
Hepatobiliary: Symptomatic hepatitis with and
without hyperbilirubinaemia (rare), Peak plasma concentrations of zarlukast are achieved Childre : Not recommended for use
hyperbilirubinaemia, without elevated approximately 3 hours after oral administration of ACCOLATE. in children
liver function tests (rare), hepatic Administration of ACCOLATE with food increased the variability Renal Impairment : No dose change is
failure (very rare), fulminant hepatitis in the bioavailability of zarlukast and reduced bioavailability in recommended in patients
(very rare) most (75%) subjects. The net reduction was approximately 40%. with mild or moderate
General: malaise (common) Following twice-daily administration of ACCOLATE (30 to renal impairment
43
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ASTRAZENECA
SPDI
Hepatic Impairment :No dose change is Very common Vascular: Hot ushes, mainly A single dose of ARIMIDEX that results in life-threatening
recommended in patients mild or moderate in symptoms has not been established. There is no specic antidote
( 10%)
with mild hepatic disease. nature. to overdosage and treatment must be symptomatic.
For early disease, the recommended duration of treatment should In the management of an overdose, consideration should be
Uncommon Reproductive Vaginal bleeding,
be 5 years. given to the possibility that multiple agents may have been taken.
( 0.1% and system and breast: mainly mild or
Vomiting may be induced if the patient is alert. Dialysis may be
CONTRAINDICATIONS <1%) moderate in nature*.
helpful because ARIMIDEX is not highly protein bound. General
Arimidex is contraindicated in: Metabolism and Anorexia, mainly mild supportive care, including frequent monitoring of vital signs and
- pre-menopausal women nutrition: in nature. close observation of the patient, is indicated.
- pregnant or lactating women Hypercholesterolaemia,
- patients with severe renal impairment (creatinine clearance less mainly mild or PHARMACODYNAMIC PROPERTIES
than 20 ml/min) moderate in nature. ATC Code: L02B G03 (Enzyme inhibitors)
- patients with moderate or severe hepatic disease Gastrointestinal: Vomiting, mainly mild ARIMIDEX is a potent and highly selective non-steroidal
- patients with known hypersensitivity to anastrozole or to any of or moderate in nature. aromatase inhibitor. In post-menopausal women, oestradiol is
the excipients as referenced in the List of excipients. Nervous system: Somnolence, mainly produced primarily from the conversion of androstenedione to
Oestrogen-containing therapies should not be co-administered mild or moderate in oestrone through the aromatase enzyme complex in peripheral
with Arimidex as they would negate its pharmacological action. nature. tissues. Oestrone is subsequently converted to oestradiol.
Very rare Skin and Erythema multiforme Reducing circulating oestradiol levels has been shown to produce a
Concurrent tamoxifen therapy (see Interaction).
(<0.01%) subcutaneous Stevens-Johnson benecial effect in women with breast cancer. In post-menopausal
SPECIAL WARNINGS AND PRECAUTIONS FOR USE tissue: syndrome women, ARIMIDEX at a daily dose of 1 mg produced oestradiol
ARIMIDEX is not recommended for use in children as safety and Allergic reactions suppression of greater than 80% using a highly sensitive assay.
efcacy have not been established in this group of patients. including ARIMIDEX does not possess any progestogenic, androgenic or
The menopause should be dened biochemically in any patient angioedema, urticaria oestrogenic activity.
where there is doubt about hormonal status. and anaphylaxis. Daily doses of Arimidex up to 10 mg do not have any effect on
There are no data to support the safe use of ARIMIDEX in * Vaginal bleeding has been reported uncommonly, mainly in cortisol or aldosterone secretion, measured before or after standard
patients with moderate or severe hepatic impairment, or patients patients with advanced breast cancer during the rst few weeks ACTH challenge testing. Corticoid supplements are therefore not
with severe impairment of renal function (creatinine clearance less after changing from existing hormonal therapy to treatment with needed.
than 20 ml/min). ARIMIDEX. If bleeding persists, further evaluation should be Primary adjuvant treatment of early breast cancer
Women with osteoporosis or at risk of osteoporosis should have considered. In a large phase III study conducted in 9366 post-menopausal
their bone mineral density formally assessed by bone densitometry As ARIMIDEX lowers circulating oestrogen levels, it may cause women with operable breast cancer treated for 5 years,
e.g. DEXA scanning at the commencement of treatment and a reduction in bone mineral density placing some patients at a ARIMIDEX was shown to be statistically superior to tamoxifen
at regular intervals thereafter. Treatment or prophylaxis for higher risk of fracture (see Special warnings and precautions for in disease-free survival. A greater magnitude of benet was
osteoporosis should be initiated as appropriate and carefully use). observed for disease-free survival in favour of ARIMIDEX
monitored. Elevated gamma-GT and alkaline phosphatase have been reported versus tamoxifen for the prospectively dened hormone receptor
There are no data available for the use of anastrozole with LHRH uncommonly ( 0.1% and <1%). A causal relationship for these positive population. ARIMIDEX was statistically superior to
analogues. This combination should not be used outside clinical changes has not been established. tamoxifen in time to recurrence. The difference was of even greater
trials. The table below presents the frequency of pre-specied adverse magnitude than in disease-free survival for both the Intention To
As ARIMIDEX lowers circulating oestrogen levels it may cause events in the ATAC study, irrespective of causality, reported in Treat (ITT) population and hormone receptor positive population.
a reduction in bone mineral density. Adequate data to show the patients receiving trial therapy and up to 14 days after cessation ARIMIDEX was statistically superior to tamoxifen in terms of
effect of bisphosphonates on bone mineral density loss caused by of trial therapy. time to distant recurrence. The incidence of contralateral breast
anastrozole, or their utility when used prophylactically, are not Tamoxifen cancer was statistically reduced for ARIMIDEX compared to
Adverse effects Arimidex
currently available. tamoxifen. Following 5 years of therapy, anastrozole is at least as
(N=3092) (N=3094) effective as tamoxifen in terms of overall survival. However, due
This product contains lactose. Patients with rare hereditary
Hot ushes 1104 (35.7%) 1264 (40.9%) to low death rates, additional follow-up is required to determine
problems of galactose intolerance, the Lapp lactase deciency or
Joint pain/stiffness 1100 (35.6%) 911 (29.4%) more precisely the long-term survival for anastrozole relative
glucose-galactose malabsorption should not take this medicine.
to tamoxifen. With 68 months median follow-up, patients in the
Mood disturbances 597 (19.3%) 554 (17.9%)
INTERACTION ATAC study have not been followed up for sufcient time after
Fatigue/asthenia 575 (18.6%) 544 (17.6%) 5 years of treatment, to enable a comparison of long-term post
Antipyrine and cimetidine clinical interaction studies indicate that
the co administration of ARIMIDEX with other drugs is unlikely Nausea and vomiting 393 (12.7%) 384 (12.4%) treatment effects of ARIMIDEX relative to tamoxifen.
to result in clinically signicant drug interactions mediated by Fractures 315 (10.2%) 209 (6.8%) ATAC endpoint summary: 5-year treatment completion
cytochrome P450. Fractures of the spine, hip, or 133 (4.3%) 91 (2.9%) analysis
A review of the clinical trial safety database did not reveal wrist/Colles Efcacy Number of events (frequency)
evidence of clinically signicant interaction in patients treated endpoints
Wrist/Colles fractures 67 (2.2%) 50 (1.6%) Intention-to- Hormone-
with ARIMIDEX who also received other commonly prescribed
Spine fractures 43 (1.4%) 22 (0.7%) treat population receptor-positive
drugs.
Hip fractures 28 (0.9%) 26 (0.8%) tumour status
Oestrogen-containing therapies should not be co-administered with
Arimidex Tamoxifen Arimidex Tamoxifen
ARIMIDEX as they would negate its pharmacological action. Cataracts 182 (5.9%) 213 (6.9%)
(N=3125) (N=3116) (N=2618) (N=2598)
Tamoxifen should not be co-administered with ARIMIDEX, as this Vaginal bleeding 167 (5.4%) 317 (10.2%)
may diminish its pharmacological action (see Contraindications). Ischaemic cardiovascular 127 (4.1%) 104 (3.4%) Disease-free 575(18.4) 651(20.9) 424(16.2) 497(19.1)
survivala
PREGNANCY AND LACTATION disease
ARIMIDEX is contraindicated in pregnant or lactating women. Angina pectoris 71 (2.3%) 51 (1.6%) Hazard ratio 0.87 0.83
Myocardial infarct 37 (1.2%) 34 (1.1%) 2-sided 95% CI 0.78 to 0.97 0.73 to 0.94
Coronary artery disorder 25 (0.8%) 23 (0.7%) p-value 0.0127 0.0049
ARIMIDEX is unlikely to impair the ability of patients to drive
and operate machinery. However, asthenia and somnolence have Myocardial ischaemia 22 (0.7%) 14 (0.5%) Distant disease- 500 (16.0) 530 (17.0) 370 (14.1) 394(15.2)
been reported with the use of ARIMIDEX and caution should Vaginal discharge 109 (3.5%) 408 (13.2%) free survivalb
be observed when driving or operating machinery while such Hazard ratio 0.94 0.93
Any venous thromboembolic 87 (2.8%) 140 (4.5%)
symptoms persist. 2-sided 95% CI 0.83 to 1.06 0.80 to 1.07
event
UNDESIRABLE EFFECTS Deep venous thromboembolic 48(1.6%) 74 (2.4%) p-value 0.2850 0.2838
Time to 402(12.9) 498(16.0) 282(10.8) 370(14.2)
Very common Vascular: Hot ushes, mainly events including PE
mild or moderate in recurrencec
( 10%) Ischaemic cerebrovascular 62(2.0%) 88 (2.8%)
nature. Hazard ratio 0.79 0.74
events
Common General: Asthenia, mainly mild 2-sided 95% CI 0.70 to 0.90 0.64 to 0.87
or moderate in nature. Endometrial cancer 4(0.2%) 13(0.6%)
((1% and <10%) p-value 0.0005 0.0002
Musculoskeletal, Joint pain/stiffness, Fracture rates of 22 per 1000 patient-years and 15 per 1000 Time to distant 324(10.4) 375(12.0) 226(8.6) 265(10.2)
connective tissue mainly mild or patient-years were observed for the ARIMIDEX and tamoxifen
recurrenced
and bone: moderate in nature. groups, respectively, after a median follow-up of 68 months. The
Reproductive Vaginal dryness, mainly observed fracture rate for ARIMIDEX is similar to the range Hazard ratio 0.86 0.84
system and breast: mild or moderate in reported in age-matched post-menopausal populations. It has not 2-sided 95% CI 0.74 to 0.99 0.70 to 1.00
nature. been determined whether the rates of fracture and osteoporosis seen p-value 0.0427 0.0559
Skin and Hair thinning, mainly in ATAC in patients on anastrozole treatment reect a protective
Contralateral 35 (1.1) 59 (1.9) 26 (1.0) 54 (2.1)
subcutaneous tissue: mild or moderate in effect of tamoxifen, a specic effect of anastrozole, or both.
The incidence of osteoporosis was 10.5% in patients treated with breast primary
nature.
Rash, mainly mild or Arimidex and 7.3% in patients treated with tamoxifen. Odds ratio 0.59 0.47
moderate in nature. 2-sided 95% CI 0.39 to 0.89 0.30 to 0.76
OVERDOSE
Gastrointestinal: Nausea, mainly mild or p-value 0.0131 0.0018
There is limited clinical experience of accidental overdosage.
moderate in nature. Overall survival e 411(13.2) 420(13.5) 296(11.3) 301(11.6)
In animal studies, anastrozole demonstrated low acute toxicity.
Diarrhoea, mainly mild Clinical trials have been conducted with various dosages of Hazard ratio 0.97 0.97
or moderate in nature. Arimidex, up to 60 mg in a single dose given to healthy male
Headache, mainly mild 2-sided 95% CI 0.85 to 1.12 0.83 to 1.14
Nervous system: volunteers and up to 10 mg daily given to post-menopausal women
or moderate in nature. with advanced breast cancer; these dosages were well tolerated. p-value 0.7142 0.7339
44
Book_01.indd 44 6/4/2008 2:19:16 PM

ASTRAZENECA
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a Disease-free survival includes all recurrence events and is dosing of ARIMIDEX tablets. Approximately 90 to 95% of
dened as the rst occurrence of loco-regional recurrence, plasma anastrozole steady-state concentrations are attained after ATACAND 4 mg, 8 mg, 16 mg Tablets
contralateral new breast cancer, distant recurrence or death (for 7 daily doses. There is no evidence of time or dose-dependency of ATACAND 32 mg Tablets (N.R)
any reason). anastrozole pharmacokinetic parameters.
b Distant disease-free survival is dened as the rst occurrence Anastrozole pharmacokinetics are independent of age in post-
of distant recurrence or death (for any reason). menopausal women.
(Candesartan cilexetil)
c Time to recurrence is dened as the rst occurrence of loco- Pharmacokinetics have not been studied in children. COMPOSITION
regional recurrence, contralateral new breast cancer, distant
Anastrozole is only 40% bound to plasma proteins. Each tablet contains 4 mg, 8 mg, 16 mg.
recurrence or death due to breast cancer.
Anastrozole is extensively metabolised by post-menopausal 32 mg(N.R) candesartan cilexetil.
d Time to distant recurrence is dened as the rst occurrence of
women with less than 10% of the dose excreted in the urine
distant recurrence or death due to breast cancer. PHARMACEUTICAL FORM
unchanged within 72 hours of dosing. Metabolism of anastrozole
e Number (%) of patients who had died. occurs by N-dealkylation, hydroxylation and glucuronidation. ATACAND 4 mg are round (diameter 7mm), white tablets marked
As with all treatment decisions, women with breast cancer and The metabolites are excreted primarily via the urine. Triazole, the A/CF on one side and marked 004 on the other side.
their physician should assess the relative benets and risks of the major metabolite in plasma, does not inhibit aromatase. ATACAND 8 mg are round (diameter 7mm), light pink tablets
treatment. with a score and marked A/CG on one side and marked 008 on
The apparent oral clearance of anastrozole in volunteers with
When ARIMIDEX and tamoxifen were co-administered, the the other side.
stable hepatic cirrhosis or renal impairment was in the range
efcacy and safety were similar to tamoxifen when given alone, ATACAND 16 mg are round (diameter 7mm), pink tablets with a
observed in healthy volunteers.
irrespective of hormone receptor status. The exact mechanism of score and marked A/CH on one side and marked 016 on the other
this is not yet clear. It is not believed to be due to a reduction in the PRECLINICAL SAFETY DATA RELEVANT TO THE side.
degree of oestradiol suppression produced by ARIMIDEX. PRESCRIBER ATACAND 32 mg(N.R) are round (diameter 9.5 mm), pink
Adjuvant treatment of early breast cancer for patients being Acute toxicity tablets with a score and marked A/CL on one side and marked 032
on the other side.
treated with adjuvant tamoxifen In acute toxicity studies in rodents the median lethal dose of
In a phase III trial (ABCSG 8) conducted in 2579 post-menopausal anastrozole was greater than 100 mg/kg/day by the oral route and THERAPEUTIC INDICATION
women with hormone receptor positive early breast cancer greater than 50 mg/kg/day by the intraperitoneal route. In an oral Essential hypertension.
who had received surgery with or without radiotherapy and no acute toxicity study in the dog the median lethal dose was greater Treatment of patients with heart failure and impaired left ventricle
chemotherapy, switching to Arimidex after 2 years adjuvant than 45 mg/kg/day. systolic function (left ventricular ejection fraction 40%) as add-
treatment with tamoxifen was statistically superior in disease- Chronic toxicity on therapy to ACE inhibitors or when ACE inhibitors are not
free survival when compared to remaining on tamoxifen, after a tolerated (see Pharmacodynamic properties).
Multiple dose toxicity studies utilised rats and dogs. No no-effect
median follow-up of 24 months.
levels were established for anastrozole in the toxicity studies, but POSOLOGY AND METHOD OF ADMINISTRATION
Time to any recurrence, time to local or distant recurrence and those effects that were observed at the low doses (1 mg/kg/day) Dosage in Hypertension
time to distant recurrence conrmed a statistical advantage for and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related
ARIMIDEX, consistent with the results of disease-free survival. The recommended initial dose and usual maintenance dose is 8 mg
to either the pharmacological or enzyme inducing properties of once daily. The dose may be increased to 16 mg once daily. If blood
The incidence of contralateral breast cancer was very low in the
anastrozole and were unaccompanied by signicant toxic or pressure is not sufciently controlled after 4 weeks of treatment
two treatment arms with a numerical advantage for ARIMIDEX.
degenerative changes. with 16 mg once daily, the dose may be further increased to a
Overall survival was similar for the two treatment groups.
Mutagenicity maximum of 32 mg once daily (see Pharmacodynamic properties).
ABCSG 8 trial endpoint and results summary If blood pressure control is not achieved with this dose, alternative
Genetic toxicology studies with anastrozole show that it is not a
Efcacy endpoints Number of events (frequency) strategies should be considered.
mutagen or a clastogen.
Arimidex Tamoxifen Therapy should be adjusted according to blood pressure response.
Reproductive toxicology Most of the antihypertensive effect is attained within 4 weeks of
(N=1297) (N=1282)
Oral administration of anastrozole to pregnant rats and rabbits initiation of treatment.
Disease-free 65(5.0) 93(7.3) caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day
survival Use in the elderly
respectively. Those effects that were seen (placental enlargement No initial dosage adjustment is necessary in elderly patients.
Hazard ratio 0.67 in rats and pregnancy failure in rabbits) were related to the
2-sided 95% CI 0.49 to 0.92 Use in impaired renal function
pharmacology of the compound.
p-value 0.014 No initial dosage adjustment is necessary in patients with mild
The survival of litters born to rats given anastrozole at 0.02 mg/ to moderate renal impairment (i.e. creatinine clearance >30
Time to any 36(2.8) 66(5.1) kg/day and above (from day 17 of pregnancy to day 22 post- ml/min/1.73 m2 BSA). In patients with severe renal impairment
recurrence partum) was compromised. These effects were related to the (i.e. creatinine clearance <30 ml/ min/1.73 m2 BSA), the clinical
Hazard ratio 0.53 pharmacological effects of the compound on parturition. There experience is limited and a lower initial dose of 4 mg should be
were no adverse effects on behaviour or reproductive performance considered.
2-sided 95% CI 0.35 to 0.79
of the rst generation offspring attributable to maternal treatment Use in impaired hepatic function
p-value 0.002
with anastrozole.
Time to local or 29(2.2) 51(4.0) No initial dosage adjustment is necessary in patients with mild to
Carcinogenicity moderate chronic liver disease. There is only limited experience
distant recurrence available in patients with severe hepatic impairment and/or
A two year rat oncogenicity study resulted in an increase in
Hazard ratio 0.55 incidence of hepatic neoplasms and uterine stromal polyps in cholestasis. A lower initial dose of 4 mg should therefore be
2-sided 95% CI 0.35 to 0.87 females and thyroid adenomas in males at the high dose (25 mg/ considered in these patients.
p-value 0.011 kg/day) only. These changes occurred at a dose which represents Concomitant therapy
Time to distant recurrence 22 (1.7) 41(3.2) 100-fold greater exposure than occurs at human therapeutic doses, Addition of a thiazide-type diuretic such as hydrochlorothiazide
Hazard ratio 0.52 and are considered not to be clinically relevant to the treatment of has been shown to have an additive antihypertensive effect with
patients with anastrazole. ATACAND.
2-sided 95% CI 0.31 to 0.88
A two year mouse oncogenicity study resulted in the induction Use in black patients
p-value 0.015
of benign ovarian tumours and a disturbance in the incidence of The antihypertensive effect of candesartan is less in black than
New contralateral 7(0.5) 15(1.2)
lymphoreticular neoplasms (fewer histiocytic sarcomas in females non-black patients. Consequently, uptitration of ATACAND
breast cancer and more deaths as a result of lymphomas). These changes are and concomitant therapy may be more frequently needed for
Odds ratio 0.46 considered to be mouse-specic effects of aromatase inhibition blood pressure control in black than non-black patients (see
2-sided 95% CI 0.19 to 1.13 and not clinically relevant to the treatment of patients with Pharmacodynamic properties).
p-value 0.090 anastrozole. Dosage in Heart Failure
Overall survival 43(3.3) 45(3.5) The usual recommended initial dose of ATACAND is 4 mg once
LIST OF EXCIPIENTS daily. Up-titration to the target dose of 32 mg once daily or the
Hazard ratio 0.96 Lactose Monohydrate highest tolerated dose is done by doubling the dose at intervals of
2-sided 95% CI 0.63 1.46 Povidone at least 2 weeks (see Special warnings and precautions for use).
p-value 0.840 Sodium Starch Glycolate Special patient populations
Magnesium Stearate No initial dose adjustment is necessary for elderly patients or in
Two further similar trials (GABG/ARNO 95 and ITA), in one of
patients with renal or hepatic impairment.
which patients had received surgery and chemotherapy, as well Hypromellose
Concomitant therapy
as a combined analysis of ABCSG 8 and GABG/ARNO 95, Macrogol 300
supported these results. ATACAND can be administered with other heart failure treatment,
Titanium Dioxide including ACE inhibitors, beta-blockers, diuretics and digitalis or
The ARIMIDEX safety prole in these 3 studies was consistent a combination of these medicinal products (see Special warnings
with the known safety prole established in post-menopausal SHELF-LIFE
and precautions for use and Pharmacodynamic properties).
women with hormone receptor positive early breast cancer. Please refer to expiry date on the blister strip or outer carton.
ADMINISTRATION
PHARMACOKINETIC PROPERTIES SPECIAL PRECAUTIONS FOR STORAGE
ATACAND should be taken once daily with or without food.
Absorption of anastrozole is rapid and maximum plasma Do not store above 30C. Use in children and adolescents
concentrations typically occur within two hours of dosing (under The safety and efcacy of Atacand have not been established in
PACK SIZE
fasted conditions). Anastrozole is eliminated slowly with a plasma children and adolescents (under 18 years).
Please refer to the outer carton for pack size.
elimination half-life of 40 to 50 hours. Food slightly decreases the
rate but not the extent of absorption. The small change in the rate ARIMIDEX is a trade mark of the AstraZeneca group of CONTRAINDICATIONS
of absorption is not expected to result in a clinically signicant companies. Hypersensitivity to any component of ATACAND.
effect on steady-state plasma concentrations during once daily AstraZeneca 2006 Pregnancy and lactation (see Pregnancy and lactation).
45
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SPDI
SPECIAL WARNINGS AND PRECAUTIONS FOR USE pharmacokinetic studies include hydrochlorothiazide, warfarin, Renal and urinary disorders:
Renal impairment digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), Renal impairment
glibenclamide,nifedipine and enalapril.
As with other agents inhibiting the renin-angiotensin-aldosterone Laboratory ndings:
system, changes in renal function may be anticipated in susceptible Candesartan is eliminated only to a minor extent by hepatic
Increases in creatinine, urea and potassium. Periodic monitoring
patients treated with ATACAND. metabolism (CYP2C9). Available interaction studies indicate no
of serum creatinine and potassium is recommended (see Special
effect on CYP2C9 and CYP3A4 but the effect on other cytochrome
When ATACAND is used in hypertensive patients with severe warnings and precautions for use).
P450 isoenzymes is presently unknown.
renal impairment, periodic monitoring of serum potassium and Post Marketing
creatinine levels is recommended. There is limited experience The antihypertensive effect of candesartan may be enhanced by
other antihypertensives. The following adverse reactions have been reported very rarely
in patients with very severe or end-stage renal impairment (i.e.
(<1/10.000) in post marketing experience:
creatinine clearance <15 ml/min). In these patients Atacand should Based on experience with the use of other drugs that affect
be carefully titrated with thorough monitoring of blood pressure. the renin-angiotensin-aldosterone system, concomitant use Blood and lymphatic system disorders:
Evaluation of patients with heart failure should include periodic of potassium-sparing diuretics, potassium supplements, salt Leukopenia, neutropenia and agranulocytosis.
assessments of renal function, especially in elderly patients 75 substitutes containing potassium, or other drugs that may increase Metabolism and nutrition disorders:
years or older, and patients with impaired renal function. During potassium levels (e.g. heparin) may lead to increases in serum
Hyperkalaemia, hyponatraemia.
dose titration of ATACAND, monitoring of serum creatinine and potassium.
Nervous system disorders:
potassium is recommended. Clinical trials in heart failure did not Reversible increases in serum lithium concentrations and toxicity
have been reported during concomitant administration of lithium Dizziness, headache.
include patients with serum creatinine >265 mol/L (>3 mg/dL).
with ACE inhibitors. A similar effect may occur with angiotensin Gastrointestinal disorders:
Concomitant therapy with an ACE inhibitor in heart failure
II receptor antagonists and careful monitoring of serum lithium Nausea.
The risk of adverse events, especially renal function impairment levels is recommended during concomitant use.
and hyperkalaemia, may increase when candesartan is used in Hepato-biliary disorders:
The bioavailability of candesartan is not affected by food.
combination with an ACE inhibitor (see Undesirable effects). Increased liver enzymes, abnormal hepatic function or hepatitis.
Patients with such treatment should be monitored regularly and PREGNANCY AND LACTATION Skin and subcutaneous tissue disorders:
carefully. Pregnancy Angioedema, rash, urticaria, pruritus.
Renal artery stenosis In humans, foetal renal perfusion, which is dependent on the Musculoskeletal, connective tissue and bone disorders:
Other drugs that affect the renin-angiotensin-aldosterone system, development of the renin-angiotensin-aldosterone system, begins Back pain, arthralgia, myalgia.
i.e. angiotensin converting enzyme (ACE) inhibitors, may increase to develop in the second trimester of pregnancy. Thus, the risk to
blood urea and serum creatinine in patients with bilateral renal the foetus increases if ATACAND is used during the second or Renal and urinary disorders:
artery stenosis or stenosis of the artery to a solitary kidney. A third trimesters of pregnancy. Drugs that act directly on the renin- Renal impairment, including renal failure in susceptible patients
similar effect may be anticipated with angiotensin II receptor angiotensin system can cause foetal and neonatal injury and death (see Special warnings and precautions for use).
antagonists. when used in pregnancy during the second and third trimesters. OVERDOSE
Kidney transplantation Animal studies with candesartan cilexetil have shown foetal
and neonatal injuries in the kidney. The mechanism is believed Symptoms
There is no experience regarding the administration of Atacand in Based on pharmacological considerations, the main manifestation
to be pharmacologically mediated through effects on the renin-
patients with a recent kidney transplantation. of an overdose is likely to be symptomatic hypotension and
angiotensin-aldosterone system.
Hypotension dizziness. In individual case reports of overdose (of up to 672 mg
Based on the above information, Atacand should not be used in
Hypotension may occur during treatment with ATACAND in pregnancy. If pregnancy is detected during treatment, ATACAND candesartan cilexetil) patient recovery was uneventful.
heart failure patients. As described for other agents acting on should be discontinued (see Contraindications). Management
the renin-angiotensin-aldosterone system, it may also occur in If symptomatic hypotension should occur, symptomatic treatment
Lactation
hypertensive patients with intravascular volume depletion such as should be instituted and vital signs monitored. The patient should
those receiving high dose diuretics. Caution should be observed It is not known whether candesartan is excreted in human milk.
However, candesartan is excreted in the milk of lactating rats. be placed supine with the legs elevated. If this is not sufcient,
when initiating therapy and correction of hypovolemia should be plasma volume should be increased by infusion of, for example,
attempted. Because of the potential for adverse effects on the nursing infant,
ATACAND should not be given during breast-feeding (see isotonic saline solution. Sympathomimetic drugs may be
Anaesthesia and surgery Contraindications). administered if the above-mentioned measures are not sufcient.
Hypotension may occur during anaesthesia and surgery in patients Candesartan is not removed by haemodialysis.
treated with angiotensin II antagonists due to blockade of the EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
renin-angiotensin system. Very rarely, hypotension may be severe The effect of ATACAND on the ability to drive and use machines PHARMACODYNAMIC PROPERTIES
such that it may warrant the use of intravenous uids and/or has not been studied, but based on its pharmacodynamic properties Pharmacotherapeutic group:
vasopressors. candesartan is unlikely to affect this ability. When driving vehicles Angiotensin II antagonists (candesartan),
Aortic and mitral valve stenosis (obstructive hypertrophic or operating machines, it should be taken into account that
ATC code C09C A06.
cardiomyopathy) dizziness or weariness may occur during treatment.
Angiotensin II is the primary vasoactive hormone of the
As with other vasodilators, special caution is indicated in patients UNDESIRABLE EFFECTS renin-angiotensin-aldosterone system and plays a role in
suffering from haemodynamically relevant aortic or mitral valve Treatment of Hypertension the pathophysiology of hypertension, heart failure and other
stenosis, or obstructive hypertrophic cardiomyopathy. In controlled clinical studies adverse events were mild and transient cardiovascular disorders. It also has a role in the pathogenesis of end
Primary hyperaldosteronism and comparable to placebo. The overall incidence of adverse organ hypertrophy and damage. The major physiological effects of
Patients with primary hyperaldosteronism will not generally events showed no association with dose or age. Withdrawals from angiotensin II, such as vasoconstriction, aldosterone stimulation,
respond to antihypertensive drugs acting through inhibition of the treatment due to adverse events were similar with candesartan regulation of salt and water homeostasis and stimulation of cell
renin-angitensin-aldosterone system. ATACAND is therefore not cilexetil (3.1%) and placebo (3.2%). growth, are mediated via the type 1 (AT1) receptor.
recommended in those patients. In a pooled analysis of clinical trial data, the following common Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly
Hyperkalaemia (>1/100) adverse reactions with candesartan cilexetil were reported converted to the active drug, candesartan, by ester hydrolysis
based on an incidence of adverse events with candesartan cilexetil during absorption from the gastrointestinal tract. Candesartan is
Based on experience with the use of other drugs that affect the
at least 1% higher than the incidence seen with placebo: an angiotensin II receptor antagonist, selective for AT1 receptors,
renin-angiotensin-aldosterone system, concomitant use of Atacand
Nervous system disorders: with tight binding to and slow dissociation from the receptor.
with potassium-sparing diuretics, potassium supplements, salt
Candesartan has no agonist activity.
substitutes containing potassium, or other drugs that may increase Dizziness/vertigo, headache.
potassium levels (e.g. heparin) may lead to increases in serum Candesartan does not inhibit ACE, which converts angiotensin I
Infections and infestations:
potassium in hypertensive patients. to angiotensin II and degrades bradykinin. Candesartan does not
Respiratory infection. affect ACE and gives no potentiation of bradykinin or substance
In heart failure patients treated with ATACAND, hyperkalaemia Laboratory ndings P. In controlled clinical trials comparing candesartan with ACE
may occur. During treatment with ATACAND in patients
In general, there were no clinically important inuences of inhibitors, the incidence of cough was lower in patients receiving
with heart failure, periodic monitoring of serum potassium is
ATACAND on routine laboratory variables. As for other inhibitors candesartan cilexetil. Candesartan does not bind to or block other
recommended, especially when taken concomitantly with ACE
of the renin-angiotensin-aldosterone system, small decreases hormone receptors or ion channels known to be important in
inhibitors and potassium-sparing diuretics such as spironolactone.
in haemoglobin have been seen. Increases in creatinine, urea or cardiovascular regulation. The antagonism of the angiotensin II
General potassium and decrease in sodium have been observed. Increases (AT1) receptors results in dose related increases in plasma renin
In patients whose vascular tone and renal function depend in S-ALAT (S-GPT) were reported as adverse events slightly levels, angiotensin I and angiotensin II levels, and a decrease in
predominantly on the activity of the renin-angiotensin-aldosterone more often with Atacand than with placebo (1.3% vs 0.5%). No plasma aldosterone concentration.
system (e.g. patients with severe congestive heart failure or routine monitoring of laboratory variables is usually necessary Hypertension
underlying renal disease, including renal artery stenosis), treatment for patients receiving ATACAND. However, in patients with
In hypertension, candesartan causes a dose-dependent, long-
with other drugs that affect this system has been associated with renal impairment, periodic monitoring of serum potassium and
lasting reduction in arterial blood pressure. The antihypertensive
acute hypotension, azotaemia, oliguria or, rarely, acute renal creatinine levels is recommended.
action is due to decreased systemic peripheral resistance, without
failure. The possibility of similar effects cannot be excluded with Treatment of Heart Failure reex increase in heart rate. There is no indication of serious
angiotensin II receptor antagonists.
The adverse experience prole of ATACAND in heart failure or exaggerated rst dose hypotension or rebound effect after
As with any antihypertensive agent, excessive blood pressure patients was consistent with the pharmacology of the drug and the cessation of treatment.
decrease in patients with ischaemic cardiopathy or ischaemic health status of the patients. In the CHARM clinical programme, After administration of a single dose of candesartan cilexetil, onset
cerebrovascular disease could result in a myocardial infarction or comparing ATACAND in doses up to 32 mg (n=3,803) to placebo of antihypertensive effect generally occurs within 2 hours. With
stroke. (n=3,796), 21.0% of the candesartan cilexetil group and 16.1% continuous treatment, most of the reduction in blood pressure with
Patients with rare hereditary problems of galactose intolerance, of the placebo group discontinued treatment because of adverse any dose is generally attained within four weeks and is sustained
the Lapp lactase deciency or glucose-galactose malabsorption events. Adverse reactions commonly ( 1/100, <1/10) seen were: during long-term treatment.
should not take this medicinal product. Vascular disorders: Candesartan cilexetil once daily provides effective and smooth
INTERACTIONS Hypotension blood pressure reduction over 24 hours, with little difference
No drug interactions of clinical signicance have been Metabolism and nutrition disorders: between maximum and trough effects during the dosing interval.
identied. Compounds which have been investigated in clinical Hyperkalaemia The antihypertensive effect and tolerability of candesartan and
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losartan were compared in two randomised, double-blind studies morbidity components of these composite endpoints contributed to
in a total of 1,268 patients with mild to moderate hypertension. the favourable effects of candesartan. Treatment with candesartan ATACAND PLUS 16/12.5 mg tablets
The trough blood pressure reduction (systolic/diastolic) was 13.1 cilexetil resulted in improved NYHA functional class (p=0.020).
/10.5 mmHg with candesartan cilexetil 32 mg once daily and 10.0 In CHARM-Preserved, no statistically signicant reduction was
/8.7 mmHg with losartan potassium 100 mg once daily (difference achieved in the composite endpoint of cardiovascular mortality or
(Candesartan cilexetil/Hydrochlorothiazide)
in blood pressure reduction 3.1/1.8 mmHg, p<0.0001/p<0.0001). rst CHF hospitalisation (HR 0.89, 95% CI 0.77-1.03, p=0.118).
COMPOSITION
The most common adverse events were respiratory infection The numerical reduction was attributable to reduced CHF
hospitalisation. There was no evidence of effect on mortality in One ATACAND PLUS tablet contains 16 mg candesartan cilexetil
(candesartan 6.6%, losartan 8.9%), headache (candesartan 5.8%,
this study. and 12.5 mg hydrochlorothiazide.
losartan 5.6%) and dizziness (candesartan 4.4%, losartan 1.9%).
When candesartan cilexetil is used together with All-cause mortality was not statistically signicant when examined PHARMACEUTICAL FORM
hydrochlorothiazide, the reduction in blood pressure is additive. separately in each of the three CHARM studies. However, Tablets.
Concomitant administration of candesartan cilexetil with all-cause mortality was also assessed in pooled populations,
ATACAND PLUS are peach, oval, biconvex tablets with a score
hydrochlorothiazide or amlodipine is well tolerated. CHARM-Alternative and CHARM-Added (HR 0.88, 95% CI
on both sides and engraved A/CS on one side.
0.79-0.98, p=0.018) and all three studies (HR 0.91, 95% CI 0.83-
Candesartan is similarly effective in patients irrespective of age 1.00, p=0.055). THERAPEUTIC INDICATIONS
and gender.
The benecial effects of candesartan on cardiovascular mortality Essential hypertension, where monotherapy with candesartan
Medicinal products that block the renin-angiotensin-aldosterone and CHF hospitalisation were consistent irrespective of age, cilexetil or hydrochlorothiazide is not sufcient.
system have less pronounced antihypertensive effect in black gender and concomitant medication. Candesartan was effective
patients (usually a low-renin population) than in non-black POSOLOGY AND METHOD OF ADMINISTRATION
also in patients taking both beta-blockers and ACE inhibitors at
patients. This is also the case for candesartan. In an open the same time, and the benet was obtained whether or not patients Dosage
label clinical experience trial in 5,156 patients with diastolic were taking ACE inhibitors at the target dose recommended by The recommended dose of ATACAND PLUS is 1 tablet once
hypertension, the blood pressure reduction during candesartan treatment guidelines. daily.
treatment was signicantly less in black than non-black patients In patients with CHF and depressed left ventricular systolic The dose of candesartan cilexetil should be titrated before
(14.4/10.3 mmHg vs 19.0/12.7 mmHg, p<0.0001/p<0.0001). function (left ventricular ejection fraction, LVEF 40%), switching to ATACAND PLUS.
Candesartan increases renal blood ow, and does not inuence candesartan decreases systemic vascular resistance and pulmonary When clinically appropriate a direct change from monotherapy
or increase glomerular ltration rate whereas the renal vascular capillary wedge pressure, increases plasma renin activity and
to ATACAND PLUS may be considered.
resistance and ltration fraction are reduced. In hypertensive angiotensin II concentration, and decreases aldosterone levels.
Most of the antihypertensive effect is usually attained within 4
patients with type II diabetes mellitus, 12 weeks treatment with PHARMACOKINETIC PROPERTIES weeks of initiation of treatment.
candesartan cilexetil 8 -16 mg had no negative effects on blood Absorption and distribution
glucose or lipid prole. ADMINISTRATION
Following oral administration, candesartan cilexetil is converted
The effects of candesartan cilexetil 8-16 mg (mean dose 12 ATACAND PLUS should be taken once daily with or without
to the active drug candesartan. The absolute bioavailability
mg), once daily, on cardiovascular morbidity and mortality were food.
of candesartan is approximately 40% after an oral solution of
evaluated in a randomised clinical trial with 4,937 elderly patients candesartan cilexetil. The relative bioavailability of the tablet Use in the elderly
(aged 70-89 years; 21% aged 80 or above) with mild to moderate formulation compared with the same oral solution is approximately Dose titration of candesartan cilexetil is recommended in elderly
hypertension followed for a mean of 3.7 years (Study on Cognition 34% with very little variability. The absolute bioavailability of patients before treatment with Atacand Plus.
and Prognosis in the Elderly). Patients received candesartan or the tablet is therefore estimated at 14%. The mean peak serum Use in impaired renal function
placebo with other antihypertensive treatment added as needed. concentration (Cmax) is obtained 3-4 hours after the tablet intake. Loop diuretics are preferred to thiazides in this population. Dose
The blood pressure was reduced from 166/90 to 145/80 mmHg in The candesartan serum concentrations increase linearly with titration of candesartan cilexetil is recommended in patients with
the candesartan group, and from 167/90 to 149/82 mmHg in the increasing doses in the therapeutic dose range. No gender related renal impairment whose creatinine clearance is 30 ml/min/1.73
control group. There was no statistically signicant difference in differences in the pharmacokinetics of candesartan have been m2 BSA before treatment with ATACAND PLUS.
observed. The area under the serum concentration versus time
the primary endpoint, major cardiovascular events (cardiovascular ATACAND PLUS should not be used in patients with severe renal
curve (AUC) of candesartan is not signicantly affected by food.
mortality, non-fatal stroke and non-fatal myocardial infarction). impairment (creatinine clearance <30 ml/min/1.73 m2 BSA).
There were 26.7 events per 1000 patient-years in the candesartan Candesartan is highly bound to plasma protein (more than 99%).
The apparent volume of distribution of candesartan is 0.1 l/kg. Use in impaired hepatic function
group versus 30.0 events per 1000 patient-years in the control
Metabolism and elimination Dose titration of candesartan cilexetil is recommended in patients
group (relative risk 0.89, 95% CI 0.75 to 1.06, p=0.19). with mild to moderate hepatic impairment before treatment with
Heart Failure Candesartan is mainly eliminated unchanged via urine and bile ATACAND PLUS.
and only to a minor extent eliminated by hepatic metabolism. The
Treatment with candesartan cilexetil reduces mortality, reduces ATACAND PLUS should not be used in patients with severe
terminal half-life of candesartan is approximately 9 hours. There
hospitalisation due to heart failure, and improves symptoms in is no accumulation following multiple doses. hepatic impairment and/or cholestasis.
patients with left ventricular systolic dysfunction as shown in Use in children
Total plasma clearance of candesartan is about 0.37 ml/min/
the Candesartan in Heart failure Assessment of Reduction in The safety and efcacy of ATACAND PLUS have not been
kg, with a renal clearance of about 0.19 ml/min/kg. The renal
Mortality and morbidity (CHARM) programme. established in children.
elimination of candesartan is both by glomerular ltration and
This multinational, placebo controlled, double-blind study active tubular secretion. Following an oral dose of radioactively
CONTRA-INDICATIONS
programme in chronic heart failure (CHF) patients with NYHA labelled candesartan cilexetil, approximately 26% of the dose
functional class II to IV consisted of three separate studies: is excreted in the urine as candesartan and 7% as an inactive Hypersensitivity to the active substances or to any of the
CHARM-Alternative (n=2,028) in patients with LVEF 40% not metabolite while approximately 56% of the dose is recovered in excipients or to sulfonamide derived drugs (hydrochlorothiazide
treated with an ACE inhibitor because of intolerance (mainly due the faeces as candesartan and 10% as the inactive metabolite. is a sulfonamide derived drug).
to cough, 72%), CHARM-Added (n=2,548) in patients with LVEF Patient factors Pregnancy and lactation
>40% and treated with an ACE inhibitor, and CHARM-Preserved In the elderly (over 65 years) Cmax and AUC of candesartan Severe renal impairment (creatinine clearance <30 ml/min/1.73
(n=3,023) in patients with LVEF >40%. Patients on optimal CHF are increased by approximately 50% and 80%, respectively in m2 BSA).
therapy at baseline were randomised to placebo or candesartan comparison to younger subjects. However, the blood pressure Severe hepatic impairment and/or cholestasis.
cilexetil (titrated from 4 mg or 8 mg once daily to 32 mg once response and the incidence of adverse events are similar after a Refractory hypokalaemia and hypercalcaemia.
daily or the highest tolerated dose, mean dose 24 mg) and followed given dose of ATACAND in young and elderly patients. Gout.
for a median of 37.7 months. After 6 months of treatment 63% In patients with mild to moderate renal impairment Cmax
of the patients still taking candesartan cilexetil (89%) were at the SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
and AUC of candesartan increased during repeated dosing by
target dose of 32 mg. FOR USE
approximately 50% and 70%, respectively, but the half-life was
In CHARM-Alternative, the composite endpoint of cardiovascular not altered, compared to patients with normal renal function. The Renal impairment/Kidney transplantation
mortality or rst CHF hospitalisation was signicantly reduced corresponding changes in patients with severe renal impairment Loop diuretics are preferred to thiazides in this population. When
with candesartan in comparison with placebo (hazard ratio (HR) were approximately 50% and 110%, respectively. The terminal ATACAND PLUS is used in patients with impaired renal function,
0.77, 95% CI 0.67-0.89, p<0.001). This corresponds to a relative half-life of candesartan was approximately doubled in patients a periodic monitoring of potassium, creatinine and uric acid levels
risk reduction of 23%. Fourteen patients needed to be treated for with severe renal impairment. The pharmacokinetics in patients is recommended.
the duration of the study to prevent one patient from dying of a undergoing haemodialysis was similar to that in patients with There is no experience regarding the administration of ATACAND
cardiovascular event or being hospitalised for treatment of heart severe renal impairment. PLUS in patients with a recent kidney transplantation.
failure. The composite endpoint of all-cause mortality or rst CHF In patients with mild to moderate hepatic impairment, 23% Renal artery stenosis
hospitalisation was also signicantly reduced with candesartan increase in the AUC of candesartan was observed. Other drugs that affect the renin-angiotensin-aldosterone system,
(HR 0.80, 95% CI 0.70-0.92, p=0.001). Both the mortality and LIST OF EXCIPIENTS i.e. angiotensin converting enzyme (ACE) inhibitors, may increase
morbidity (CHF hospitalisation) components of these composite Carmellose calcium, hydroxypropyl cellulose, iron oxide E 172 blood urea and serum creatinine in patients with bilateral renal
endpoints contributed to the favourable effects of candesartan. (only 8 mg,16 mg and 32 mg tablets), lactose monohydrate, artery stenosis or stenosis of the artery to a solitary kidney. A
Treatment with candesartan cilexetil resulted in improved NYHA magnesium stearate, maize starch and macrogol. similar effect may be anticipated with angiotensin II receptor
functional class (p=0.008). antagonists.
SHELF LIFE Intravascular volume depletion
In CHARM-Added, the composite endpoint of cardiovascular
mortality or rst CHF hospitalisation was signicantly reduced Please refer to expiry date on the outer carton. In patients with intravascular volume and/or sodium depletion
with candesartan in comparison with placebo (HR 0.85, 95% SPECIAL PRECAUTIONS FOR STORAGE symptomatic hypotension may occur, as described for other agents
CI 0.75-0.96, p=0.011). This corresponds to a relative risk acting on the renin-angiotensin-aldosterone system. Therefore, the
Do not store above 30C.
reduction of 15%. Twenty-three patients needed to be treated for use of ATACAND PLUS is not recommended until this condition
the duration of the study to prevent one patient from dying of a PACK SIZE has been corrected.
cardiovascular event or being hospitalised for treatment of heart Please refer to outer carton for pack size. Anaesthesia and surgery
failure. The composite endpoint of all-cause mortality or rst CHF ATACAND is a trade mark of the AstraZeneca group of Hypotension may occur during anaesthesia and surgery in patients
hospitalisation was also signicantly reduced with candesartan companies treated with angiotensin II antagonists due to blockade of the
(HR 0.87, 95% CI 0.78-0.98, p=0.021). Both the mortality and AstraZeneca 2004-2007 renin-angiotensin system. Very rarely, hypotension may be severe
47
Book_01.indd 47 6/4/2008 2:19:18 PM

ASTRAZENECA
SPDI
such that it may warrant the use of intravenous uids and/or be expected to be potentiated by other drugs associated with properties ATACAND PLUS is unlikely to affect this ability.
vasopressors. potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, When driving vehicles or operating machines, it should be taken
Hepatic impairment laxatives, amphotericin, carbenoxolone, penicillin G sodium, into account that occasionally dizziness or weariness may occur
salicylic acid derivates). during treatment of hypertension.
Thiazides should be used with caution in patients with impaired
hepatic function or progressive liver disease, since minor Based on experience with the use of other drugs that affect UNDESIRABLE EFFECTS
alterations of uid and electrolyte balance may precipitate hepatic the renin-angiotensin-aldosterone system, concomitant use of
In controlled clinical studies adverse events were mild and transient
coma. There is no clinical experience with Atacand Plus in patients ATACAND PLUS and potassium-sparing diuretics, potassium
and comparable to placebo.The overall incidence of adverse events
with hepatic impairment. supplements or salt substitutes or other drugs that may increase
showed no association with age or gender. Withdrawals from
serum potassium levels (e.g. heparin sodium) may lead to increases
Aortic and mitral valve stenosis (obstructive hypertrophic treatment due to adverse events were similar with candesartan
in serum potassium.
cardiomyopathy) cilexetil/hydrochlorothiazide (3.3%) and placebo (2.7%).
Diuretic-induced hypokalaemia and hypomagnesaemia predisposes
As with other vasodilators, special caution is indicated in patients In a pooled analysis of clinical trial data, the following
to the potential cardiotoxic effects of digitalis glycosides and
suffering from haemodynamically relevant aortic or mitral valve common (>1/100) adverse reactions with candesartan cilexetil/
antiarrhythmics. Periodic monitoring of serum potassium is
stenosis, or obstructive hypertrophic cardiomyopathy. hydrochlorothiazide were reported based on an incidence of
recommended when ATACAND PLUS is administered with such
Primary hyperaldosteronism adverse events with candesartan cilexetil/hydrochlorothiazide at
drugs.
least 1% higher than the incidence seen with placebo:
Patients with primary hyperaldosteronism generally will not Reversible increases in serum lithium concentrations and toxicity
respond to antihypertensive drugs acting through inhibition of Nervous system disorders:
have been reported during concomitant administration of lithium
the renin-angiotensin-aldosterone system. Therefore the use of with ACE inhibitors or hydrochlorothiazide. A similar effect Dizziness/vertigo
ATACAND PLUS is not recommended. may occur with angiotensin II receptor antagonists and careful Candesartan cilexetil
Electrolyte imbalance monitoring of serum lithium levels is recommended during The following adverse reactions have been reported very
As for any patient receiving diuretic therapy, periodic concomitant use. rarely (<1/10000) with candesartan cilexetil in post marketing
determination of serum electrolytes should be performed at The diuretic, natriuretic and antihypertensive effect of experience:
appropriate intervals. hydrochlorothiazide is blunted by NSAIDs. Blood and lymphatic system disorders:
Thiazides, including hydrochlorothiazide, can cause uid The absorption of hydrochlorothiazide is reduced by colestipol or Leukopenia, neutropenia and agranulocytosis
or electrolyte imbalance (hypercalcaemia, hypokalaemia, cholestyramine.
Metabolism and nutrition disorders:
hyponatraemia, hypomagnesaemia and hypochloraemic The effect on nondepolarizing skeletal muscle relaxants (e.g.
Hyperkalaemia, hyponatraemia
alkalosis). tubocurarine) may be potentiated by hydrochlorothiazide.
Nervous system disorders:
Thiazide diuretics may decrease the urinary calcium excretion Thiazide diuretics may increase serum calcium levels due to
and may cause intermittent and slightly increased serum calcium decreased excretion. If calcium supplements or Vitamin D must Dizziness, headache
concentrations. beprescribed, serum calcium levels should be monitored and Gastrointestinal disorders:
Marked hypercalcaemia may be a sign of hidden hyperparathy- dosage adjusted accordingly. Nausea
roidism. Thiazides should be discontinued before carrying out The hyperglycaemic effect of beta-blockers and diazoxide may be Hepato-biliary disorders:
tests for parathyroid function. enhanced by thiazides. Increased liver enzymes, abnormal hepatic function or hepatitis
Hydrochlorothiazide dose-dependently increases urinary potassium Anticholinergic agents (e.g. atropine, biperiden) may increase Skin and subcutaneous tissue disorders:
excretion which may result in hypokalaemia. This effect of the bioavailability of thiazide-type diuretics by decreasing
hydrochlorothiazide seems to be less evident when combined with Angioedema, rash, urticaria, pruritus
gastrointestinal motility and stomach emptying rate.
candesartan cilexetil. The risk for hypokalaemia may be increased Musculoskeletal, connective tissue and bone disorders:
Thiazide may increase the risk of adverse effects caused by
in patients with cirrhosis of the liver, in patients experiencing brisk amantadine. Back pain, arthralgia, myalgia
diuresis, in patients with an inadequate oral intake of electrolytes Renal and urinary disorders:
Thiazides may reduce the renal excretion of cytotoxic drugs
and in patients receiving concomitant therapy with corticosteroids
(e.g. cyclophosphamide, methotrexate) and potentiate their Renal impairment, including renal failure in susceptible patients
or adrenocorticotropic hormone (ACTH).
myelosuppressive effects.
Based on experience with the use of other drugs that affect HYDROCHLOROTHIAZIDE
The risk for hypokalaemia may be increased during concomitant
the renin-angiotensin-aldosterone system, concomitant use of The following adverse reactions have been reported with
use of steroids or adrenocorticotropic hormone (ACTH).
ATACAND PLUS and potassium-sparing diuretics, potassium hydrochlorothiazide monotherapy, usually with doses of 25 mg or
supplements or salt substitutes or other drugs that may increase Postural hypotension may become aggravated by simultaneous
intake of alcohol, barbiturates or anaesthetics. greater. The frequencies used are: Common (>1/100), uncommon
serum potassium levels (e.g. heparin sodium) may lead to increases (>1/1000 and <1/100 ) and rare (<1/1000).
in serum potassium. Treatment with a thiazide diuretic may impair glucose tolerance.
Dosage adjustment of antidiabetic drugs, including insulin, may Blood and lymphatic system disorders:
Although not documented with ATACAND PLUS treatment
be required. Rare: Leucopenia, neutropenia/agranulocytosis, thrombocyto-
with angiotensin converting enzyme inhibitors or angiotensin II
Hydrochlorothiazide may cause the arterial response to pressor penia, aplastic anaemia, bone marrow depression, haemolytic
receptor antagonists may cause hyperkalaemia, especially in the
amines (e.g. adrenaline) to decrease but not enough to exclude a anaemia
presence of heart failure and/or renal impairment.
pressor effect. Immune system disorders:
Thiazides have been shown to increase the urinary excretion of
magnesium, which may result in hypomagnesaemia. Hydrochlorothiazide may increase the risk of acute renal Rare: Anaphylactic reactions
Metabolic and endocrine effects insufciency especially with high doses of iodinated contrast Metabolism and nutrition disorders:
media. Common: Hyperglycaemia, hyperuricaemia, electrolyte imbalance
Treatment with a thiazide diuretic may impair glucose tolerance.
Dosage adjustment of antidiabetic drugs, including insulin, may There is no clinically signicant interaction between (including hyponatraemia and hypokalaemia)
hydrochlorothiazide and food. Psychiatric disorders:
be required. Latent diabetes mellitus may become manifest during
thiazide therapy. Increases in cholesterol and triglyceride levels PREGNANCY AND LACTATION Rare: Sleep disturbances, depression, restlessness
have been associated with thiazide diuretic therapy. However, at Nervous system disorders:
the 12.5 mg dose contained in ATACAND PLUS minimal or no USE IN PREGNANCY
In humans, foetal renal perfusion, which is dependent upon the Common: Light-headedness, vertigo
effects were reported. Thiazide diuretics increase serum uric acid
concentration and may precipitate gout in susceptible patients. development of the renin-angiotensin-aldosterone system, begins Rare: Paraesthesia
General in the second trimester. Thus risk to the foetus increases if Atacand Eye disorders:
Plus is administered during the second or third trimesters of Rare: Transient blurred vision
In patients whose vascular tone and renal function depend pregnancy.
predominantly on the activity of the renin-angiotensin-aldosterone Cardiac disorders:
system (e.g. patients with severe congestive heart failure or When used in pregnancy during the second and third trimesters,
Rare: Cardiac arrhythmias
underlying renal disease, including renal artery stenosis), treatment drugs that act directly on the renin-angiotensin system can cause
foetal and neonatal injury and death. Vascular disorders:
with other drugs that affect this system has been associated with
Animal studies with candesartan cilexetil have demonstrated Uncommon: Postural hypotension
acute hypotension, azotaemia, oliguria or, rarely, acute renal
failure. The possibility of similar effects cannot be excluded with late foetal and neonatal injury in the kidney. The mechanism is Rare: Necrotising angitis (vasculitis, cutaneous vasculitis)
angiotensin II receptor antagonists. As with any antihypertensive believed to be pharmacologically mediated through effects on the Respiratory, thoracic and mediastinal disorders:
agent, excessive blood pressure decrease in patients with ischaemic renin-angiotensin-aldosterone system. Rare: Respiratory distress (including pneumonitis and pulmonary
heart disease or atherosclerotic cerebrovascular disease could Hydrochlorothiazide can reduce the plasma volume as well oedema)
result in a myocardial infarction or stroke. as the uteroplacental blood ow. It may also cause neonatal Gastrointestinal disorders:
Hypersensitivity reactions to hydrochlorothiazide may occur in thrombocytopenia.
Uncommon: Anorexia, loss of appetite, gastric irritation, diarrhoea,
patients with or without a history of allergy or bronchial asthma, Based on the above information, ATACAND PLUSshould not be constipation
but are more likely in patients with such a history. used in pregnancy.
Rare: Pancreatitis
Exacerbation or activation of systemic lupus erythematosus has If pregnancy is detected during treatment, ATACAND PLUS
Hepatobiliary disorders:
been reported with the use of thiazide diuretics. should be discontinued (see Contraindications).
Rare: Jaundice (intrahepatic cholestatic jaundice)
INTERACTIONS USE IN LACTATION
Skin and subcutaneous tissue disorders:
No drug interactions of clinical signicance have been identied It is not known whether candesartan is excreted in human milk.
Uncommon: Rash, urticaria, photosensitivity reactions
for candesartan cilexetil. Compounds which have been investigated However, candesartan is excreted in the milk of lactating rats.
in clinical pharmacokinetic studies include hydrochlorothiazide, Hydrochlorothiazide passes into mothers milk. Because of Rare: Toxic epidermal necrolysis, cutaneous lupus erythematosus-
the potential for adverse effects on the nursing infant, Atacand like reactions, reactivation of cutaneous lupus erythematosus
warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/
levonorgestrel), glibenclamide and nifedipine. Plus should not be given during breast-feeding (see Contra- Musculoskeletal and connective tissue disorders:
The bioavailability of candesartan is not affected by food. indications). Rare: Muscle spasm
The antihypertensive effect of ATACAND PLUS may be EFFECTS ON ABILITY TO DRIVE AND USE MACHINES Renal and urinary disorders:
enhanced by other antihypertensives. The effect of ATACAND PLUS on the ability to drive and use Common: Glycosuria
The potassium depleting effect of hydrochlorothiazide could machines has not been studied, but based on its pharmacodynamic Rare: Renal dysfunction and interstitial nephritis
48
Book_01.indd 48 6/4/2008 2:19:19 PM

ASTRAZENECA
SPDI
General disorders and administration site conditions: and magnesium increases dose-dependently, while calcium is while approximately 56% of the dose is recovered in the faeces as
Common: Weakness reabsorbed to a greater extent. Hydrochlorothiazide decreases candesartan and 10% as the inactive metabolite.
Rare: Fever plasma volume and extracellular uid and reduces cardiac output Hydrochlorothiazide
and blood pressure. During long-term therapy, reduced peripheral
Investigations: Hydrochlorothiazide is not metabolized and is excreted almost
resistance contributes to the blood pressure reduction.
Common: Increases in cholesterol and triglycerides entirely as unchanged drug by glomerular ltration and active
Large clinical studies have shown that long-term treatment with tubular secretion. The terminal t of hydrochlorothiazide is
Rare: Increases in BUN and serum creatinine hydrochloro-thiazide reduces the risk for cardiovascular morbidity approximately 8 hours. Approximately 70% of an oral dose
Laboratory ndings and mortality. is eliminated in the urine within 48 hours. The half-life of
Increases in serum uric acid, blood glucose and serum ALAT Candesartan and hydrochlorothiazide have additive antihyperten- hydrochlorothiazide remains unchanged (approximately 8 h)
(SGPT) were reported as adverse events slightly more often with sive effects. after administration of hydrochlorothiazide in combination
candesartan cilexetil/hydrochlorothiazide (crude rates 1.1%, 1.0% In hypertensive patients, ATACAND PLUS causes an effective with candesartan cilexetil. No additional accumulation of
and 0.9%, respectively) than with placebo (0.4%, 0.2% and 0%, and long-lasting reduction in arterial blood pressure without reex hydrochlorothiazide occurs after repeated doses of the combination
respectively). Minor decreases in haemoglobin and increases increase in heart rate. compared to monotherapy.
in serum ASAT (SGOT) have been observed in single patients There is no indication of serious or exaggerated rst dose PHARMACOKINETICS IN SPECIAL POPULATIONS
receiving candesartan cilexetil/hydrochlorothiazide. Increases in hypotension or rebound effect after cessation of treatment. After
creatinine, urea or potassium and decrease in sodium have been Candesartan cilexetil
administration of a single dose of ATACAND PLUS, onset of
observed. the antihypertensive effect generally occurs within 2 hours. With In elderly subjects (over 65 years), Cmax and AUC of candesartan
continuous treatment, most of the reduction in blood pressure are increased by approximately 50% and 80%, respectively in
OVERDOSE
is attained within four weeks and is sustained during long-term comparison to young subjects. However, the blood pressure
Symptoms response and the incidence of adverse events are similar after a
treatment. ATACAND PLUS once daily provides effective
Based on pharmacological considerations, the main manifestation given dose of ATACAND PLUS in young and elderly patients
and smooth blood pressure reduction over 24 hours, with little
of an overdose of candesartan cilexetil is likely to be symptomatic (see Posology and method of administration).
difference between maximum and trough effects during the
hypotension and dizziness. In individual case reports of overdose In patients with mild to moderate renal impairment, Cmax
dosing interval. In a double-blind randomised study, ATACAND
(of up to 672 mg candesartan cilexetil) patient recovery was and AUC of candesartan increased during repeated dosing by
PLUS once daily reduced blood pressure signicantly more,
uneventful. approximately 50% and 70%, respectively, but the terminal t was
and controlled signicantly more patients, than an approved
The main manifestation of an overdose of hydrochlorothiazide is similar xed combination product containing an angiotensin II not altered, compared to patients with normal renal function. The
acute loss of uid and electrolytes. Symptoms such as dizziness, receptor antagonist and hydrochlorothiazide. In double-blind, corresponding changes in patients with severe renal impairment
hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/ randomised studies, the incidence of adverse events, especially were approximately 50% and 110%, respectively. The terminal t
impairment of consciousness and muscle cramps can also be cough, was lower during treatment with candesartan cilexetil/ of candesartan was approximately doubled in patients with severe
observed. hydrochlorothiazide than during treatment with combinations of renal impairment. The pharmacokinetics in patients undergoing
Management ACE inhibitors and hydrochlorothiazide. haemodialysis were similar to those in patients with severe renal
No specic information is available on the treatment of overdosage Candesartan cilexetil/hydrochlorothiazide is similarly effective in impairment.
with ATACAND PLUS. The following measures are, however, patients irrespective of age and gender. In patients with mild to moderate hepatic impairment, there was a
suggested in case of overdosage. Currently there are no data on the use of candesartan cilexetil/ 23% increase in the AUC of candesartan.
When indicated, induction of vomiting or gastric lavage should be hydrochloro-thiazide in patients with renal disease/nephropathy, Hydrochlorothiazide
considered. If symptomatic hypotension should occur, symptomatic reduced left ventricular function/congestive heart failure and post The terminal t of hydrochlorothiazide is prolonged in patients
treatment should be instituted and vital signs monitored. The myocardial infarction. with renal impairment.
patient should be placed supine with the legs elevated. If this is
PHARMACOKINETIC PROPERTIES LIST OF EXCIPIENTS
not sufcient, plasma volume should be increased by infusion of
isotonic saline solution. Serum electrolyte and acid balance should Absorption and distribution Carmellose calcium, hydroxypropyl cellulose, iron oxide reddish-
be checked and corrected, if needed. Sympathomimetic drugs Candesartan cilexetil brown E 172, iron oxide yellow E 172, lactose monohydrate,
may be administered if the above-mentioned measures are not Following oral administration, candesartan cilexetil is converted magnesium stearate, maize starch and macrogol.
sufcient. to the active drug candesartan. The absolute bioavailability SHELF LIFE
Candesartan can not be removed by haemodialysis. It is not known of candesartan is approximately 40% after an oral solution of
Please refer to expiry date on the outer carton.
to what extent hydrochlorothiazide is removed by haemodialysis. candesartan cilexetil. The relative bioavailability of a tablet
formulation of candesartan cilexetil compared with the same Special precautions for storage
PHARMACODYNAMIC PROPERTIES oral solution is approximately 34% with very little variability. Do not store above 30 C.
Angiotensin II is the primary vasoactive hormone of the The mean peak serum concentration (Cmax) is reached 3-4 hours
PACK SIZE
renin-angiotensin-aldosterone system and plays a role in the following tablet intake. The candesartan serum concentrations
pathophysiology of hypertension and other cardiovascular increase linearly with increasing doses in the therapeutic dose Please refer to outer carton for pack
disorders. It also has a role in the pathogenesis of organ hypertrophy range. No gender related differences in the pharmacokinetics ATACAND Plus is a trade mark of the of the AstraZeneca group
and end organ damage. The major physiological effects of of candesartan have been observed. The area under the serum of companies.
angiotensin II, such as vasoconstriction, aldosterone stimulation, concentration versus time curve (AUC) of candesartan is not AstraZeneca 2002- 2005
regulation of salt and water homeostasis and stimulation of cell signicantly affected by food.
growth, are mediated via the type 1 (AT1) receptor. Candesartan is highly bound to plasma protein (more than 99%).
Candesartan cilexetil is a prodrug which is rapidly converted to The apparent volume of distribution of candesartan is 0.1 l/kg.
BRICANYL 0.5 mg/ml solution for injection
the active drug, candesartan, by ester hydrolysis during absorption Hydrochlorothiazide
from the gastrointestinal tract. Candesartan is an angiotensin II Hydrochlorothiazide is rapidly absorbed from the gastrointestinal
receptor antagonist, selective for AT1 receptors, with tight binding (Terbutaline sulphate)
tract with an absolute bioavailability of approximately 70%.
to and slow dissociation from the receptor. It has no agonist Concomitant intake of food increases the absorption by
activity. COMPOSITION
approximately 15%. The bioavailability may decrease in patients
Candesartan does not inuence ACE or other enzyme systems 1 ml contains:
with cardiac failure and pronounced oedema.
usually associated with the use of ACE inhibitors. Since there Terbutaline sulphate 0.5 mg.
The plasma protein binding of hydrochlorothiazide is
is no effect on the degradation of kinins, or on the metabolism
approximately 60%. The apparent volume of distribution is PHARMACEUTICAL FORM
of other substances, such as substance P, angiotensin II receptor
approximately 0.8 l/kg. Solution for injection.
antagonists are unlikely to be associated with cough. In controlled
clinical trials comparing candesartan cilexetil with ACE Metabolism and elimination BRICANYL solution for injection contains no preservatives.
inhibitors, the incidence of cough was lower in patients receiving Candesartan cilexetil
INDICATIONS
candesartan cilexetil. Candesartan does not bind to or block other Candesartan is mainly eliminated unchanged via urine and bile
hormone receptors or ion channels known to be important in and only to a minor extent eliminated by hepatic metabolism BRICANYL asthma. Chronic bronchitis, emphysema and other
cardiovascular regulation. The antagonism of the AT1 receptors (CYP2C9). Available interaction studies indicate no effect on lung diseases where bronchospasm is a complicating factor.
results in dose related increases in plasma renin levels, angiotensin CYP2C9 and CYP3A4. Based on in vitro data, no interaction Preterm labour.
I and angiotensin II levels, and a decrease in plasma aldosterone would be expected to occur in vivo with drugs whose metabolism DOSAGE AND METHOD OF ADMINISTRATION
concentration. is dependent upon cytochrome P450 isoenzymes CYP1A2, The dose may be given intravenously or subcutaneously.
The effects of candesartan cilexetil 8-16 mg (mean dose 12 CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4.
The terminal half-life (t) of candesartan is approximately 9 BRICANYL solution for injection, 1 ml ampoule, is intended for
mg) once daily on cardiovascular morbidity and mortality were
hours. There is no accumulation following multiple doses. The subcutaneous and intravenous injection.
evaluated in a randomised clinical trial with 4937 elderly patients
(aged 70-89 years, 21% aged 80 or above) with mild to moderate half-life of candesartan remains unchanged (approximately 9 h) BRICANYL solution for injection, 5 ml ampoule, is intended for
hypertension followed for a mean of 3.7 years (Study on Cognition after administration of candesartan cilexetil in combination with infusion after dilution with infusion solutions.
and Prognosis in the Elderly). Patients received candesartan or hydrochlorothiazide. There is an increase in AUC (15-18%) Dosage should be individual.
placebo with other antihypertensive treatment added as needed. and Cmax (23-24%) of candesartan when given together with Bronchospasm:
The blood pressure was reduced from 166/90 to 145/80 mmHg in hydrochlorothiazide. This is of no clinical importance. Furthermore
Intravenous injection
the candesartan group, and from 167/90 to 149/82 mmHg in the titration of the individual components is recommended before
control group. There was no statistically signicant difference in switching to ATACAND PLUS. No additional accumulation Adults: 0.25-0.5 mg (0.5-1 ml) is injected slowly intravenously.
the primary endpoint, major cardiovascular events (cardiovascular of candesartan occurs after repeated doses of the combination The solution for injection is diluted with sterile physiological
mortality, non-fatal stroke and non-fatal myocardial infarction). compared to monotherapy. saline up to 10 ml and is given slowly intravenously during 5
There were 26.7 events per 1000 patient-years in the candesartan minutes. The dose may have to be repeated with short intervals (a
Total plasma clearance of candesartan is about 0.37 ml/min/
group versus 30.0 events per 1000 patient-years in the control few hours). The dose should not exceed 2 mg in 24 hours.
kg, with a renal clearance of about 0.19 ml/min/kg. The renal
group (relative risk 0.89, 95% CI 0.75 to 1.06, p=0.19). elimination of candesartan is both by glomerular ltration and Intravenous infusion
Hydrochlorothiazide inhibits the active reabsorption of sodium, active tubular secretion. Following an oral dose of 14C-labelled Adults: 1-2 mg (2-4 ml) is given during a 24 hour interval as a
mainly in the distal kidney tubules, and promotes the excretion candesartan cilexetil, approximately 26% of the dose is excreted continuous infusion. An initial loading dose up to 0.10 mg (0.2 ml)
of sodium, chloride and water. The renal excretion of potassium in the urine as candesartan and 7% as an inactive metabolite can be given over 10 minutes.
49
Book_01.indd 49 6/4/2008 2:19:19 PM

ASTRAZENECA
SPDI
Children: Up to 25 g/kg b.w. (0.05 ml/kg b.w.) is given during tendency to bleeding has been described in connection with Adults: 3-4.5 mg (10-15 ml) 3 times in 24 hours.
a 24 hour interval as a continuous infusion. An initial loading caesarean section (give Propranolol, 1-2 mg i.v.) in patients treated Children: 0.075 mg (0.25 ml)/kg body weight 3 times in a 24 h
dose up to 1.5 g/kg b.w. (0.003 ml/kg b.w.) can be given over with Bricanyl for preterm labour. period. Suitable dosage:
10 minutes.
OVERDOSAGE Body weight (kg) Dosage
Subcutaneous injection
Possible symptoms and signs: Headache, anxiety, tremor, tonic 4 1 ml x 3
Adults: 1-2 mg (2-4 ml) is given during a 24 hour interval, split muscle cramps, palpitations, arrhythmia. A fall in blood pressure
into at least 4 occasions. sometimes occurs. 6 1.5 ml x 3
Children: Up to 25 g/kg b.w. (0.05 ml/kg b.w.) is given during a Laboratory ndings: Hyperglycemia and lactacidosis sometimes 8 2 ml x 3
24 hour interval, split into at least 4 occasions. occur. 2-agonists may cause hypokalemia as a result of 10 2.5 ml x 3
Preterm labour: redistribution of potassium. 12 3 ml x 3
The dose must be individually titrated. Pulse rate and blood Treatment of overdosage: 14 3.5 ml x 3
pressure should be carefully monitored during treatment. Initially 5 Usually no treatment is required. In severe cases of overdosage, 16 4 ml x 3
g/min could be given as an infusion during 20 minutes. The dose the following measures should be considered: 18 4.5 ml x 3
can then be increased by 2.5 g/min at 20 minute intervals until
Determine acid-base balance, blood glucose and electrolytes. 20 5 ml x 3
contractions stop. More than 10 g/min should seldom be given,
Monitor heart rate and rhythm and blood pressure. The preferred
and 20 g/min should not be exceeded. Let the infusion continue 24 6 ml x 3
antidote for overdosage with Bricanyl is a cardioselective beta-
for 1 h at the chosen infusion rate, and then decrease the rate of receptor blocking agent, but beta-receptor blocking drugs should 28 7 ml x 3
infusion in steps of 2.5 g/min at 20 minute intervals down to the be used with caution in patients with a history of bronchospasm. 32 8 ml x 3
lowest maintenance dose that produces continued suppression of If the 2-mediated reduction in peripheral vascular resistance
the contractions. Keep the infusion at this rate for 12 h and then 36 9 ml x 3
signicantly contributes to the fall in blood pressure, a volume
continue with oral maintenance therapy (5 mg x 3). 40 10 ml x 3
expander should be given.
The oral treatment should be continued until the end of the 36th In preterm labour yesIf an adequate response is not obtained with this dose, the dose
week of pregnancy. As an alternative treatment, subcutaneous may be doubled, provided adverse reactions are not pronounced.
Pulmonary edema: A normal dose of a loop diuretic (e.g.
injections (0.25 mg four times in a 24 h period) could be given for
furosemide) should be given intravenously. Increased tendency to CONTRAINDICATIONS
a few days before oral treatment is started.
bleeding in connection with caesarean section: Give propranolol, Hypersensitivity to any of the ingredients.
Suggestion for dilution: 1-2 mg, intravenously.
5 mg (2 ampoules of 5 ml) in 1 000 ml of dextrose solution or SPECIAL WARNINGS AND PRECAUTIONS FOR USE
physiological saline. Prepared solution contains 5 g/ml and PHARMACODYNAMIC PROPERTIES
As for all 2 - agonists caution should be observed in patients with
should be used within 12 hours. BRICANYL should not be diluted Terbutaline is an adrenergic agonist which predominantly stimulates
thyrotoxicosis and in patients with severe cardiovascular disorder,
in alkaline solutions. Saline should be avoided during pregnancy 2-receptors, thus producing relaxation of bronchial smooth
such as ischemic heart disease, tachyarrhythmias or severe heart
since the risk of producing pulmonary edema may increase when muscle, inhibition of the release of endogenous spasmogens,
failure.
this diluent is used in pregnant women. If saline has to be used, inhibition of edema caused by endogenous mediators, increased
mucociliary clearance and relaxation of the uterine muscle. Due to the hyperglycemic effects of 2 - agonists, additional blood
the patient should be carefully monitored. BRICANYL can be
glucose controls are recommended initially in diabetic patients.
added to infusion solutions in glass bottles as well as in PVC After subcutaneous injection of terbutaline the duration of onset
plastic bags. regarding the bronchodilating effect is less than 5 minutes. Potentially serious hypokalemia may result from 2 -agonist
Maximum effect is reached within 30 minutes. therapy. Particular caution is recommended in acute severe
CONTRAINDICATIONS asthma as the associated risk may be augmented by hypoxia. The
Hypersensitivity to any of the ingredients. In obstetrics: Intrauterine PHARMACOKINETIC PROPERTIES hypokalemic effect may be potentiated by concomitant treatments
infection, severe preeclampsia, ablatio placentae. Terbutaline is metabolized mainly by conjugation with sulphuric (see Interactions). It is recommended that serum potassium
acid and excreted as the sulphate conjugate. No active metabolites levels are monitored in such situations.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
are formed. The plasma half life is about 16 hours. After
As for all 2-agonists caution should be observed in patients with intravenous and subcutaneous administration of terbutaline 90% INTERACTIONS
thyrotoxicosis and in patients with severe cardiovascular disorder, is excreted renally during 48-96 hours. Of this, about 60% consists Beta-receptor blocking agents (including eye-drops), especially
such as ischemic heart disease, tachyarrhythmias or severe heart of unmetabolized terbutaline. those which are non-selective, may partly or totally inhibit the
failure. effect of beta-receptor stimulants.
PRECLINICAL SAFETY DATA
Due to the hyperglycemic effects of 2-agonists, additional blood Hypokalemia may result from 2-agonist therapy and may be
glucose controls are recommended initially in diabetic patients. The major toxic effect of terbutaline, observed in toxicological
potentiated by concomitant treatment with xanthine derivatives,
studies, is focal myocardial necrosis. This type of cardiotoxicity
Potentially serious hypokalemia may result from 2-agonist steroids and diuretics (see Warnings and Precautions).
is a well-known class-effect, and the effect of terbutaline is similar
therapy. Particular caution is recommended in acute severe
to or less pronounced than that of other beta-receptor agonists. USE DURING PREGNANCY AND LACTATION
asthma as the associated risk may be augmented by hypoxia. The
Terbutaline has been used extensively over many years for the No teratogenic effects have been observed in patients or in animals.
hypokalemic effect may be potentiated by concomitant treatments
relief of bronchospasm without identifying any areas of concern. However, caution is recommended during the rst trimester of
(see Interactions). It is recommended that serum potassium levels
are monitored in such situations. LIST OF EXCIPIENTS pregnancy.
Sodium chloride, hydrochloric acid, water. Terbutaline passes over to breast milk but an inuence on the child
INTERACTIONS
is unlikely with therapeutic doses.
Beta-receptor blocking agents (including eye-drops), especially INCOMPATIBILITIES
Transient hypoglycemia has been reported in newborn preterm
those which are non-selective, may partly or totally inhibit the BRICANYL solution for injection should not be mixed with infants after maternal 2-agonist treatment.
effect of beta-receptor stimulants. alkaline solutions, i.e. solutions with a pH higher than 7.0.
Hypokalemia may result from 2-agonist therapy and may be EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
potentiated by concomitant treatment with xanthine derivatives, SPECIAL PRECAUTIONS FOR STORAGE
Bricanyl does not affect the ability to drive or use machines.
steroids and diuretics (see Warnings and Precautions). The ampoules should be stored at temperatures not exceeding
UNDESIRABLE EFFECTS
25C and be protected from light.
USE DURING PREGNANCY AND LACTATION The intensity of the adverse reactions depends on dosage and route
No teratogenic effects have been observed in patients or in animals. SHELF-LIFE of administration. Adverse reactions which have been recorded,
However, caution is recommended during the rst trimester of Please see outer pack e.g. tremor, headache, tonic muscle cramps and palpitations, are all
pregnancy. characteristic of sympathomimetic amines. The majority of these
PACK SIZE
Terbutaline passes over to breast milk but an inuence on the child effects have reversed spontaneously within the rst 1-2 weeks of
Please see outer pack treatment.
is unlikely with therapeutic doses.
Trade mark herein are the property of the AstraZeneca group of Urticaria and exanthema may occur.
Transient hypoglycemia has been reported in newborn preterm
companies.
infants after maternal 2-agonist treatment. Sleep disturbances and behavioural disturbances, such as agitation,
hyperactivity and restlessness, have been observed.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES BRICANYL elixir 0.3 mg/ml Syrup/Elixir
Bricanyl does not affect the ability to drive or use machines. OVERDOSAGE
Possible symptoms and signs: Headache, anxiety, tremor, tonic
UNDESIRABLE EFFECTS
(Terbutaline sulphate) muscle cramps, palpitations, arrhythmia. A fall in blood pressure
The intensity of the adverse reactions depends on dosage and route sometimes occurs.
of administration. An initial dose titration will often reduce the
COMPOSITION Laboratory ndings: Hyperglycemia and lactacidosis sometimes
adverse reactions. Adverse reactions which have been recorded,
occur. 2-agonists may cause hypokalemia as a result of
e.g. tremor, headache, tonic muscle cramps and palpitations, are all 1 ml contains:
redistribution of potassium.
characteristic of sympathomimetic amines. The majority of these Terbutaline sulphate 0.3 mg.
effects have reversed spontaneously within the rst 1-2 weeks of TREATMENT OF OVERDOSAGE:
treatment. PHARMACEUTICAL FORM
Usually no treatment is required. If it can be suspected that
Urticaria and exanthema may occur. BRICANYL elixir is sugar-free and has a raspberry avour. signicant amounts of terbutaline sulphate have been swallowed,
Sleep disturbances and behavioural disturbances, such as agitation, INDICATIONS the following measures should be considered:
hyperactivity and restlessness, have been observed. Bronchial asthma. Chronic bronchitis, emphysema and other lung Gastric lavage, activated charcoal. Determine acid-base balance,
During treatment of preterm labour, when high doses of diseases where bronchospasm is a complicating factor. blood glucose and electrolytes. Monitor heart rate and rhythm
BRICANYL are used, diabetic mothers may develop and blood pressure. The preferred antidote for overdosage with
hyperglycaemia and lactacidosis. In these patients glucose and DOSAGE AND METHOD OF ADMINISTRATIONS Bricanyl is a cardioselective beta-receptor blocking agent, but beta-
acid-base balance should be carefully monitored. High doses of BRICANYL elixir should be used as maintenance therapy in receptor blocking drugs should be used with caution in patients
2-stimulants may cause hypokalemia as a result of redistribution asthma and other pulmonary diseases where bronchospasm is a with a history of bronchospasm. If the 2 - mediated reduction in
of potassium. Symptoms of pulmonary edema have also been complicating factor. peripheral vascular resistance signicantly contributes to the fall
reported following treatment of preterm labour. An increased Dosage should be individual. in blood pressure, a volume expander should be given.
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PHARMACODYNAMIC PROPERTIES Dosage in patients with renal insufciency alcohol abuse
Terbutaline is an adrenergic agonist which predominantly stimulates No dose adjustment is necessary in patients with mild to moderate age >70 years
2-receptors, thus producing relaxation of bronchial smooth renal impairment. The recommended start dose is 5 mg in situations where an increase in plasma levels may occur (see
muscle, inhibition of the release of endogenous spasmogens, patients with moderate renal impairment (creatinine clearance Pharmacokinetic properties)
inhibition of edema caused by endogenous mediators, increased <60ml/min). The 40 mg dose is contraindicated in patients with concomitant use of brates.
mucociliary clearance and relaxation of the uterine muscle. moderate renal impairment. The use of CRESTOR in patients In such patients the risk of treatment should be considered in relation
The bronchodilating effect of BRICANYL elixir has in clinical with severe renal impairment is contraindicated for all doses (see to possible benet and clinical monitoring is recommended. If CK
trials been shown to have a duration for up to 8 hours. Contraindications and Pharmacokinetic properties). levels are signicantly elevated at baseline (>5xULN) treatment
Dosage in patients with hepatic impairment should not be started.
There was no increase in systemic exposure to rosuvastatin Whilst on treatment
There is a considerable rst-pass metabolism in the intestinal wall
and in the liver. The bioavailability is around 10% and increases in subjects with Child-Pugh scores of 7 or below. However, Patients should be asked to report inexplicable muscle pain,
to around 15% if terbutaline is taken on an empty stomach. increased systemic exposure has been observed in subjects with weakness or cramps immediately, particularly if associated with
Maximum plasma concentration of terbutaline is reached within Child-Pugh scores of 8 and 9 (see Pharmacokinetic properties). malaise or fever. CK levels should be measured in these patients.
3 hours. Terbutaline is metabolized mainly by conjugation with In these patients an assessment of renal function should be Therapy should be discontinued if CK levels are markedly
sulphuric acid and excreted as the sulphate conjugate. No active considered (see Special warnings and precautions for use). There elevated (>5xULN) or if muscular symptoms are severe and cause
metabolites are formed. is no experience in subjects with Child-Pugh scores above 9. daily discomfort (even if CK levels are 5x ULN). If symptoms
CRESTOR is contraindicated in patients with active liver disease resolve and CK levels return to normal, then consideration should
LIST OF EXCIPIENTS (see Contraindications). be given to re-introducing CRESTOR or an alternative HMG-
Citric acid, disodium edetate, ethanol, glycerol, sodium hydroxide, Race CoA reductase inhibitor at the lowest dose with close monitoring.
sorbitol, sodium benzoate, avour lemon limette, avour raspberry, Increased systemic exposure has been seen in Asian subjects (see Routine monitoring of CK levels in asymptomatic patients is not
water. Special warnings and precautions for use and Pharmacokinetic warranted.
SPECIAL PRECAUTIONS FOR STORAGE properties). The recommended start dose is 5 mg for patients In clinical trials there was no evidence of increased skeletal
Do not store above 30C. of Asian ancestry. The 40mg dose is contraindicated in these muscle effects in the small number of patients dosed with
patients. CRESTOR and concomitant therapy. However, an increase
SHELF LIFE Dosage in patients with pre-disposing factors to myopathy in the incidence of myositis and myopathy has been seen in
Please see outer pack. The recommended start dose is 5 mg in patients with patients receiving other HMG-CoA reductase inhibitors together
predisposing factors to myopathy (see Special warnings and with bric acid derivatives including gembrozil, cyclosporin,
PACK SIZE
precautions for use). nicotinic acid, azole antifungals, protease inhibitors and macrolide
Please see outer pack. antibiotics. Gembrozil increases the risk of myopathy when
Trade marks herein are the property of the AstraZeneca group of The 40 mg dose is contraindicated in some of these patients given concomitantly with some HMG-CoA reductase inhibitors.
companies. (see Contraindications). Therefore, the combination of Crestor and gembrozil is not
CONTRAINDICATIONS recommended. The benet of further alterations in lipid levels by
CRESTOR, 10 mg, 20 mg, Film coated tablets CRESTOR is contraindicated: the combined use of CRESTOR with brates or niacin should be
carefully weighed against the potential risks of such combinations.
[40 mg (N.R) and 5 mg (N.R)] - in patients with hypersensitivity to rosuvastatin or to any of the
The 40 mg dose is contraindicated with concomitant use of a
excipients.
brate.(See Interactions and Undesirable effects.)
- in patients with active liver disease including unexplained,
(Rosuvastatin calcium) CRESTOR should not be used in any patient with an acute,
persistent elevations of serum transaminases and any serum
serious condition suggestive of myopathy or predisposing to the
transaminase elevation exceeding 3 x the upper limit of normal
COMPOSITION development of renal failure secondary to rhabdomyolysis (e.g.
(ULN).
sepsis, hypotension, major surgery, trauma, severe metabolic,
Each tablet contains 5 mg(N.R), 10 mg, 20 mg, or 40 mg(N.R) of - in patients with severe renal impairment (creatinine clearance
endocrine and electrolyte disorders; or uncontrolled seizures).
rosuvastatin (as calcium salt). Also contains glycerol. <30 ml/min).
Liver effects
PHARMACEUTICAL FORM - in patients with myopathy.
- in patients receiving concomitant cyclosporin. As with other HMG-CoA reductase inhibitors, CRESTOR should
Film-coated tablet. be used with caution in patients who consume excessive quantities
- during pregnancy and lactation and in women of childbearing
Round, yellow coloured (5 mg)(N.R); round, pink coloured (10 of alcohol and/or have a history of liver disease.
potential not using appropriate contraceptive measures.
mg and 20 mg); oval, pink coloured (40 mg)(N.R). It is recommended that liver function tests be carried out prior to,
The 40 mg dose is contraindicated in patients with pre-disposing
THERAPEUTIC INDICATIONS and 3 months following, the initiation of treatment. CRESTOR
factors for myopathy/rhabdomyolysis. Such factors include:
should be discontinued or the dose reduced if the level of serum
Primary hypercholesterolaemia (type IIa including heterozygous - moderate renal impairment (creatinine clearance < 60 ml/min) transaminases is greater than 3 times the upper limit of normal.
familial hypercholesterolaemia) or mixed dyslipidaemia (type - hypothyroidism
IIb) as an adjunct to diet when response to diet and other non- In patients with secondary hypercholesterolaemia caused by
- personal or family history of hereditary muscular disorders hypothyroidism or nephrotic syndrome, the underlying disease
pharmacological treatments (e.g. exercise, weight reduction) is
- previous history of muscular toxicity with another HMG should be treated prior to initiating therapy with CRESTOR.
inadequate.
CoA reductase inhibitor or brate Race
Homozygous familial hypercholesterolaemia as an adjunct to diet
- alcohol abuse Pharmacokinetic studies show an increase in exposure in Asian
and other lipid lowering treatments (e.g. LDL apheresis) or if such
treatments are not appropriate. - situations where an increase in plasma levels may occur subjects compared with Caucasians (see Posology and method of
- Asian patients administration and Pharmacokinetic properties).
POSOLOGY AND METHOD OF ADMINISTRATION - concomitant use of brates.
Before treatment initiation the patient should be placed on a INTERACTIONS
(see Special warnings and precautions for use, Interactions and
standard cholesterol-lowering diet that should continue during Cyclosporin: During concomitant treatment with CRESTOR
Pharmacokinetic properties)
treatment. The dose should be individualised according to the and cyclosporin, rosuvastatin AUC values were on average 7
goal of therapy and patient response, using current consensus SPECIAL WARNINGS AND PRECAUTIONS FOR USE times higher than those observed in healthy volunteers (see
guidelines. Renal effects Contraindications).
The recommended start dose is 5 mg or 10 mg orally once Proteinuria, detected by dipstick testing and mostly tubular in Concomitant administration did not affect plasma concentrations
daily in both statin nave or patients switched from another origin, has been observed in patients treated with higher doses of cyclosporin.
HMG CoA reductase inhibitor. The choice of start dose of CRESTOR, in particular 40 mg, where it was transient or Vitamin K antagonists: As with other HMG-CoA reductase
should take into account the individual patients cholesterol intermittent in most cases. Proteinuria has not been shown to be inhibitors, the initiation of treatment or dosage up-titration of
level and future cardiovascular risk as well as the potential predictive of acute or progressive renal disease (see Undesirable CRESTOR in patients treated concomitantly with vitamin K
risk for adverse reactions (see below). A dose adjustment to effects). An assessment of renal function should be considered antagonists (e.g. warfarin) may result in an increase in International
the next dose level can be made after 4 weeks, if necessary (see during routine follow-up of patients treated with a dose of 40 mg. Normalised Ratio (INR). Discontinuation or down-titration of
Pharmacodynamic properties). In light of the increased reporting Skeletal muscle effects CRESTOR may result in a decrease in INR. In such situations,
rate of adverse reactions with the 40 mg dose compared to lower appropriate monitoring of INR is desirable.
Effects on skeletal muscle e.g. myalgia, myopathy and, rarely,
doses (see Undesirable effects), a nal titration to the maximum
rhabdomyolysis have been reported in CRESTOR-treated patients Gembrozil and other lipid-lowering products: Concomitant
dose of 40 mg should only be considered in patients with severe
with all doses and in particular with doses > 20 mg. use of CRESTOR and gembrozil resulted in a 2-fold increase
hypercholesterolaemia at high cardiovascular risk (in particular
Creatine Kinase measurement in rosuvastatin C max and AUC (see Special warnings and
those with familial hypercholesterolaemia), who do not achieve
precautions for use).
their treatment goal on 20 mg, and in whom routine follow-up Creatine Kinase (CK) should not be measured following strenuous
will be performed (see Special warnings and precautions for use). exercise or in the presence of a plausible alternative cause of Based on data from specic interaction studies no pharmacokinetic
Specialist supervision is recommended when the 40 mg dose is CK increase which may confound interpretation of the result. relevant interaction with fenobrate is expected, however
initiated. If CK levels are signicantly elevated at baseline (>5xULN) a a pharmacodynamic interaction may occur. Gembrozil,
conrmatory test should be carried out within 5 7 days. If the fenobrate, other brates and lipid lowering doses (> or equal to
CRESTOR may be given at any time of day, with or without
repeat test conrms a baseline CK >5xULN, treatment should not 1g/day) of niacin (nicotinic acid) increase the risk of myopathy
food.
be started. when given concomitantly with HMG-CoA reductase inhibitors,
Paediatric use probably because they can produce myopathy when given alone.
Safety and efcacy have not been established in children. Paediatric Before treatment
The 40 mg dose is contraindicated with concomitant use of a brate
experience is limited to a small number of children (aged 8 years CRESTOR, as with other HMG-CoA reductase inhibitors, should (see Contraindications and Special warnings and precautions for
or above) with homozygous familial hypercholesterolaemia. be prescribed with caution in patients with pre-disposing factors use). These patients should also start with the 5 mg dose.
Therefore, CRESTOR is not recommended for paediatric use at for myopathy/rhabdomyolysis. Such factors include:
Antacid: The simultaneous dosing of CRESTOR with an antacid
this time. renal impairment suspension containing aluminium and magnesium hydroxide
Use in the elderly hypothyroidism resulted in a decrease in rosuvastatin plasma concentration of
A start dose of 5 mg is recommended in patients >70 years personal or family history of hereditary muscular disorders approximately 50%. This effect was mitigated when the antacid
(see Special warnings and precautions for use). No other dose previous history of muscular toxicity with another HMG-CoA was dosed 2 hours after CRESTOR. The clinical relevance of this
adjustment is necessary in relation to age. reductase inhibitor or brate interaction has not been studied.
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Erythromycin: Concomitant use of CRESTOR and erythromycin Liver effects: As with other HMG-CoA reductase inhibitors, achieved approximately 5 hours after oral administration. The
resulted in a 20% decrease in AUC (0-t) and a 30% decrease in a dose-related increase in transaminases has been observed in a absolute bioavailability is approximately 20%.
Cmax of rosuvastatin. This interaction may be caused by the small number of patients taking rosuvastatin; the majority of cases Distribution: Rosuvastatin is taken up extensively by the liver
increase in gut motility caused by erythromycin. were mild, asymptomatic and transient. which is the primary site of cholesterol synthesis and LDL-
Oral contraceptive/hormone replacement therapy (HRT): Post marketing experience: C clearance. The volume of distribution of rosuvastatin is
Concomitant use of CRESTOR and an oral contraceptive resulted In addition to the above, the following adverse events have been approximately 134 L. Approximately 90% of rosuvastatin is
in an increase in ethinyl oestradiol and norgestrel AUC of 26% reported during post-marketing experience for CRESTOR: bound to plasma proteins, mainly to albumin.
and 34%, respectively. These increased plasma levels should be
Hepatobiliary disorders: Very rare: jaundice, hepatitis; rare: Metabolism: Rosuvastatin undergoes limited metabolism
considered when selecting oral contraceptive doses. There are no
increased hepatic transaminases. (approximately 10%). In vitro metabolism studies using human
pharmacokinetic data available in subjects taking concomitant
CRESTOR and HRT and therefore a similar effect cannot be Musculosceletal disorders: Rare: arthralgia. hepatocytes indicate that rosuvastatin is a poor substrate for
excluded. However, the combination has been extensively used in cytochrome P450-based metabolism. CYP2C9 was the principal
Nervous system disorders: Very rare: polyneuropathy
women in clinical trials and was well tolerated. isoenzyme involved, with 2C19, 3A4 and 2D6 involved to a lesser
OVERDOSE extent. The main metabolites identied are the N-desmethyl and
Other medicinal products: Based on data from specic
There is no specic treatment in the event of overdose. In the lactone metabolites. The N-desmethyl metabolite is approximately
interaction studies no clinically relevant interactions with digoxin
event of overdose, the patient should be treated symptomatically 50% less active than rosuvastatin whereas the lactone form is
is expected.
and supportive measures instituted as required. Liver function and considered clinically inactive. Rosuvastatin accounts for greater
Cytochrome P450 enzymes: Results from in vitro and in vivo
CK levels should be monitored. Haemodialysis is unlikely to be than 90% of the circulating HMG-CoA reductase inhibitor
studies show that rosuvastatin is neither an inhibitor nor an inducer
of benet. activity.
of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor
substrate for these isoenzymes. No clinically relevant interactions Excretion: Approximately 90% of the rosuvastatin dose is
have been observed between rosuvastatin and either uconazole excreted unchanged in the faeces (consisting of absorbed and non-
Pharmacotherapeutic group: HMG-CoA reductase inhibitors absorbed active substance) and the remaining part is excreted in
(an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an
inhibitor of CYP2A6 and CYP3A4). Concomitant administration ATC code: C10A A07 urine. Approximately 5% is excreted unchanged in urine. The
of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted plasma elimination half-life is approximately 19 hours. The
MECHANISM OF ACTION
in a 28% increase in AUC of rosuvastatin. This small increase is elimination half-life does not increase at higher doses. The
not considered clinically signicant. Therefore, drug interactions Rosuvastatin is a selective and competitive inhibitor of HMG- geometric mean plasma clearance is approximately 50 litres/
resulting from cytochrome P450-mediated metabolism are not CoA reductase, the rate-limiting enzyme that converts 3-hydroxy- hour (coefcient of variation 21.7%). As with other HMG-CoA
expected. 3-methylglutaryl coenzyme A to mevalonate, a precursor for reductase inhibitors, the hepatic uptake of rosuvastatin involves
cholesterol. The primary site of action of rosuvastatin is the liver, the membrane transporter OATP-C. This transporter is important
PREGNANCY AND LACTATION the target organ for cholesterol lowering. in the hepatic elimination of rosuvastatin.
CRESTOR is contraindicated in pregnancy and lactation. Rosuvastatin increases the number of hepatic LDL receptors on Linearity: Systemic exposure of rosuvastatin increases in
Women of child-bearing potential should use appropriate the cell-surface, enhancing uptake and catabolism of LDL and it proportion to dose. There are no changes in pharmacokinetic
contraceptive measures. inhibits the hepatic synthesis of VLDL, thereby reducing the total parameters following multiple daily doses.
Since cholesterol and other products of cholesterol biosynthesis number of VLDL and LDL particles.
are essential for the development of the foetus, the potential risk SPECIAL POPULATIONS:
PHARMACODYNAMIC EFFECTS
from inhibition of HMG-CoA reductase outweighs the advantage Age and sex: There was no clinically relevant effect of age or sex
of treatment during pregnancy. Animal studies provide limited CRESTOR reduces elevated LDL-cholesterol, total cholesterol on the pharmacokinetics of rosuvastatin.
evidence of reproductive toxicity (see Preclinical safety data). If and triglycerides and increases HDL-cholesterol. It also lowers
Race: Pharmacokinetic studies (conducted in subjects of Chinese,
a patient becomes pregnant during use of this product, treatment ApoB, nonHDL-C, VLDL-C, VLDL-TG and increases ApoA-I
(see Table 1). Crestor also lowers the LDL-C/HDL-C, total C/ Filipino, Asian Indian, Korean, Vietnamese, Japanese or Malay
should be discontinued immediately.
HDL-C and nonHDL-C/HDL-C and the ApoB/ApoA-I ratios. origin) show an approximate 2-fold elevation in median AUC and
Rosuvastatin is excreted in the milk of rats. There are no data with Cmax in Asian subjects in Asia compared with Caucasians living in
respect to excretion in milk in humans (see Contraindications). Table 1 Dose response in patients with primary
Asia and Europe. The contribution of environmental and genetic
hypercholesterolaemia (type IIa and IIb)
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES factors to these observed differences has not been determined.
(adjusted mean percent change from baseline) A population pharmacokinetic analysis revealed no clinically
Studies to determine the effect of CRESTOR on the ability to
drive and use machines have not been conducted. However, based Dose N LDL-C Total-C HDL-C TG non ApoB ApoA-I relevant differences in pharmacokinetics between Caucasian and
on its pharmacodynamic properties, CRESTOR is unlikely to HDL-C Black groups.
affect this ability. When driving vehicles or operating machines, Plac- Renal insufciency: In a study in subjects with varying degrees of
it should be taken into account that dizziness may occur during ebo 13 -7 -5 3 -3 -7 -3 0 renal impairment, mild to moderate renal disease had no inuence
treatment. 5 17 -45 -33 13 -35 -44 -38 4 on plasma concentration of rosuvastatin or the N-desmethyl
UNDESIRABLE EFFECTS 10 17 -52 -36 14 -10 -48 -42 4 metabolite. Subjects with severe impairment (CrCl <30 ml/min)
The adverse events seen with CRESTOR are generally mild and had a 3-fold increase in plasma concentration and a 9-fold increase
20 17 -55 -40 8 -23 -51 -46 5
transient. In controlled clinical trials, less than 4% of CRESTOR- in the N-desmethyl metabolite concentration compared to healthy
40 18 -63 -46 10 -28 -60 -54 0 volunteers. Steady-state plasma concentrations of rosuvastatin
treated patients were withdrawn due to adverse events.
The frequencies of adverse events are ranked according to the therapeutic effect is obtained within 1 week following treatment in subjects undergoing haemodialysis were approximately 50%
following: Common (>1/100, <1/10); Uncommon (>1/1,000, <1/ initiation and 90% of maximum response is achieved in 2 weeks. greater compared to healthy volunteers.
100); Rare (>1/10,000, <1/1000); Very rare (<1/10,000) The maximum response is usually achieved by 4 weeks and is Hepatic insufciency: In a study with subjects with varying
Immune system disorders maintained after that. degrees of hepatic impairment there was no evidence of increased
exposure to rosuvastatin in subjects with Child-Pugh scores of
Rare: hypersensitivity reactions including angioedema CLINICAL EFFICACY
7 or below. However, two subjects with Child-Pugh scores of 8
Nervous system disorders CRESTOR is effective in adults with hypercholesterolaemia, and 9 showed an increase in systemic exposure of at least 2-fold
Common: headache, dizziness with and without hypertriglyceridaemia, regardless of race, sex, or compared to subjects with lower Child-Pugh scores. There is no
Gastrointestinal disorders age and in special populations such as diabetics, or patients with experience in subjects with Child-Pugh scores above 9.
Common: constipation, nausea, abdominal pain familial hypercholesterolaemia.
From pooled phase III data, CRESTOR has been shown to be PRECLINICAL SAFETY DATA
Skin and subcutaneous tissue disorders
effective at treating the majority of patients with type IIa and Preclinical data reveal no special hazard for humans based on
Uncommon: pruritus, rash and urticaria conventional studies of safety pharmacology, repeated dose
IIb hypercholesterolaemia (mean baseline LDL-C about 4.8
Musculoskeletal, connective tissue and bone disorders mmol/l) to recognised European Atherosclerosis Society (EAS; toxicity, genotoxicity and carcinogenicity potential. In a rat
Common: myalgia 1998) guideline targets; about 80% of patients treated with 10 mg pre- and postnatal study, reproductive toxicity was evident from
Rare: myopathy and rhabdomyolysis reached the EAS targets for LDL-C levels (<3 mmol/l). reduced litter sizes, litter weight and pup survival. These effects
In a large study, 435 patients with heterozygous familial were observed at maternotoxic doses at systemic exposures several
General disorders
hypercholesterolaemia were given CRESTOR from 20 mg to times above the therapeutic exposure level.
Common: asthenia
80 mg in a force-titration design. All doses showed a benecial LIST OF EXCIPIENTS
As with other HMG-CoA reductase inhibitors, the incidence of
effect on lipid parameters and treatment to target goals. Following
adverse drug reactions tends to be dose dependent. Tablet core
titration to a daily dose of 40 mg (12 weeks of treatment), LDL-C
Renal effects: Proteinuria, detected by dipstick testing and mostly was reduced by 53%. 33% of patients reached EAS guidelines for Lactose monohydrate
tubular in origin, has been observed in patients treated with Microcrystalline cellulose
LDL-C levels (<3 mmol/l).
CRESTOR. Shifts in urine protein from none or trace to ++ or Calcium phosphate
more were seen in <1% of patients at some time during treatment In a force-titration, open label trial, 42 patients with homozygous
familial hypercholesterolaemia were evaluated for their response Crospovidone
with 10 and 20 mg, and in approximately 3% of patients treated
with 40 mg. A minor increase in shift from none or trace to + to CRESTOR 20 - 40 mg. In the overall population, the mean Magnesium stearate
was observed with the 20 mg dose. In most cases, proteinuria LDL-C reduction was 22%. Tablet coat
decreases or disappears spontaneously on continued therapy, and In clinical studies with a limited number of patients, CRESTOR Lactose monohydrate
has not been shown to be predictive of acute or progressive renal has been shown to have additive efcacy in lowering triglycerides Hypromellose
disease. when used in combination with fenobrate and in increasing Glycerol triacetate
Skeletal muscle effects: Effects on skeletal muscle e.g. myalgia, HDL-C levels when used in combination with niacin (see Special Titanium dioxide (E171)
myopathy and, rarely, rhabdomyolysis have been reported in warnings and precautions for use). Ferric oxide, yellow (E172) (5mg tablet)
CRESTOR-treated patients with all doses and in particular with Rosuvastatin has not been proven to prevent the associated Ferric oxide, red (E172) (10mg. 20mg and 40mg tablets)
doses > 20 mg. complications of lipid abnormalities, such as coronary heart
A dose-related increase in CK levels has been observed in patients disease as mortality and morbidity studies with CRESTOR have INCOMPATIBILITIES
taking rosuvastatin; the majority of cases were mild, asymptomatic not yet been completed. Not applicable.
and transient. If CK levels are elevated (>5xULN), treatment
should be discontinued (see Special warnings and precautions for PHARMACOKINETIC PROPERTIES SHELF LIFE
use). Absorption: Maximum rosuvastatin plasma concentrations are Please refer to expiry date on outer carton.
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SPECIAL PRECAUTIONS FOR STORAGE Elevated plasma levels and enhanced effects of corticosteroids LIST OF EXCIPIENTS
Do not store above 30C have been reported in women also receiving oestrogens and 1 tablet for rectal suspension contains:
contraceptive steroids, but no effects on the plasma concentrations
PACK SIZE Lactose anhydrous 263 mg, lactose monohydrate 1.3 mg,
of budesonide were observed at concomitant intake of low-dose
Please refer to outer carton for pack size. riboavine sodium phosphate (E 101), crospovidone, colloidal
combination oral contraceptives.
silica, magnesium stearate
INSTRUCTIONS FOR USE AND HANDLING In recommended doses, cimetidine has a slight but clinically
insignicant effect, and omeprazole no effect, on the 1 ml solution for rectal suspension contains:
No special requirements.
pharmacokinetics of orally administered budesonide. Sodium chloride 9 mg, methyl parahydroxybenzoate (E 218),
CRESTOR is a trade mark of the of the AstraZeneca group of propyl parahydroxybenzoate (E 216), water, puried
companies. PREGNANCY AND LACTATION
Pregnancy SPECIAL PRECAUTIONS FOR STORAGE
AstraZeneca 2002- 2005
Clinical experience from pregnant women is limited. In animal Do not store above 30C.
ENTOCORT 2 mg studies corticosteroids have been shown to cause malformations SHELF LIFE
of various types (cleft palate, skeletal malformations). However,
Tablet and solution for rectal suspension Please see outer pack.
these experimental animal results are not thought to have any
relevance for humans. PACK SIZE
(Budesonide) Until further experience is available, ENTOCORT should not be Please see outer pack
given during pregnancy except after special consideration.
INSTRUCTIONS FOR USE AND HANDLING
COMPOSITION Lactation
How to use ENTOCORT
Budesonide 2 mg. It is not known whether budesonide passes into breast milk.
ENTOCORT should be administered in the evening before going
The total quantity of budesonide in a dose of prepared rectal EFFECTS ON ABILITY TO DRIVE AND USE MACHINES to bed.
suspension (115 ml) is 2.3 mg. On administration of the rectal No effects have been observed. ENTOCORT rectal suspension consists of two components
suspension, a residual volume remains in the pack. This means that
UNDESIRABLE EFFECTS - a tablet and a liquid.
the administered dose of budesonide is approximately 2 mg.
In clinical trials side effects occurred in approximately 20 % of The tablet must be dissolved in 1 bottle of liquid before use.
PHARMACEUTICAL FORM the treated patients. Follow the instructions carefully.
Tablet and solution for rectal suspension. Common (>1/100): GI: Flatulence, diarrhoea, nausea. How to prepare ENTOCORT
ENTOCORT rectal suspension consists of two parts: a dispersible Skin: Urticaria, rash. 1. Remove the nozzle, with the protective cap on, from the bottle.
tablet, containing micronised budesonide, and an isotonic solution.
Less common: Psych.: Agitation, insomnia. 2. Take a tablet from the aluminum foil pack and put it into the
The rectal suspension is prepared before use.
Rare (<1/1000): Psych.: Anxiety. bottle.
The tablet(N.R) is round, faintly yellow, marked BAI on one side
3. Put the nozzle back on the bottle and make sure that the
and 2.3 on the other. The solution is clear and colourless. In rare cases, signs and/or symptoms of systemic
protective cap is rmly on.
glucocorticosteroid effects, including adrenal hypofunction, may
THERAPEUTIC INDICATION occur on rectal administration of glucocorticosteroids. Whether or Shake the bottle vigorously for at least 10 seconds or until the
Ulcerative colitis, proctitis. not these effects occur is probably depending on dose, treatment tablet has dissolved and a slightly yellowish liquid has been
time, concomitant use of other glucocorticosteroids, previous use formed.
POSOLOGY AND METHOD OF ADMINISTRATION
of glucocorticosteroids, and individual sensitivity. A plastic bag has been enclosed which you may use to protect
Adults: 1 dose of prepared rectal suspension containing 2 mg is your hand when you administer the enema.
applied into the rectum every evening for approximately 4 weeks. OVERDOSE
4. Lie down on your left side. Shake the bottle again before
Full effect is usually achieved within 2-4 weeks. The treatment Acute overdose, even with high doses, is not expected to be a
removing the protective cap.
may be extended to 8 weeks if required. clinical problem.
Empty the contents into the rectum.
For administration, the patient should lie on the left side, and then PHARMACODYNAMIC PROPERTIES
on the stomach for 5 minutes. The rectal suspension should be 5. Roll over on your stomach. Stay in this position for 5 minutes.
ATC-code: A07E A06 Glucocorticosteroids for local treatment.
retained for as long as possible, preferably overnight. 6. Choose a suitable position to sleep in. Try to retain the enema as
Administered rectally, budesonide has a local anti-inammatory long as possible, preferably the whole night.
Elderly: Dosage as for adults. effect on the intestinal mucous membrane.
Children: At present, there is no experience of treatment with Note: The prepared rectal suspension must be used immediately.
The mechanism of action of glucocorticosteroids in the treatment
ENTOCORT rectal suspension in children. Trade Marks herein are the property of the AstraZeneca group
of ulcerative colitis is not fully understood. Anti-inammatory
Patients with liver disease: Impaired liver function increases the actions, such as inhibition of inammatory mediator release and AstraZeneca 2003
systemic availability of budesonide. inhibition of cytokine mediated immune responses, are probably
important. The intrinsic potency of budesonide, measured as the INDERAL
CONTRAINDICATIONS afnity to the glucocorticoid receptor, is about 15 times higher
Bacterial, fungal or viral infections. Hypersensitivity to budesonide than that of prednisolone.
or any other ingredient in the product. In the recommended doses, ENTOCORT rectal suspension can (Propranolol hydrochloride)
SPECIAL WARNING AND PRECAUTIONS FOR USE in rare cases cause clinically signicant changes in basal plasma
cortisol levels or in the response to ACTH stimulation. PRESENTATION
Special caution is required in the treatment of patients who are
changed over from oral steroids, as disturbances of the endogenous The effects on morning plasma cortisol and adrenal function are Tablets containing 10mg, 40mg or 80mg Propranolol
cortisol balance (HPA-axis) may be expected. In these patients the signicantly less than with a 25 mg prednisolone enema daily. Hydrochloride Ph. Eur.
dosage of systemic steroid should be cautiously reduced. A value PHARMACOKINETIC PROPERTIES Injection for intravenous use containing Propranolol Hydrochloride
on the hypothalamus-pituitary-adrenocortical function could be of Absorption Ph. Eur. 1mg per 1ml, presented in glass ampoules of 1ml.
use for the change-over. The systemic availability after oral administration of budesonide is INDICATIONS
Some patients feel generally unwell during the withdrawal phase, approximately 10%. After rectal administration of ENTOCORT
i) Control of hypertension
with e.g. muscle and joint pain. An inadequate general steroid rectal suspension to healthy volunteers the systemic availability
is approximately 15% (3-50%). As can be expected for drugs ii) Management of angina pectoris
effect must be suspected if symptoms such as fatigue, headache,
nausea and vomiting occur. In these cases a temporary increase in with high rst pass metabolism given rectally, the variability is iii) Long term prophylaxis after recovery from acute myocardial
the oral dose of glucocorticosteroids is sometimes necessary. larger than after oral dosing. This is due to individual differences infarction
in rectal venous drainage leading to hepatic by-pass. After rectal iv) Control of cardiac arrhythmias
When ENTOCORT rectal suspension replaces a systemic
administration, absorption of budesonide is rapid and essentially v) Prophylaxis of migraine
steroid treatment, this sometimes unmasks allergies, e.g. rhinitis
terminated within 3 hours. vi) Management of essential tremor
and eczema, which were previously controlled by the systemic
treatment. These allergies should be controlled symptomatically Distribution vii) Control of anxiety and anxiety tachycardia
with an antihistamine and/or with local treatment. Budesonide has a volume of distribution of approximately viii) Adjunctive management of thyrotoxicosis and thyrotoxic
In vivo studies have shown that oral administration of ketoconazole 3 litres/kg. Plasma protein binding averages 85-90%. Mean crisis
maximal plasma concentration after rectal administration of 2 mg ix) Management of hypertrophic obstructive cardiomyopathy
(a known inhibitor of CYP3A activity in the liver and in the
budesonide is 2-3 nanomol/litre (range 1-9 nanomol/litre), reached
intestinal mucosa) caused a severalfold increase of the systemic x) Management of phaeochromocytoma (INDERAL should
within 1.5 hours.
exposure to oral budesonide. Therefore, it cannot be excluded only be started in the presence of effective alpha blockade)
that also concomitant administration of ENTOCORT rectal Biotransformation
Budesonide undergoes an extensive degree (approximately 90%) of DOSAGE AND ADMINISTRATION
suspension and ketoconazole may result in increased systemic
availability of budesonide. See also Interactions. biotransformation on rst passage through the liver to metabolites Since the half-life may be increased in patients with signicant
of low glucocorticosteroid activity. The glucocorticosteroid hepatic or renal impairment, caution must be exercised when
If ENTOCORT is used chronically in excessive doses,
activity of the major metabolites (6-beta-hydroxybudesonide starting treatment and selecting the initial dose.
characteristic systemic glucocorticosteroid effects such as
and 16-alpha-hydroxyprednisolone) is less than 1% of that of
hypercorticism and adrenal suppression may appear. If this occur, ORAL DOSAGE
budesonide. The metabolism of budesonide is primarily mediated
the dosing of ENTOCORT should be withdrawn gradually in the Adults
by CYP3A, a subfamily of cytochrome 450.
same way as after long-term use of oral glucocorticosteroids. The
Elimination Hypertension: A starting dose of 80mg twice a day may be
dosage form - rectal suspension - and the route of administration
The metabolites are excreted unchanged or in conjugated increased at weekly intervals according to response. The usual
make any prolonged overdosage of ENTOCORT rectal
form, mainly via the kidneys. No intact budesonide has been dose range is 160-320mg per day and the maximum daily dose
suspension unlikely.
detected in the urine. Budesonide has a high systemic clearance must not exceed 640mg per day (see summary table below).
INTERACTION (approximately 1.2 litres/minute), and the plasma half-life after i.v. With concurrent diuretic or other antihypertensive drugs a further
The metabolism of budesonide is primarily mediated by CYP3A, dosing averages 2-3 hours. reduction of blood pressure is obtained.
a subfamily of cytochrome 450. Inhibition of this enzyme by e.g. The kinetics of budesonide are linear with dose (as evidenced by Angina, anxiety, migraine and essential tremor: A starting
ketoconazole can therefore increase the systemic exposure to dose-proportional increases of Cmax and AUC after oral dosing of dose of 40mg two or three times daily may be increased by the
budesonide, see Special warning and precautions for use. 3.9 and 15 mg budesonide given as ENTOCORT capsules). same amount at weekly intervals according to patient response.
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An adequate response in anxiety, migraine and essential tremor is responses to hypoglycaemia which includes glycogenolysis, beta-blocker therapy, the introduction of beta-blockers should
usually seen in the range 80-160mg/day, and in angina in the range gluconeogenesis and/or impaired modulation of insulin secretion. be delayed for several days after clonidine administration has
120-240mg/day. A maximum daily dose of 240mg for migraine Patients at risk for an inadequate response to hypoglycaemia stopped.
and 480mg for angina must not be exceeded (see summary table). includes individuals with malnutrition, prolonged fasting, Caution must be exercised if ergotamine, dihydroergotamine or
Arrhythmias, anxiety tachycardia, hypertrophic obstructive starvation, chronic liver disease, diabetes and concomitant use of related compounds are given in combination with INDERAL
cardiomyopathy and thyrotoxicosis: A dosage range of 10- drugs which block the full response to catecholamines. since vasospastic reactions have been reported in a few patients.
40mg three or four times a day usually achieves the required WARNINGS AND PRECAUTIONS Concomitant use of prostaglandin synthetase inhibiting drugs, e.g.
response. A maximum daily dose of 240mg for arrhythmias must INDERAL as with other beta-blockers: ibuprofen and indomethacin, may decrease the hypotensive effects
not be exceeded. (see summary table). of INDERAL.
- although contraindicated in uncontrolled heart failure (see
Post-myocardial infarction: Treatment should start between days Contra-Indications), may be used in patients whose signs of Concomitant administration of INDERAL and chlorpromazine
5 and 21 after myocardial infarction, with an initial dose of 40mg heart failure have been controlled. Caution must be exercised may result in an increase in plasma levels of both drugs. This may
four times a day for 2 or 3 days. In order to improve compliance in patients whose cardiac reserve is poor. lead to an enhanced antipsychotic effect for chlorpromazine and an
the total daily dosage may thereafter be given as 80mg twice a day - although contraindicated in severe peripheral arterial circulatory increased antihypertensive effect for INDERAL.
(see summary table). disturbances (see Contra-Indications), may also aggravate less Caution must be exercised when using anaesthetic agents with
Phaeochromocytoma: (INDERAL is to be used only in the severe peripheral arterial circulatory disturbances. INDERAL. The anaesthetist should be informed and the choice
presence of effective alpha-blockade). Preoperative: 60mg daily - due to its negative effect on conduction time, caution must be of anaesthetic should be an agent with as little negative inotropic
for three days is recommended. Non-operable malignant cases: exercised if it is given to patients with rst degree heart block. activity as possible. Use of beta-blockers with anaesthetic drugs
30mg daily (see summary table). may block/modify the signs and symptoms of hypoglycaemia may result in attenuation of the reex tachycardia and increase
(especially tachycardia). INDERAL occasionally causes the risk of hypotension. Anaesthetic agents causing myocardial
Summary Table of Inderal Oral Dosage - Adults depression are best avoided.
hypoglycaemia, even in non-diabetic patients, e.g., neonates,
(in divided daily doses)
infants, children, elderly patients, patients on haemodialysis Pharmacokinetic studies have shown that the following agents
Min/day Max/day or patients suffering from chronic liver disease and patients may interact with propranolol due to effects on enzyme systems
Hypertension 160mg 640mg suffering from overdose. in the liver which metabolise propranolol and these agents:
Angina pectoris 80mg 480mg Severe hypoglycaemia associated with INDERAL has rarely quinidine, propafenone, rifampicin, theophylline, warfarin,
Arrhythmias 30mg 240mg presented with seizures and/or coma in isolated patients. Caution thioridazine and dihydropyridine calcium channel blockers such
must be exercised in the concurrent use of INDERAL and as nifedipine, nisoldipine, nicardipine, isradipine and lacidipine.
Migraine 80mg 240mg
hypoglycaemic therapy in diabetic patients. INDERAL may Owing to the fact that blood concentrations of either agent may
Tremor 40mg 160mg prolong the hypoglycaemic response to insulin. be affected dosage adjustments may be needed according to
Anxiety 80mg 160mg - may mask the signs of thyrotoxicosis. clinical judgement. (See also the Interaction above concerning
Anxiety Tachycardia 30mg 160mg the concomitant therapy with dihydropyridine calcium channel
- will reduce heart rate, as a result of its pharmacological action.
blockers).
Thyrotoxicosis 30mg 160mg In the rare instances when a treated patient develops symptoms
Cardiomyopathy 30mg 160mg which may be attributable to a slow heart rate, the dose may PREGNANCY AND LACTATION
Phaeochromocytoma 60mg (pre op) 60mg be reduced. Pregnancy
30mg (maintenance) 30mg - should not be discontinued abruptly in patients suffering from As with all drugs INDERAL should not be given during
ischaemic heart disease. pregnancy unless its use is essential. There is no evidence of
Post-infarction 160mg 160mg
Either the equivalent dosage of another beta-blocker may be teratogenicity with INDERAL. However beta-blockers reduce
Elderly substituted or the withdrawal of INDERAL should be placental perfusion, which may result in intra-uterine foetal death,
Evidence concerning the relation between blood level and age is gradual. immature and premature deliveries. In addition, adverse effects
conicting. With regard to the elderly, the optimum dose should - may cause a more severe reaction to a variety of allergens, when (especially hypoglycaemia and bradycardia in the neonate and
be individually determined according to clinical response. given to patients with a history of anaphylactic reaction to such bradycardia in the foetus) may occur. There is an increased risk
Children allergens. Such patients may be unresponsive to the usual doses of cardiac and pulmonary complications in the neonate in the post-
of adrenalin used to treat the allergic reactions. natal period.
Dosage should be individually determined and the following is
only a guide: INDERAL must be used with caution in patients with Lactation
decompensated cirrhosis. Most beta-blockers, particularly lipophilic compounds, will pass
Arrhythmias, phaeochromocytoma, thyrotoxicosis: Oral: 0.25
- 0.5mg/kg three or four times daily as required. In patients with signicant hepatic or renal impairment care should into breast milk although to a variable extent. Breast-feeding is
be taken when starting treatment and selecting the initial dose. therefore not recommended following administration of these
Migraine: Oral: Under the age of 12: 20mg two or three times
In patients with portal hypertension, liver function may deteriorate compounds.
daily.
and hepatic encephalopathy may develop. There have been reports EFFECT ON ABILITY TO DRIVE OR OPERATE
Over the age of 12: the adult dose
suggesting that treatment with propranolol may increase the risk of MACHINERY
Intravenous Dosage developing hepatic encephalopathy.
The intravenous injection is intended for the emergency treatment Use is unlikely to result in any impairment of the ability of patients
INTERACTIONS WITH OTHER MEDICAMENTS AND to drive or operate machinery. However it should be taken into
of cardiac arrhythmias and thyrotoxic crisis only. OTHER FORMS OF INTERACTION account that occasionally dizziness or fatigue may occur.
Adults INDERAL modies the tachycardia of hypoglycaemia. POSSIBLE ADVERSE REACTIONS
The initial dose is 1mg (1 ml) injected over one minute. This may Caution must be exercised in the concurrent use of INDERAL
be repeated at two minute intervals until a response is observed, and hypoglycaemic therapy in diabetic patients. INDERAL INDERAL is usually well tolerated. In clinical studies the
or to a maximum dose of 10 mg in conscious patients or 5mg in may prolong the hypoglycaemic response to insulin (see possible adverse reactions reported are usually attributable to the
patients under anaesthesia. Contraindications, Warnings and Precautions). pharmacological actions of propranolol.
Children Caution must be exercised in prescribing a beta-blocker with Class The following possible adverse reactions, listed by body system,
I antiarrhythmic agents such as disopyramide. have been reported.
Arrhythmias ) 0.025-0.05mg/kg injected slowly,
preferably Digitalis gyclosides in association with beta-blockers may increase Cardiovascular: bradycardia; heart failure deterioration;
atrioventricular conduction time. postural hypotension which may be associated with syncope;
Phaeochromocytoma ) under ECG control and repeated
cold extremities. In susceptible patients: precipitation of heart
3-4 times Combined use of beta-blockers and calcium channel blockers with
block; exacerbation of intermittent claudication; Raynauds
Thyrotoxicosis) daily as required. negative inotropic effects (eg verapamil, diltiazem) can lead to an
phenomenon.
exaggeration of these effects particularly in patients with impaired
CONTRA-INDICATIONS ventricular function and/or SA or AV conduction abnormalities. CNS: confusion; dizziness; mood changes; nightmares; psychoses
INDERAL must not be used if there is a history of bronchial This may result in severe hypotension, bradycardia and cardiac and hallucinations; sleep disturbances.
asthma or bronchospasm. failure. Neither the beta-blocker nor the calcium channel Endocrine: Hypoglycaemia in neonates, infants, children, elderly
Bronchospasm can usually be reversed by beta2- agonist blocker should be administered intravenously within 48 hours of patients, patients on hemodialysis, patients on concomitant
bronchodilators such as salbutamol. Large doses of the beta2- discontinuing the other. antidiabetic therapy, patients with prolonged fasting and patients
agonist bronchodilator may be required to overcome the beta- Concomitant therapy with dihydropyridine calcium channel with chronic liver disease has been reported. (see Contraindications,
blockade produced by propranolol and the dose should be blockers, e.g. nifedipine, may increase the risk of hypotension Warnings and Precautions and Interactions)
titrated according to the clinical response; both intravenous and and cardiac failure may occur in patients with latent cardiac Gastrointestinal: gastrointestinal disturbance.
inhalational administration should be considered. The use of insufciency. Haematological: purpura; thrombocytopenia.
intravenous aminophylline and/or the use of ipratropium, (given Concomitant use of sympathomimetic agents, e.g. adrenalin, may Integumentary: alopecia; dry eyes; psoriasiform skin reactions;
by nebuliser), may also be considered. Glucagon (1 to 2 mg given counteract the effect of beta-blockers. Caution must be exercised in exacerbation of psoriasis; skin rashes.
intravenously) has also been reported to produce a bronchodilator the parenteral administration of preparations containing adrenalin
effect in asthmatic patients. Oxygen or articial ventilation may to patients taking beta-blockers as, in rare cases, vasoconstriction, Neurological: paraesthesia.
be required in severe cases. hypertension and bradycardia may result. Respiratory: bronchospasm may occur in patients with bronchial
INDERAL as with other beta-blockers must not be used in Administration of INDERAL during infusion of lignocaine may asthma or a history of asthmatic complaints, sometimes with fatal
patients with any of the following: known hypersensitivity to the increase the plasma concentration of lignocaine by approximately outcome (see Contra-Indications).
substance; bradycardia; cardiogenic shock; hypotension; metabolic 30%. Patients already receiving INDERAL tend to have higher Special senses: visual disturbances.
acidosis; after prolonged fasting; severe peripheral arterial lignocaine levels than controls. The combination should be Others: fatigue and/or lassitude (often transient); an increase in
circulatory disturbances; second or third degree heart block; sick avoided. ANA (Antinuclear Antibodies) has been observed, however the
sinus syndrome; untreated (with an alpha adrenoceptor antagonist) Concomitant use of cimetidine or hydralazine increases, whereas clinical relevance of this is not clear; isolated reports of myasthenia
phaeochromocytoma; uncontrolled heart failure; Prinzmetal's concomitant use of alcohol decreases, the plasma levels of gravis like syndrome or exacerbation of myasthenia gravis have
angina. propranolol. been reported.
INDERAL must not be used in patients prone to hypoglycaemia, Beta-blockers may exacerbate the rebound hypertension which Discontinuance of the drug should be considered if, according
i.e., patients after prolonged fasting or patients with restricted can follow the withdrawal of clonidine. If the two drugs are to clinical judgement, the well-being of the patient is adversely
counter-regulatory reserves. Patients with restricted-counter co-administered, the beta-blocker should be withdrawn several affected by any of the above reactions. Cessation of therapy with
regulatory reserves may have reduced autonomic and hormonal days before discontinuing clonidine. If replacing clonidine by a beta-blocker should be gradual. In the rare event of intolerance,
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manifested as bradycardia and hypotension, the drug should be THERAPEUTIC INDICATIONS Potential For Inuence Of Other Drugs On Plasma Levels
withdrawn and, if necessary, treatment for overdosage instituted. Maintenance treatment to prevent recurrence of brillation, Effect Of Quinidine
OVERDOSAGE Paroxyamal supraventricular and ventricular tachycardia. Concomitant treatment with drugs that are substrates, inhibitors
Symptomatic ventricular ectopic beats. e.g. antimicrobials (such as erythromycin, troleandomycin &
The symptoms of overdosage may include bradycardia, clarithromycin)
hypotension, acute cardiac insufciency and bronchospasm. POSOLOGY & METHOD OF ADMINISTRATION
Antifungal (such as ketoconazole, uconazole, itraconazole
General treatment should include: close supervision, treatment in Initiation of treatment, as with other antiaarrhythmic agent used
&miconazole & ritonavir) or inducers of CYP3A4 (e.g
an intensive care ward, the use of gastric lavage, activated charcoal to treat life threatening ventricular anhythmias, should be carried
carbamazepine, rifampicine & Phenobarbital) has the potential to
and a laxative to prevent absorption of any drug still present in the out in hospital.
inuence the metabolism & hence the plasma levels & affected
gastrointestinal tract, the use of plasma or plasma substitutes to The quinidine dose should be adjusted individually, & and the dose of quinidine. Concomitant administration with the substrate
treat hypotension and shock. should preferably be established by determination of the serum /inhibitors erythromycin, itraconazole, ketoconazole & the
Excessive bradycardia can be countered with atropine 1-2mg concentration after about one week of treatment .Therapeutic substrates amiodarone,ditiazem,nifedipine,& varepamil have in
intravenously and/or a cardiac pacemaker. If necessary, this may plasma concentration range is 1-6 mg /l (3-18 mcg mol/l).The Qt- increased plasma levels of quinidine.
be followed by a bolus dose of glucagon 10mg intravenously. time should be checked before & during treatment .Normal dose
Furthermore, the plasma levels of quinidine have been reported
If required, this may be repeated or followed by an intravenous is 2-5 tablet (0.4-1.0 g) morning & evening .The normal dose for
to increase during concomitant administration with cimetidine,
infusion of glucagon 1-10mg/hour depending on response. If no maintenance treatment after conversion of atrial brillation is 3
which has an unspecied inhibitory effect on CYP (including
response to glucagon occurs or if glucagon is unavailable, a beta- tablets (0.6 g) morning &evening.
CYP3A4) mediated metabolism.
adrenoceptor stimulant such as dobutamine 2.5 to 10 micrograms/ Concomitant food intake may increase the tolerability.
During concomitant administration with Phenobarbital, phenytoin,
kg/minute by intravenous infusion may be given. Dobutamine, The tablets should not be broken or chewed, but must be swallowed & rifampicin, which are inducers of CYP3A4, decreased plasma
because of its positive inotropic effect could also be used to treat whole together with liquid. levels of quinidine have been reported.
hypotension and acute cardiac insufciency. It is likely that Impaired Renal function
these doses would be inadequate to reverse the cardiac effects of USE IN PREGNENCY & LACTATION.
No dose adjustment is needed. Among patients with advanced
beta-blockade if a large overdose has been taken. The dose of In both animal & man, high doses of quinine have led to fetal
renal disease, quinidine clearance is modesty decreased .Thus;
dobutamine should therefore be increased if necessary to achieve damage in the form of deafness, impaired development &
dosage requirements in this patient are similar to those in other
the required response according to the clinical condition of the malformation of extremities & cranium.Owing to the contractile
patients.
patient. effect on the uterus, there is also a risk of induction of abortion. In
Impaired Hepatic Function view of the chemical similarities between quinine & quinidine, the
PHARMACOLOGICAL PROPERTIES Reduced dosage should be considered for patient hepatic latter should not be given during pregnancy.
PHARMACODYNAMIC PROPERTIES impairment Enters breast milk is not likely to affect the infant when therapeutic
Propranolol is a competitive antagonist at both the beta1- and beta2- The quinidine dose should preferably be established by doses are used
adrenoceptors. It has no agonist activity at the beta-adrenoceptor, determination of the serum concentration .the therapeutic plasma
but has membrane stabilising activity at concentrations exceeding concentration range is 1-6 mg/l EFFECT ON ABILITY TO DRIVE OR USE MACHINES.
1-3mg/litre, though such concentrations are rarely achieved during Elderly Patients should know how they react to quinidine before they drive
oral therapy. Competitive beta-adrenoceptor blockade has been or use machines.
Reduced dosage should be considered.
demonstrated in man by a parallel shift to the right in the dose- UNDESIRABLE EFFECTS:
Children
heart rate response curve to beta agonists such as isoprenaline.
Reduced dosage should be considered. Gastrointestinal adverse reaction is frequent & occurs in
Propranolol, as with other beta-blockers, has negative inotropic approximately 30 % of the patients.
effects, and is therefore contraindicated in uncontrolled heart CONTRAINDICATIONS
Gastrointestinal: Diarrhea, nausea & vomiting.
failure (See Warnings/Precautions). Known hypersensitivity to quinidine or quinine.Second- degree or
Central & peripheral nervous system: rarely signs of
Propranolol is a racemic mixture and the active form is the S(-) complete AV block in absence of pacemaker.Previous or current
cinchonism, e.g. tinnitus, blurred vision, headache & dizziness.
isomer, of propranolol. With the exception of inhibition of the thrombocytopenia. Prolonged Qt interval .Digital intoxication.
conversion of thyroxine to triiodothyronine it is unlikely that any Cardiovascular: Arrhythmias such as ventricular tachycardia,
SPECIAL WARNING & PRECAUTION FOR USE mostly of the tosades de pointes type or ventricular brillation.
additional ancillary properties possessed by R(+) propranolol, in
comparison with the racemic mixture will give rise to different The patient should be observed after the rst dose with special Rarely hypotension & bradycardia, which lead to cardiac arrest.
therapeutic effects. attention to hypersensitivity reaction .Quinidine should be Hypersensitivity reactions: Rarely urticaria, skin rash & fever
administered with caution to patients with prolonged AV- in isolated cases hepatitis, thrombocytopenia, pancytopenia
Propranolol is effective and well-tolerated in most ethnic
conduction, sustained decompensation, cardiogenic shock, .agranulocytosis, photosensitization, lupus erythematosis like
populations, although the response may be less in black patients.
hypotension, bradycardia or disturbed potassium balance. syndrome, vasculitis, myalgia & arthralgia.
PHARMACOKINETIC PROPERTIES Hypokalaemia should be corrected before quinidine treatment is Miscellaneous: In isolated cases fatigue.
Following intravenous administration the plasma half-life of started.
propranolol is about 2 hours and the ratio of metabolites to parent Heart failure, myocanitis or severe myocardial damage also OVER DOSAGE
drug in the blood is lower than after oral administration. In requires caution Symptoms
particular 4-hydroxypropranolol is not present after intravenous Caution is indicated in combined therapy with other class 1 Blurred vision, deafness, vertigo, linnitus, headache, hypotension,
administration. Propranolol is completely absorbed after oral antiarrhythmic drugs, blockers & digital glucocides nausea, vomiting & diarrhea may be present in varying degrees.
administration and peak plasma concentrations occur 1-2 hours Over dosage may give rise to widening of the QRS complex,
In patients treated with digoxin, the digoxin dosage should be
after dosing in fasting patients. The liver removes up to 90% of an halved if quinidine is given in addition. atrioventricular block, ventricular brillation & asystole.
oral dose with an elimination half-life of 3 to 6 hours. Propranolol
Like other antiarrhythmic drugs quinidine may worsen Serious hypersensitivity reactions are manifested by respiratory
is widely and rapidly distributed throughout the body with highest
arrhythmias. embarrassment or vascular collapse. Sedation & convulsion may
levels occurring in the lungs, liver, kidney, brain and heart.
At toxic quinidine concentration, & in some patients even at also occur. Lethal outcome has been reported after 4-8 g.
Propranolol is highly protein bound (80-95%).
therapeutic levels, the Qt- interval may be considerably prolonged, Management
PHARMACEUTICAL PARTICULARS which increases the risk of ventricular tachycardia, often of Discontinue medication at rst sign of toxicity. Delay absorption
Compatibility With Intravenous Infusion Fluids the torsades de pointes type & in some cases also ventricular of ingested quinidine by giving water, milk or activated charcoal
INDERAL injection is compatible with 0.9% w/v sodium brillation. & then remove by gastric lavage or emesis.General supportive
chloride and 5% w/v dextrose. KINIDIN DURULES should be used with caution in presence measures should be employed as indicated by patient response.
STORAGE of obstruction of the esophagus in the digestive tract, especially in PHARMACOLOGICAL PROPERTIES
patients with constriction of complications.
INDERAL tablets: do not store above 30C. Protect from light Quinidine reduces the excitability , automaticity & the duration
and moisture. INTERACTIONS of the action potential & the effective refractory period (class 1
INDERAL injection: do not store above 30C. Protect from It is possible to explain observed drug-drug interactions even in A according to Vaughan William & Harrison).These effect are
light. certain cases predict the potential for drug-drug interactions based closely related to the blockade of the Fast sodium channels in
on the site of metabolism or excretion or other pharmacologic the cell membranes, resulting in a reduced rate of the rise of the
SHELF LIFE effects of a drug .Quinidine is completely metabolized. action potential (phase 0) & thus slower conduction & reduced
INDERAL tablets: Please refer to expiry date on the blister Potential for inuence of quinidine on the plasma levels, effects automaticity in Purkinje bers (phase 4) , & to blockade of
strip or outer carton. of other drugs: potassium channels, resulting in delayed repolarisation .The
` Please refer to expiry date on the label or outer carton. sodium channel effect is considerably diminished when the
Quinidine is metabolized by cytochroma p4503aa (cyp3a4) & extracellular potassium concentration is reduced , while the
PACK SIZE thus has the potential to inhibit the metabolism of other drugs potassium channel effect potentiated.
metabolized by this enzymes, resulting in increased plasma levels
Please refer to the outer carton for pack size. The direct electrophysiological effect of quinidine is modied
of these. This has been reported for contain derivatives, such as
Trade Marks herein are the property of the AstraZeneca group. warfarin & nifedipine by a relatively pronounced anticholinergic effect, dominating
particularly at lower plasma concentrations. The frequency of the
Quinidine has also been shown to every potently inhibit another sinus node & the AV node velocity concentrations. The frequency
KINIDIN DURULES 200 mg Tablets CYP isoform CYP2D6 . Consequently quinidine has the potential of the sinus node & the AV node velocity may therefore
to inhibit the metabolized by CYP2D6, resulting in increased increase.
plasma levels of these. This has been reported for amitriptyline,
(Quinidine sulphate) codeine, desipramine, desmethylclomipramine ,dextromethorphan, Quinidine in therapeutic plasma concentration increases the PQ,
ecainide, uxetine, haloperiodol, imipramine, metoprolol, QRS & QT interval(see also special warnings and precautions
COMPOSITION mexiletine, mianserin,noruxoetine, nortriptyline, perphenazine, for use).
Each tablet contains: 250 mg of quinidine bisulphate, equivalent to phenoliazines, propafenono, propranolol, thioridazine, tiolol, & Quinidine has a negative intropic action which is of no important
zucopenthixol. at therapeutic plasma concentration if myocardial contractility is
200mg of quinidine sulphate excipient, coloring (titanium dioxide)
In addition, quinidine has reported to increase the plasma levels of not impaired. If the myocardial function is reduced, however, heart
q.s
digitioxin, digoxin & procainamide.Part of the explanation for the failure may result.
PHARMACEUTICAL FORM effect on digoxin & procainamid is a decreased renal excretion of Quinidine has a certain vasodilatation affect & thus decreases the
Prolonged action quinidine preparation. this quinidine & atenolol has resulted in ortostatic hypotension. peripheral vascular resistance
55
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The oral bioavaiability of quinidine is 70%-80% .The absorption is any of the following alarm symptoms: signicant unintentional Rare Liver: Encephalopathy in patients
not inuenced by concomitant intake of food. weight loss, recurrent vomiting, dysphagia, haematemesis or
(>1/10000, with severe hepatic disease,
The apparent volume of distribution is approximately 3 L per melena, malignancy should be excluded as treatment may alleviate
<1/1000) hepatitis with or without
kg .Plasma protein binding is 70-95%.The biological half life symptoms and delay diagnosis.
jaundice, liver failure.
in the elimination phase is approximately 6 hours & the dose is INTERACTIONS Respiratory tract: Bronchospasm.
almost entirely excreted in the urine, 10-20% as unchanged drug
.Alkaline urine prolongs the elimination time. Effects of omeprazole on the pharmacokinetics of other drugs Musculoskeletal: Arthralgia, muscular
The following combinations with LOSEC powder for solution for weakness and myalgia.
Therapeutic afcacy has been shown to occur when plasma levels
infusion should be avoided: ketoconazole and itraconazole. Psychiatric: Reversible confusion,
range from 1 to 6 mg/l (3 to 18 mol/l), using modern, more
specic, and hplc methodology. Omeprazole might inuence the absorption of other drugs due to agitation, depression,
its effect on the gastric pH. aggression and hallucinations,
The Durules formulation provides gradual release of active
substance, thereby reducing the plasma concentration peaks. The dissolution of ketoconazole tablets in the stomach is adversely especially in severely ill
Compared to ordinary tablets, the absorption phase is prolonged affected if the pH of the gastric juice increases as a result of drug patients.
& a mole constant & prolonged effect is achieved, reducing the treatment (antacids, secretion-inhibiting agents, sucralfate). This Genitourinary: Interstitial nephritis.
number of doses needed per day .The peak serum concentration leads to ineffective plasma concentrations of ketoconazole. During Eyes: Blurred vision.
is reached 4 hours after intake of kindin Durules .The continuous concomitant administration of omeprazole and itraconazole the
administration of quinidine reduces the risk of reoccurrence of Isolated cases of Stevens-Johnson syndrome and toxic epidermal
plasma concentration and AUC of itraconazole are reduced by
arrhythmia. necrolysis have been reported, but a relationship with omeprazole
approximately 65 %, probably as a result of poorer absorption,
could not be established. In severely ill patients, in isolated cases
The durules matrix in KINDLIN DURULES is completely which is dependent on pH.
irreversible visual disturbances have been reported in connection
insoluble in the digestive juices but usually distingrates into small Omeprazole inhibits the enzyme CYP2C19 and therefore increased with treatment with high doses of omeprazole given as intravenous
particles when all active drugs have been released. plasma levels of other drugs (diazepam, warfarin, phenytoin) injection. However, no causal relationship with omeprazole could
The empty skeleton occasionally passes through the gastrointestinal metabolised via this enzyme might be expected. A dose reduction be established.
tract without disintegrating, however, & appears in the feces in of these drugs may be necessary.
apparently unchanged form. OVERDOSE
During concomitant administration of clarithromycin or
Intravenous doses up to 270 mg in a day and up to 650 mg over
LIST OF EXCIPIENTS: erythromycin and omeprazole the plasma concentrations of
a three-day period have been studied in clinical trials without any
omeprazole were increased. The plasma concentrations of
Polyvinyl chloride, polyvinyl acetate, polyethylene glycol, dose-related adverse reactions.
omeprazole are not inuenced during concomitant administration
magnesium atearate, ethanol 95% (v/v), hydroxypropyl Symptoms: Dizziness, apathy, headache, tachycardia. Nausea,
methylcellulose Titanium dioxide E171, Parafn, Hydrogen with amoxicillin or metronidazole.
vomiting, atulence, diarrhoea. See also Undesirable effects.
peroxide 30%, Water puried .Evaporate during manufacturing Co-administration of omeprazole (40 mg once daily) with
process atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted PHARMACODYNAMIC PROPERTIES
in a substantial reduction in atazanavir exposure (approximately ATC code: A02B C01
SPECIAL PRECAUTION FOR STORAGE: 75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir Acid-inhibiting agents proton pump inhibitors.
Do not above 30 C. dose to 400 mg did not compensate for the impact of omeprazole Omeprazole is a substituted benzimidazole. Omeprazole is a
PACK SIZE on atazanavir exposure. PPIs including omeprazole should not be racemate of two active enantiomers. The secretion of hydrochloric
co-administered with atazanavir (see Contraindications). acid in the stomach is inhibited by omeprazole through its specic
Please see outer pack.
Concomitant administration of omeprazole and tacrolimus may effect on the proton pump in the parietal cells. The effect on
SHELF LIFE: result in increased serum concentration of tacrolimus. Monitoring acid secretion is reversible. Omeprazole is a weak base, which
Please see cuter pack. of the tacrolimus plasma concentration is recommended when is concentrated and converted into active form in the acidic
Trade Marks herein are the propery of the Astrazeneca group. omeprazole treatment is initiated or ended. environment in the parietal cell, where it inhibits H+, K+-ATPase,
i.e. the nal step in the production of the gastric acid. The inhibition
EFFECTS OF OTHER DRUGS ON THE PHARMACOKI- is dose-dependent, and affects both basal and stimulated acid
LOSEC 40 mg Powder for solution for infusion NETICS OF OMEPRAZOLE secretion, irrespective of the type of stimulation. Omeprazole does
Drugs inhibiting the enzymes CYP2C19 or CYP3A (HIV protease not affect cholinergic or histaminergic receptors. Like treatment
inhibitors, ketoconazole, itraconazole) might increase the plasma with H2-receptor blockers, treatment with omeprazole results in
(Omeprazole Sodium) concentrations of omeprazole. reduced acidity in the stomach and thus an increase in gastrin
in proportion to the reduction in acidity. The gastrin increase is
No interactions between omeprazole and antacids, theophylline,
COMPOSITION reversible. During long-term treatment the frequency of glandular
caffeine, quinidine, lidocaine, propranolol, metoprolol or ethanol
cysts in the stomach may increase. These changes are physiological
1 vial of dry substance contains: Omeprazole sodium equivalent have been detected.
and a consequence of the inhibition of acid secretion. They are
to omeprazole 40 mg.
PREGNANCY AND LACTATION benign and reversible.
For excipients see List of excipients.
Pregnancy. Well-conducted epidemiological studies indicate no Decreased gastric acidity with proton pump inhibitors or other
PHARMACEUTICAL FORM adverse effects of omeprazole on pregnancy or on the health of the acid-inhibiting agents, increases the amount of bacteria normally
Powder for solution for infusion foetus/newborn child. Omeprazole can be used during pregnancy. present in the gastrointestinal tract, why such treatment may lead
INDICATIONS to a slightly increased risk of gastrointestinal infections such as
Lactation. Omeprazole is excreted in breast milk. Inuence, if
Salmonella and Campylobacter.
Duodenal ulcer, gastric ulcer and reux oesophagitis. Zollinger- any, on the child is unknown.
Ellison syndrome. No pharmacodynamic effects of clinical signicance other than
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES those due to the effect of omeprazole on acid secretion have been
POSOLOGY AND METHOD OF ADMINISTRATION found. The effect on acid secretion is directly correlated to the area
LOSEC is not likely to affect the ability to drive or use machines
Duodenal ulcer, gastric ulcer and reux oesophagitis: Patients under the plasma concentration curve (AUC), but not to the actual
who cannot be given oral medication can be treated parenterally UNDESIRABLE EFFECTS plasma concentration of omeprazole.
with 40 mg once daily. The usual treatment period before transfer The most common symptoms that have been reported in clinical Intravenous administration of LOSEC 40 mg results in an
to oral treatment is 2-3 days. trials with LOSEC have been gastrointestinal, such as diarrhoea, immediate reduction of hydrochloric acid secretion. A single dose
In Zollinger-Ellison syndrome the dose should be adjusted nausea and constipation, and also headache, each one in 1 3 % of 40 mg intravenously has approximately the same effect on the
individually. Higher doses and/or several doses daily may be of cases. acidity of the gastric juice for 24 hours as a single oral dose of 80
required. mg or repeated oral administration of 20 mg once daily
Common General: Headache.
Intravenous treatment can be given as an infusion over a (>1/100, Gastrointestinal: Headache.Diarrhoea, nausea/ PHARMACOKINETIC PROPERTIES
period of 20-30 minutes. After reconstitution start the infusion <1/10) vomiting, constipation, Absorption
immediately. abdominal pain, atulence. Binding to plasma proteins is approximately 95 % and the volume
Impaired renal function Less common General: Fatigue. of distribution is 0,3 L/kg.
A dose adjustment is not necessary for patients with impaired renal (>1/1000, Skin: Rash, pruritus, urticaria. Metabolism
function. <1/100) Liver: Changes in liver function Omeprazole is metabolised completely, mainly in the liver. Mainly
Impaired liver function tests. the enzymes CYP2C19 and CYP3A4 catalyse the metabolism.
In patients with impaired liver function clearance is greatly Neurological: Paraesthesia, dizziness, Identied metabolites are the sulphone, the sulphide and hydroxy-
reduced. drowsiness. omeprazole, which have no signicant effect on the acid secretion.
Elderly patients Psychiatric: Sleep disturbance. Total plasma clearance is 0.3-0.6 L/min.
A dose adjustment is not necessary in elderly patients. Rare General: Increased sweating, peripheral Elimination
Children (>1/10000, oedema, hyponatraemia. The half-life in plasma in the elimination phase is approximately
<1/1000) Hypersensitivity reactions 40 minutes (30-90 minutes) after multiple doses. Approximately 80
There is only limited experience of treatment in children. % of the metabolites are excreted via the urine and the remainder
such as angioedema, fever and
CONTRAINDICATIONS in the faeces.
anaphylactic shock.
Known hypersensitivity to omeprazole. Patient factors
Blood: Leukopenia,
Omeprazole like other PPIs should not be administered with ` thrombocytopenia, Clearance is greatly reduced in patients with impaired liver
atazanavir (see Interactions). function.
agranulocytosis,
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS pancytopenia. LIST OF EXCIPIENTS
FOR USE Endocrine: Gynaecomastia. Vial of active substance: Disodium edetate 1.5 mg, sodium
Suspected ulcer disease must be veried objectively at an early Gastrointestinal: Dry mouth, taste disturbances, hydroxide for pH adjustment.
stage by means of X-ray or endoscopy in order to avoid inadequate stomatitis, candidiasis. INCOMPATIBILITIES
treatment. Skin: Hair loss, photosensitivity, No known incompatibility when recommended instructions are
When gastric ulcer is present or suspected or in the presence of erythema multiforme. followed.
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SHELF LIFE A/OM. Each capsule contains omeprazole 20 mg as enteric coated doses for two weeks. In clinical studies daily doses of 1.5-3 g of
Please refer to the expiry date on the outer carton. pellets. amoxicillin have been used
LOSEC capsules 40 mg : hard gelatine capsules with an opaque or
PACK SIZE
reddish-brown body, marked 40 and an opaque reddish-brown cap LOSEC 40 mg once daily and clarithromycin 500 mg three
Please refer to the outer carton for pack size. marked A/OL. Each capsule contains omeprazole 40 mg as enteric times a day for two weeks.
SPECIAL PRECAUTIONS FOR STORAGE coated pellets.
To ensure healing in patients with active peptic ulcer disease, see
Do not store above 25C. Store in the outer carton. Sensitive to THERAPEUTIC INDICATIONS further dosage recommendations for Duodenal and Gastric ulcer.
light. LOSEC is indicated for the treatment of: In each regimen if the patient is still Hp positive, therapy may
Vials that have been taken out of their outer pack can be kept in - Duodenal ulcer be repeated.
normal indoor light for up to 24 hours. - Gastric ulcer, Reux oesophagitis
INSTRUCTIONS FOR USE AND HANDLING - NSAID associated gastric and duodenal ulcers or erosions The recommended dosage is LOSEC 20 mg once daily.
- Helicobacter pylori eradication in peptic ulcer disease Symptom resolution is rapid and in most patients healing occurs
Solution for infusion is obtained by dissolving powder for solution
- Reux oesophagitis, within 4 weeks. For those patients who may not be fully healed
for infusion in 100 ml sodium chloride 9 mg/ml or in 100 ml
- Symptomatic gastro-oesophageal reux disease after the initial course, healing usually occurs during a further 4
glucose 50 mg/ml. The stability of omeprazole is inuenced by the weeks' treatment period.
pH of the solution for infusion, why no other solvents or quantities - Acid related dyspepsia
should be used for dilution. - Zollinger Ellison syndrome In patients with severe reux oesophagitis LOSEC 40 mg once
daily is recommended and healing is usually achieved within 8
Reconstituted solution for infusion must be used within 12 hours POSOLOGY AND METHOD OF ADMINISTRATION weeks.
after reconstitution with sodium chloride 9 mg/ml. LOSEC capsules are recommended to be given in the morning For the long term management of patients with healed reux
Reconstituted solution for infusion must be used within 6 hours and swallowed whole with half a glass of water. The capsules oesophagitis the recommended dose is LOSEC 10 mg once
after reconstitution with glucose 50 mg/ml. should not be chewed or crushed. daily. If needed the dose can be increased to LOSEC 20-40 mg
PREPARATION For patients with swallowing difculties once daily.
1. With a syringe draw 5 ml of infusion solution from the infusion The capsule can be opened and the contents swallowed directly Symptomatic gastro-oesophageal reux disease
bottle or bag. with half a glass of water or after mixing the contents in a slightly The recommended dosage is LOSEC 20 mg daily. Symptom
acidic uid e.g. fruit juice or applesauce, or in non-carbonated relief is rapid. Patients may respond adequately to 10 mg daily,
water. The dispersion should be taken immediately (or within 30 and therefore individual dose adjustment should be considered.
minutes). Always stir just before drinking. Rinse it down with
If symptom control has not been achieved after 4 weeks treatment
half a glass of water.
with LOSEC mg daily, further investigation is recommended.
Alternatively patients can suck the capsule and swallow the pellets
with half a glass of water. Ingest without chewing the enteric- Acid related dyspepsia
coated pellets. In the relief of symptoms in patients with epigastric pain/
Duodenal ulcer discomfort with or without heartburn the recommended dosage is
LOSEC 20 mg once daily.
The recommended dosage in patients with an active duodenal ulcer
2. Add the infusion solution to the vial with the freeze-dried Patients may respond adequately to 10 mg daily and therefore this
is LOSEC 20 mg once daily. Symptom resolution is rapid and in
omeprazole, mix thoroughly making sure all omeprazole is dose could be considered as a starting dose.
most patients healing occurs within 2 weeks. For those patients
dissolved. If symptom control has not been achieved after 4 weeks
who may not be fully healed after the initial course, healing
usually occurs during a further 2 week treatment period. treatment with LOSEC 20 mg daily, further investigation is
In patients with poorly responsive duodenal ulcer LOSEC 40 mg recommended.
once daily is recommended and healing is usually achieved within Zollinger Ellison syndrome
4 weeks. In patients with Zollinger-Ellison syndrome the dosage should
For the prevention of relapse in patients with duodenal ulcer be individually adjusted and treatment continued as long as is
3. Draw the omeprazole solution back into the syringe. disease the recommended dose is LOSEC 10 mg once daily. clinically indicated. The recommended initial dosage is LOSEC
If needed the dose can be increased to LOSEC 20 40 mg once 60 mg daily. All patients with severe disease and inadequate
daily. response to other therapies have been effectively controlled and
For NSAID associated duodenal ulcers see NSAID associated more than 90% of the patients maintained on doses of LOSEC
4. Transfer the solution into the infusion bottle or bag. gastroduodenal lesions. 20 120 mg daily. When doses exceed Losec 80 mg daily, the dose
should be divided and given twice daily.
For eradication of Helicobacter pylori see Helicobacter pylori
(Hp) eradication regimens in peptic ulcer disease. Impaired renal function
Gastric ulcer Dose adjustment is not needed in patients with impaired
renal function.
The recommended dosage is LOSEC 20 mg once daily.
Symptom resolution is rapid and in most patients healing occurs Impaired hepatic function
within 4 weeks. For those patients who may not be fully healed As bioavailability and plasma half-life of omeprazole are increased
after the initial course, healing usually occurs during a further 4 in patients with impaired hepatic function a daily dose of 10-20 mg
weeks' treatment period. may be sufcient.
In patients with poorly responsive gastric ulcer LOSEC 40 mg Elderly
once daily is recommended and healing is usually achieved within Dose adjustment is not needed in the elderly.
5. Repeat 1-4 to make sure all omeprazole is transferred from the 8 weeks.
vial into the infusion bottle or bag. Children
For the prevention of relapse in patients with poorly responsive
There is only limited experience of treatment in children.
Alternative preparation for infusions in exible containers. gastric ulcer the recommended dose is LOSEC 20 mg once
1. Use a double ended transfer needle and attach to the injection daily. If needed the dose can be increased to LOSEC 40 mg once CONTRA-INDICATIONS
membrane of the infusion bag. Connect the other needle-end daily. Known hypersensitivity to omeprazole.
to the vial with freeze dried omeprazole. For eradication of Helicobacter pylori see Helicobacter pylori Omeprazole like other PPIs should not be administered with
2. Dissolve the omeprazole substance by pumping the infusion (Hp) eradication regimens in peptic ulcer disease. atazanavir (see Interactions).
solution back and forward between the infusion bag and the NSAID associated gastric ulcers, duodenal ulcers or SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
vial. gastroduodenal erosions in patients with or without continued FOR USE
3. Make sure all omeprazole is dissolved and remove the empty NSAID treatment
Suspected ulcer disease must be veried objectively at an early
vial and needle from the bag. The recommended dosage of LOSEC is 20 mg once daily. stage in the anamnesis by means of X-ray or endoscopy in order to
Losec is a trade mark of the AstraZeneca group of companies. Symptom resolution is rapid and in most patients healing occurs avoid inadequate treatment.
AstraZeneca 2006 within 4 weeks. For those patients who may not be fully healed
In the case of treatment of conrmed or suspected gastric ulcer, or
after the initial course, healing usually occurs during a further 4
if one or more of the following alarm symptoms occur, malignancy
weeks treatment period.
must be excluded, as treatment can mask symptoms and delay
LOSEC 20mg Capsules For the prevention of NSAID associated gastric ulcers, duodenal diagnosis: signicant unintentional weight loss, repeated vomiting,
LOSEC 10mg (N.R) and 40mg(N.R) ulcers, gastroduodenal erosions and dyspeptic symptoms the dysphagia, haematemesis or melaena. LOSEC has no effect on
recommended dosage of LOSEC is 20 mg once daily. motility disturbances in the gastrointestinal tract.
Helicobacter pylori (Hp) eradication regimens in peptic ulcer Since the frequency of remission in long-term treatment of
(Omeprazole) disease
endoscopically conrmed oesophagitis is lower in patients
Triple therapy regimens: treated with omeprazole 10 mg than in those treated with 20 mg
COMPOSITION LOSEC 20 mg, amoxicillin 1 g and clarithromycin 500 mg, all daily, patients who are being treated with 10 mg daily should be
Each capsule contains: Omeprazole 10 mg(N.R), 20 mg or 40 twice a day for one week monitored at regular intervals with endoscopy.
mg(N.R). or INTERACTIONS
For excipients see List of excipients. LOSEC 20 mg, metronidazole 400 mg (or tinidazole 500 mg), Effects of omeprazole on the pharmakokinetics of other drugs
PHARMACEUTICAL FORM and clarithromycin 250 mg all twice a day for one week
The following combinations with Losec should be avoided:
LOSEC capsules 10 mg : hard gelatine capsules with an opaque or ketoconazole and itraconazole.
pink body, marked 10 and an opaque pink cap marked A/OS. Each LOSEC 40 mg once daily with amoxicillin 500 mg and Omeprazole might inuence the absorption of other drugs due to
capsule contains omeprazole 10 mg as enteric coated pellets. metronidazole 400 mg both three times a day for one week. its effect on the gastric pH.
LOSEC capsules 20 mg : hard gelatine capsules with an opaque Dual therapy regimens: The dissolution of ketoconazole tablets in the stomach is adversely
pink body, marked 20 and an opaque reddish-brown cap marked LOSEC 40-80 mg daily with amoxicillin 1.5 g daily in divided affected if the pH of the gastric juice increases as a result of drug
57
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ASTRAZENECA
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treatment (antacids, secretion-inhibiting agents, sucralfate). This Frequency/ Common Less common Rare Binding to plasma proteins is approximately 95 % and the volume
leads to ineffective plasma concentrations of ketoconazole. During Organ system (>1/100, of distribution is 0,3 L/kg.
(>1/1000, (>1/10 000,
concomitant administration of omeprazole and itraconazole the Metabolism
plasma concentration and AUC of itraconazole are reduced by <1/10) <1/100) <1/1000)
Omeprazole is metabolised completely, mainly in the liver. Mainly
approximately 65 %, probably as a result of poorer absorption, Neurological: Paraesthesia. the enzymes CYP2C19 and CYP3A4 catalyse the metabolism.
which is dependent on pH. Dizziness, Identied metabolites are the sulphone, the sulphide and hydroxy-
Omeprazole inhibits the enzyme CYP2C19 and therefore increased drowsiness omeprazole, which have no signicant effect on the acid secretion.
plasma levels of other drugs (diazepam, warfarin, phenytoin) Psychiatric Sleep Reversible Total plasma clearance is 0.3-0.6 L/min. Omeprazole inhibits its
metabolised via this enzyme might be expected. A dose reduction disturbance confusion, own CYP2C19 catalysed metabolism. Therefore the bioavailability
of these drugs may be necessary. agitation, of omeprazole increases with approx. 50 % during multiple dose
During concomitant administration of clarithromycin or depression, treatment compare to single dose.
erythromycin and omeprazole the plasma concentrations of aggression and Elimination
omeprazole were increased. The plasma concentrations of hallucinations, The half-life in plasma in the elimination phase is approximately
omeprazole are not inuenced during concomitant administration especially in 40 minutes (30-90 minutes) after multiple doses. Approximately 80
with amoxicillin or metronidazole. severely ill % of the metabolites are excreted via the urine and the remainder
Co-administration of omeprazole (40 mg once daily) with patients. in the faeces.
atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted Genito-urinary: Interstitial nephritis. Patient factors
in a substantial reduction in atazanavir exposure (approximately Eyes: Blurred vision The bioavailability of omeprazole is not changed signicantly
75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir in elderly patients or patients with impaired renal function. In
dose to 400 mg did not compensate for the impact of omeprazole Isolated cases of Stevens-Johnson syndrome and toxic epidermal patients with impaired liver function the bioavailability increases.
on atazanavir exposure. PPIs including omeprazole should not be necrolysis have been reported, but a relationship with omeprazole Clearance is greatly reduced in these patients.
co-administered with atazanavir (see Contraindications). could not be established.
LIST OF EXCIPIENTS
Concomitant administration of omeprazole and tacrolimus may In clinical trials an increased frequency of adverse reactions
result in increased serum concentration of tacrolimus. Monitoring Disodium hydrogen phosphate dihydrate, hydroxypropyl cellulose,
involving the CNS (especially headache) and gastrointestinal
of the tacrolimus plasma concentration is recommended when hydroxypropyl methylcellulose, lactose anhydrous, magnesium
adverse reactions have been observed when omeprazole was given
omeprazole treatment is initiated or ended. stearate, mannitol, methacrylic acid co-polymer, microcrystalline
together with clarithromycin.
cellulose, macrogol (polyethylene glycol), sodium lauryl sulphate,
EFFECTS OF OTHER DRUGS ON THE PHARMACOKI- OVERDOSE iron oxide (E 172), titanium dioxide (E 171) and gelatine.
NETICS OF OMEPRAZOLE Probably low acute toxicity, 320-800 mg to adults resulted in low INCOMPATIBILITIES
Drugs inhibiting the enzymes CYP2C19 or CYP3A (HIV protease intoxication, 560 mg to adults resulted in moderate intoxication.
None known when instructions in Method of administration are
inhibitors, ketoconazole, itraconazole) might increase the plasma Symptoms: Dizziness, apathy, headache, confusion, blood vessel followed.
concentrations of omeprazole. dilatation, tachycardia. Nausea, vomiting, atulence, diarrhoea.
No interactions between omeprazole and antacids, theophylline, See also Undesirable effects. SHELF-LIFE
caffeine, quinidine, lidocaine, propranolol, metoprolol or ethanol Treatment: If necessary, gastric lavage, charcoal. Symptomatic Please refer to expiry date on the outer carton.
have been detected. therapy.
SPECIAL PRECAUTIONS FOR STORAGE
PREGNANCY AND LACTATION PHARMACOLOGICAL PROPERTIES Do not store above 30C. Replace cap rmly after use.
Pregnancy: Well-conducted epidemiological studies indicate no PHARMACODYNAMIC PROPERTIES PACK SIZE
adverse effects of omeprazole on pregnancy or on the health of the
Pharmacotherapeutic group: ATC-code: A02B C01 Please refer to outer carton for pack size.
fetus/newborn child. Omeprazole can be used during pregnancy.
Substance reducing gastric acid secretion proton pump inhibitor LOSEC is a trade mark of the of the AstraZeneca group of
Lactation: Omeprazole is excreted in breast milk. Inuence, if
Omeprazole is a substituted benzimidazole. Omeprazole is a companies.
any, on the child is unknown.
racemate of two active enantiomers. The secretion of hydrochloric AstraZeneca 2006
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES acid in the stomach is inhibited by omeprazole through its specic
LOSEC is not likely to affect the ability to drive or use effect on the proton pump in the parietal cells. The effect on
acid secretion is reversible. Omeprazole is a weak base, which LOSEC MUPS 10 mg, 20 mg, Tablet
machines.
is concentrated and converted into active form in the acidic LOSEC MUPS 40 MG(N.R)
UNDESIRABLE EFFECTS environment in the parietal cell, where it inhibits H+, K+-ATPase,
The most common symptoms that were reported in clinical trials i.e. the nal step in the production of the gastric acid. The
with omeprazole have been gastrointestinal, such as diarrhoea, inhibition is dose-dependent, and affects both basal and stimulated (Omeprazole Magnesium)
nausea and constipation, and also headache, each in 1-3 %. acid secretion, irrespective of the type of stimulation. Omeprazole
does not affect cholinergic or histaminergic receptors. COMPOSITION
Frequency/ Common Less common Rare
Like treatment with H2-receptor blockers, treatment with Each tablet contains: Omeprazole magnesium 10.3 mg, 20.6 mg
Organ system (>1/100, (>1/1000, (>1/10 000, omeprazole results in reduced acidity in the stomach and thus an and 41.3 mg(N.R) (corresponding to omeprazole 10 mg, 20 mg
<1/10) <1/100) <1/1000) increase in gastrin in proportion to the reduction in acidity. The and 40 mg).
General: Headache. Fatigue Increased sweating. gastrin increase is reversible. During long-term treatment the For excipients see List of excipients.
Peripheral oedema. frequency of glandular cysts in the stomach may increase. These
changes are physiological and a consequence of the inhibition of PHARMACEUTICAL FORM
Hyponatraemia.
Hypersensitivity acid secretion. They are benign and reversible. LOSEC MUPS tablets 10 mg : Light-pink, oblong, biconvex,
reactions such as Decreased gastric acidity with proton pump inhibitors or other lm-coated tablets engraved with on one side and 10 mg on
angio-oedema, fever acid-inhibiting agents, increases the amount of bacteria normally the other side. Each tablet contains omeprazole magnesium 10.3
and anaphylactic present in the gastrointestinal tract, why such treatment may lead mg as enteric coated pellets.
shock. to a slightly increased risk of gastrointestinal infections such as LOSEC MUPS tablets 20 mg: Pink, oblong, biconvex, lm-
Blood: Leucopenia, Salmonella and Campylobacter. coated tablets, engraved with on one side and 20 mg on the other
thrombocytopenia. No other pharmacodynamic effects of clinical signicance, other side. Each tablet contains omeprazole magnesium 20.6 mg as
agranulocytosis, than those due to the effect of omeprazole on acid secretion, have enteric coated pellets.
pancytopenia. been found. LOSEC MUPS tablets 40 mg(N.R): Dark red-brown, oblong,
Gynaecomastia. The effect on acid secretion is directly correlated to the area under biconvex, lm-coated tablets, engraved with on one side
Endocrine:
the plasma concentration curve (AUC), but not to the actual plasma and 40 mg and a score on the other side. Each tablet contains
Gastrointes Diarrhoea, Dry mouth, taste concentration of omeprazole. Oral administration of LOSEC 20 omeprazole magnesium 41.3 mg as enteric coated pellets.
tinal: nausea/ disturbances, mg produces a reduction in hydrochloric acid secretion within 2
vomiting, stomatitis, hours after administration. With repeated treatment once daily, THERAPEUTIC INDICATIONS
constipation, candidiasis. the full effect is obtained within 3-5 days. The degree of acidity LOSEC MUPS is indicated for the treatment of:
abdominal measured over 24 hours in duodenal ulcer patients is then reduced Duodenal ulcer
pain, on average by 80 %, and the reduction in pentagastrin-stimulated
Gastric ulcer
atulence. hydrochloric acid production is approximately 70 % 24 hours after
administration. The secretion-inhibiting effect is characterised by NSAID associated gastric and duodenal ulcers or erosions
Skin: Rash, Hair loss,
its long duration, and has subsided after approximately 5 days Helicobacter pylori eradication in peptic ulcer disease
pruritus, photosensitivity,
from the end of treatment. Reux oesophagitis
urticaria. erythema
multiforme. 1 capsule (20 mg) daily gives symptomatic relief after the rst Symptomatic gastro-oesophageal reux disease
Liver: Changes in Encephalopathy in dose, and healing is obtained within 2 weeks for the majority
of patients with duodenal ulcer; for gastric ulcer and reux Acid related dyspepsia
liver function patients with severe
oesophagitis within 4 weeks. Zollinger Ellison syndrome
tests. hepatic disease,
hepatitis with or Treatment with omeprazole increases the antibacterial effect of POSOLOGY AND METHOD OF ADMINISTRATION
without jaundice, some antibiotics on the bacterium Helicobacter pylori.
LOSEC MUPS tablets are recommended to be given in the
liver failure. PHARMACOKINETICS morning and swallowed whole with half a glass of water. The
Respiratory Bronchospasms. Absorption tablets must not be chewed or crushed.
tract For patients with swallowing difculties
The absorption of omeprazole takes place in the small intestine,
Musculoskel- Arthralgia, and is usually completed within 3-6 hours. The bioavailability of Break the MUPS tablet and disperse it in a spoonful of non-
etal: myalgia, muscle omeprazole after repeated oral administration is approximately 60 carbonated water - if so wished, mix with some fruit juices or
weakness. %. Concomitant intake of food does not affect the bioavailability. applesauce. The dispersion should be taken immediately (or within
58
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30 minutes). Always stir just before drinking. Rinse it down with Acid related dyspepsia No interactions between omeprazole and antacids, theophylline,
half a glass of water. DO NOT USE milk or carbonated water. In the relief of symptoms in patients with epigastric pain/ caffeine, quinidine, lidocaine, propranolol, metoprolol or ethanol
Ingest without chewing the enteric-coated pellets. discomfort with or without heartburn the recommended dosage is have been detected.
Duodenal ulcer LOSEC MUPS 20 mg once daily. PREGNANCY AND LACTATION
The recommended dosage in patients with an active duodenal Patients may respond adequately to 10 mg daily and therefore this Pregnancy: Well-conducted epidemiological studies indicate no
ulcer is LOSEC MUPS 20 mg once daily. Symptom resolution dose could be considered as a starting dose.
adverse effects of omeprazole on pregnancy or on the health of the
is rapid and in most patients healing occurs within 2 weeks. For If symptom control has not been achieved after 4 weeks treatment fetus/newborn child. Omeprazole can be used during pregnancy.
those patients who may not be fully healed after the initial course, with LOSEC MUPS 20 mg daily, further investigation is
healing usually occurs during a further 2 week treatment period. Lactation: Omeprazole is excreted in breast milk. Inuence, if
recommended.
any, on the child is unknown.
In patients with poorly responsive duodenal ulcer LOSEC Zollinger Ellison syndrome
MUPS 40 mg once daily is recommended and healing is usually EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
In patients with Zollinger-Ellison syndrome the dosage should
achieved within 4 weeks. Losec MUPS is not likely to affect the ability to drive or use.
be individually adjusted and treatment continued as long as is
For the prevention of relapse in patients with duodenal ulcer clinically indicated. The recommended initial dosage is LOSEC
disease the recommended dose is LOSEC MUPS 10 mg once UNDESIRABLE EFFECTS
MUPS 60 mg daily. All patients with severe disease and inadequate
daily. If needed the dose can be increased to LOSEC MUPS response to other therapies have been effectively controlled and The most common symptoms that were reported in clinical trials
20-40mg once daily. more than 90% of the patients maintained on doses of LOSEC with omeprazole have been gastrointestinal, such as diarrhoea,
For NSAID associated duodenal ulcers see NSAID associated 20 120 mg daily. When doses exceed LOSEC MUPS 80 mg nausea and constipation, and also headache, each in 1-3 %.
gastroduodenal lesions. daily, the dose should be divided and given twice daily. Frequency/ Common Less common Rare
For eradication of Helicobacter pylori see Helicobacter pylori Impaired renal function Organ (>1/100, <1/10) (>1/1000, (>1/10 000,
(Hp) eradication regimens in peptic ulcer disease. Dose adjustment is not needed in patients with impaired renal system <1/100) <1/1000)
Gastric ulcer function. General: Headache. Fatigue ncreased
The recommended dosage is LOSEC MUPS 20 mg once daily. Impaired hepatic function sweating.
Symptom resolution is rapid and in most patients healing occurs Peripheral
As bioavailability and plasma half-life of omeprazole are increased oedema.
within 4 weeks. For those patients who may not be fully healed in patients with impaired hepatic function a daily dose of 10-20 mg
after the initial course, healing usually occurs during a further 4 Hyponatraemia.
may be sufcient.
weeks' treatment period. Hypersensitivity
Elderly reactions such as
In patients with poorly responsive gastric ulcer LOSEC MUPS
Dose adjustment is not needed in the elderly. angio-oedema,
40 mg once daily is recommended and healing is usually achieved
Children fever and
within 8 weeks.
There is only limited experience of treatment in children. anaphylactic
For the prevention of relapse in patients with poorly responsive shock.
gastric ulcer the recommended dose is LOSEC MUPS 20 mg CONTRA-INDICATIONS Blood: Leucopenia,
once daily. If needed the dose can be increased to LOSEC
Known hypersensitivity to omeprazole. thrombocytope-
MUPS 40 mg once daily.
Omeprazole like other PPIs should not be administered with nia.
For eradication of Helicobacter pylori see Helicobacter pylori agranulocytosis,
atazanavir (see Interactions).
(Hp) eradication regimens in peptic ulcer disease pancytopenia..
NSAID associated ulcers or gastroduodenal erosions SPECIAL WARNINGS AND SPECIAL PRECAUTIONS Endocrine: Gynaecomastia.
NSAID associated gastric ulcers, duodenal ulcers or gastroduodenal FOR USE
erosions in patients with or without continued NSAID treatment Suspected ulcer disease must be veried objectively at an early Frequency/ Common Less common Rare
the recommended dosage of LOSEC MUPS is 20 mg once daily. stage in the anamnesis by means of X-ray or endoscopy in order to Organ (>1/100, <1/10) (>1/1000, (>1/10 000,
Symptom resolution is rapid and in most patients healing occurs avoid inadequate treatment. system <1/100) <1/1000)
within 4 weeks. For those patients who may not be fully healed In the case of treatment of conrmed or suspected gastric ulcer, or Gastrointes- Diarrhoea, Dry mouth, taste
after the initial course, healing usually occurs during a further 4 if one or more of the following alarm symptoms occur, malignancy tinal: nausea/ disturbances,
weeks treatment period. must be excluded, as treatment can mask symptoms and delay vomiting, stomatitis,
For the prevention of NSAID associated gastric ulcers, duodenal diagnosis: signicant unintentional weight loss, repeated vomiting, constipation, candidiasis.
ulcers, gastroduodenal erosions and dyspeptic symptoms the dysphagia, haematemesis or melaena. LOSEC MUPS has no abdominal pain,
recommended dosage of LOSEC MUPS is 20 mg once daily. effect on motility disturbances in the gastrointestinal tract. atulence.
Helicobacter pylori (Hp) eradication regimens in peptic ulcer Since the frequency of remission in long-term treatment of Skin: Rash, pruritus, Hair loss,
disease endoscopically conrmed oesophagitis is lower in patients urticaria. photosensitivity,
Triple therapy regimens: treated with omeprazole 10 mg than in those treated with 20 mg erythema
daily, patients who are being treated with 10 mg daily should be multiforme.
LOSEC MUPS 20 mg, amoxicillin 1 g and clarithromycin 500 Changes in Encephalopathy
monitored at regular intervals with endoscopy. Liver:
mg, all twice a day for one week
liver function in patients with
or INTERACTIONS
tests. severe hepatic
LOSEC MUPS 20 mg, metronidazole 400 mg (or tinidazole 500 Effects of omeprazole on the pharmakokinetics of other drugs disease, hepatitis
mg) and clarithromycin 250 mg, all twice a day for one week The following combinations with LOSEC MUPS should be with or without
or avoided: ketoconazole and itraconazole. jaundice, liver
LOSEC MUPS 40 mg once daily with amoxicillin 500 mg and Omeprazole might inuence the absorption of other drugs due to failure.
metronidazole 400 mg both three times a day for one week. its effect on the gastric pH. Respiratory Bronchospasms.
The dissolution of ketoconazole tablets in the stomach is adversely tract
Dual therapy regimens:
affected if the pH of the gastric juice increases as a result of drug Musculosk- Arthralgia,
LOSEC MUPS 40-80 mg daily with amoxicillin 1.5 g daily in eletal: myalgia,
divided doses for two weeks. In clinical studies daily doses of 1.5- treatment (antacids, secretion-inhibiting agents, sucralfate). This
leads to ineffective plasma concentrations of ketoconazole. During muscle weakness.
3 g of amoxicillin have been used Neurological: Paraesthesia.
concomitant administration of omeprazole and itraconazole the
or plasma concentration and AUC of itraconazole are reduced by Dizziness,
LOSEC MUPS 40 mg once daily and clarithromycin 500 mg approximately 65 %, probably as a result of poorer absorption, drowsiness
three times a day for two weeks. which is dependent on pH. Psychiatric Sleep Reversible
To ensure healing in patients with active peptic ulcer disease, see disturbance confusion,
Omeprazole inhibits the enzyme CYP2C19 and therefore increased
further dosage recommendations for Duodenal and Gastric ulcer. plasma levels of other drugs (diazepam, warfarin, phenytoin) agitation,
metabolised via this enzyme might be expected. A dose reduction depression,
In each regimen if the patient is still Hp positive, therapy may
be repeated. of these drugs may be necessary. aggression and
hallucinations,
Reux oesophagitis During concomitant administration of clarithromycin or
especially in
The recommended dosage is LOSEC MUPS 20 mg once daily. erythromycin and omeprazole the plasma concentrations of
severely ill
Symptom resolution is rapid and in most patients healing occurs omeprazole were increased. The plasma concentrations of
patients.
within 4 weeks. For those patients who may not be fully healed omeprazole are not inuenced during concomitant administration
with amoxicillin or metronidazole. Genito- Interstitial
after the initial course, healing usually occurs during a further 4 urinary: nephritis.
weeks' treatment period. Co-administration of omeprazole (40 mg once daily) with
atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted Eyes: Blurred vision
In patients with severe reux oesophagitis LOSEC MUPS 40
mg once daily is recommended and healing is usually achieved in a substantial reduction in atazanavir exposure (approximately Isolated cases of Stevens-Johnson syndrome and toxic epidermal
within 8 weeks. 75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir
necrolysis have been reported, but a relationship with omeprazole
dose to 400 mg did not compensate for the impact of omeprazole
For the long term management of patients with healed reux could not be established.
on atazanavir exposure. PPIs including omeprazole should not be
oesophagitis the recommended dose is LOSEC MUPS 10 mg In clinical trials an increased frequency of adverse reactions
co-administered with atazanavir (see Contraindications).
once daily. If needed the dose can be increased to LOSEC involving the CNS (especially headache) and gastrointestinal
MUPS 20-40 mg once daily. Concomitant administration of omeprazole and tacrolimus may
adverse reactions have been observed when omeprazole was given
result in increased serum concentration of tacrolimus. Monitoring
Symptomatic gastro-oesophageal reux disease together with clarithromycin.
of the tacrolimus plasma concentration is recommended when
The recommended dosage is LOSEC MUPS 20 mg daily. omeprazole treatment is initiated or ended. OVERDOSE
Symptom relief is rapid. Patients may respond adequately to 10
mg daily, and therefore individual dose adjustment should be EFFECTS OF OTHER DRUGS ON THE PHARMACOKI- Probably low acute toxicity, 320-800 mg to adults resulted in low
considered. NETICS OF OMEPRAZOLE intoxication, 560 mg to adults resulted in moderate intoxication.
If symptom control has not been achieved after 4 weeks treatment Drugs inhibiting the enzymes CYP2C19 or CYP3A (HIV protease Symptoms: Dizziness, apathy, headache, confusion, blood vessel
with LOSEC MUPS 20 mg daily, further investigation is inhibitors, ketoconazole, itraconazole) might increase the plasma dilatation, tachycardia. Nausea, vomiting, atulence, diarrhoea.
recommended. concentrations of omeprazole. See also Undesirable effects.
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Treatment: If necessary, gastric lavage, charcoal. Symptomatic SHELF-LIFE dose (based on the type and severity of infection) is administered
therapy. Please refer to expiry date on the outer carton. at the completion of the haemodialysis procedure to restore
therapeutically effective plasma concentrations.
PHARMACOLOGICAL PROPERTIES SPECIAL PRECAUTIONS FOR STORAGE
There is no experience with the use of 'MERONEM' in patients
PHARMACODYNAMIC PROPERTIES Do not store above 25C. Replace cap rmly after use. under peritoneal dialysis.
Pharmacotherapeutic group: ATC-code: A02B C01 PACK SIZE Dosage in Adults with Hepatic Insufciency
Substance reducing gastric acid secretion proton pump inhibitor Please refer to outer carton for pack size. No dosage adjustment is necessary in patients with hepatic
Omeprazole is a substituted benzimidazole. Omeprazole is a LOSEC is a trade mark of the AstraZeneca group of companies. insufciency (See " Special warnings and precautions for use").
racemate of two active enantiomers. The secretion of hydrochloric Elderly Patients
acid in the stomach is inhibited by omeprazole through its specic
effect on the proton pump in the parietal cells. The effect on MERONEM No dosage adjustment is required for the elderly with normal renal
function or creatinine clearance values above 50 ml/min.
acid secretion is reversible. Omeprazole is a weak base, which FOR INTRAVENOUS ADMINISTRATION
is concentrated and converted into active form in the acidic Children
environment in the parietal cell, where it inhibits H+, K+-ATPase, For children over 3 months and up to 12 years of age the
i.e. the nal step in the production of the gastric acid. The [Meropenem (as trihydrate)] recommended dose is 10 - 20 mg/kg every 8 hours depending on
inhibition is dose-dependent, and affects both basal and stimulated type and severity of infection, susceptibility of the pathogen and
acid secretion, irrespective of the type of stimulation. Omeprazole COMPOSITION the condition of the patient. In children over 50 kg weight, adult
does not affect cholinergic or histaminergic receptors. MERONEM IV is presented as a sterile white powder dosage should be used.
Like treatment with H2-receptor blockers, treatment with containing meropenem; 500mg or 1g as the trihydrate blended In meningitis the recommended dose is 40 mg/kg every 8 hours.
omeprazole results in reduced acidity in the stomach and thus an with anhydrous sodium carbonate for constitution. Meronem There is no experience in children with renal impairment.
increase in gastrin in proportion to the reduction in acidity. The IV injection contains 208mg sodium carbonate for each gram of
gastrin increase is reversible. During long-term treatment the meropenem (anhydrous potency). METHOD OF ADMINISTRATION
frequency of glandular cysts in the stomach may increase. These Vial for I.V. injection or infusion MERONEM MERONEM 'MERONEM' IV can be given as an intravenous bolus injection
changes are physiological and a consequence of the inhibition of over approximately 5 minutes or by intravenous infusion over
500mg 1000mg
acid secretion. They are benign and reversible. approximately 15 to 30 minutes using the specic available
Active ingredient:
Decreased gastric acidity with proton pump inhibitors or other Meropenem trihydrate 570mg 1140mg presentations.
acid-inhibiting agents, increases the amount of bacteria normally equivalent to anhydrous 500mg 1000mg 'MERONEM' IV to be used for bolus intravenous injection
present in the gastrointestinal tract, why such treatment may lead meropenem should be constituted with sterile Water for Injections (5ml per
to a slightly increased risk of gastrointestinal infections such as 250mg Meropenem). This provides an approximate concentration
Excipient:
Salmonella and Campylobacter. of 50 mg/ml. Constituted solutions are clear, and colourless or
Anhydrous sodium carbonate 104mg 208mg
No other pharmacodynamic effects of clinical signicance, other pale yellow.
than those due to the effect of omeprazole on acid secretion, have For each gram of meropenem (anhydrous potency) the vial
'MERONEM' IV for intravenous infusion may be constituted with
been found. contains 90mg (3.9mmol) of sodium.
compatible infusion uids (50 to 200 ml) (see Incompatibilities
The effect on acid secretion is directly correlated to the area under PHARMACEUTICAL FORM and Special precautions for storage).
the plasma concentration curve (AUC), but not to the actual plasma
concentration of omeprazole. Oral administration of Losec MUPS MERONEM is presented as a powder for constitution for CONTRAINDICATIONS
20 mg produces a reduction in hydrochloric acid secretion within intravenous administration . 'MERONEM' is contraindicated in patients who have
2 hours after administration. With repeated treatment once daily, THERAPEUTIC INDICATIONS demonstrated hypersensitivity to this product.
the full effect is obtained within 3-5 days. The degree of acidity 'MERONEM' IV is indicated for treatment, in adults and children, SPECIAL WARNINGS AND PRECAUTIONS FOR USE
measured over 24 hours in duodenal ulcer patients is then reduced of the following infections caused by single or multiple bacteria
on average by 80 %, and the reduction in pentagastrin-stimulated There is some clinical and laboratory evidence of partial cross-
sensitive to meropenem. allergenicity between other carbapenems and beta-lactam
hydrochloric acid production is approximately 70 % 24 hours after
- Pneumonias and Nosocomial Pneumonias antibiotics, penicillins and cephalosporins. As with all beta-lactam
administration. The secretion-inhibiting effect is characterised by
- Urinary Tract Infections antibiotics, rare hypersensitivity reactions have been reported
its long duration, and has subsided after approximately 5 days
from the end of treatment. - Intra abdominal Infections (See Undesirable effects). Before initiating therapy with
- Gynaecological Infections, such as endometritis and pelvic meropenem, careful inquiry should be made concerning previous
1 tablet (20 mg) daily gives symptomatic relief after the rst dose,
inammatory disease. hypersensitivity reactions to beta-lactam antibiotics. 'Meronem'
and healing is obtained within 2 weeks for the majority of patients
- Skin and Skin Structure Infections should be used with caution in patients with such a history. If
with duodenal ulcer; for gastric ulcer and reux oesophagitis
- Meningitis an allergic reaction to meropenem occurs, the drug should be
within 4 weeks.
- Septicaemia discontinued and appropriate measures taken.
Treatment with omeprazole increases the antibacterial effect of
some antibiotics on the bacterium Helicobacter pylori. - Empiric treatment, for presumed infections in adult patients with Use of 'MERONEM' in patients with hepatic disease should
febrile neutropenia, used as monotherapy or in combination be made with careful monitoring of transaminase and bilirubin
PHARMACOKINETICS with anti-viral or anti-fungal agents. levels.
Absorption MERONEM has proved efcacious alone or in combination As with other antibiotics, overgrowth of non susceptible organisms
The absorption of omeprazole takes place in the small intestine, with other antimicrobial agents in the treatment of polymicrobial may occur and, therefore, continuous monitoring of each patient is
and is usually completed within 3-6 hours. The bioavailability of infections. necessary.
omeprazole after repeated oral administration is approximately 60 There is no experience in paediatric patients with neutropenia or Use in infections caused by methicillin resistant staphylococci is
%. Concomitant intake of food does not affect the bioavailability. primary or secondary immunodeciency. not recommended.
Binding to plasma proteins is approximately 95 % and the volume POSOLOGY AND METHOD OF ADMINISTRATION Rarely, pseudomembranous colitis has been reported on
of distribution is 0,3 L/kg. 'MERONEM' as with practically all antibiotics and may vary
Adults
Metabolism in severity from slight to life threatening. Therefore, antibiotics
The dosage and duration of therapy shall be established depending
Omeprazole is metabolised completely, mainly in the liver. Mainly should be prescribed with care for individuals with a history of
on type and severity of infection and the condition of the patient.
the enzymes CYP2C19 and CYP3A4 catalyse the metabolism. gastro intestinal complaints, particularly colitis.
The recommended daily dosage is as follows:-
Identied metabolites are the sulphone, the sulphide and hydroxy- It is important to consider the diagnosis of pseudomembranous
omeprazole, which have no signicant effect on the acid secretion. 500 mg IV every 8 hours in the treatment of pneumonia, UTI, colitis in the case of patients who develop diarrhoea in association
Total plasma clearance is 0.3-0.6 L/min. Omeprazole inhibits its gynaecological infections such as endometritis, skin and skin with the use of 'MERONEM'. Although studies indicate that a
own CYP2C19 catalysed metabolism. Therefore the bioavailability structure infections. toxin produced by Clostridium difcile is one of the main causes
of omeprazole increases with approx. 50 % during multiple dose 1 g IV every 8 hours in the treatment of nosocomial pneumonias, of antibiotic associated colitis, other causes should be considered.
treatment compare to single dose. peritonitis, presumed infections in neutropenic patients, The co-administration of 'Meronem' with potentially nephrotoxic
Elimination septicaemia.
drugs should be considered with caution. (For dosage see
The half-life in plasma in the elimination phase is approximately In meningitis the recommended dosage is 2g every 8 hours. Posology and method of administration).
40 minutes (30-90 minutes) after multiple doses. Approximately 80 As with other antibiotics, particular caution is recommended in Paediatric use
% of the metabolites are excreted via the urine and the remainder using meropenem as monotherapy in critically ill patients with
Efcacy and tolerability in infants under 3 months old have not
in the faeces. known or suspected Pseudomonas aeruginosa lower respiratory
been established; therefore, 'Meronem' is not recommended for
Patient factors tract infection.
use below this age. There is no experience in children with altered
The bioavailability of omeprazole is not changed signicantly Regular sensitivity testing is recommended when treating hepatic or renal function.
in elderly patients or patients with impaired renal function. In Pseudomonas aeruginosa infection.
Keep all medicines away from children.
patients with impaired liver function the bioavailability increases. Dosage Schedule for Adults with Impaired Renal Function
Clearance is greatly reduced in these patients. Dosage should be reduced in patients with creatinine clearance INTERACTIONS
less than 51 ml/min, as scheduled below. Probenecid competes with meropenem for active tubular secretion
LIST OF EXCIPIENTS
Dose (based on Frequency and thus inhibits the renal excretion, with the effect of increasing
Microcrystalline cellulose, glyceryl monostearate,hydroxypropy Creatinine Clearance
the elimination half life and plasma concentration of meropenem.
lcellulose, hydroxypropyl methylcellulose, magnesium stearate, (ml/min) unit doses of
As the potency and duration of action of 'MERONEM' dosed
methacrylic acid-ethyl acrylate co-polymer, sugar spheres, 500mg, 1g, 2g) without probenecid are adequate, the co administration of
synthetic parafn, macrogol (polyethylene glycol), polysorbate probenecid with 'MERONEM' is not recommended.
26 - 50 one unit dose every 12 hours
80, krospovidon, sodium stearyl fumarate, talc, triethyl citrate,
iron oxide (E 172), titanium dioxide (E 171). 10 - 25 one half unit dose every 12 hours The potential effect of 'Meronem' on the protein binding of other
<10 one half unit dose every 24 hours drugs or metabolism has not been studied. The protein binding
INCOMPATIBILITIES of 'MERONEM' is low (approximately 2%) and, therefore, no
None known when instructions in Method of administration are Meropenem is cleared by haemodialysis; if continued treatment interactions with other compounds based on displacement from
followed. with 'Meronem' is necessary, it is recommended that the unit plasma proteins would be expected.
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'MERONEM' may reduce serum valproic acid levels. The in vitro antibacterial spectrum of meropenem includes volunteers results in peak plasma levels of approximately 52 g/
Subtherapeutic levels may be reached in some patients. the majority of clinically signicant Gram positive and Gram ml for the 500 mg dose and 112 g/ml for the 1g dose.
'MERONEM' has been administered concomitantly with other negative, aerobic and anaerobic strains of bacteria, as shown Intravenous infusions of 1 g over 2 minutes, 3 minutes and 5
medications without adverse pharmacological interactions. below: minutes were compared in a three-way crossover trial. These
However, no specic data regarding potential drug interactions is Gram positive aerobes: durations of infusion resulted in peak plasma levels of 110, 91 and
available (apart from probenecid as mentioned above). Bacillus spp., Corynebacterium diphtheriae, Enterococcus 94 microgram/ml, respectively.
PREGNANCY AND LACTATION faecalis, Enterococcus liquifaciens, Enterococcus avium, After an IV dose of 500 mg, plasma levels of meropenem decline
Listeria monocytogenes, Lactobacillus spp., Nocardia asteroides, to values of 1 g/ml or less, 6 hours after administration.
Pregnancy
Staphylococcus aureus (penicillinase negative and positive), When multiple doses are administered at 8 hourly intervals to
The safety of 'Meronem' in human pregnancy has not been
Staphylococci coagulase negative; including, Staphylococcus subjects with normal renal function, accumulation of meropenem
evaluated. Animal studies have not shown any adverse effect on
epidermidis, Staphylococcus saprophyticus, Staphylococcus does not occur.
the developing foetus. The only adverse effect observed in animal
capitis, Staphylococcus cohnii, Staphylococcus xylosus, In subjects with normal renal function, meropenem's elimination
reproductive studies was an increased incidence of abortions in
Staphylococcus warneri, Staphylococcus hominis, Staphylococcus half life is approximately 1 hour.
monkeys at 13 times the expected exposure in man. 'Meronem'
simulans, Staphylococcus intermedius, Staphylococcus sciuri,
should not be used in pregnancy unless the potential benet Plasma protein binding of meropenem is approximately 2%.
Staphylococcus lugdunensis, Streptococcus pneumoniae
justies the potential risk to the foetus. In every case, it should be Approximately 70% of the administered dose is recovered as
used under the direct supervision of the physician. (penicillin susceptible and resistant), Streptococcus agalactiae,
Streptococcus pyogenes, Streptococcus equi, Streptococcus bovis, unchanged meropenem in the urine over 12 hours, after which little
Lactation further urinary excretion is detectable. Urinary concentrations of
Streptococcus mitis, Streptococcus mitior, Streptococcus milleri,
Meropenem is detectable at very low concentrations in animal Streptococcus sanguis, Streptococcus viridans, Streptococcus meropenem in excess of 10 g/ml are maintained for up to 5 hours
breast milk. 'MERONEM' should not be used in breast feeding salivarius, Streptococcus morbillorum, Streptococcus Group G, after the administration of a 500 mg dose. No accumulation of
women unless the potential benet justies the potential risk to Streptococcus Group F, Rhodococcus equi. meropenem in plasma or urine was observed with regimens using
the baby. 500 mg administered every 8 hours or 1g administered every 6
Gram negative aerobes:
hours in volunteers with normal renal function.
EFFECT ON ABILITY TO DRIVE AND USE MACHINES Achromobacter xylosoxidans, Acinetobacter anitratus,
The only metabolite of meropenem is microbiologically inactive.
No data is available, but it is not anticipated that 'Meronem' will Acinetobacter lwofi, Acinetobacter baumannii, Aeromonas
affect the ability to drive and use machines. hydrophila, Aeromonas sorbria, Aeromonas caviae, Alcaligenes Meropenem penetrates well into most body uids and tissues
including cerebrospinal uid of patients with bacterial meningitis,
faecalis, Bordetella bronchiseptica, Brucella melitensis,
UNDESIRABLE EFFECTS achieving concentrations in excess of those required to inhibit
Campylobacter coli, Campylobacter jejuni, Citrobacter freundii,
Serious adverse events are rare. During the clinical trials the most bacteria.
Citrobacter diversus, Citrobacter koseri, Citrobacter amalonaticus,
following adverse events have been reported: Studies in children have shown that the pharmacokinetics
Enterobacter aerogenes, Enterobacter (Pantoea) agglomerans,
* Local intravenous injection site reactions: inammation, Enterobacter cloacae, Enterobacter sakazakii, Escherichia coli, of 'Meronem' in children are similar to those in adults. The
thrombophlebitis, pain at the site of injection Escherichia hermannii, Gardnerella vaginalis, Haemophilus elimination half life for meropenem was approximately 1.5
* Systemic allergic reactions: rarely, systemic allergic reactions inuenzae (including lactamase positive and ampicillin to 2.3 hours in children under the age of 2 years and the
(hypersensitivity) may occur following administration of resistant strains), Haemophilus parainuenzae, Haemophilus pharmacokinetics are linear over the dose range of 10 to 40 mg/kg.
meropenem. These reactions may include angioedema and ducreyi, Helicobacter pylori, Neisseria meningitidis, Neisseria Pharmacokinetic studies in patients with renal insufciency
manifestations of anaphylaxis. gonorrhoeae (including lactamase positive, penicillin resistant have shown the plasma clearance of meropenem correlates with
* Skin reactions: rash, pruritus, urticaria: Rarely severe skin and spectinomycin resistant strains) Hafnia alvei, Klebsiella creatinine clearance. Dosage adjustments are necessary in subjects
reactions, such as erythema multiforme, Stevens-Johnson pneumoniae, Klebsiella aerogenes, Klebsiella ozaenae, Klebsiella with renal impairment.
Syndrome and toxic epidermal necrolysis, have been observed. oxytoca, Moraxella (Branhamella) catarrhalis, Morganella Pharmacokinetic studies in the elderly have shown a reduction
* Gastro intestinal: abdominal pain, nausea, vomiting, diarrhoea. morganii, Proteus mirabilis, Proteus vulgaris, Proteus penneri, in plasma clearance of meropenem which correlated with age
Pseudomembranous colitis has been reported. Providencia rettgeri, Providencia stuartii, Providencia alcalifaciens, associated reduction in creatinine clearance.
* Blood: Reversible thrombocythaemia, eosinophilia, Pasteurella multocida, Plesiomonas shigelloides, Pseudomonas Pharmacokinetic studies in patients with liver disease have
thrombocytopenia, leucopenia and neutropenia (including very aeruginosa, Pseudomonas putida, Pseudomonas alcaligenes, shown no effects of liver disease on the pharmacokinetics of
rare cases of agranulocytosis). A positive direct or indirect Burkholderia (Pseudomonas) cepacia, Pseudomonas uorescens, meropenem.
Coombs test may develop in some subjects; there have been Pseudomonas stutzeri, Pseudomonas pseudomallei, Pseudomonas
reports of reduction in partial thromboplastin time; PRE CLINICAL SAFETY DATA
acidovorans, Salmonella spp. including Salmonella enteritidis/
* Liver function: Increases in serum concentrations of bilirubin, typhi Serratia marcescens, Serratia liquefaciens, Serratia rubidaea, Animal studies indicate that meropenem is well tolerated by the
transaminases, alkaline phosphatase and lactic dehydrogenase Shigella sonnei, Shigella exneri, Shigella boydii, Shigella kidney. In animal studies meropenem has shown nephrotoxic
alone or in combination have been reported; dysenteriae, Vibrio cholerae, Vibrio parahaemolyticus,Vibrio effects, only at high dose levels (500 mg/kg).
* Central nervous system: headache, paraesthesiae. Convulsions vulnicus, Yersinia enterocolitica. Effects on the CNS; convulsions in rats and vomiting in dogs, were
have been reported although a causal relationship with Anaerobic bacteria: seen only at high doses (>2000 mg/kg).
'MERONEM' has not been established. For an IV dose the LD50 in rodents is greater than 2000 mg/kg. In
Actinomyces odontolyticus, Actinomyces meyeri, Bacteroides
* Other: Oral and vaginal candidosis. repeat dose studies (up to 6 months) only minor effects were seen
Prevotella Porphyromonas spp., Bacteroides fragilis, Bacteroides
OVERDOSE vulgatus, Bacteroides variabilis, Bacteroides pneumosintes, including a small decrease in red cell parameters and an increase in
Bacteroides coagulans, Bacteroides uniformis, Bacteroides liver weight in dogs treated with doses of 500 mg/kg.
Accidental overdosage could occur during therapy, particularly in
patients with renal impairment. Treatment of overdosage should distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, There was no evidence of mutagenic potential in the 5 tests
be symptomatic. In normal individuals rapid renal elimination Bacteroides eggerthii, Bacteroides capsillosis, Prevotella conducted and no evidence of reproductive and teratogenic toxicity
will occur; in subjects with renal impairment haemodialysis will buccalis, Prevotella corporis, Bacteroides gracilis, Prevotella in studies at the highest possible doses in rats and monkeys; the no
remove meropenem and its metabolite. melaninogenica, Prevotella intermedia, Prevotella bivia, Prevotella effect dose level of a (small) reduction in F1 body weight in rat
splanchnicus, Prevotella oralis, Prevotella disiens, Prevotella was 120 mg/kg. There was an increased incidence of abortions at
PHARMACODYNAMIC PROPERTIES 500 mg/kg in a preliminary study in monkeys.
rumenicola, Bacteroides ureolyticus, Prevotella oris, Prevotella
Meropenem is a carbapenem antibiotic for parenteral use, that buccae, Prevotella denticola, Bacteroides levii, Porphyromonas There was no evidence of increased sensitivity to meropenem in
is relatively stable to human dehydropeptidase 1 (DHP 1) and asaccharolytica, Bidobacterium spp., Bilophila wadsworthia, juveniles compared to adult animals. The intravenous formulation
therefore, does not require the addition of an inhibitor of DHP-1. Clostridium perfringens, Clostridium bifermentans, Clostridium was well tolerated in animal studies.
Meropenem exerts its bactericidal action by interfering with ramosum, Clostridium sporogenes, Clostridium cadaveris, The sole metabolite of meropenem had a similar prole of toxicity
vital bacterial cell wall synthesis. The ease with which it Clostridium sordellii, Clostridium butyricum, Clostridium in animal studies.
penetrates bacterial cell walls, its high level of stability to all clostridiiformis, Clostridium innocuum, Clostridium subterminale,
serine -lactamases and its marked afnity for the Penicillin Clostridium tertium, Eubacterium lentum, Eubacterium INCOMPATIBILITIES
Binding Proteins (PBPs) explain the potent bactericidal action of aerofaciens, Fusobacterium mortiferum, Fusobacterium 'MERONEM' should not be mixed with or added to other drugs.
meropenem against a broad spectrum of aerobic and anaerobic necrophorum, Fusobacterium nucleatum, Fusobacterium varium, 'MERONEM' is compatible with the following infusion uids:
bacteria. Minimum bactericidal concentrations (MBC) are Mobiluncus curtisii, Mobiluncus mulieris, Peptostreptococcus 0.9% Sodium Chloride solution
commonly the same as the minimum inhibitory concentrations anaerobius, Peptostreptococcus micros, Peptostreptococcus
(MIC). For 76% of the bacteria tested, the MBC:MIC ratios were 5% or 10% Glucose solution
saccharolyticus, Peptococcus saccharolyticus, Peptostreptococcus
2 or less. asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus 5% Glucose solution with 0.02% Sodium Bicarbonate
Meropenem is stable in susceptibility tests and these tests can be prevotii, Propionibacterium acnes, Propionibacterium avidum, 0.9% Sodium Chloride and 5% Glucose solution
performed using normal routine methods. In vitro tests show that Propionibacterium granulosum. 5% Glucose with 0.225% Sodium Chloride solution
meropenem acts synergistically with various antibiotics. It has Stenotrophomonas maltophilia, Enterococcus faecium and methi- 5% Glucose with 0.15% Potassium Chloride solution
been demonstrated both in vitro and in vivo that meropenem has
cillin resistant staphylococci have been found to be resistant to Mannitol 2.5% or 10% solution.
a post antibiotic effect.
meropenem.
A single set of meropenem susceptibility criteria are recommended SHELF-LIFE
based on pharmacokinetics and correlation of clinical and PHARMACOKINETIC PROPERTIES
Please refer to the expiry date on the outer carton
microbiological outcomes with zone diameter and minimum A 30 minute intravenous infusion of a single dose of 'Meronem' in
inhibitory concentrations (MIC) of the infecting organisms. healthy volunteers results in peak plasma levels of approximately SPECIAL PRECAUTIONS FOR STORAGE
CATEGORISATION METHOD OF ASSESSMENT 11 g/ml for the 250 mg dose, 23 g/ml for the 500 mg dose and 49 Do not store above 30C.
g/ml for the 1g dose. Do not freeze
Zone Diameter MIC breakpoints
(mm) (mg/L) However, there is no absolute pharmacokinetic proportionality It is recommended to use freshly prepared solutions of
4 with the administered dose both as regards Cmax and AUC. 'MERONEM' for I.V. injection and infusion. Reconstituted
Susceptible 14
Furthermore, a reduction in plasma clearance from 287 to 205 ml/ product, constituted as described above, maintains satisfactory
Intermediate 12 to 13 8
min for the range of dosage 250 mg to 2 g has been observed. potency at room temperature (up to 25C) or under refrigeration
Resistant 11 16
A 5 minute intravenous bolus injection of 'Meronem' in healthy (4C) as shown in the following table:-
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Diluent Hours stable at should be further investigated. Once symptoms have resolved, warfarin-treated patients in a clinical trial showed that coagulation
15-25C 4C subsequent symptom control can be achieved using an on times were within the accepted range. However, post-marketing,
Vials constituted with 8 48 demand regimen taking 20 mg once daily, when needed. In a few isolated cases of elevated INR of clinical signicance
Water for Injections NSAID treated patients at risk of developing gastric and have been reported during concomitant treatment. Monitoring is
for bolus injection duodenal ulcers, subsequent symptom control using an on recommended when initiating and ending concomitant treatment.
demand regimen is not recommended. In healthy volunteers, concomitant administration of 40 mg
Solutions (1 20 mg/ml) prepared with: 8 48
* 0.9% sodium chlorid In combination with an appropriate antibacterial therapeutic esomeprazole resulted in a 32% increase in area under the plasma
regimen for the eradication of Helicobacter pylori and concentration-time curve (AUC) and a 31% prolongation of
* 5% glucose 3 14
- healing of Helicobacter pylori associated duodenal ulcer and elimination half-life(t) but no signicant increase in peak plasma
* 5% glucose and 0.225% sodium chloride 3 14
- prevention of relapse of peptic ulcers in patients with levels of cisapride. The slightly prolonged QTc interval observed
* 5% glucose and 0.9% sodium chloride 3 14 Helicobacter pylori associated ulcers after administration of cisapride alone, was not further prolonged
* 5% glucose and 0.15% potassium chloride 3 14 20 mg NEXIUM with 1 g amoxicillin and 500 mg when cisapride was given in combination with esomeprazole(See
* 2.5% or 10% mannitol intravenous infusion 3 14 clarithromycin, all twice daily for 7 days. section Special warnings and special precautions for use).
* 10% glucose 2 8 Patients requiring continued NSAID therapy Co-administration of omeprazole (40 mg once daily) with atazana-
* 5% glucose and 0.02% sodium 2 8 - healing of gastric ulcers associated with NSAID therapy: The vir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a
usual dose is 20 mg once daily. The treatment duration is 4-8 substantial reduction in atazanavir exposure (approximately 75%
bicarbonate Intravenous Infusion
weeks. decrease in AUC, Cmax and Cmin). Increasing the atazanavir dose
PACK SIZE - prevention of gastric and duodenal ulcers associated with to 400 mg did not compensate for the impact of omeprazole on
Please refer to the outer carton for pack size NSAID therapy in patients at risk: 20 mg once daily. atazanavir exposure. PPIs including esomeprazole should not be
Children and adolescents co-administered with atazanavir (see Contraindications section ).
Instructions for Use/Handling
NEXIUM should not be used in children since no data is Esomeprazole has been shown to have no clinically relevant
Refer to " Posology and method of administration" above. Standard
available. effects on the pharmacokinetics of amoxicillin or quinidine.
aseptic technique should be employed during constitution. Shake
Studies evaluating concomitant administration of esomeprazole
constituted solution before use. Impaired renal function
and either naproxen or rofecoxib did not identify any clinically
All vials are for single use only. Dose adjustment is not required in patients with impaired renal relevant pharmacokinetic interactions during short-term studies.
'MERONEM' is a trade mark of the AstraZeneca group of function. Due to limited experience in patients with severe renal
companies. insufciency, such patients should be treated with caution. (See EFFECTS OF OTHER DRUGS ON THE PHARMACOKI-
section Pharmacokinetic Properties). NETICS OF ESOMEPRAZOLE
Impaired hepatic function Esomeprazole is metabolised by CYP2C19 and CYP3A4.
NEXIUM 20 mg and 40 mg Tablets Concomitant administration of esomeprazole and a CYP3A4
Dose adjustment is not required in patients with mild to moderate
liver impairment. For patients with severe liver impairment, a inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling
maximum dose of 20 mg NEXIUM should not be exceeded. (See of the exposure (AUC) to esomeprazole. Dose adjustment of
[Esomeprazole (as magnesium trihydrate)] esomeprazole is not required.
section Pharmacokinetic Properties).
COMPOSITION Elderly PREGNANCY AND LACTATION
Each tablet contains: 20 mg or 40 mg esomeprazole (as magnesium Dose adjustment is not required in the elderly. For NEXIUM, clinical data on exposed pregnancies are
trihydrate). insufcient.With the racemic mixture omeprazole data on a larger
CONTRAINDICATIONS
For excipients see section List of excipients. number of exposed pregnancies from epidemiological studies
Known hypersensitivity to esomeprazole, substituted
indicate no malformative nor foetotoxic effects. Animal studies
PHARMACEUTICAL FORM benzimidazoles or any other constituents of the formulation.
with esomeprazole do not indicate direct or indirect harmful
Gastro-resistant tablet Esomeprazole like other PPIs should not be administered with
effects with respect to embryonal/fetal development. Animal
atazanavir (see Interactions section).
20 mg: A light pink, oblong, biconvex, lm-coated tablet engraved studies with the racemic mixture do not indicate direct or indirect
20 mg on one side and on the other side. SPECIAL WARNINGS AND SPECIAL PRECAUTIONS harmful effects with respect to pregnancy, parturition or postnatal
40 mg: A pink, oblong, biconvex, lm-coated tablet engraved 40 FOR USE development. Caution should be exercised when prescribing to
mg on one side and on the other side. In the presence of any alarm symptom (e.g. signicant unintentional pregnant women.
weight loss, recurrent vomiting, dysphagia, haematemesis It is not known whether esomeprazole is excreted in human
THERAPEUTIC INDICATIONS
or melaena) and when gastric ulcer is suspected or present, breast milk. No studies in lactating women have been performed.
NEXIUM tablets are indicated for: malignancy should be excluded, as treatment with NEXIUM may Therefore NEXIUM should not be used during breast-feeding.
Gastroesophageal Reux Disease (GERD) alleviate symptoms and delay diagnosis.
- treatment of erosive reux esophagitis EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Patients on long-term treatment (particularly those treated for
- long-term management of patients with healed esophagitis to more than a year) should be kept under regular surveillance. No effects have been observed.
prevent relapse Patients on on-demand treatment should be instructed to contact UNDESIRABLE EFFECTS
- symptomatic treatment of gastroesophageal reux disease their physician if their symptoms change in character. When The following adverse drug reactions have been identied or
(GERD). prescribing esomeprazole for on demand therapy, the implications suspected in the clinical trials programme for esomeprazole and
In combination with an appropriate antibacterial therapeutic for interactions with other pharmaceuticals, due to uctuating post-marketing. None was found to be dose-related. The reactions
regimen for the eradication of Helicobacter pylori and plasma concentrations of esomeprazole should be considered (See are classied according to frequency (common >1/100, <1/10;
- healing of Helicobacter pylori associated duodenal ulcer and section Interactions). uncommon >1/1000, <1/100; rare >1/10000, <1/1000; very rare
- prevention of relapse of peptic ulcers in patients with When prescribing esomeprazole for eradication of Helicobacter <1/10000).
Helicobacter pylori associated ulcers. pylori possible drug interactions for all components in the triple
Blood and lymphatic system disorders
Patients requiring continued NSAID therapy therapy should be considered. Clarithromycin is a potent inhibitor
- healing of gastric ulcers associated with NSAID therapy. of CYP3A4 and hence contraindications and interactions for Rare: Leukopenia, thrombocytopenia
- prevention of gastric and duodenal ulcers associated with clarithromycin should be considered when the triple therapy is Very rare: Agranulocytosis, pancytopenia
NSAID therapy in patients at risk. used in patients concurrently taking other drugs metabolised via Immune system disorders
CYP3A4 such as cisapride. Rare: Hypersensitivity reactions e.g. fever, angioedema and
This medicinal product contains sucrose. Patients with rare anaphylactic reaction/shock
The tablets should be swallowed whole with liquid. The tablets hereditary problems of fructose intolerance, glucose-galactose
should not be chewed or crushed. Metabolism and nutrition disorders
malabsorption or sucrase-isomaltase insufciency should not take
For patients who have difculty in swallowing, the tablets can this medicine. Uncommon: Peripheral oedema
also be dispersed in half a glass of non-carbonated water. No other Rare: Hyponatraemia
liquids should be used as the enteric coating may be dissolved. Stir INTERACTIONS
Psychiatric disorders
until the tablets disintegrate and drink the liquid with the pellets Effects of esomeprazole on the pharmacokinetics of other
immediately or within 30 minutes. Rinse the glass with half a glass drugs Uncommon: Insomnia
of water and drink. The pellets must not be chewed or crushed. The decreased intragastric acidity during treatment with Rare: Agitation, confusion, depression
For patients who cannot swallow, the tablets can be dispersed in esomeprazole, might increase or decrease the absorption of drugs Very rare: Aggression, hallucinations
non-carbonated water and administered through a gastric tube. if the mechanism of absorption is inuenced by gastric acidity. Nervous system disorders
It is important that the appropriateness of the selected syringe and In common with the use of other inhibitors of acid secretion or Common: Headache
tube is carefully tested. antacids, the absorption of ketoconazole and itraconazole can
decrease during treatment with esomeprazole. Uncommon: Dizziness, paraesthesia, somnolence
For preparation and administration instructions see section
Esomeprazole inhibits CYP2C19, the major esomeprazole Rare: Taste disturbance
Instructions for use and handling.
metabolising enzyme. Thus, when esomeprazole is combined Eye disorders
Gastroesophageal Reux Disease (GERD)
with drugs metabolised by CYP2C19, such as diazepam, Rare: Blurred vision
- treatment of erosive reux esophagitis
citalopram, imipramine, clomipramine, phenytoin etc., the Ear and labyrinth disorders
40 mg once daily for 4 weeks. plasma concentrations of these drugs may be increased and
An additional 4 weeks treatment is recommended for patients a dose reduction could be needed. This should be considered Uncommon: Vertigo
in whom esophagitis has not healed or who have persistent especially when prescribing esomeprazole for on demand therapy. Respiratory, thoracic and mediastinal disorders
symptoms. Concomitant administration of 30 mg esomeprazole resulted in a Rare: Bronchospasm
- long-term management of patients with healed esophagitis to 45% decrease in clearance of the CYP2C19 substrate diazepam. Gastrointestinal disorders
prevent relapse 20 mg once daily. Concomitant administration of 40 mg esomeprazole resulted in
- symptomatic treatment of gastroesophageal reux disease Common: Abdominal pain, constipation, diarrhoea, atulence,
a 13% increase in trough plasma levels of phenytoin in epileptic
(GERD) nausea/vomiting
patients. It is recommended to monitor the plasma concentrations
20 mg once daily in patients without esophagitis. If symptom of phenytoin when treatment with esomeprazole is introduced or Uncommon: Dry mouth
control has not been achieved after four weeks, the patient withdrawn. Concomitant administration of 40 mg esomeprazole to Rare: Stomatitis, gastrointestinal candidiasis
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Hepatobiliary disorders PHARMACOKINETIC PROPERTIES PACK SIZE
Uncommon: Increased liver enzymes Absorption and distribution Please refer to the outer carton for pack size.
Rare: Hepatitis with or without jaundice Esomeprazole is acid labile and is administered orally as INSTRUCTIONS FOR USE AND HANDLING
Very rare: Hepatic failure, encephalopathy in patients with pre- enteric-coated granules. In vivo conversion to the R-isomer
Administration through gastric tube
existing liver disease is negligible. Absorption of esomeprazole is rapid, with peak
plasma levels occurring approximately 1-2 hours after dose. 1. Put the tablet into an appropriate syringe and ll the syringe
Skin and subcutaneous tissue disorders with approximately 25 mL water and approximately 5 mL
The absolute bioavailability is 64% after a single dose of 40 mg
Uncommon: Dermatitis, pruritus, rash, urticaria and increases to 89% after repeated once-daily administration. air. For some tubes, dispersion in 50 mL water is needed to
Rare: Alopecia, photosensitivity For 20 mg esomeprazole the corresponding values are 50% and prevent the pellets from clogging the tube.
Very rare: Erythema multiforme, Stevens-Johnson syndrome, 68%, respectively. The apparent volume of distribution at steady 2. Immediately shake the syringe for approximately 2 minutes to
toxic epidermal necrolysis (TEN) state in healthy subjects is approximately 0.22 L/kg body weight. disperse the tablet.
Esomeprazole is 97% plasma protein bound. 3. Hold the syringe with the tip up and check that the tip has not
Musculoskeletal, connective tissue and bone disorders
clogged.
Rare: Arthralgia, myalgia Food intake both delays and decreases the absorption of
esomeprazole although this has no signicant inuence on the 4. Attach the syringe to the tube whilst maintaining the above
Very rare: Muscular weakness position.
effect of esomeprazole on intragastric acidity.
Renal and urinary disorders 5. Shake the syringe and position it with the tip pointing down.
Metabolism and excretion
Very rare: Interstitial nephritis Immediately inject 5-10 mL into the tube. Invert the syringe
Esomeprazole is completely metabolised by the cytochrome P450 after injection and shake (the syringe must be held with the tip
Reproductive system and breast disorders system (CYP). The major part of the metabolism of esomeprazole pointing up to avoid clogging of the tip).
Very rare: Gynaecomastia is dependent on the polymorphic CYP2C19, responsible for 6. Turn the syringe with the tip down and immediately inject
General disorders and administration site conditions the formation of the hydroxy- and desmethyl metabolites of another 5-10 mL into the tube. Repeat this procedure until the
Rare: Malaise, increased sweating esomeprazole. The remaining part is dependent on another specic syringe is empty.
isoform, CYP3A4, responsible for the formation of esomeprazole
OVERDOSE 7. Fill the syringe with 25 mL of water and 5 mL of air and
sulphone, the main metabolite in plasma.
repeat step 5 if necessary to wash down any sediment left in
There is very limited experience to date with deliberate overdose. The parameters below reect mainly the pharmacokinetics in the syringe. For some tubes, 50 mL water is needed.
The symptoms described in connection with 280 mg were individuals with a functional CYP2C19 enzyme, extensive
gastrointestinal symptoms and weakness. Single doses of 80 mg NEXIUM is a trade mark of the Astrazeneca group of companies.
metabolisers.
esomeprazole were uneventful. No specic antidote is known. Astrazeneca 2006
Total plasma clearance is about 17 L/h after a single dose and
Esomeprazole is extensively plasma protein bound and is therefore
about 9 L/h after repeated administration. The plasma elimination
not readily dialyzable. As in any case of overdose, treatment NEXIUM 40 mg
half-life is about 1.3 hours after repeated once-daily dosing. The
should be symptomatic and general supportive measures should
area under the plasma concentration-time curve increases with Powder for solution for injection/infusion
be utilised.
repeated administration of esomeprazole. This increase is dose-
PHARMACODYNAMIC PROPERTIES dependent and results in a non-linear dose-AUC relationship after
Pharmacotherapeutic group: Proton pump inhibitor. repeated administration. This time - and dose-dependency is due [Esomeprazole (as sodium)]
to a decrease of rst pass metabolism and systemic clearance
ATC Code: A02B C05
probably caused by an inhibition of the CYP2C19 enzyme by COMPOSITION
Esomeprazole is the S-isomer of omeprazole and reduces gastric esomeprazole and/or its sulphone metabolite. Esomeprazole Each vial contains esomeprazole 40 mg (as sodium salt).
acid secretion through a specic targeted mechanism of action. It is completely eliminated from plasma between doses with no
is a specic inhibitor of the acid pump in the parietal cell. Both the tendency for accumulation during once-daily administration. PHARMACEUTICAL FORM
R- and S-isomer of omeprazole have similar pharmacodynamic Powder for solution for injection/infusion
activity. The major metabolites of esomeprazole have no effect on gastric
acid secretion. Almost 80% of an oral dose of esomeprazole is White to off-white porous cake or powder
Site and mechanism of action excreted as metabolites in the urine, the remainder in the faeces.
Esomeprazole is a weak base and is concentrated and converted to THERAPEUTIC INDICATIONS
Less than 1% of the parent drug is found in urine.
the active form in the highly acidic environment of the secretory NEXIUM for injection and infusion is indicated for gastric
canaliculi of the parietal cell, where it inhibits the enzyme H+K+- SPECIAL PATIENT POPULATIONS antisecretory treatment when the oral route is not possible, such
ATPase - the acid pump and inhibits both basal and stimulated Approximately 1-2% of the population lack a functional CYP2C19 as:
acid secretion. enzyme and are called poor metabolisers. In these individuals - gastroesophageal reux disease in patients with esophagitis
Effect on gastric acid secretion the metabolism of esomeprazole is probably mainly catalysed and/or severe symptoms of reux
by CYP3A4. After repeated once-daily administration of 40 mg - healing of gastric ulcers associated with NSAID therapy.
After oral dosing with esomeprazole 20 mg and 40 mg the onset
esomeprazole, the mean area under the plasma concentration- - prevention of gastric and duodenal ulcers associated with
of effect occurs within one hour. After repeated administration
time curve was approximately 100% higher in poor metabolisers NSAID therapy, in patients at risk
with 20 mg esomeprazole once daily for ve days, mean peak
acid output after pentagastrin stimulation is decreased 90% when than in subjects having a functional CYP2C19 enzyme (extensive
metabolisers). Mean peak plasma concentrations were increased POSOLOGY AND METHOD OF ADMINISTRATION
measured 6 - 7 hours after dosing on day ve.
by about 60%. Patients who cannot take oral medication may be treated
After ve days of oral dosing with 20 mg and 40 mg of
These ndings have no implications for the posology of parenterally with 20-40 mg once daily. Patients with reux
esomeprazole, intragastric pH above 4 was maintained for a
esomeprazole. oesophagitis should be treated with 40 mg once daily. Patients
mean time of 13 hours and 17 hours, respectively over 24 hours
The metabolism of esomeprazole is not signicantly changed in treated symptomatically for reux disease should be treated with
in symptomatic GERD patients. The proportion of patients
elderly subjects (71-80 years of age). 20 mg once daily. For healing of gastric ulcers associated with
maintaining an intragastric pH above 4 for at least 8, 12 and 16
NSAID therapy the usual dose is 20 mg once daily. For prevention
hours respectively were for esomeprazole 20 mg 76%, 54% and Following a single dose of 40 mg esomeprazole the mean area
of gastric and duodenal ulcers associated with NSAID therapy,
24%. Corresponding proportions for esomeprazole 40 mg were under the plasma concentration-time curve is approximately 30%
patients at risk should be treated with 20 mg once daily. Usually
97%, 92% and 56%. higher in females than in males. No gender difference is seen
the IV treatment duration is short and transfer to oral treatment
Using AUC as a surrogate parameter for plasma concentration, a after repeated once-daily administration. These ndings have no
should be made as soon as possible.
relationship between inhibition of acid secretion and exposure has implications for the posology of esomeprazole.
been shown. The metabolism of esomeprazole in patients with mild to METHOD OF ADMINISTRATION
Therapeutic effects of acid inhibition moderate liver dysfunction may be impaired. The metabolic rate Injection
Healing of reux esophagitis with esomeprazole 40 mg occurs in is decreased in patients with severe liver dysfunction resulting in 40 mg dose
approximately 78% of patients after four weeks, and in 93% after a doubling of the area under the plasma concentration-time curve The reconstituted solution should be given as an intravenous
eight weeks. of esomeprazole. Therefore, a maximum of 20 mg should not be injection over a period of at least 3 minutes.
exceeded in patients with severe dysfunction. Esomeprazole or its
One week treatment with esomeprazole 20 mg b.i.d. and appropriate 20 mg dose
major metabolites do not show any tendency to accumulate with
antibiotics, results in successful eradication of Helicobacter pylori Half of the reconstituted solution should be given as an intravenous
once-daily dosing.
in approximately 90% of patients. After eradication treatment injection over a period of approximately 3 minutes. Any unused
for one week there is no need for subsequent monotherapy with No studies have been performed in patients with decreased renal
function. Since the kidney is responsible for the excretion of the solution should be discarded.
antisecretory drugs for effective ulcer healing and symptom
resolution in uncomplicated duodenal ulcers. metabolites of esomeprazole but not for the elimination of the Infusion
parent compound, the metabolism of esomeprazole is not expected 40 mg dose
Other effects related to acid inhibition
to be changed in patients with impaired renal function. The reconstituted solution should be given as an intravenous
During treatment with antisecretory drugs serum gastrin increases
in response to the decreased acid secretion. An increased number LIST OF EXCIPIENTS infusion over a period of 10 to 30 minutes.
of ECL cells possibly related to the increased serum gastrin levels, Glycerol monostearate 40-55, hyprolose, hypromellose, iron oxide 20 mg dose
have been observed in some patients during long term treatment (20mg & 40mg tablets: reddish-brown; 20mg tablets: yellow) Half of the reconstituted solution should be given as an intravenous
with esomeprazole. (E 172), magnesium stearate, methacrylic acid ethyl acrylate infusion over a period of 10 to 30 minutes. Any unused solution
During long-term treatment with antisecretory drugs gastric copolymer (1:1) dispersion 30 per cent, cellulose microcrystalline, should be discarded.
glandular cysts have been reported to occur at a somewhat increased synthetic parafn, macrogols, polysorbate 80, crospovidone, Children and adolescents
frequency. These changes are a physiological consequence of sodium stearyl fumarate, sugar spheres (sucrose and maize starch), NEXIUM should not be used in children since no data is
pronounced inhibition of acid secretion, are benign and appear to talc, titanium dioxide (E 171), triethyl citrate.
available.
be reversible.
INCOMPATIBILITIES Impaired renal function
In two studies with ranitidine as an active comparator, NEXIUM
Not applicable Dose adjustment is not required in patients with impaired renal
showed better effect in healing of gastric ulcers in patients using
NSAIDs, including COX-2 selective NSAIDs. function. Due to limited experience in patients with severe renal
SHELF LIFE
insufciency, such patients should be treated with caution. (See
In two studies with placebo as comparator, NEXIUM showed Please refer to expiry date on the outer carton. section Pharmacokinetic properties)
better effect in the prevention of gastric and duodenal ulcers in
patients using NSAIDs (aged >60 and/or with previous ulcer), SPECIAL PRECAUTIONS FOR STORAGE Impaired hepatic function
including COX-2 selective NSAIDs. Do not store above 30C. Store in the original package. Dose adjustment is not required in patients with mild to moderate
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liver impairment. For patients with severe liver impairment, a suspected in the clinical trials programme for esomeprazole hours and 17 hours, respectively over 24 hours in symptomatic
maximum daily dose of 20 mg NEXIUM should not be exceeded. administered orally or intravenously and post-marketing when GORD patients. The effect is similar irrespective of whether
(See section Pharmacokinetic properties) administered orally. The reactions are classied according to esomeprazole is administered orally or intravenously.
Elderly frequency (common >1/100, <1/10; uncommon >1/1000, <1/100; Using AUC as a surrogate parameter for plasma concentration, a
rare >1/10000, <1/1000; very rare <1/10000). relationship between inhibition of acid secretion and exposure has
Dose adjustment is not required in the elderly.
Blood and lymphatic system disorders been shown after oral administration of esomeprazole.
CONTRAINDICATIONS
Rare: Leukopenia, thrombocytopenia Therapeutic effects of acid inhibition
Hypersensitivity to the active substance esomeprazole or to other
Very rare: Agranulocytosis, pancytopenia Healing of reux esophagitis with esomeprazole 40 mg occurs in
substituted benzimidazoles or to any of the excipients of this
Immune system disorders approximately 78% of patients after 4 weeks, and in 93% after 8
medicinal product.
weeks of oral treatment.
Esomeprazole like other PPIs should not be administered with Rare: Hypersensitivity reactions e.g. fever, angioedema and
anaphylactic reaction/shock Other effects related to acid inhibition
atazanavir (see Interactions section).
Metabolism and nutrition disorders During treatment with antisecretory drugs serum gastrin increases
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS in response to the decreased acid secretion.
Uncommon: Peripheral oedema
FOR USE An increased number of ECL cells possibly related to the increased
Rare: Hyponatraemia
In the presence of any alarm symptom (e.g. signicant unintentional serum gastrin levels, have been observed in some patients during
weight loss, recurrent vomiting, dysphagia, haematemesis Psychiatric disorders long term treatment with orally administered esomeprazole.
or melaena) and when gastric ulcer is suspected or present, Uncommon: Insomnia During long-term oral treatment with antisecretory drugs gastric
malignancy should be excluded, as treatment with NEXIUM may Rare: Agitation, confusion, depression glandular cysts have been reported to occur at a somewhat increased
alleviate symptoms and delay diagnosis. frequency. These changes are a physiological consequence of
Very rare: Aggression, hallucinations
INTERACTIONS Nervous system disorders pronounced inhibition of acid secretion, are benign and appear to
be reversible.
Effects of esomeprazole on the pharmacokinetics of other Common: Headache
drugs Uncommon: Dizziness, paraesthesia, somnolence PHARMACOKINETIC PROPERTIES
The decreased intragastric acidity during treatment with NEXIUM Rare: Taste disturbance Distribution
might increase or decrease the absorption of drugs if the mechanism The apparent volume of distribution at steady state in healthy
Eye disorders
of absorption is inuenced by gastric acidity. In common with the subjects is approximately 0.22 L/kg body weight. Esomeprazole
use of other inhibitors of acid secretion or antacids, the absorption Uncommon: Blurred vision
is 97% plasma protein bound.
of ketoconazole and itraconazole can decrease during treatment Ear and labyrinth disorders
Metabolism and excretion
with NEXIUM. Uncommon: Vertigo
Esomeprazole is completely metabolised by the cytochrome P450
Esomeprazole inhibits CYP2C19, the major esomeprazole Respiratory, thoracic and mediastinal disorders system (CYP). The major part of the metabolism of esomeprazole
metabolising enzyme. Thus, when esomeprazole is combined Rare: Bronchospasm is dependent on the polymorphic CYP2C19, responsible for
with drugs metabolised by CYP2C19, such as diazepam,
Gastrointestinal disorders the formation of the hydroxy- and desmethyl metabolites of
citalopram, imipramine, clomipramine, phenytoin etc., the
Common: Abdominal pain, constipation, diarrhoea, atulence, esomeprazole. The remaining part is dependent on another specic
plasma concentrations of these drugs may be increased and a dose
nausea/vomiting isoform, CYP3A4, responsible for the formation of esomeprazole
reduction could be needed. Concomitant oral administration of 30
sulphone, the main metabolite in plasma.
mg esomeprazole resulted in a 45% decrease in clearance of the Uncommon: Dry mouth
CYP2C19 substrate diazepam. Concomitant oral administration of The parameters below reect mainly the pharmacokinetics in
Rare: Stomatitis, gastrointestinal candidiasis individuals with a functional CYP2C19 enzyme, extensive
40 mg esomeprazole and phenytoin resulted in a 13% increase
Hepatobiliary disorders metabolisers.
in trough plasma levels of phenytoin in epileptic patients. It is
recommended to monitor the plasma concentrations of phenytoin Uncommon: Increased liver enzymes Total plasma clearance is about 17 L/h after a single dose and
when treatment with esomeprazole is introduced or withdrawn. Rare: Hepatitis with or without jaundice about 9 L/h after repeated administration. The plasma elimination
Concomitant oral administration of 40 mg esomeprazole to Very rare: Hepatic failure, encephalopathy in patients with pre- half-life is about 1.3 hours after repeated once-daily dosing.
warfarin-treated patients in a clinical trial showed that coagulation existing liver disease Total exposure (AUC) increases with repeated administration of
times were within the accepted range. However, post-marketing of esomeprazole. This increase is dose-dependent and results in a
Skin and subcutaneous tissue disorders
oral esomeprazole, a few isolated cases of elevated INR of clinical non-linear dose-AUC relationship after repeated administration.
Uncommon: Dermatitis, pruritus, rash, urticaria This time - and dose-dependency is due to a decrease of rst pass
signicance have been reported during concomitant treatment.
Rare: Alopecia, photosensitivity metabolism and systemic clearance probably caused by inhibition
Monitoring is recommended when initiating and ending
Very rare: Erythema multiforme, Stevens-Johnson syndrome, of the CYP2C19 enzyme by esomeprazole and/or its sulphone
concomitant treatment. metabolite.
toxic epidermal necrolysis (TEN)
In healthy volunteers, concomitant oral administration of 40 mg Esomeprazole is completely eliminated from plasma between
Musculoskeletal, connective tissue and bone disorders
esomeprazole and cisapride resulted in a 32% increase in area doses with no tendency for accumulation during once-daily
under the plasma concentration-time curve (AUC) and a 31% Rare: Arthralgia, myalgia
administration.
prolongation of elimination half-life (t1/2) but no signicant Very rare: Muscular weakness
increase in peak plasma levels of cisapride. The slightly prolonged Following repeated doses of 40 mg administered as intravenous
Renal and urinary disorders injections, the mean peak plasma concentration is approx.
QTc interval observed after administration of cisapride alone, was
Very rare: Interstitial nephritis 13.6 micromol/L. The mean peak plasma concentration after
not further prolonged when cisapride was given in combination
with esomeprazole. Reproductive system and breast disorders corresponding oral doses is approx. 4.6 micromol/L. A smaller
Very rare: Gynaecomastia increase (of approx. 30%) can be seen in the total exposure after
Co-administration of omeprazole (40 mg once daily) with intravenous administration compared to oral administration.
atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted General disorders and administration site conditions
in a substantial reduction in atazanavir exposure (approximately The major metabolites of esomeprazole have no effect on gastric
Rare: malaise, increased sweating
75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir acid secretion. Almost 80% of an oral dose of esomeprazole is
Irreversible visual impairment has been reported in isolated excreted as metabolites in the urine, the remainder in the faeces.
dose to 400 mg did not compensate for the impact of omeprazole cases of critically ill patients who have received omeprazole (the
on atazanavir exposure. PPIs including esomeprazole should Less than 1% of the parent drug is found in urine.
racemate) intravenous injection, especially at high doses, but no
not be co-administered with atazanavir (see Contraindications causal relationship has been established. SPECIAL PATIENT POPULATIONS
section). Approximately 1-2% of the population lacks a functional
Esomeprazole has been shown to have no clinically relevant OVERDOSE
CYP2C19 enzyme and is called poor metabolisers. In these
effects on the pharmacokinetics of amoxicillin or quinidine. There is very limited experience to date with deliberate overdose. individuals the metabolism of esomeprazole is probably mainly
Effects of other drugs on the pharmacokinetics of The symptoms described in connection with an oral dose of 280 catalysed by CYP3A4. After repeated once-daily administration
esomeprazole mg were gastrointestinal symptoms and weakness. Single oral of 40 mg oral esomeprazole, the mean total exposure was
doses of 80 mg esomeprazole and intravenous doses of 100 mg approximately 100% higher in poor metabolisers than in subjects
Esomeprazole is metabolised by CYP2C19 and CYP3A4. were uneventful. No specic antidote is known. Esomeprazole
Concomitant oral administration of esomeprazole and a CYP3A4 with a functional CYP2C19 enzyme (extensive metabolisers).
is extensively plasma protein bound and is therefore not readily Mean peak plasma concentrations were increased by about 60%.
inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling dialyzable. As in any case of overdose, treatment should be
of the exposure (AUC) to esomeprazole. Dose adjustment of Similar differences have been seen for intravenous administration
symptomatic and general supportive measures should be utilised. of esomeprazole. These ndings have no implications for the
esomeprazole is not required.
PHARMACODYNAMIC PROPERTIES posology of esomeprazole.
PREGNANCY AND LACTATION The metabolism of esomeprazole is not signicantly changed in
Pharmacotherapeutic group: Proton pump inhibitor
For esomeprazole limited data on exposed pregnancies are elderly subjects (71-80 years of age).
available. Animal studies with esomeprazole do not indicate ATC Code: A02B C05
Following a single oral dose of 40 mg esomeprazole the mean
direct or indirect harmful effects with respect to embryonal/ Esomeprazole is the S-isomer of omeprazole and reduces gastric
total exposure is approximately 30% higher in females than in
fetal development. Animal studies with the racemic mixture acid secretion through a specic targeted mechanism of action. It
males. No gender difference is seen after repeated once-daily
do not indicate direct or indirect harmful effects with respect to is a specic inhibitor of the acid pump in the parietal cell. Both the
administration. Similar differences have been observed for
pregnancy, parturition or postnatal development. Caution should R- and S-isomer of omeprazole have similar pharmacodynamic
intravenous administration of esomeprazole. These ndings have
be exercised when prescribing NEXIUM to pregnant women. activity.
no implications for the posology of esomeprazole.
It is not known whether esomeprazole is excreted in human Site and mechanism of action
The metabolism of esomeprazole in patients with mild to moderate
breast milk. No studies in lactating women have been performed. Esomeprazole is a weak base and is concentrated and converted to liver dysfunction may be impaired. The metabolic rate is decreased
Therefore NEXIUM should not be used during breast-feeding. the active form in the highly acidic environment of the secretory in patients with severe liver dysfunction resulting in a doubling of
canaliculi of the parietal cell, where it inhibits the enzyme H+K+- the total exposure of esomeprazole. Therefore, a maximum dose of
ATPase the acid pump and inhibits both basal and stimulated 20 mg should not be exceeded in patients with severe dysfunction.
NEXIUM is not likely to affect the ability to drive or use acid secretion. Esomeprazole or its major metabolites do not show any tendency
machines.
Effect on gastric acid secretion to accumulate with once-daily dosing.
UNDESIRABLE EFFECTS After 5 days of oral dosing with 20 mg and 40 mg of esomeprazole, No studies have been performed in patients with decreased renal
The following adverse drug reactions have been identied or intragastric pH above 4 was maintained for a mean time of 13 function. Since the kidney is responsible for the excretion of the
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metabolites of esomeprazole but not for the elimination of the POSOLOGY AND METHOD OF ADMINISTRATION milk and therefore the drug is not recommended during lactation.
parent compound, the metabolism of esomeprazole is not expected Breast cancer The decision either to discontinue nursing or discontinue
to be changed in patients with impaired renal function. NOLVADEX should take into account the importance of the
Adults (including elderly): The dosage range is 20 to 40mg
drug to the mother.
LIST OF EXCIPIENTS daily, given either in divided doses twice daily or as a single dose
once daily. EFFECT ON ABILITY TO DRIVE AND OPERATE
Disodium edetate
Anovulatory Infertility MACHINES
Sodium hydroxide
Pregnancy must be excluded before starting a course of therapy, There is no evidence that NOLVADEX results in impairment of
INCOMPATIBILITIES whether initial or subsequent. For women who are menstruating these activities.
This medicinal product should not be used with other medicinal regularly but with anovular cycles, the initial course of treatment
UNDESIRABLE EFFECTS
products except those mentioned in Instruction for use and consists of daily doses of 20mg of Nolvadex administered on
handling. the second, third, fourth and fth days of the menstrual cycle. If Side effects can be classied as either due to the pharmacological
unsatisfactory basal temperature or poor pre-ovulatory cervical action of the drug, e.g. hot ushes, vaginal bleeding, vaginal
SHELF LIFE mucus indicate that this initial course of treatment has been discharge, pruritus vulvae and tumour are or as more general
Please refer to expiry date on the outer carton. unsuccessful, further courses may be given during subsequent side effects, e.g. gastro intestinal intolerance, headache, light-
menstrual cycles, increasing the dosage to 40mg and then to 80mg headedness and occasionally, uid retention and alopecia.
Shelf-life after reconstitution
daily. When such side effects are severe, it may be possible to control
Chemical and physical in-use stability has been demonstrated
For women who are not menstruating regularly, the initial course them by a simple reduction of dosage (within the recommended
for 12 hours at 30C. From a microbiological point of view, the
may begin on any day. If no signs of ovulation are demonstrable, dose range) without loss of control of the disease.
product should be used immediately.
a subsequent course of treatment should start 45 days later with Skin rashes including isolated reports of erythema multiforme,
SPECIAL PRECAUTIONS FOR STORAGE the dosage increased as described above. If a patient responds by Stevens-Johnson syndrome and bullous pemphigoid and rare
Store in the original package, in order to protect from light. Vials menstruating, further courses of treatment should commence on hypersensitivity reactions, including angioedema have been
can however be stored exposed to normal in door light outside the the second day of each cycle. reported.
box for up to 24 hours. Do not store above 30C. Children: Not applicable A small number of patients with bony metastases have developed
hypercalcaemia on initiation of therapy.
PACK SIZE CONTRA-INDICATIONS
Falls in platelet count, usually only to 80,000 90,000 per cu
Please refer to the outer carton for pack size. Pregnancy: NOLVADEX must not be given during pregnancy. mm but occasionally lower, have been reported in patients taking
INSTRUCTIONS FOR USE AND HANDLING There have been a small number of reports of spontaneous NOLVADEX for breast cancer.
abortions, birth defects and foetal deaths after women have
Injection A number of cases of visual disturbances including infrequent
taken NOLVADEX, although no causal relationship has been
A solution for injection is prepared by adding 5 mL of 0.9% reports of corneal changes and retinopathy have been described in
established. (see also Pregnancy and Lactation).
sodium chloride for intravenous use to the vial with esomeprazole. patients receiving Nolvadex therapy. An increased incidence of
NOLVADEX should not be given to patients who have cataracts has been reported in association with the administration
The reconstituted solution for injection is clear and colourless to experienced hypersensitivity to the product or any of its
very slightly yellow. of NOLVADEX.
ingredients.
The degradation of reconstituted solution is highly pH dependent Uterine broids, endometriosis and other endometrial changes
SPECIAL WARNINGS AND PRECAUTIONS including hyperplasia and polyps have been reported.
and the product must therefore only be reconstituted in the
specied volume of 0.9% sodium chloride for intravenous use. Menstruation is suppressed in a proportion of premenopausal Cystic ovarian swellings have occasionally been observed in
The reconstituted solution should not be mixed or co-administered women receiving Nolvadex for the treatment of breast cancer. premenopausal women receiving NOLVADEX.
in the same infusion set with any other drug. An increased incidence of endometrial cancer and uterine An increased incidence of endometrial cancer and uterine
The reconstituted solution should be inspected visually for sarcoma(mostly malignant mixed Mullerian tumours) has sarcoma (mostly malignant mixed Mullerian tumours) has
particulate matter and discoloration prior to administration. Only been reported in association with NOLVADEX treatment. The been associated with NOLVADEX treatment.
clear solution should be used. underlying mechanism is unknown, but may be related to the Leucopenia has been observed following the administration of
oestrogen-like effect of NOLVADEX. Any patients receiving or NOLVADEX, sometimes in association with anaemia and/
The reconstituted solution should be used within 12 hours. From
having previously received NOLVADEX, who report abnormal or thrombocytopenia. Neutropenia has been reported on rare
a microbiological point of view, the product should be used gynaecological symptoms, especially vaginal bleeding, should be
immediately. Do not store above 30 C. occasions; this can sometimes be severe.
promptly investigated.
The reconstituted solution should be given as an intravenous There is evidence of an increased incidence of thromboembolic
A number of second primary tumours, occurring at sites other than events including deep vein thrombosis and pulmonary embolism
injection over a period of at least 3 minutes. the endometrium and the opposite breast, have been reported in during NOLVADEX therapy. Very rarely, cases of interstitial
Half of the volume should be given if 20 mg should be clinical trials, following the treatment of breast cancer patients pneumonitis have been reported.
administrated. Any unused solution should be discarded. with tamoxifen. No causal link has been established and the
When NOLVADEX is used in combination with cytotoxic agents,
Infusion clinical signicance of these observations remains unclear.
there is an increased risk of thromboembolic events occurring.
A solution for infusion is prepared by dissolving the content of INTERACTIONS NOLVADEX has been associated with changes in liver enzyme
one vial with esomeprazole in up to 100 mL 0.9% sodium chloride When NOLVADEX is used in combination with coumarin levels and on rare occasions with a spectrum of more severe liver
for intravenous use. type anticoagulants, a signicant increase in anticoagulant effect abnormalities, including fatty liver, cholestasis and hepatitis.
The reconstituted solution for infusion is clear and colourless to may occur. Where such co administration is initiated, careful Rarely, elevation of serum triglyceride levels, in some cases with
very slightly yellow. monitoring of the patient is recommended. pancreatitis, may be associated with the use of NOLVADEX.
The degradation of reconstituted solution is highly pH dependent When NOLVADEX is used in combination with cytotoxic
OVERDOSE
and the product must therefore only be reconstituted in the agents, there is an increased risk of thromboembolic events
specied volume of 0.9% sodium chloride for intravenous use. occurring. (see also Undesirable effects) On theoretical grounds, overdosage would be expected to cause
enhancement of the pharmacological side effects mentioned above.
The reconstituted solution should not be mixed or co-administered As NOLVADEX is metabolised by cytochrome P450 3A4,
Observations in animals show that extreme overdosage (100 200
in the same infusion set with any other drug. care is required when co-administering with drugs, such as
times recommended daily dose) may produce oestrogenic effects.
The reconstituted solution should be administrated separately rifampicin, known to induce this enzyme as tamoxifen levels
may be reduced. The relevance of this to clinical practice is There have been reports in the literature that NOLVADEX
from other drugs. given at several times the standard dose may be associated with
not known.
The reconstituted solution should be inspected visually for prolongation of QT interval of the ECG.
particulate matter and discoloration prior to administration. Only PREGANCY AND LACTATION There is no specic antidote to overdosage and treatment must be
clear solution should be used. Pregnancy: NOLVADEX must not be administered during symptomatic.
The reconstituted solution should be used within 12 hours. From pregnancy. There have been a small number of reports of
a microbiological point of view, the product should be used spontaneous abortions, birth defects and foetal deaths after women PHARMACOLOGICAL PROPERTIES
immediately. Do not store above 30 C. have taken NOLVADEX, although no causal relationship has PHARMACODYNAMIC PROPERTIES
The reconstituted solution should be given as an intravenous been established. NOLVADEX (tamoxifen) is a non steroidal, triphenylene-based
infusion over a period of 10 to 30 minutes. Reproductive toxicology studies in rats, rabbits and monkeys have drug which displays a complex spectrum of oestrogen antagonist
shown no teratogenic potential. and oestrogen agonist-like pharmacological effects in different
Half of the volume should be given if 20 mg should be
In rodent models of foetal reproductive tract development, tissues. In breast cancer patients, at the tumour level, tamoxifen
administrated. Any unused solution should be discarded.
tamoxifen was associated with changes similar to those caused by acts primarily as an antioestrogen, preventing oestrogen binding
NEXIUM is a trade mark of the Astrazeneca group of companies. to the oestrogen receptor. However, clinical studies have shown
oestradiol, ethynyloestradiol, clomiphene and diethylstilboestrol
Astrazeneca 2006 (DES). Although the clinical relevance of these changes is some benet in oestrogen receptor negative tumours which may
unknown, some of them, especially vaginal adenosis, are similar indicate other mechanisms of action. In the clinical situation, it
NOLVADEX 10mg and 20mg Tablets to those seen in young women who were exposed to DES in utero is recognised that tamoxifen leads to reductions in levels of blood
and who have a 1 in 1000 risk of developing clear-cell carcinoma total cholesterol and low density lipoproteins in postmenopausal
of the vagina or cervix. Only a small number of pregnant women women of the order of 10-20%. Additionally tamoxifen has
(Tamoxifen Citrate) have been exposed to tamoxifen. Such exposure has not been been reported to lead to maintenance of bone mineral density in
reported to cause subsequent vaginal adenosis or clear-cell postmenopausal women.
PRESENTATION carcinoma of the vagina or cervix in young women exposed in PHARMACOKINETIC PROPERTIES
NOLVADEX is available as tablets containing Tamoxifen Citrate utero to tamoxifen.
After oral administration, NOLVADEX is absorbed rapidly
Ph. Eur. equivalent to 10mg of tamoxifen. Women should be advised not to become pregnant whilst taking with maximum serum concentrations attained within 4 7 hours.
NOLVADEX D is available as tablets containing Tamoxifen NOLVADEX and should use barrier or other non-hormonal Steady state concentrations (about 300 ng/ml) are achieved after
Citrate Ph. Eur. equivalent to 20mg of tamoxifen. contraceptive methods if sexually active. Premenopausal patients four weeks treatment with 40 mg daily. The drug is highly protein
must be carefully examined before treatment to exclude pregnancy. bound to serum albumin (>99%). Metabolism is by hydroxylation,
THERAPEUTIC INDICATION Women should be informed of the potential risks to the foetus, demethylation and conjugation, giving rise to several metabolites,
NOLVADEX is indicated for: should they become pregnant whilst taking NOLVADEX or which have a similar pharmacological prole to the parent
1. The treatment of breast cancer. within two months of cessation of therapy. compound and thus contribute to the therapeutic effect. Excretion
2. The treatment of anovulatory infertility. Lactation: It is not known if NOLVADEX is excreted in human occurs primarily via the faeces and an elimination half life of
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approximately seven days has been calculated for the drug itself, Adults aged > 18 years: delivered dose (corresponding to 600 micrograms per metered
whereas that for N desmethyltamoxifen, the principal circulating RELIEF MEDICATION: 1 inhalation for the relief of acute dose). This amount does not normally cause problems in lactose
metabolite, is 14 days. broncho-obstructive symptoms. intolerant people.
PRE-CLINICAL SAFETY DATA RELEVANT TO THE REGULAR DOSAGE: 1 inhalation once or twice daily. Some Children up to the age of 6 years should not be treated with OXIS
PRESCRIBER patients may need 2 inhalations once or twice daily. TURBUHALER , as no sufcient experience is available for this
Prevention of exercise-induced bronchoconstriction: 1 group.
Tamoxifen was not mutagenic in a range of in vitro and in vivo
inhalation before exercise. The effect of decreased liver or kidney function on the
mutagenicity tests. Tamoxifen was genotoxic in some in vitro
The daily dose for regular use should not exceed 4 inhalations, pharmacokinetics of formoterol and the pharmacokinetics in the
tests and in vivo genotoxicity tests in rodents. Gonadal tumours
however occasionally up to a maximum of 6 inhalations may elderly is not known. As formoterol is primarily eliminated via
in mice and liver tumours in rats receiving tamoxifen have been
be allowed within a 24-hour period. No more than 3 inhalations metabolism an increased exposure can be expected in patients with
reported in long term studies. The clinical relevance of these
should be taken on any single occasion. severe liver cirrhosis.
ndings has not been established.
Children and adolescents, 6 years and older: INTERACTION
PHARMACEUTICAL PRECAUTIONS
Relief medication: 1 inhalation for the relief of acute broncho- No specic interaction studies have been carried out with Oxis
SPECIAL PRECAUTIONS FOR STORAGE obstructive symptoms. Turbuhaler.
Do not store above 30 C. Store in original container. Regular dosage: 1 inhalation once or twice daily. Concomitant treatment with other sympathomimetic substances
Prevention of exercise-induced bronchoconstriction: 1 such as other 2-agonists or ephedrine may potentiate the
SHELF LIFE:
inhalation before exercise. undesirable effects of OXIS TURBUHALER and may require
Please refer to expiry date on blister strip and carton. titration of the dose.
The regular daily dose should not exceed 2 inhalations, however
PACK SIZE: occasionally up to a maximum of 4 inhalations may be allowed Concomitant treatment with xanthine derivatives, steroids or
Please refer to outer carton for pack size. within a 24-hour period. No more than 1 inhalation should be diuretics such as thiazides and loop diuretics may potentiate a rare
taken on any single occasion. hypokalaemic adverse effect of 2-agonists. Hypokalaemia may
Trademarks herein are the property of the AstraZeneca group of
increase the disposition towards arrhythmias in patients who are
companies. COPD:
treated with digitalis glycosides.
Regular dosage: 1 inhalation once or twice daily.
There is a theoretical risk that concomitant treatment with other
OXIS TURBUHALER Inhalation powder The daily dose for regular use should not exceed 2 inhalations. drugs known to prolong the QTc-interval may give rise to a
4.5 g/dose and 9 g/dose If required, additional inhalations above those prescribed for regular pharmacodynamic interaction with formoterol and increase the
therapy may be used for relief of symptoms, up to a maximum total possible risk of ventricular arrhythmias. Examples of such drugs
daily dose of 4inhalations, (regular plus as required). No more than include certain antihistamines (e.g. terfenadine, astemizole,
(Formoterol fumarate dihydrate) 2 inhalations should be taken on any single occasion. mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide,
Special patient groups: No adjustment of dose should be required procainamide), erythromycin and tricyclic antidepressants.
COMPOSITION in the elderly, or in patients with renal or hepatic impairment at There is an elevated risk of arrhythmias in patients receiving
Each delivered dose (i.e. the dose leaving the mouthpiece) from the recommended normal doses. (See Special warnings and concomitant anaesthesia with halogenated hydrocarbons.
OXIS TURBUHALER contains 4.5 or 9 micrograms formoterol precautions for use.) Beta-adrenergic blockers can weaken or inhibit the effect of OXIS
fumarate dihydrate which is derived from a metered dose of 6 or OXIS TURBUHALER is inspiratory ow driven which means TURBUHALER. OXIS TURBUHALER should therefore not
12 micrograms. that, when the patient inhales through the mouthpiece, the be given together with beta-adrenergic blockers (including eye
substance will follow the inspired air into the airways. drops) unless there are compelling reasons.
PHARMACEUTICAL FORM
Note! It is important to instruct the patient to breathe in forcefully PREGNANCY AND LACTATION
Inhalation powder. White powder. and deeply through the mouthpiece to ensure that an optimal dose
is obtained. Clinical experience in pregnant women is limited. In animal studies
THERAPEUTIC INDICATION
formoterol has caused implantation losses as well as decreased
OXIS TURBUHALER is indicated, as add on therapy to It is important to instruct the patient never to chew or bite on the early postnatal survival and birth weight. The effects appeared at
maintenance treatment with inhaled corticosteroids, for the relief of mouthpiece and never to use the inhaler if it has been damaged or considerably higher systemic exposures than those reached during
broncho-obstructive symptoms and prevention of exercise-induced if the mouthpiece has become detached. clinical use of OXIS TURBUHALER. Treatment with OXIS
symptoms in patients with asthma when adequate treatment with The patient may not taste or feel any medication when using Oxis TURBUHALERmay be considered at all stages of pregnancy if
corticosteroids is not sufcient. OXIS TURBUHALER is also Turbuhaler due to the small amount of drug dispensed. needed to obtain asthma control, and if the expected benet to the
indicated for the relief of broncho-obstructive symptoms in mother is greater than any possible risk to the foetus.
CONTRAINDICATIONS
patients with chronic obstructive pulmonary disease (COPD). It is not known whether formoterol passes into human breast milk.
Hypersensitivity to formoterol or to inhaled lactose.
POSOLOGY AND METHOD OF ADMINISTRATION In rats, small amounts of formoterol have been detected in maternal
SPECIAL WARNINGS AND PRECAUTIONS FOR USE milk. Administration of OXIS TURBUHALERto women who
Use of doses above those normally required by the individual
patient on more than 2 days per week is a sign of suboptimal Asthmatic patients who require therapy with long-acting are breastfeeding should only be considered if the expected benet
2-agonists, should also receive optimal maintenance anti- to the mother is greater than any possible risk to the child.
disease control and maintenance treatment should be reassessed.
inammatory therapy with corticosteroids. Patients must be EFFECTS ON THE ABILITY TO DRIVE AND USE
4.5 g/dose advised to continue taking their anti-inammatory therapy after MACHINES
Asthma: the introduction of OXIS TURBUHALER even when symptoms
decrease. Should symptoms persist, or treatment with 2-agonists OXIS TURBUHALER does not affect the ability to drive or use
In asthma, OXIS TURBUHALER can be used once or twice
need to be increased, this indicates a worsening of the underlying machines.
daily (regular dosage), and as relief medication to relieve acute
broncho-obstructive symptoms. condition and warrants a reassessment of the maintenance therapy. UNDESIRABLE EFFECTS
OXIS TURBUHALER should not be initiated to treat a severe
Adults aged > 18 years: The most commonly reported adverse events of 2-agonist therapy,
asthma exacerbation.
Relief medication: 1 or 2 inhalations for the relief of acute such as tremor and palpitations, tend to be mild and disappear
The maximum daily dose should not be exceeded. The long term within a few days of treatment.
broncho-obstructive symptoms.
safety of regular treatment at higher doses than 36 micrograms per
Regular dosage: 1 or 2 inhalations once or twice daily. Common Cardiac disorders: Palpitations
day in adults with asthma, 18 micrograms per day in children with
1% to 10% Nervous system disorders: Headache,
Some patients may need 4 inhalations once or twice daily. asthma and 18 micrograms per day in patients with COPD has not
tremor
Prevention of exercise-induced bronchoconstriction: 2 inhalations been established.
before exercise. Frequent need of medication for the prevention of exercise- Uncommon Cardiac disorders: Tachycardia
induced bronchoconstriction can be a sign of suboptimal asthma 0.1% to 1% Musculoskeletal and connective
The daily dose for regular use should not exceed 8 inhalations, tissue disorders: Muscle cramps
however occasionally up to a maximum of 12 inhalations may control, and warrants a reassessment of the asthma therapy and
an evaluation of the compliance. If the patient needs prophylactic Psychiatric disorders: Agitation,
be allowed within a 24-hour period. No more than 6 inhalations
treatment for exercise-induced bronchoconstriction several times restlessness, sleep disturbance
should be taken on any single occasion.
every week despite an adequate maintenance treatment (e.g. Rare Cardiac disorders: Cardiac
Children and adolescents, 6 years and older:
corticosteroids and long-acting 2-agonists), the total asthma 0.01% to 0.1% arrhythmias, e.g. atrial brillation,
Relief medication: 1 or 2 inhalations for the relief of acute management should be reassessed by a specialist. supraventricular tachycardia,
broncho-obstructive symptoms. extrasystoles
Caution should be observed when treating patients with
Regular dosage: 2 inhalations once or twice daily. thyrotoxicosis, phaeochromocytoma, hypertrophic obstructive Gastrointestinal disorders: Nausea
Prevention of exercise-induced bronchoconstriction: 1 or 2 cardiomyopathy, idiopathic subvalvular aortic stenosis, severe Immune system disorders:
inhalation before exercise. hypertension, aneurysm or other severe cardiovascular disorders, Hypersensitivity reactions, e.g.
The regular daily dose should not exceed 4 inhalations, however such as ischaemic heart disease, tachyarrhythmias or severe heart bronchospasm, exanthema, urticaria,
occasionally up to a maximum of 8 inhalations may be allowed failure. pruritus
within a 24-hour period. No more than 2 inhalations should be Formoterol may induce prolongation of the QTc-interval. Caution Metabolism and nutrition
taken on any single occasion. should be observed when treating patients with prolongation of disorders: Hypokalaemia/
the QTc-interval and in patients treated with drugs affecting the hyperkalaemia
COPD: QTc-interval (see Interactions). Very rare Cardiac disorders: Angina pectoris
Regular dosage: 2 inhalations once or twice daily. Due to the hyperglycaemic effects of 2-agonists, additional blood <0.01% Investigations: Prolongation of the
The daily dose for regular use should not exceed 4 inhalations. If glucose monitoring is recommended initially in diabetic patients. QTc-interval
required, additional inhalations above those prescribed for regular Potentially serious hypokalaemia may result from 2-agonist Metabolism and nutrition
therapy may be used for relief of symptoms, up to a maximum therapy. Particular caution is recommended in acute severe disorders:
total daily dose of 8 inhalations, (regular plus as required). No asthma as the associated risk may be augmented by hypoxia. The Hyperglycaemia
more than 4 inhalations should be taken on any single occasion. hypokalaemic effect may be potentiated by concomitant treatment Nervous system disorders: Taste
9 g/dose with xanthine-derivatives, steroids and diuretics. The serum disturbance, dizziness
Asthma: potassium levels should therefore be monitored. Vascular disorders: Variations in
As with other inhalation therapy, the potential for paradoxial blood pressure
In asthma, OXIS TURBUHALER can be used once or twice
daily (regular dosage), and as relief medication to relieve acute bronchospasm should be considered. As with all inhalation therapy, paradoxical bronchospasm may
broncho-obstructive symptoms. OXIS TURBUHALER contains lactose 450 micrograms per occur in very rare cases.
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Treatment with 2-agonists may result in an increase in blood 3.Breathe out. Do not vreathe out through the inhaler. 2.5 mg once daily may be sufcient. Doses higher than 10 mg once
levels of insulin, free fatty acids, glycerol and ketone bodies. 4. Place the mouthpiece gently between your teeth, close your lips daily are usually not needed.
OVERDOSE and breathe in farcefully and deeply through your mouth. Angina pectoris
There is limited clinical experience on the management of Do not chew or bite on the mouthpiece. Do not use Turbuhaler if The dose should be adjusted individually. Treatment should be
overdose. An overdose would likely lead to effects that are it has been damaged or if the mouthpiece has become detached initiated with 5 mg once daily and, if needed, increased to 10 mg
typical of 2-agonists: tremor, headache, palpitations. Symptoms (Fig. 3) once daily. PLENDIL may be combined with -blockers.
reported from isolated cases are tachycardia, hyperglycaemia, Impaired renal function
hypokalaemia, prolonged QTc-interval, arrythmia, nausea and Impaired renal function does not affect plasma concentrations of
vomiting. Supportive and symptomatic treatment is indicated. felodipine. No dose adjustment is required. PLENDIL should be
Use of cardioselective beta-blockers may be considered, but only used with caution in patients with severely impaired renal function
subject to extreme caution since the use of -adrenergic blocker (see Special warnings and precautions for use and Interactions).
medication may provoke bronchospasm. Serum potassium should
Children
be monitored.
Experience from treatment of children with felodipine is limited.
Formoterol is a selective 2-adrenoceptor agonist that produces CONTRAINDICATIONS
relaxation of bronchial smooth muscle. Formoterol thus has Pregnancy
a bronchodilating effect in patients with reversible airways 5. Before breathing out, remove the inhaler from your mouth. Known hypersensitivity to felodipine or any other component of
obstruction. The bronchodilating effect sets in rapidly, within 1-3 if more than one dose has been prescribed, repeat steps2-5. the product
minutes after inhalation and has a mean duration of 12 hours after Uncompensated heart failure
a single dose. 6. Replace the cover.
7. Rinse your mouth out with water after inhalling your prescribed Acute myocardial infarction
PHARMACOKINETIC PROPERTIES dose. Unstable angina pectoris
Absorption
NOTE! SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Inhaled formoterol is rapidly absorbed. Peak plasma concentration
Never breathe out through the mouthplece. Always replace the Aortic stenosis, liver impairment, severely impaired renal function
is reached about 10 minutes after inhalation.
cover properly after use. (GFR<30 ml/min), heart failure after acute myocardial infarction.
In studies the mean lung deposition of formoterol after inhalation Hypotension, which may cause myocardial ischaemia in sensitive
via Turbuhaler ranged from 28-49% of the delivered dose As the amount of the power dispensed is very smail, you may
not be able to taste it after inhalation. However, you can still be patients.
(corresponding to 21-37% of the metered dose). The total systemic
availability for the higher lung deposition was around 61% of the condent that the dose has been inhaled if you have followed the Concomitant administration of drugs that induce CYP 3A4 leads
delivered dose (corresponding to 46% of the metered dose). instructions. to strongly reduced levels of felodipine and the risk of a lack of
Cleaning effect of PLENDIL (see Interactions). This combination should
Distribution and metabolism
Clean the outside of the mouthpiece regularly (Weekly) with a dry be avoided.
Plasma protein binding is approximately 50%.
tissue. Concomitant administration of drugs that are potent inhibitors
Formoterol is metabolised via direct glucuronidation and O-
Do not use water for cleaning the mouthpiece. of CYP 3A4 leads to markedly elevated levels of felodipine (see
demethylation. The enzyme responsible for O-demethylation
Interactions). This combination should be avoided.
has not been identied. Total plasma clearance and volume of Dose indicator
distribution has not been determined. Concomitant intake of grapefruit juice leads to markedly elevated
When a red mark is rst seen in the indicator window there are levels of felodipine (see Interactions). This combination should be
Elimination approximately 20 doses left(Fig.4). When the red mark has reached avoided.
The major part of the dose of formoterol is eliminated via the lower edge of the Window the inhaler will no longer deliver the
metabolism. After inhalation 8-13% of the delivered dose correct amount of medicine, and should be discarded(Fig,5). INTERACTIONS
(corresponding to 6-10% of the metered dose) of formoterol is Felodipine is a CYP 3A4 substrate. Drugs that inhibit or induce
excreted unmetabolised in the urine. About 20% of an intravenous CYP 3A4 have signicant effects on the plasma concentration of
dose is excreted unchanged in the urine. The terminal half-life felodipine.
after inhalation is estimated to be 17 hours.
Cytochrome P450 inducers: Drugs that increase the metabolism
LIST OF EXCIPIENTS of felodipine by induction of P450 are, for example, carbamazepine,
Lactose monohydrate. phenytoin, phenobarbital and rifampicin, as well as St. Johns wort
(hypericum perforatum). When PLENDIL was administered
INCOMPATIBILITIES The sound heard as you shake the inhaler is not produced by the together with carbamazepine, phenytoin and phenobarbital, the
Not applicable medication but by a drying agent. AUC of felodipine was reduced by 93% and Cmax by 82%.
Disposal Combination with CYP 3A4 inducers should be avoided.
SHELF LIFE
Always be sure to dispose of your used turbuhaler responsibly/in Cytochrome P450 inhibitors: Drugs that are potent CYP 3A4
Please see outer pack.
the recommended way, since some of the medicine will remain inhibitors are, for example, azole antimycotics (itraconazole,
SPECIAL PRECAUTIONS FOR STORAGE insde it. ketoconazole), macrolide antibiotics (erythromycin) and HIV
Do not store above 30 C. protease inhibitors. Concomitant administration of itraconazole
Should be stored with cover tightened. PLENDIL 2.5 mg (N.R), 5 mg and 10 mg resulted in eight-fold increases of the Cmax of felodipine and
six-fold increases of the AUC. Concomitant administration of
PACK SIZE Tablets erythromycin led to approximately 2.5-fold increases of the Cmax
Please see outer carton for pack size. and the AUC of felodipine. Combination with potent CYP 3A4
HOW TO USE OXIS TURBUHALER (Felodipine) inhibitors should be avoided.
Turbuhaler is a multidose inhaler from whisn the drug is Grapefruit juice inhibits CYP 3A4. Administration of felodipine
administered without the use of additives. When you breathe COMPOSITION together with grapefruit juice resulted in approximately two-fold
in through Turbuhaler the powder is delivered to the lungs. it is Felodipine 2.5 mg(N.R), 5 mg and 10 mg increases of the Cmax and the AUC of felodipine. Combination
therefore important that yuo inhale forcefully and deeply through with grapefruit juice should be avoided.
the mouthpiece, PHARMACEUTICAL FORM Tacrolimus: Felodipine may increase the concentration of
Turbuhaler is very easy to use, simply follow the instructions Film-coated extended-release tablets based on the hydrophilic gel tacrolimus. When used together, the concentration in serum of
given below. matrix principle. tacrolimus should be monitored and the tacrolimus dose may need
1. Unscrew and lift off cover (Fig). The PLENDIL 2.5 mg tablet(N.R) is yellow, circular, biconvex, to be adjusted.
engraved A/FL on one side and 2.5 on the other side, with a Cyclosporin: Concomitant treatment with cyclosporin and
diameter of 8.5 mm. felodipine increased the plasma concentration of felodipine by
The PLENDIL 5 mg tablet is pink, circular, biconvex, engraved 150 % and the AUC by 60 %. The effect of felodipine on the
A/Fm on one side and 5 on the other side, with a diameter of 9 pharmacokinetics of cyclosporin is, however, limited.
mm. Cimetidine: Concomitant treatment with cimetidine and felodipine
The PLENDIL 10 mg tablet is reddish-brown, circular, increased the Cmax and AUC of felodipine by approx. 55%.
biconvex, engraved A/FE on one side and 10 on the other side, PREGNANCY AND LACTATION
with a diameter of 9 mm.
Pregnancy
THERAPEUTIC INDICATIONS Relevant data from treatment of pregnant women with PLENDIL
Hypertension is lacking. PLENDIL should not be used during pregnancy, as
Angina pectoris teratogenic effects have been seen in animal studies. Calcium
2. Hold the inhaler upright with the grip downwards. Load the antagonists may inhibit premature contractions in the uterus,
inhaler with a dose by turning the grip as far as it will go and then POSOLOGY AND METHOD OF ADMINISTRATION but there is no denite evidence of delayed delivery in a full-
back to the original position (g.2) The extended-release tablet should be given once daily, preferably term pregnancy. There is a risk of development of hypoxia in the
in the morning. The duration of effect is 24 hours. The tablet should foetus in hypotensive mothers and of decreased perfusion of the
be swallowed with water but must not be chewed or crushed. The uterus, due to a redistribution of the blood ow through peripheral
extended-release tablet may be taken on an empty stomach or vasodilatation.
together with a light meal that is low in fat and carbohydrates. Lactation
Hypertension Felodipine is excreted in the breast milk. If the mother uses
The dose should be adjusted individually. Treatment should be therapeutic doses of felodipine, only a very small dose is
initiated with 5 mg once daily. The normal dosage is 5 mg once transferred via the breast milk to the child. There is insufcient
daily. If necessary, the dose may be further increased or another experience of treatment with felodipine during lactation for an
antihypertensive agent added to PLENDIL. For some patients, for assessment of the risks to the child. For this reason, Plendil should
example, elderly patients and patients with impaired liver function, not be given during lactation. In cases where the medical benet
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of continued treatment is considered to be greater than the risk, intravenously to adults, 10-20 mcg/kg to children) should be given with a -blocker. The time to onset of effect is two hours and the
stopping lactation should be considered. before gastric lavage (due to the risk of vagal stimulation). ECG effect duration is 24 hours.
monitoring. Respirator treatment on broad indication. Correction Felodipine can be used in combination with -adrenoceptor
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES of acid-base and electrolyte status. In bradycardia and AV block: blockers or as monotherapy for the treatment of patients with
As dizziness and fatigue may occur in connection with PLENDIL Atropine 0.5-1.0 mg intravenously to adults (20-50 mcg/kg to angina pectoris.
treatment, this should be considered when enhanced attention is children), which may be repeated, or isoprenaline initially, 0.05-
required, for example, when driving or operating machines. 0.1 mcg/kg/minute. Use pacemaker early in severe cases. In PHARMACOKINETIC PROPERTIES
hypotension: uid i.v., calcium glubionate (9 mg Ca/ml), 20 (-30 The active substance in PLENDIL extended-release tablets,
UNDESIRABLE EFFECTS
ml) i.v. for 5 minutes to adults (3-5 mg Ca/kg to children) initially felodipine, is imbedded in a polymer that forms a gel layer in
The most common adverse reaction to PLENDIL is mild to and repeated, if needed, or as infusion. Adrenalin or dopamine if contact with water, from which felodipine is released continuously,
moderate ankle swelling, which is dose-related and caused by needed. Glucagone may be used in severe cases. In circulatory which leads to a slow onset of effect.
precapillary vasodilatation. Experience from clinical trials has arrest, resuscitation attempts may be required during several The bioavailability of felodipine is approximately 15% and is
shown that 2 % of patients interrupted treatment due to ankle hours. In the case of spasms, diazepam should be given. Otherwise independent of concomitant food intake. However, the rate of
swelling. symptomatic therapy. absorption although not the degree of absorption is affected
Flushing, headache, palpitations, dizziness and fatigue may occur by concomitant intake of food, and the maximum plasma
at the start of treatment or after a dose increase. These reactions concentration is thereby increased by approx. 65%. The maximum
are normally transient. Pharmacotherapeutic group: Calcium antagonist plasma concentration is reached after 3-5 hours. The degree of
ATC code: C08C A02 binding to plasma proteins is approximately 99%. The distribution
Occasional cases of confusion and sleep disturbances have been
reported, but a connection with felodipine has not been established Felodipine (PLENDIL) is a vasoselective calcium antagonist for volume at steady state is 10 L/kg. The half-life of felodipine in
with certainty. the treatment of hypertension and stable angina pectoris. the elimination phase is approximately 25 hours and steady state
The active substance in PLENDIL, felodipine, is a dihydropyridine is reached after 5 days. There is no risk of accumulation during
Cases of gingival enlargement have been reported in patients long-term treatment.
derivate. Felodipine is a racemate.
with pronounced gingivitis/periodontitis. The enlargement can be
Felodipine exerts its effect by reducing peripheral vascular Average clearance is 1200 ml/min. Reduced clearance in elderly
avoided or reversed by careful dental hygiene.
resistance, particularly in arterial resistance vessels. The electrical patients and patients with impaired liver function leads to higher
Hyperglycaemia is a class-related undesirable effect, but has only plasma concentrations of felodipine. However, age can only partly
and contractile activity of vascular smooth muscle cells is inhibited
been reported in individual cases for felodipine. explain the interindividual variations in plasma concentrations.
via an effect on the calcium channels in the cell membranes.
Frequency/ Common Less common Rare Very rare Felodipine is metabolised in the liver and none of the identied
Due to the selective effect on smooth muscle in arterial
Organ ( 1/100) (1/1000, (1/10 000, (<1/10 000) metabolites has a vasodilating effect. About 70% of a given dose
resistance vessels, felodipine in therapeutic doses has no negative
<1/100) <1/1000) is excreted as metabolites in the urine and the rest is excreted in
inotropic effects on the heart, nor any clinically signicant
General fatigue fever the faeces. Less than 0.5% of a given dose is recovered unchanged
electrophysiological cardiac effects.
Circulation ushing palpitations, extrasystole, in the urine.
Felodipine relaxes smooth muscle in the airways. Clinical
with hot tachycardia hypotension Impaired renal function does not affect plasma concentrations of
experience has shown that felodipine has little effect on
feeling, with felodipine, although there is accumulation of inactive metabolites.
gastrointestinal muscle motor function. No clinically signicant Felodipine is not eliminated by haemodialysis.
ankle tachycardia
effect of felodipine on blood lipids has been observed during
swelling that may
long-term treatment, nor have any clinically signicant effects on LIST OF EXCIPIENTS
aggravate
metabolic control (HbA1c) been observed in patients with type II Carnauba wax, hydroxypropylcellulose, hydroxypropyl
angina diabetes during six months of treatment. methylcellulose, iron oxides E 172, lactose anhydrous,
pectoris in
Felodipine can generally also be given to patients with microcrystalline cellulose, polyethylene glycol 6000, polyoxyl 40
sensitive
concomitant impairment of left ventricular function who receive hydrogenated castor oil, propyl gallate, sodium aluminium silicate,
individuals,
conventional therapy or with asthma, diabetes mellitus, gout or sodium stearyl fumarate, titanium dioxide E 171, water puried.
leucocy-
hyperlipidaemia.
toclastic SHELF LIFE
vasculitis Anti-hypertensive effect: Felodipine lowers arterial blood
Please refer to expiry date on the label and outer carton.
pressure by decreasing peripheral vascular resistance. Treatment of
Frequency/ Common Less common Rare Very rare hypertensive patients with Plendil reduces the blood pressure, both SPECIAL PRECAUTIONS FOR STORAGE
Organ ( 1/100) (1/1000, (1/10 000, (<1/10 000) in the sitting and standing position and at rest and during exercise. Do not store above 30C.
<1/100) <1/1000) Felodipine does not give rise to orthostatic hypotension, as the
General fatigue fever substance has no effect of venous smooth muscle or adrenergic PACK SIZE
Endochrine hypergly- control mechanisms. Please refer to outer carton for pack size.
caemia The lowered blood pressure may initially cause a temporary reex Trade Marks herein are the property of the AstraZeneca group
Gastrointes- nausea, vomiting gingival increase in heart rate and cardiac output. The increased heart rate is
tinal stomach pain hyperplasia, counteracted when felodipine is given together with beta-blockers.
gingivitis
PULMICORT Nebuliser suspension
Plasma concentrations of felodipine are positively correlated to
Skin exanthema, urticaria photosensi- the decrease in total peripheral resistance and blood pressure. At 0.25 mg/ml and 0.5 mg/ml
pruritus tivity, steady state the effect remains over the entire dose range and gives
angio-oe- a 24-hour reduction in blood pressure.
dema with Treatment with felodipine is associated with regression of left
(Budesonide)
swollen lips ventricular hypertrophy. COMPOSITION
or tongue Felodipine has a natriuretic and diuretic effect but no potassiuretic Each single-dose unit of 2 ml contains: 0.5 mg or 1 mg (N.R)
Immu- hypersensi- effect. The tubular reabsorption of sodium and water is reduced, budesonide.
nological tivity reac- which may explain the absence of salt and uid retention in the
reactions tions patient. Felodipine reduces renal vascular resistance and increases PHARMACEUTICAL FORM
Liver elevated renal perfusion. The glomerular ltration rate is unchanged. Nebuliser suspension.
liver Felodipine does not inuence urinary albumin excretion. Whitish suspension in single-dose unit made of plastic.
enzymes In the so-called HOT (Hypertension Optimal Treatment) study,
Musculosk- arthralgia, including 18,790 patients with mild to moderate hypertension, THERAPEUTIC INDICATIONS
eletal myalgia treatment with PLENDIL, in combination with an ACE inhibitor, Bronchial asthma
Neurologi- headache paraesthesia, syncope a -blocker and/or a diuretic, if needed, resulted in a diastolic POSOLOGY AND METHOD OF ADMINISTRATION
cal dizziness secondary blood pressure (DBP) of 90 mm Hg in 93 % of the patients. The dosage of PULMICORT is individual. In the case of
to hypoten- In the same study, the incidence of cardiovascular events in patients daily doses up to 1 mg the whole dose may be given in one
sion with type II diabetes (n=1501) was signicantly lower (50%) in the administration. In the case of higher daily doses the dose is divided
Psychiatric impotence/ group where the target DBP was 80 mm Hg (11.9/1000 patient into two administrations per day.
sexual dys- years), compared with the group where the target DBP was below Initially the dosage should be:
function 90 mmHg (24.4/1000 patient years).
Children from 6 months: 0.25-0.5 mg per day. If necessary, the
Urogenital pollakisuria PLENDIL was included as one of two calcium antagonists in the dose may be increased to 1 mg per day.
Swedish STOP-2 study, performed in 6,614 patients aged 70-84
OVERDOSE Adults: 1-2 mg per day.
years. The study indicates that hypertensive treatment initiated
Toxicity: 10 mg to a two-year-old child caused mild intoxication. with dihydropyridine calcium antagonists and with the addition For maintenance treatment:
150-200 mg to a 17-year-old and 250 mg to an adult caused of -blockers, if needed, has no effect of cardiovascular mortality Children from 6 months: 0.25-2 mg per day.
mild to moderate intoxication. Felodipine probably has a more compared with conventional treatment with -blockers and/or Adults: 0.5 4 mg per day. In very severe cases the dose may be
pronounced effect on the peripheral circulation than on the heart, diuretics. increased further.
compared with other drugs in the same group. For the treatment of hypertensive patients, PLENDIL can be used Dosage table
Symptoms: The symptoms of intoxication with extended-release as monotherapy or in combination with other antihypertensive Dose (mg) Volume of Pulmicort nebuliser suspension
tablets may be delayed 12-16 hours and severe symptoms may set drugs, such as -blockers, diuretics or ACE inhibitors.
0.25 mg/ml 0.5 mg/ml
in after several days. Circulatory effects constitute the greatest Anti-anginal effect: Felodipine exerts its effect through dilatation
of coronary vessels, which also improves perfusion and the oxygen 0.25 1 ml* -
risk: bradycardia (sometimes tachycardia), AV block I-III, AV
dissociation, VES, ventricular brillation, asystole. Dizziness, supply to the heart. Cardiac work load is decreased through a 0.5 2 ml -
headache, impaired consciousness, coma, spasms. Dyspnoea, reduction of the peripheral arterial resistance (reduced afterload), 0.75 3 ml -
lung oedema (non-cardiac) and apnoea. Possibly ARDS (Adult which results in reduced oxygen demand in the myocardium. 1 4 ml 2 ml
Respiratory Distress Syndrome). Acidosis, hypokalaemia, Coronary vasospasm is counteracted by felodipine.
1.5 - 3 ml
hyperglycaemia, potentially hypocalcaemia. Flush, hypothermia. Felodipine improves exercise capacity and reduces anginal attacks
Nausea and vomiting. in patients with stable effort-induced angina pectoris. 2 - 4 ml
Management: Charcoal, gastric lavage if indicated, in certain Initially during treatment there is a transient reex increase in heart *should be diluted to 2 ml with 0.9% saline or solution for
cases also late after exposure. Note: Atropine (0.25-0.5 mg rate, which is counteracted if PLENDIL is given in combination nebuliser
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The maintenance dose should be the lowest possible. corticosteroid treatment must be placed in relation to possible risks detected with doses up to 400 micrograms per day. In the range
Following a single dose an effect may be expected after a few of inhibition of growth. 400-800 micrograms per day biochemical signs of a systemic effect
hours. The full therapeutic effect is achieved only after a few Patients must be instructed to contact their physician if the effect may occur. With daily doses in excess of 800 micrograms such
weeks of treatment. Treatment with Pulmicort is prophylactic of the treatment generally diminishes, as repeated inhalations signs are common. This information applies to PULMICORT
therapy with no demonstrated effect on acute disorders. for severe asthma attacks must not delay the initiation of other administered as inhalation spray and inhalation powder.
In patients in whom an increased therapeutic effect is desired, important therapy. If there is a sudden deterioration the treatment Asthma itself, like inhaled corticosteroids, can delay growth.
in general an increase of the PULMICORT dose is to be must be supplemented with a short course of oral steroids. However, studies in children and adolescents who were treated
recommended in preference to combination treatment with oral with budesonide for a long period (up to 11 years) show that the
INTERACTIONS
corticosteroids because of the lower risk of systemic side effects. patients reach expected adult height.
No clinically relevant interactions with asthma agents are known.
Patients dependent on oral steroids: Inhalation therapy with budesonide is effective in preventing
Ketoconazole 200 mg once daily increased the plasma exercise-induced asthma.
When transfer from oral steroids is initiated the patient must be concentrations of oral budesonide (3 mg in a single dose) on
in a relatively stable condition. A high dose of PULMICORT is average six-fold when administered concomitantly. When PHARMACOKINETIC PROPERTIES
given in combination with the previously used oral steroid dose ketoconazole was administered 12 hours after budesonide, the Absorption
for 10 days. After that, the oral dose should be gradually reduced concentration was increased on average three-fold. Information Inhaled budesonide is rapidly absorbed. The peak plasma
by e.g. 2.5 mg prednisolone or equivalent per month to the lowest about this interaction is lacking for inhaled budesonide, but
possible level. The oral steroid can often be discontinued entirely. concentration is reached within 30 minutes after the start of
markedly increased plasma levels are also expected in such cases. nebulisation.
Since budesonide given as PULMICORT suspension for nebuliser The combination should be avoided since data to support dose
is deposited in the lungs with the aid of inspiration, it is important Distribution and metabolism
recommendations are lacking. If this is not possible, the time
that the patient inhales calmly and with even breaths through the interval between administration of ketoconazole and budesonide Plasma protein binding is approx. 90 %. The volume of distribution
mouthpiece of the nebuliser. should be as long as possible. A reduction of the budesonide dose is approx. 3 l/kg.
There is no experience of treatment of patients with impaired must also be considered. Other potent inhibitors of CYP3A4 , i.e. Budesonide undergoes extensive (approx. 90 %) rst pass
hepatic or renal function. Since budesonide is eliminated itraconazole also cause a marked increase in the plasma levels of metabolism in the liver to metabolites with low glucocorticosteroid
predominantly through metabolism in the liver, increased exposure budesonide. activity. The glucocorticosteroid activity of the major metabolites,
may be expected in patients with severe cirrhosis of the liver. 6-hydroxybudesonide and 16-hydroxyprednisolone, is less than
PREGNANCY AND LACTATION
1 % of that of budesonide.
INSTRUCTIONS FOR CORRECT USE OF PULMICORT Pregnancy
Elimination
NEBULISER Data from approximately 2000 pregnancies have not revealed
Budesonide is eliminated through metabolism, catalysed primarily
Pumicort suspension for nebuliser should be administered via a any increased risk of malformations as a result of treatment with
by the enzyme CYP3A4. The metabolites are excreted in the
jet nebuliser equipped with a mouthpiece or suitable facemask. budesonide. Animal studies have shown that glucocorticosteroids
urine in unchanged or conjugated form. Only negligible amounts
The nebuliser should be connected to an air compressor with an can induce malformations, but this is judged not to be relevant for
of unchanged budesonide are recovered in the urine. Budesonide
adequate airow (5-8 l/min), and the ll volume should be 2-4 humans with the recommended dosage.
has a high systemic clearance (approx. 1.2 l/min), and the plasma
ml. During pregnancy the aim must be the lowest effective dose of half-life after intravenous administration is on average 4 hours.
Note It is important to instruct the patient budesonide while taking account of the risk of a worsening of the The pharmacokinetics of budesonide is proportional to the dose
to carefully read the instructions for use: How to use asthma. at relevant dosages.
PULMICORT Nebuliser Lactation The pharmacokinetics of budesonide in children and in patients
that Ultrasonic nebulisers are not suitable for the administration It is not known whether budesonide passes into breast milk. with impaired renal function is unknown. Exposure to budesonide
of PULMICORT Nebuliser Suspension and therefore are not may be increased in patients with hepatic disease.
recommended EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
PULMICORT Nebuliser Suspension can be mixed with PULMICORT does not affect ability to drive or use machines. LIST OF EXCIPIENTS
0.9% saline and with solutions for nebuliser of terbutaline, Undesirable effects Disodium edetate
salbutamol, sodium cromoglycate and ipratropium Up to 10 % of treated patients may be expected to experience Sodium chloride
to rinse the mouth out with water after inhaling the prescribed adverse reactions of a local nature. Polysorbate 80
dose to minimise the risk of oropharyngeal thrush Anhydrous citric acid
Common Airways: Candida infection in the oropharynx,
to wash the facial skin with water after using the face mask to Sodium citrate
(> 1/100) irritation in the throat, coughing,
prevent irritation Puried water
to adequately clean and maintain the nebuliser according to the hoarseness
manufacturers instructions Rare General: Angioedema. INCOMPATIBILITIES
A facemask can be used for children who cannot breathe in through (< 1/1000) Skin: Urticaria, rash, dermatitis PULMICORT nebuliser suspension can be mixed with sodium
the mouthpiece. Airways: Bronchospasm chloride solution 9 mg/ml (0.9 %) and/or with nebuliser solutions
containing terbutaline, salbutamol, fenoterol , acetylcysteine,
CONTRAINDICATIONS Occasional cases of nervousness, restlessness, depression and sodium cromoglycate or ipratropium bromide. The admixture
Hypersensitivity to budesonide or any of the other ingredients. behavioural disturbances have been observed. On account of the should be used within 30 minutes.
risk of Candida infections in the oropharynx the patient must rinse
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS SHELF-LIFE
the mouth with water after every dose.
FOR USE Please refer to expiry date on outer carton.
In isolated cases signs or symptoms of systemic glucocorticoid
In order to minimise the risk of Candida infections in the oral Single-dose units that are stored in an opened envelope must be
effects may occur, including adrenal hypofunction.
cavity and throat, the patient should be instructed to rinse the used within 3 months. The contents of an opened single-dose unit
mouth with water after each dose administration. Isolated cases of bruising have occurred.
must be used within 12 hours.
Concomitant treatment with ketoconazole, itraconazole or other Facial skin irritation has been reported in some cases when a
facemask was used. In order to prevent this, the face should be SPECIAL PRECAUTIONS FOR STORAGE
potent CYP3A4 inhibitors should be avoided. If this is not
possible, the interval between administrations of the medications washed when a facemask is used. Do not store above 30C. Do not freeze.
should be as long as possible. OVERDOSE Always keep unopened single-dose units in the foil envelope in
Particular care is needed in patients transferring from oral steroids, Acute overdose with PULMICORT suspension for nebuliser, order to protect from light.
since they may remain at risk of impaired adrenal function even high doses, is not expected to cause any clinical problems. PACK SIZE
for a considerable time. Patients who have required high dose If it is used chronically in high doses, systemic effects of Please refer to outer carton for pack size.
emergency corticosteroid therapy or prolonged treatment at the glucocorticosteroids such as hypercortisolism and adrenal
highest recommended dose of inhaled corticosteroids, may also be suppression may occur. How to use PULMICORT Nebuliser.
at risk. These patients may exhibit signs and symptoms of adrenal 1. Before use, re-suspend the contents of the single dose unit by
insufciency when exposed to severe stress. Additional systemic PHARMACODYNAMIC PROPERTIES using a gently swirling motion.
corticosteroid cover should be considered during periods of stress Budesonide is a glucocorticosteroid with a high local anti- 2. Hold the single dose unit upright (see picture)
or elective surgery. inammatory effect.
and open by twisting off the wing.
Caution must be observed in treatment of patients who The precise mechanism of action of glucocorticosteroids in the
3. Place the open end of the unit well into the
are transferred from systemically acting corticosteroids to treatment of asthma is not fully understood. Anti-inammatory
PULMICORT and in cases of suspected disturbance of pituitary- effects such as inhibited release of inammatory mediators and reservoir of the nebuliser, and squeeze slowly.
adrenocortical function. In these patients there should be a cautious inhibition of cytokine-mediated immune response are probably
reduction of the dose of systemic steroid, and tests of hypothalamic- important. The activity of budesonide, measured as afnity for
pituitary-adrenocortical function should be considered. They may glucocorticosteroid receptors is approx. 15 times higher than that
also require the adjunct of systemic steroids in connection with of prednisolone.
periods of stress, e.g. surgery, trauma, etc. Budesonide has anti-inammatory effects shown as reduced
During transfer from oral steroid therapy to PULMICORT, bronchial obstruction during both the early and the late phase of an
patients may experience previous symptoms such as muscle and allergic reaction. In hyper-reactive patients budesonide reduces the
joint pain. In these cases a temporary increase of the oral steroid histamine and metacholine reactivity in the airways.
dose may be necessary. If, in isolated cases, fatigue, headache, The single dose unit is marked with a line (PULMICORT 0.25
Studies have shown that the earlier budesonide treatment is
nausea, vomiting or similar symptoms occur, a generally mg/ml and 0.5 mg/ml only). This line indicates the 1 ml volume
inititated after the onset of asthma, the better lung function can
unsatisfactory effect of the steroid should be suspected. when the single dose unit is held up-side down.
be expected.
Replacement of systemic steroid treatment by PULMICORT Studies in healthy volunteers with PULMICORT Turbuhaler If only 1 ml is to be used, empty the contents until the level of the
sometimes reveals allergies, e.g. rhinitis and eczema, that were have shown dose-related effects on plasma and urinary cortisol. liquid reaches the indicator line.
previously controlled by the systemic treatment. At recommended doses, PULMICORT Turbuhaler, causes Store the opened single dose unit protected from light. Opened
Regular monitoring of growth is recommended in children and signicantly less effect on the adrenal function than prednisone 10 single dose units must be used within 12 hours.
adolescents receiving long-term treatment with corticosteroids, mg, as shown by ACTH tests. Before using the rest of the liquid, re-suspend the contents of the
irrespective of the administration form. The benets of In children over the age of 3 years, no systemic effects have been single dose unit by using a gently swirling motion.
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NOTE: CONTRAINDICATIONS Common (>1/100) Airways: Candida infection in the
1. Rinse your mouth out with water after each dosing occasion. Hypersensitivity to budesonide. oropharynx, irritation in
2. If you use a facemask, make sure that the mask ts tightly while the throat, coughing,
you are inhaling. Wash your face after treatment. SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
FOR USE hoarseness
Cleaning
In order to minimise the risk of Candida infections in the oral Rare General: Angiooedema
The nebuliser chamber and the mouthpiece, or the facemask, (<1/1000) Skin: Urticaria, rash, dermatitis
should be cleaned after each use. Wash the parts in hot tap water cavity and throat, the patient should be instructed to rinse the
mouth with water after each dose administration. Airways: Bronchospasm
using a mild detergent or according to the instructions supplied by
the manufacturer of the nebuliser. Rinse well and dry by connecting Concomitant treatment with ketoconazole, itraconazole or other Occasional cases of nervousness, restlessness, depression and
the nebuliser chamber to the compressor or air inlet. potent CYP3A4 inhibitors should be avoided. If this is not behavioural disturbances have been observed. On account of the
Pulmicort is a trademark of the AstraZeneca group of companies possible, the interval between the administrations of the drugs risk of Candida infections in the oropharynx the patient must rinse
should be as long as possible. the mouth with water after every dose.
AstraZeneca 2005
In isolated cases signs or symptoms of systemic glucocorticoid
Particular care is needed in patients transferring from oral steroids,
effects may occur, including adrenal hypofunction.
PULMICORT TURBUHALER since they may remain at risk of impaired adrenal function
for a considerable time. Patients who have required high dose Isolated cases of bruising have occurred.
Inhalation powder emergency corticosteroid therapy or prolonged treatment at the OVERDOSE
100mcg/dose highest recommended dose of inhaled corticosteroids, may also be Acute overdose with PULMICORT TURBUHALER, even in
200mcg/dose at risk. These patients may exhibit signs and symptoms of adrenal high doses, is not expected to cause any clinical problems. If used
insufciency when exposed to severe stress. Additional systemic chronically in high doses, systemic effects of glucocorticosteroids
400(N.R)mcg/dose corticosteroid cover should be considered during periods of stress such as hypercortisolism and adrenal suppression can occur.
or elective surgery.
(Budesonide ) Caution must be observed in treatment of patients who
Budesonide is a glucocorticosteroid with a high local anti-
are transferred from systemically acting corticosteroids to
inammatory effect.
COMPOSITION PULMICORT and in cases of suspected disturbance of pituitary-
The precise mechanism of action of glucocorticosteroids in the
1 metered dose contains budesonide 100 micrograms, 200 adrenocortical function. In these patients there should be a cautious
treatment of asthma is not fully understood. Anti-inammatory
micrograms or 400 micrograms.(N.R) reduction of the dose of systemic steroid, and tests of hypothalamic-
effects such as inhibited release of inammatory mediators and
pituitary-adrenocortical function should be considered. They may
PHARMACEUTICAL FORM inhibition of cytokine-mediated immune response are probably
also require the adjunct of systemic steroids in connection with important. The activity of budesonide, measured as its afnity for
Inhalation powder
periods of stress, e.g. surgery, trauma, etc. glucocorticosteroid receptors is approx. 15 times higher than that
THERAPEUTIC INDICATIONS During the transfer from oral steroid therapy to PULMICORT of prednisolone.
Bronchial asthma TURBUHALER, patients may experience the return of previous Budesonide has anti-inammatory effects shown as reduced
symptoms such as muscle and joint pain. In these cases a temporary bronchial obstruction during both the early and the late phase of an
increase of the oral steroid dose may sometimes be necessary. If, allergic reaction. In hyper-reactive patients budesonide reduces the
The dosage of PULMICORT TURBUHALER is individual. histamine and metacholine reactivity in the airways.
in isolated cases, fatigue, headache, nausea, vomiting or similar
Initially, at the beginning of inhaled corticosteroid therapy, for symptoms occur, a generally unsatisfactory effect of the steroid Studies have shown that the earlier budesonide treatment is
therapy during periods of severe asthma or when scaling down or should be suspected. inititated after the onset of asthma, the better lung function can
withdrawing oral corticosteroids the dosage should be: be expected.
Replacement of systemic steroid treatment by PULMICORT
Children aged 6 years and older: Studies in healthy volunteers with PULMICORT TURBUHALER
TURBUHALER sometimes reveals allergies, e.g. rhinitis
100-800 micrograms per day, divided into 2-4 inhalations. With and eczema, that were previously controlled by the systemic have shown dose-related effects on plasma and urinary cortisol. At
daily doses up to 400 micrograms the full dose may be given in treatment. recommended doses, PULMICORT TURBUHALER, causes
one administration. signicantly less effect on the adrenal function than prednisone 10
Regular monitoring of growth is recommended in children and
Adults: mg, as shown by ACTH tests.
adolescents receiving long-term treatment with corticosteroids,
The normal dose range is 200-800 micrograms per day, divided irrespective of the administration form. The benets of In children over the age of 3 years, no systemic effects have been
into 2-4 inhalations. In more severe cases daily doses of up to detected with doses up to 400 micrograms per day. In the range
corticosteroid treatment must be placed in relation to possible risks
1600 micrograms may be needed. With daily doses up to 400 400-800 micrograms per day biochemical signs of a systemic
of inhibition of growth.
micrograms the full dose may be given in one administration. effect may occur. With daily doses in excess of 800 micrograms
Patients must be instructed to contact their physician if the effect such signs are common.
The maintenance dose should be the lowest possible.
of the treatment generally diminishes, as repeated inhalations Asthma, like inhaled corticosteroids, can delay growth. However,
Following a single dose an effect may be expected after a few
for severe asthma attacks must not delay the initiation of other studies in children and adolescents who were treated with
hours. The full therapeutic effect is only achieved after a few weeks
important therapy. If there is a sudden deterioration the treatment budesonide for a long period (up to 11 years) show that the patients
of treatment. Treatment with PULMICORT TURBUHALER
is prophylactic therapy with no demonstrated effect on acute must be supplemented with a short course of oral steroids. reach the expected adult height.
disorders. INTERACTIONS Inhalation therapy with budesonide is effective in preventing
Clinical trials indicate that a larger amount of budesonide is exercise-induced asthma.
No clinically relevant interactions with other agents for asthma
deposited in the lungs when administered with PULMICORT are known. PHARMACOKINETIC PROPERTIES
TURBUHALER, compared with Pulmicort pMDI. If a
Ketoconazole 200 mg once daily increased the plasma Absorption
patient in a stable phase is transferred from Pulmicort pMDI
to PULMICORT TURBUHALER a reduction in dose may concentrations of oral budesonide (3 mg in a single dose) on Inhaled budesonide is rapidly absorbed. The peak plasma
therefore be appropriate. average six-fold when administered concomitantly. When concentration is reached within 30 minutes after inhalation. In
ketoconazole was administered 12 hours after budesonide, the studies, the average deposition of budesonide in the lungs after
In patients in whom an increased therapeutic effect is desired, in
concentration was increased on average three-fold. Information inhalation via Turbuhaler has been shown to be 25-35 % of the
general an increase of the PULMICORT TURBUHALER dose
about this interaction is lacking for inhaled budesonide, but metered dose. The systemic bioavailability is approx. 38 % of the
is to be recommended in preference to combination treatment with
markedly increased plasma levels are also expected in such cases. metered dose.
oral corticosteroids because of the lower risk of systemic side
effects. The combination should be avoided since data to support dose Distribution and metabolism
Patients dependent on oral steroids: recommendations are lacking. If this is not possible, the time Plasma protein binding is approx. 90 %. The volume of distribution
interval between administration of ketoconazole and budesonide is approx. 3 l/kg.
When transfer from oral steroids is initiated the patient must be
in a relatively stable condition. A high dose of PULMICORT is should be as long as possible. A reduction of the budesonide dose Budesonide undergoes extensive (approx. 90 %) rst pass
given in combination with the previously used oral steroid dose must also be considered. Other potent inhibitors of CYP3A4 , i.e. metabolism in the liver to metabolites with low glucocorticosteroid
for 10 days. After that, the oral dose should be gradually reduced itraconazole also cause a marked increase in the plasma levels of activity. The glucocorticosteroid activity of the major metabolites,
by e.g. 2.5 mg prednisolone or equivalent per month to the lowest budesonide. 6-hydroxybudesonide and 16-hydroxyprednisolone, is less than
possible level. The oral steroid can often be discontinued entirely. 1 % of that of budesonide.
There is no experience of treatment of patients with impaired Elimination
Pregnancy
hepatic or renal function. Since budesonide is predominantly Budesonide is eliminated through metabolism, catalysed primarily
eliminated through hepatic metabolism, increased exposure may Data from approximately 2000 pregnancies have not revealed by the enzyme CYP3A4. The metabolites are excreted in the
be expected in patients with severe cirrhosis of the liver. any increased risk of malformations as a result of treatment with urine in unchanged or conjugated form. Only negligible amounts
budesonide. Animal studies have shown that glucocorticosteroids of unchanged budesonide are recovered in the urine. Budesonide
INSTRUCTIONS FOR CORRECT USE OF TURBUHALER can induce malformations, but this is judged not to be relevant for has a high systemic clearance (approx. 1.2 l/min), and the plasma
Turbuhaler is inspiratory ow-driven which means that, when the humans with the recommended dosage. half-life after intravenous administration is on average 4 hours.
patient inhales through the mouthpiece, the substance will follow The pharmacokinetics of budesonide is proportional to the dose
During pregnancy the aim must be the lowest effective dose of
the inspired air into the airways. at relevant dosages.
budesonide while taking account of the risk of a worsening of the
Note It is important to instruct the patient The pharmacokinetics of budesonide in children and in patients
asthma.
To carefully read the instructions for use: How to use with impaired renal function is unknown. Exposure to budesonide
PULMICORT TURBUHALER Lactation
may be increased in patients with hepatic disease.
To breathe in forcefully and deeply through the mouthpiece to It is not known whether budesonide passes into breast milk.
LIST OF EXCIPIENTS
ensure that an optimal dose is delivered to the lungs EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Never to breath out through the mouthpiece PULMICORT TURBUHALER contains no excipients.
PULMICORT TURBUHALER does not affect ability to drive
To rinse the mouth out with water after inhaling the prescribed INCOMPATIBILITIES
or use machines.
dose to minimise the risk of orpharyngeal thrush Not relevant.
It is possible that the patient will not taste or perceive any medicine Undesirable effects
when PULMICORT TURBUHALER is used; this is because Up to 10 % of patients treated may be expected to experience SHELF-LIFE
such a small amount of substance is dispensed. adverse reactions of a local nature. Please refer to expiry date on outer carton.
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SPECIAL PRECAUTIONS FOR STORAGE PULMICORT is a trademark of the AstraZeneca group of Tardive dyskinesia
Do not store above 30C. companies As with other antipsychotics, there is a potential for SEROQUEL
Store with the cover tightly closed. AstraZeneca 2005 to cause tardive dyskinesia after long-term treatment. If signs
and symptoms of tardive dyskinesia appear, dose reduction or
PACK SIZE discontinuation of SEROQUEL should be considered.
Please refer to outer carton for pack size.
SEROQUEL
Neuroleptic malignant syndrome
HOW TO USE PULMICORT TURBUHALER Neuroleptic malignant syndrome has been associated with
Turbuhaler is a multidose inhaler from which the drug is
(Quetiapine fumarate) antipsychotic treatment, including SEROQUEL (see Undesirable
administered without the use of additives. when you breathe in Effects). Clinical manifestations include hyperthermia, altered
through Turbuhaler the powder is delivered to the lungs. it is PRESENTATION mental status, muscular rigidity, autonomic instability, and
therefore important that you inhale forcefully and deeply through 25 mg tablet: round, 6 mm, peach coloured, biconvex, lm coated increased creatine phosphokinase. In such an event, SEROQUEL
the mouthpiece. tablet containing quetiapine fumarate delivering a dose of 25 mg should be discontinued and appropriate medical treatment given.
Turbuhaler is very easy to use. Simply follow the instructions of quetiapine free base. Acute withdrawal reactions
given below. 100 mg tablet: round, 8.5 mm, yellow coloured, biconvex, lm Acute withdrawal symptoms including nausea, vomiting and
1 Unscrew and lift off the cover. coated. tablet containing quetiapine fumarate delivering a dose of insomnia have very rarely been described after abrupt cessation
100 mg of quetiapine free base. of high doses of antipsychotic drugs. Recurrence of psychotic
200 mg tablet: round, 11 mm, white, biconvex, lm coated tablet symptoms may also occur, and the emergence of involuntary
containing quetiapine fumarate delivering a dose of 200 mg of movement disorders (such as akathisia, dystonia and dyskinesia)
quetiapine free base. has been reported. Therefore, gradual withdrawal is advisable.
300 mg tablet: capsule-shaped, 19 mm x 7.62 mm,, white, lm INTERACTIONS
coated tablet containing quetiapine fumarate delivering a dose of
300 mg of quetiapine free base. See also Interactions with other medicinal products and other
forms of interaction.
For excipients see Pharmaceutical Particulars.
Concomitant use of SEROQUEL with hepatic enzyme inducers
INDICATIONS such as carbamezepine may substantially decrease systemic
Treatment of schizophrenia. exposure to quetiapine. Depending on clinical response, higher
Treatment of manic episodes associated with bipolar disorder. doses of SEROQUEL may need to be considered if SEROQUEL
2 Hold the inhaler upright with the grip downwards. Load the is used concomitantly with a hepatic enzyme inducer.
inhaler with a dose by turning the grip as far as it will go and POSOLOGY AND METHOD OF ADMINISTRATION During concomitant administration of drugs which are potent
then back to the original position. SEROQUEL should be administered twice daily, with or without CYP3A4 inhibitors (such as azole antifungals and macrolide
food. antibiotics), plasma concentrations of quetiapine can be
Adults signicantly higher than observed in patients in clinical trials.(see
For the treatment of schizophrenia: the total daily dose for the rst also Pharmacokinetics). As a consequence of this, lower doses
4 days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day of SEROQUEL should be used. Special consideration should be
3) and 300 mg (Day 4). given in elderly and debilitated patients. The risk-benet ratio
needs to be considered on an individual basis in all patients.
From Day 4 onwards, the dose should be titrated to the usual
effective dose range of 300 to 450 mg/day. Depending on the Interactions with other medicaments and other forms of
clinical response and tolerability of the individual patient, the dose interaction
may be adjusted within the range 150 to 750 mg/day. Given the primary central nervous system effects of quetiapine,
For the treatment of manic episodes associated with bipolar SEROQUEL should be used with caution in combination with
3 Breathe out. Do not breathe out through the inhaler.
disorder: as monotherapy or as adjunct therapy to mood other centrally acting drugs and alcohol.
4 Place the mouthpiece gently between your teeth, close your
lips and breathe in forcefully and deeply through your mouth. stabilizers, the total daily dose for the rst four days of therapy The pharmacokinetics of lithium were not altered when co-
Do not chew or bite on the mouthpiece. Do not use Turbuhaler is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3) and 400 mg administered with SEROQUEL.
if it has been damaged or if the mouthpiece has become (Day 4). Further dosage adjustments up to 800 mg per day by Day The pharmacokinetics of valproic acid and quetiapine were not
detached.(Fig.3) 6 should be in increments of no greater than 200 mg per day. altered to a clinically relevant extent when co-administered as
The dose may be adjusted depending on clinical response and valproate semisodium (also known as divalproex sodium (USAN)
tolerability of the individual patient, within the range of 200 to and SEROQUEL (quetiapine fumarate). Valproate semisodium
800 mg per day. The usual effective dose is in the range of 400 to is a stable coordination compound comprised of sodium valproate
800 mg per day. and valproic acid in a 1:1 molar relationship.
Elderly The pharmacokinetics of quetiapine were not signicantly altered
As with other antipsychotics, SEROQUEL should be used with following co-administration with the antipsychotics risperidone
caution in the elderly, especially during the initial dosing period. or haloperidol. However, co-administration of SEROQUEL and
Elderly patients should be started on SEROQUEL 25 mg/day. thioridazine caused increases in clearance of quetiapine.
The dose should be increased daily, in increments of 25 to 50 Quetiapine did not induce the hepatic enzyme systems involved
mg, to an effective dose, which is likely to be lower than that in in the metabolism of antipyrine. However, in a multiple dose trial
5 Before breathing out, remove the inhaler from your mouth. younger patients. in patients to assess the pharmacokinetics of quetiapine given
If more than one dose has been prescribed, repeat steps 2-5. Children and adolescents before and during treatment with carbamazepine (a known hepatic
6 Replace the cover. The safety and efcacy of Seroquel have not been evaluated in enzyme inducer), co-administration of carbamazepine signicantly
children and adolescents. increased the clearance of quetiapine. This increase in clearance
7 Rinse your mouth out with water after inhaling your prescribed
reduced systemic quetiapine exposure (as measured by AUC) to an
dose. Renal and hepatic impairment
average of 13% of the exposure during administration of quetiapine
NOTE! The oral clearance of quetiapine is reduced by approximately alone; although a greater effect was seen in some patients. As a
Never breathe out through the mouthpiece. 25% in patients with renal or hepatic impairment. Quetiapine is consequence of this interaction, lower plasma concentrations can
Always replace the cover properly after use. extensively metabolised by the liver, and therefore should be used occur, and hence, in each patient, consideration for a higher dose
with caution in patients with known hepatic impairment. of Seroquel, depending on clinical response, should be considered.
As the amount of the powder dispensed is very small, you may
not be able to taste it after inhalation. However, you can still be Patients with renal or hepatic impairment should be started on It should be noted that the recommended maximum daily dose of
condent that the dose has been inhaled if you have followed the SEROQUEL 25 mg/day. The dose should be increased daily, in SEROQUEL is 750mg/day for the treatment of schizophrenia and
instructions. increments of 25 to 50 mg, to an effective dose. 800mg/day for the treatment of manic episodes associated with
Cleaning CONTRAINDICATIONS bipolar disorder. Continued treatment at higher doses should only
be considered as a result of careful consideration of the benet
Clean the outside of the mouthpiece regularly (weekly) with a dry SEROQUEL is contraindicated in patients who are hypersensitive risk assessment for an individual patient. Co-administration
tissue. to any component of this product. of SEROQUEL with another microsomal enzyme inducer,
Do not use water for cleaning the mouthpiece. phenytoin, also caused increases in clearance of quetiapine.
Dose indicator Increased doses of SEROQUEL may be required to maintain
Cardiovascular disease
When a red mark is rst seen in the indicator window there are control of psychotic symptoms in patients co-administered
SEROQUEL should be used with caution in patients with
approximately 20 doses left. When the red mark has reached the SEROQUEL and phenytoin, or other hepatic enzyme inducers
known cardiovascular disease, cerebrovascular disease, or other
lower edge of the window the inhaler will no longer deliver the (eg, barbiturates, rifampicin). The dose of SEROQUEL may
conditions predisposing to hypotension.
correct amount of medicine, and should be discarded. The sound need to be reduced if phenytoin or carbamazepine or other hepatic
heard as you shake the inhaler is not produced by the medication SEROQUEL may induce orthostatic hypotension, especially enzyme inducers are withdrawn and replaced with a non-inducer
but by a drying agent. during the initial dose-titration period; this is more common in (eg, sodium valproate).
elderly patients than in younger patients.
CYP3A4 is the primary enzyme responsible for cytochrome
In clinical trials, quetiapine was not associated with a persistent P450 mediated metabolism of quetiapine. The pharmacokinetics
increase in QTc intervals. However, as with other antipsychotics, of quetiapine was not altered following co-administration with
caution should be exercised when quetiapine is prescribed with cimetidine, a known P450 enzyme inhibitor. The pharmacokinetics
drugs known to prolong the QTc interval, especially in the of quetiapine were not signicantly altered following co-
elderly. administration with the antidepressants imipramine (a known
Seizures CYP2D6 inhibitor) or uoxetine (a known CYP3A4 and CYP2D6
Disposal In controlled clinical trials there was no difference in the incidence inhibitor. However, caution is recommended when SEROQUEL
Always be sure to dispose of your used Turbuhaler responsibly/in of seizures in patients treated with SEROQUEL or placebo. As is co-administered with potent CYP3A4 inhibitors (such as
the recommended way, since some of the medicine will remain with other antipsychotics, caution is recommended when treating azole antifungals and macrolide antibiotics). (See also Special
inside it. patients with a history of seizures. Warnings and Precautions for Use and Pharmacokinetics)
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PREGNANCY AND LACTATION SEROQUEL treatment was associated with small dose-related oral administration. The principal human plasma metabolites do
The safety and efcacy of SEROQUEL during human pregnancy decreases in thyroid hormone levels, particularly total T4 and free not have signicant pharmacological activity.
have not been established (see section on Pre-clinical safety data, T4. The reduction in total and free T 4 was maximal within the The bioavailability of quetiapine is not signicantly affected by
Reproduction studies, for animal reproductive toxicology data). rst two to four weeks of SEROQUEL treatment, with no further administration with food. The elimination half-life of quetiapine
Therefore, SEROQUEL should only be used during pregnancy if reduction during long-term treatment. In nearly all cases, cessation is approximately 7 hours. Quetiapine is approximately 83% bound
the benets justify the potential risks. of Seroquel treatment was associated with a reversal of the effects to plasma proteins.
The degree to which quetiapine is excreted into human milk is on total and free T4, irrespective of the duration of treatment.
Clinical trials have demonstrated that SEROQUEL is effective
unknown. Women who are breast feeding should therefore be Smaller decreases in total T3 and reverse T3 were seen only at
when given twice a day. This is further supported by data from a
advised to avoid breast feeding while taking Seroquel. higher doses. Levels of TBG were unchanged and in general,
positron emission tomography (PET) study which identied that
reciprocal increases in TSH were not observed, with no indication
EFFECT ON ABILITY TO DRIVE AND USE MACHINES 5HT2 and D2 receptor occupancy are maintained for up to 12
that SEROQUEL causes clinically relevant hypothyroidism.
hours after dosing with quetiapine.
Because SEROQUEL may cause somnolence, patients should be Hyperglycemia and exacerbation of pre-existing diabetes have
cautioned about operating hazardous machines, including motor The pharmacokinetics of quetiapine are linear, and do not differ
been reported in very rare cases during quetiapine treatment.
vehicles. between men and women.
As with other antipsychotics, SEROQUEL may be associated with
The mean clearance of quetiapine in the elderly is approximately
UNDESIRABLE EFFECTS weight gain, predominantly during the early weeks of treatment.
30 to 50% lower than that seen in adults aged 18 to 65 years.
The most commonly reported Adverse Drug Reactions (ADRs) As with other antipsychotics, SEROQUEL may cause
The mean plasma clearance of quetiapine was reduced by
with SEROQUEL are somnolence, dizziness, dry mouth, mild prolongation of the QTc interval, but in clinical trials, this was not
approximately 25% in subjects with severe renal impairment
asthenia, constipation, tachycardia, orthostatic hypotension, and associated with a persistent increase (see Special Warnings and
(creatinine clearance less than 30 ml/min/1.73m2) and in
dyspepsia. Special Precautions for Use).
subjects with hepatic impairment (stable alcoholic cirrhosis), but
As with other antipsychotics, syncope, neuroleptic malignant Acute withdrawal reactions have been reported (see Special the individual clearance values are within the range for normal
syndrome, leucopenia, neutropenia and peripheral edema, have Warnings and Special Precautions for Use). subjects.
been associated with Seroquel.
OVERDOSE Quetiapine is extensively metabolised, with parent compound
The incidences of ADRs associated with SEROQUEL therapy, accounting for less than 5% of unchanged drug related material in
are tabulated below according to the format recommended by In clinical trials, experience with SEROQUEL in overdosage is
limited. Estimated doses of SEROQUEL up to 20g have been the urine or faeces, following the administration of radiolabelled
the Council for International Organizations of Medical Sciences quetiapine. Approximately 73% of the radioactivity is excreted in
(CIOMS III Working Group; 1995). taken; no fatalities were reported and patients recovered without
sequelae. the urine and 21% in the faeces.
Frequency System Organ Class Event In postmarketing experience, there have been very rare reports In vitro investigations established that CYP3A4 is the primary
Very common Nervous system disorders Dizziness1,6 of overdose of SEROQUEL alone, resulting in death or coma In enzyme responsible for cytochrome P450 mediated metabolism
(10%) Somnolence2 general, reported signs and symptoms were those resulting from of quetiapine.
Common Blood and lymphatic system Leucopenia3 an exaggeration of the drugs known pharmacological effects, ie, In a multiple-dose trial in healthy volunteers to assess the
(1% - <10%) disorders drowsiness and sedation, tachycardia and hypotension. pharmacokinetics of quetiapine given before and during treatment
There is no specic antidote to quetiapine. In cases of severe with ketoconazole, co-administration of ketoconazole resulted in
Cardiac disorders Tachycardia1,6
intoxication, the possibility of multiple drug involvement should an increase in mean Cmax and AUC of quetiapine of 235% and
Gastrointestinal disorders Dry mouth 522%, respectively, with a corresponding decrease in mean oral
be considered, and intensive care procedures are recommended,
Constipation clearance of 84%. The mean half-life of quetiapine increased from
including establishing and maintaining a patent airway, ensuring
Dyspepsia 2.6 to 6.8 hours, but the mean tmax was unchanged.
adequate oxygenation and ventilation, and monitoring and support
General disorders and Mild asthenia of the cardiovascular system. Quetiapine and several of its metabolites were found to be weak
administration site conditions Peripheral inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and
Close medical supervision and monitoring should be continued
edema 3A4 activities, but only at concentrations at least 10- to 50-fold
until the patient recovers.
Investigations Weight gain4 higher than those observed in the usual effective dose range of
Elevations in PHARMACOLOGICAL PROPERTIES 300 to 450 mg/day in humans. Based on these in vitro results, it is
serum Pharmacotherapeutic group : Antipsychotics unlikely that co-administration of quetiapine with other drugs will
transaminases Therapeutic classication : N05A H result in clinically signicant drug inhibition of cytochrome P450
(ALT1AST) 5 mediated metabolism of the other drug.
Nervous system disorders Syncope1.6
Mechanism of action: PRE CLINICAL SAFETY DATA
Respiratory, thoracic, and Rhinitis
mediastinal disorders Quetiapine is an atypical antipsychotic agent which interacts with Acute toxicity studies
Vascular disorders Orthostatic a broad range of neurotransmitter receptors. Quetiapine exhibits Quetiapine has low acute toxicity. Findings in mice and rats after
hypotension1,6 a higher afnity for serotonin (5HT2) receptors in the brain than it oral (500 mg/kg) or intraperitoneal (100 mg/kg) dosing were
does for dopamine D1 and D2 receptors in the brain. Quetiapine typical of an effective neuroleptic agent and included decreased
Uncommon Blood and lymphatic system Eosinophilia also has high afnity at histaminergic and adrenergic 1 receptors, motor activity, ptosis, loss of righting reex, uid around the
(0.1% - < 1%) disorders with a lower afnity at adrenergic 2 receptors, but no appreciable mouth and convulsions.
Immune system disorders Hypersensitivity afnity at cholinergic muscarinic or benzodiazepine receptors. Repeat-dose toxicity studies
Investigations Elevations in Quetiapine is active in tests for antipsychotic activity, such as
gamma-GT In multiple-dose studies in rats, dogs and monkeys, anticipated
conditioned avoidance.
levels5 central nervous system effects of an antipsychotic drug were
Pharmacodynamic effects: observed with quetiapine (eg, sedation at lower doses and tremor,
Elevations in
non-fasting The results of animal studies predictive of EPS liability revealed convulsions or prostration at higher exposures).
serum that quetiapine causes only weak catalepsy at effective dopamine Hyperprolactinaemia, induced through the dopamine D2 receptor
triglyceride D2 receptor blocking doses, that quetiapine causes selective antagonist activity of quetiapine or its metabolites, varied between
levels reduction in the ring of mesolimbic A10 dopaminergic neurones species but was most marked in the rat, and a range of effects
Elevations in versus the A9 nigrostriatal neurones involved in motor function, consequent to this were seen in the 12-month study, including
total cholesterol and that quetiapine exhibits minimal dystonic liability in mammary hyperplasia, increased pituitary weight, decreased
neuroleptic-sensitised monkeys. uterine weight and enhanced growth of females.
Nervous system disorders Seizure1
Clinical efcacy: Reversible morphological and functional effects on the liver,
Rare General disorders and Neuroleptic
(0.01% - administration site conditions malignant The results of three placebo-controlled clinical trials, including consistent with hepatic enzyme induction, were seen in mouse, rat
< 0.1%) Reproductive system and syndrome1 one that used a dose range of SEROQUEL of 75 to 750 mg/day, and monkey.
breast disorders Priapism identied no difference between SEROQUEL and placebo in the Thyroid follicular cell hypertrophy and concomitant changes in
incidence of EPS or use of concomitant anticholinergics. plasma thyroid hormone levels occurred in rat and monkey.
Very rare Blood and lymphatic system Neutropenia3
(<0.01%) disorders In four controlled trials, evaluating doses of SEROQUEL up to Pigmentation of a number of tissues, particularly the thyroid, was
800mg for the treatment of bipolar mania, two each in monotherapy not associated with any morphological or functional effects.
(1) See Special Warnings and Special Precautions for Use. and as adjunct therapy to lithium or valproate semisodium, there
(2) Somnolence may occur, usually during the rst two weeks were no differences between the SEROQUEL and placebo Transient increases in heart rate, unaccompanied by an effect on
of treatment and generally resolves with the continued treatment groups in the incidence of EPS or concomitant use of blood pressure, occurred in dogs.
administration of Seroquel. anticholinergics. Posterior triangular cataracts seen after 6 months in dogs at 100 mg/
(3) There were no cases of persistent severe neutropenia or SEROQUEL does not produce sustained elevations in prolactin. kg/day were consistent with inhibition of cholesterol biosynthesis
agranulocytosis reported in controlled clinical trials with In a multiple xed-dose clinical trial, there were no differences in in the lens. No cataracts were observed in Cynomolgus monkeys
SEROQUEL. During post-marketing experience, resolution prolactin levels at study completion between SEROQUEL, across dosed up to 225 mg/kg/day, nor in rodents. Monitoring in clinical
of leukopenia and/or neutropenia has followed cessation the recommended dose range, and placebo. studies did not reveal drug-related corneal opacities in man.
of therapy with SEROQUEL. Possible risk factors for No evidence of neutrophil reduction or agranulocytosis was seen
In clinical trials, SEROQUEL has been shown to be effective
leukopenia and/or neutropenia include pre-existing low in any of the toxicity studies.
in the treatment of both positive and negative symptoms of
white cell count and history of drug induced leukopenia and/ Carcinogenicity studies
schizophrenia. In one trial against chlorpromazine, and two
or neutropenia.
against haloperidol, SEROQUEL showed similar short-term In the rat study (doses 0, 20, 75 and 250 mg/kg/day) the incidence
(4) Occurs predominantly during the early weeks of treatment. efcacy. In clinical trials, SEROQUEL has been shown to be of mammary adenocarcinomas was increased at all doses in
(5) Asymptomatic elevations in serum transaminase (ALT, AST) effective as monotherapy or as adjunct therapy in reducing manic female rats, consequential to prolonged hyperprolactinaemia.
or gamma-GT-levels have been observed in some patients symptoms in patients with bipolar mania. The mean last week
administered Seroquel. These elevations were usually In male rat (250 mg/kg/day) and mouse (250 and 750 mg/kg/day),
median dose of SEROQUEL in responders, was approximately there was an increased incidence of thyroid follicular cell benign
reversible on continued SEROQUEL treatment. 600 mg and approximately 85% of the responders were in the dose adenomas, consistent with known rodent-specic mechanisms
(6) As with other antipsychotics with alpha 1 adrenergic blocking range of 400 to 800 mg per day. resulting from enhanced hepatic thyroxine clearance.
activity, SEROQUEL may induce orthostatic hypotension,
associated with dizziness, tachycardia and, in some patients, PHARMACOKINETIC PROPERTIES Reproduction studies
syncope, especially during the initial dose-titration period. Quetiapine is well absorbed and extensively metabolised following Effects related to elevated prolactin levels (marginal reduction in
72
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male fertility and pseudopregnancy, protracted periods of diestrus, A. Symbicort maintenance therapy COPD is potentially life threatening and the patient should undergo
increased precoital interval and reduced pregnancy rate) were seen Patients should be advised to have their separate rapid-acting urgent medical assessment. In this situation consideration should
in rats, although these are not directly relevant to humans because bronchodilator available for rescue use at all times. be given to the need for increased therapy with corticosteroids,
of species differences in hormonal control of reproduction. e.g. a course of oral corticosteroids, or antibiotic treatment if an
Recommended doses:
Quetiapine had no teratogenic effects. infection is present.
Adults (18 years and older): 1-2 inhalations twice daily. Some
Mutagenicity studies Patients should be advised to have their rescue inhaler available
patients may require up to a maximum of 4 inhalations twice
Genetic toxicity studies with quetiapine show that it is not a at all times, either SYMBICORT (for asthma patients using
daily.
mutagen or clastogen. Symbicort as maintenance and reliever therapy) or a separate
Adolescents (12-17 years): 1-2 inhalations twice daily. rapid-acting bronchodilator (for all patients using SYMBICORT
PHARMACEUTICAL PARTICULARS In usual practice when control of symptoms is achieved with the as maintenance therapy only).
List of excipients twice daily regimen, titration to the lowest effective dose could Patients should be reminded to take their SYMBICORT
Core Coating include SYMBICORT given once daily, when in the opinion of maintenance dose as prescribed, even when asymptomatic. The
Povidone (PhEur) Hypromellose (PhEur) the prescriber, a long-acting bronchodilator would be required to prophylactic use of SYMBICORT, e.g. before exercise, has not
maintain control. been studied. The reliever inhalations of SYMBICORT should
Calcium Hydrogen Phosphate (PhEur) Macrogol 400 (PhEur)
Increasing use of a separate rapid-acting bronchodilator indicates a be taken in response to asthma symptoms but are not intended
Microcrystalline Cellulose (PhEur) Titanium Dioxide
worsening of the underlying condition and warrants a reassessment for regular prophylactic use, e.g. before exercise. For such use, a
(PhEur, E171) of the asthma therapy. separate rapid-acting bronchodilator should be considered.
Sodium Starch Glycollate Type A Ferric Oxide, Yellow Children (6 years and older): A lower strength is available for Therapy with SYMBICORT should not be initiated during an
(PhEur) (PhFr, E172) children 6-11 years. exacerbation.
Lactose Monohydrate (PhEur) B. Symbicort maintenance and reliever therapy As with other inhalation therapy, paradoxical bronchospasm
Magnesium Stearate (PhEur) Patients take a daily maintenance dose of SYMBICORT and in may occur, with an immediate increase in wheezing after dosing.
addition take SYMBICORT as needed in response to symptoms. SYMBICORT should then be discontinued; treatment should be
SPECIAL PRECAUTIONS FOR STORAGE Patients should be advised to always have Symbicort available for re-assessed and alternative therapy instituted if necessary.
Do not store above 30C. rescue use. Systemic effects may occur with any inhaled corticosteroid,
SYMBICORT maintenance and reliever therapy should especially particularly at high doses prescribed for long periods. These
SHELF LIFE effects are much less likely to occur with inhalation treatment than
be considered for patients with:
Please refer to expiry date on the outer carton. inadequate asthma control and in frequent need of reliever with oral corticosteroids. Possible systemic effects include adrenal
medication suppression, growth retardation in children and adolescents,
PACK SIZE
decrease in bone mineral density, cataract and glaucoma.
Please refer to the outer carton for pack size. asthma exacerbations in the past requiring medical intervention
It is recommended that the height of children receiving prolonged
SEROQUEL is a trademark of the AstraZeneca group of Close monitoring for dose-related adverse effects is needed in
treatment with inhaled corticosteroids is regularly monitored. If
companies. patients who frequently take high numbers of SYMBICORT as-
growth is slowed, therapy should be re-evaluated with the aim of
needed inhalations.
reducing the dose of inhaled corticosteroid. The benets of the
SYMBICORT TURBUHALER Recommended doses: corticosteroid therapy and the possible risks of growth suppression
Adults (18 years and older): The recommended maintenance must be carefully weighed. In addition consideration should be
160/4.5 g/dose Inhalation powder dose is 2 inhalations per day, given either as one inhalation in the given to referring the patient to a paediatric respiratory specialist.
morning and evening or as 2 inhalations in either the morning or Limited data from long-term studies suggest that most children
(Budesonide, Formoterol fumarate dihydrate) evening. For some patients a maintenance dose of 2 inhalations and adolescents treated with inhaled budesonide will ultimately
twice daily may be appropriate. Patients should take 1 additional achieve their adult target height. However, an initial small but
COMPOSITION inhalation as needed in response to symptoms. If symptoms persist transient reduction in growth (approximately 1 cm) has been
after a few minutes, an additional inhalation should be taken. Not observed. This generally occurs within the rst year of treatment.
Each delivered dose (the dose that leaves the mouthpiece) contains:
more than 6 inhalations should be taken on any single occasion.
budesonide 160 micrograms/inhalation and formoterol fumarate Potential effects on bone density should be considered particularly
dihydrate 4.5 micrograms/inhalation. A total daily dose of more than 8 inhalations is not normally in patients on high doses for prolonged periods that have coexisting
needed; however, a total daily dose of up to 12 inhalations could risk factors for osteoporosis. Long-term studies with inhaled
SYMBICORT TURBUHALER 160/4.5 micrograms/inhalation
be used for a limited period. Patients using more than 8 inhalations budesonide in children at mean daily doses of 400 micrograms
delivers the same amount of budesonide and formoterol as
daily should be strongly recommended to seek medical advice. (metered dose) or in adults at daily doses of 800 micrograms
the corresponding Turbuhaler monoproducts, i.e. budesonide
They should be reassessed and their maintenance therapy should (metered dose) have not shown any signicant effects on bone
200 micrograms/inhalation (metered dose) and formoterol 6
be reconsidered. mineral density. No information regarding the effect of Symbicort
micrograms/inhalation (metered dose) alternatively labelled as 4.5
micrograms/inhalation (delivered dose). Children and adolescents under 18 years: SYMBICORT at higher doses is available.
maintenance and reliever therapy is not recommended for children If there is any reason to suppose that adrenal function is impaired
THERAPEUTIC INDICATIONS and adolescents. from previous systemic steroid therapy, care should be taken when
Asthma COPD transferring patients to SYMBICORT therapy.
SYMBICORT TURBUHALER is indicated in the regular Recommended doses: The benets of inhaled budesonide therapy would normally
treatment of asthma, where use of a combination (inhaled minimise the need for oral steroids, but patients transferring from
Adults: 2 inhalations twice daily.
corticosteroid and long-acting beta2-agonist) is appropriate: oral steroids may remain at risk of impaired adrenal reserve for a
- patients not adequately controlled with inhaled corticosteroids General information
considerable time. Patients who have required high dose emergency
and as needed inhaled short-acting beta2-agonists Special patient groups: There are no special dosing requirements corticosteroid therapy in the past or prolonged treatment with high
or for elderly patients. There are no data available for use of doses of inhaled corticosteroids, may also be at risk. Additional
- patients already adequately controlled on both inhaled SYMBICORT in patients with hepatic or renal impairment. As systemic corticosteroid cover should be considered during periods
corticosteroids and long- acting beta2-agonists. budesonide and formoterol are primarily eliminated via hepatic of stress or elective surgery.
metabolism, an increased exposure can be expected in patients
COPD To minimise the risk of oropharyngeal candida infection the
with severe liver cirrhosis.
SYMBICORT TURBUHALER of patients with severe COPD patient should be instructed to rinse their mouth out with water
(FEV1 <50% predicted normal) and a history of repeated INSTRUCTIONS FOR CORRECT USE OF TURBUHAL- after inhaling the maintenance dose. If oropharyngeal thrush
exacerbations, who have signicant symptoms despite regular ER: occurs, patients should also rinse their mouth with water after the
therapy with long-acting bronchodilators. TURBUHALER is inspiratory ow-driven, which means that as-needed inhalations.
when the patient inhales through the mouthpiece, the substance Concomitant treatment with itraconazole and ritonavir or other
POSOLOGY AND METHOD OF ADMINISTRATION potent CYP3A4 inhibitors should be avoided (see section
will follow the inspired air into the airways.
Asthma Interactions). If this is not possible the time interval between
Note: It is important to instruct the patient
SYMBICORT TURBUHALER is not intended for the initial administration of the interacting drugs should be as long as possible.
to carefully read the instructions for use/handling at the end of
management of asthma. The dosage of the components of In patients using potent CYP3A4 inhibitors, SYMBICORT
this leaet.
SYMBICORT is individual and should be adjusted to the maintenance and reliever therapy is not recommended.
to breathe in forcefully and deeply through the mouthpiece to
severity of the disease. This should be considered not only when SYMBICORT should be administered with caution in patients
ensure that an optimal dose is delivered to the lungs.
treatment with combination products is initiated but also when with thyrotoxicosis, phaeochromocytoma, diabetes mellitus,
the maintenance dose is adjusted. If an individual patient should never to breathe out through the mouthpiece.
untreated hypokalaemia, hypertrophic obstructive cardiomyopathy,
require a combination of doses other than those available in the to rinse their mouth out with water after inhaling the idiopathic subvalvular aortic stenosis, severe hypertension,
combination inhaler, appropriate doses of beta2-agonists and/or maintenance dose to minimise the risk of oropharyngeal thrush. aneurysm or other severe cardiovascular disorders, such as
corticosteroids by individual inhalers should be prescribed. If oropharyngeal thrush occurs, patients should also rinse their ischaemic heart disease, tachyarrhythmias or severe heart failure.
The dose should be titrated to the lowest dose at which effective mouth with water after the as-needed inhalations.
Caution should be observed when treating patients with
control of symptoms is maintained. Patients should be regularly The patient may not taste or feel any medication when using prolongation of the QTc-interval. Formoterol itself may induce
reassessed by their prescriber/health care provider so that the Turbuhaler due to the small amount of drug dispensed. prolongation of the QTc-interval.
dosage of SYMBICORT remains optimal. When control of CONTRAINDICATIONS The need for, and dose of inhaled corticosteroids should be
symptoms is maintained with the lowest recommended dosage, re-evaluated in patients with active or quiescent pulmonary
then the next step could include a test of inhaled corticosteroid Hypersensitivity (allergy) to budesonide, formoterol or inhaled
lactose. tuberculosis, fungal and viral infections in the airways.
alone.
Potentially serious hypokalaemia may result from high doses of
For SYMBICORT there are two treatment approaches: SPECIAL WARNING AND PRECAUTIONS FOR USE
beta2-agonists. Concomitant treatment of beta2-agonists with
A. SYMBICORT maintenance therapy: SYMBICORT is It is recommended that the dose is tapered when the treatment is drugs which can induce hypokalaemia or potentiate a hypokalaemic
taken as regular maintenance treatment with a separate rapid- discontinued and should not be stopped abruptly. effect, e.g. xanthine-derivatives, steroids and diuretics, may add
acting bronchodilator as rescue. If patients nd the treatment ineffective, or exceed the highest to a possible hypokalaemic effect of the beta2-agonist. Particular
B. SYMBICORT maintenance and reliever therapy: recommended dose of SYMBICORT, medical attention must caution is recommended in unstable asthma with variable use of
SYMBICORT is taken as regular maintenance treatment and be sought (see section Posology and method of administration). rescue bronchodilators, in acute severe asthma as the associated
as needed in response to symptoms. Sudden and progressive deterioration in control of asthma or risk may be augmented by hypoxia and in other conditions when
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ASTRAZENECA
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the likelihood for hypokalaemia adverse effects is increased. It is resulting in reduced symptoms and fewer asthma exacerbations.
recommended that serum potassium levels are monitored during Cardiac disorders Common Palpitations
Inhaled budesonide has less severe adverse effects than systemic
these circumstances. Uncommon Tachycardia corticosteroids. The exact mechanism responsible for the anti-
As for all beta2-agonists, additional blood glucose controls should Rare Atrial brillation, inammatory effect of glucocorticosteroids is unknown.
be considered in diabetic patients. supraventricular Formoterol
SYMBICORT TURBUHALER contains lactose (<1 mg/ tachycardia,
Formoterol is a selective beta2-adrenergic agonist that when
inhalation). This amount does not normally cause problems in extrasystoles inhaled results in rapid and long-acting relaxation of bronchial
lactose intolerant people. Very rare Angina pectoris smooth muscle in patients with reversible airways obstruction. The
Endocrine disorders Very rare Signs or symptoms of bronchodilating effect is dose dependant, with an onset of effect
INTERACTIONS
systemic within 1-3 minutes. The duration of effect is at least 12 hours after
The metabolic conversion of budesonide is impeded by substances
glucocorticosteroid a single dose.
metabolized by CYP P450 3A4 (e.g. itraconazole, ritonavir). The
concomitant administration of these potent inhibitors of CYP P450 effects (including
SYMBICORT TURBUHALER
3A4 may increase plasma levels of budesonide. The concomitant hypofunction of the
Asthma
use of these drugs should be avoided unless the benet outweighs adrenal gland)
Gastrointestinal disorders Uncommon Nausea Clinical efcacy for Symbicort maintenance therapy
the increased risk of systemic side effects. In patients using potent
CYP3A4 inhibitors, SYMBICORT maintenance and reliever Immune system disorders Rare Exanthema, urticaria, Clinical studies in adults have shown that the addition of
therapy is not recommended. ruritus, dermatitis, formoterol to budesonide improved asthma symptoms and lung
Beta-adrenergic blockers can weaken or inhibit the effect of angioedema function, and reduced exacerbations. In two 12-week studies the
formoterol. SYMBICORT should therefore not be given together effect on lung function of SYMBICORT was equal to that of the
Infections and infestations Common Candida infections in
with beta-adrenergic blockers (including eye drops) unless there free combination of budesonide and formoterol, and exceeded that
the oropharynx
are compelling reasons. of budesonide alone. All treatment arms used a short-acting beta2-
Metabolic and nutrition Rare Hypokalemia agonist as needed. There was no sign of attenuation of the anti-
Concomitant treatment with quinidine, disopyramide, procain-
disorders Very rare Hyperglycemia asthmatic effect over time.
amide, phenothiazines, antihistamines (terfenadine), monoamine
oxidase inhibitors and tricyclic anti-depressants can prolong the Musculoskeletal, Uncommon Muscle cramps In a 12-week paediatric study 85 children aged 6-11 years were
QTc-interval and increase the risk of ventricular arrhythmias. connective tissue and treated with a maintenance dose of Symbicort Turbuhaler (2
In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair bone disorders inhalations of 80/4.5 micrograms/inhalation twice daily), and
cardiac tolerance towards beta2-sympathomimetics. a short-acting beta2-agonist as needed. Lung function was
Nervous system disorders Common Headache, tremor
improved and the treatment was well tolerated compared to the
Concomitant treatment with monoamine oxidase inhibitors Uncommon Dizziness
corresponding dose of budesonide Turbuhaler.
including agents with similar properties such as furazolidone and Very rare Taste disturbances
procarbazine may precipitate hypertensive reactions. Clinical efcacy for Symbicort maintenance and reliever
Psychiatric disorders Uncommon Agitation,
therapy
There is an elevated risk of arrhythmias in patients receiving restlessness,
concomitant anaesthesia with halogenated hydrocarbons. A total of 12076 asthma patients were included in 5 double-
nervousness, sleep
Concomitant use of other beta-adrenergic drugs can have a blind efcacy and safety studies (4447 were randomised to
disturbances
potentially additive effect. SYMBICORT maintenance and reliever therapy) for 6 or 12
Very rare Depression, months. Patients were required to be symptomatic despite use of
Hypokalaemia may increase the disposition towards arrhythmias behavioural inhaled glucocorticosteroids.
in patients who are treated with digitalis glycosides. disturbances (mainly SYMBICORT maintenance and reliever therapy provided
Budesonide has not been observed to interact with any other drugs in children) statistically signicant and clinically meaningful reductions in
used in the treatment of asthma. Respiratory, thoracic and Common Mild irritation in the severe exacerbations for all comparisons in all 5 studies. This
PREGNANCY AND LACTATION mediastinal disorders throat, coughing, included a comparison with SYMBICORT at a higher maintenance
For SYMBICORT or the concomitant treatment with formoterol hoarseness dose with terbutaline as reliever (study 735) and SYMBICORT at
and budesonide, no clinical data on exposed pregnancies are Rare Bronchospasm the same maintenance dose with either formoterol or terbutaline
available. Animal studies with respect to reproductive toxicity of Skin and subcutaneous Uncommon Bruises as reliever (study 734) (Table 1). In Study 735, lung function,
the combination have not been performed. tissue disorders symptom control, and reliever use were similar in all treatment
There are no adequate data from use of formoterol in pregnant groups. In Study 734, symptoms and reliever use were reduced
Vascular disorders Very rare Variations in blood
women. In animal studies formoterol has caused adverse effects and lung function improved, compared with both comparator
pressure
in reproduction studies at very high systemic exposure levels (see treatments. In the 5 studies combined, patients receiving
section Preclinical safety data). As with other inhalation therapy, paradoxical bronchospasm SYMBICORT maintenance and reliever therapy used, on average,
may occur in very rare cases (see section Special warning and no reliever inhalations on 57% of treatment days. There was no
Data on approximately 2000 exposed pregnancies indicate no
precautions for use). sign of development of tolerance over time.
increased teratogenic risk associated with the use of inhaled
budesonide. In animal studies glucocorticosteroids have Systemic effects of inhaled corticosteroids may occur particularly Table 1 Overview of severe exacerbations in clinical studies
been shown to induce malformations (see section Preclinical at high doses prescribed for prolonged periods. These may Study No. Treatment groups N Severe exacerbationsa
safety data). This is not likely to be relevant for humans given include adrenal suppression, growth retardation in children Duration Events Events/
recommended doses. and adolescents, decrease in bone mineral density, cataract and patient-year
Animal studies have also identied an involvement of excess glaucoma (see section Special warning and precautions for use).
Treatment with beta2-agonists may result in an increase in blood
Study 735 Symbicort 160/4.5 g 1103 125 0.23b
prenatal glucocorticoids in increased risks for intrauterine growth 6 months bd + as needed
retardation, adult cardiovascular disease and permanent changes levels of insulin, free fatty acids, glycerol and ketone bodies.
in glucocorticoid receptor density, neurotransmitter turnover and Symbicort 320/9 g bd + 1099 173 0.32
OVERDOSE terbutaline 0.4 mg as
behaviour at exposures below the teratogenic dose range.
An overdose of formoterol would likely lead to effects that needed
During pregnancy, SYMBICORT should only be used when the
are typical for beta2-adrenergic agonists: tremor, headache, Salmeterol/uticasone 1119 208 0.38
benets outweigh the potential risks. The lowest effective dose of
budesonide needed to maintain adequate asthma control should be palpitations. Symptoms reported from isolated cases are 2 x 25/125 g bd +
used. tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc- terbutaline 0.4 mg as
interval, arrhythmia, nausea and vomiting. Supportive and needed
It is not known whether formoterol or budesonide passes into
symptomatic treatment may be indicated. A dose of 90 micrograms
human breast milk. In rats, small amounts of formoterol have been Study 734 Symbicort 160/4.5 g 1107 194 0.19b
administered during three hours in patients with acute bronchial
detected in maternal milk. Administration of SYMBICORT to 12 months bd + as needed
obstruction raised no safety concerns.
women who are breastfeeding should only be considered if the Symbicort 160/4.5 g bd 1137 296 0.29
expected benet to the mother is greater than any possible risk Acute overdosage with budesonide, even in excessive doses, is + formoterol 4.5 g as
to the child. not expected to be a clinical problem. When used chronically in needed
excessive doses, systemic glucocorticosteroid effects, such as Symbicort 160/4.5 g bd
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES 1138 377 0.37
hypercorticism and adrenal suppression, may appear.
+ terbutaline 0.4 mg as
SYMBICORT has no or negligible inuence on the ability to If SYMBICORT therapy has to be withdrawn due to overdose of needed
drive and use machines. the formoterol component of the drug, provision of appropriate
UNDESIRABLE EFFECTS inhaled corticosteroid therapy must be considered.
a Hospitalisation/emergency room treatment or treatment with
Since SYMBICORT contains both budesonide and formoterol, PHARMACODYNAMIC PROPERTIES oral steroids
the same pattern of undesirable effects as reported for these Pharmacotherapeutic group: Adrenergics and other drugs for b Reduction in exacerbation rate is statistically signicant (P
substances may occur. No increased incidence of adverse value <0.01) for both comparisons
obstructive airway diseases.
reactions has been seen following concurrent administration
ATC-code: R03AK07 In 2 other studies with patients seeking medical attention due
of the two compounds. The most common drug related adverse
to acute asthma symptoms, SYMBICORT provided rapid and
reactions are pharmacologically predictable side-effects of beta2- MECHANISMS OF ACTION AND PHARMACODYNAMIC effective relief of bronchoconstriction similar to salbutamol and
agonist therapy, such as tremor and palpitations. These tend to be EFFECTS formoterol.
mild and usually disappear within a few days of treatment. In a
SYMBICORT contains formoterol and budesonide, which have COPD
3-year clinical trial with budesonide in COPD, skin bruises and
different modes of action and show additive effects in terms of
pneumonia occurred at a frequency of 10% and 6%, respectively, In two 12-month studies, the effect on lung function and the rate of
compared with 4% and 3% in the placebo group (p<0.001 and reduction of asthma exacerbations. The specic properties of
exacerbation (dened as courses of oral steroids and/or course of
p<0.01, respectively). budesonide and formoterol allow the combination to be used both
antibiotics and/or hospitalisations) in patients with severe COPD
as maintenance and reliever therapy, or as maintenance treatment
Adverse reactions, which have been associated with budesonide was evaluated. Median FEV1 at inclusion in the trials was 36% of
of asthma.
or formoterol, are given below, listed by system organ class and predicted normal. The mean number of exacerbations per year (as
frequency. Frequency are dened as: very common (1/10), Budesonide dened above) was signicantly reduced with SYMBICORT as
common (1/100) and <1/10), uncommon (1/1 000 and < 1/100), Budesonide is a glucocorticosteroid which when inhaled has compared with treatment with formoterol alone or placebo (mean
rare (1/10 000 and < 1/1000) and very rare (<1/10 000). a dose-dependent anti-inammatory action in the airways, rate 1.4 compared with 1.8-1.9 in the placebo/formoterol group).
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The mean number of days on oral corticosteroids/patient during PACK SIZE The indicator is marked in intervals of 10 doses. Therefore it does
the 12 months was slightly reduced in the Symbicort group (7- Please refer to outer carton for pack size. not show the loading of each individual dose.
8 days/patient/year compared with 11-12 and 9-12 days in the You should be reassured that Turbuhaler delivers the dose even if
placebo and formoterol groups, respectively). For changes in lung- INSTRUCTIONS FOR USE/HANDLING
you may not notice a movement in the dose indicator.
function parameters, such as FEV1, Symbicort was not superior to Turbuhaler is a multidose inhaler from which very small amounts of
For the last 10 doses, the background of the indicator is red. When
treatment with formoterol alone. powder are administered. When you breathe in through Turbuhaler
the zero reaches the middle of the window, it is time for you to
the powder is delivered to your lungs. It is therefore important that discard the inhaler.
you inhale forcefully and deeply through the mouthpiece.
Absorption How to prepare a new inhaler for use Please note that even when the dose indicator registers zero, it is
SYMBICORT TURBUHALER and the corresponding still possible to turn the grip. However, the indicator stops moving
Before using Turbuhaler for the rst time you need to prepare the and the zero remains in the window.
monoproducts have been shown to be bioequivalent with regard to inhaler for use.
systemic exposure of budesonide and formoterol, respectively. In
1. Unscrew and lift off the cover. A rattling sound is heard when
spite of this, a small increase in cortisol suppression was seen after
you unscrew the cover.
administration of SYMBICORT TURBUHALER compared to
the monoproducts. The difference is considered not to have an
impact on clinical safety.
There was no evidence of pharmacokinetic interactions between
budesonide and formoterol.
Pharmacokinetic parameters for the respective substances were
comparable after the administration of budesonide and formoterol
as monoproducts or as SYMBICORT TURBUHALER
For budesonide, AUC was slightly higher, rate of absorption Cleaning
more rapid and maximal plasma concentration higher after Wipe the outside of the mouthpiece regularly (once a week)
administration of the xed combination. For formoterol, maximal with a dry tissue. Do not use water or liquids when you clean the
plasma concentration was similar after administration of the xed mouthpiece.
combination. Inhaled budesonide is rapidly absorbed and the Disposal
maximum plasma concentration is reached within 30 minutes Always be sure to dispose of your used Turbuhaler responsibly/in
after inhalation. In studies, mean lung deposition of budesonide 2. Hold the inhaler upright with the red grip downwards. Do not the recommended way, since some of the medicine will remain
after inhalation via Turbuhaler ranged from 32% to 44% of the hold the mouthpiece when you turn the grip. Turn the grip as inside it. Ask your pharmacist for advice.
delivered dose. The systemic bioavailability is approximately 49% far as it will go in one direction and then back again as far
as it will go. It does not matter which way you turn rst. During Symbicort and Turbuhaler are trademarks of the AstraZeneca
of the delivered dose.
this procedure you will hear a click. Perform this procedure group of companies.
Inhaled formoterol is rapidly absorbed and the maximum plasma
twice. AstraZeneca 2003-2006
concentration is reached within 10 minutes after inhalation. In
studies the mean lung deposition of formoterol after inhalation via
Turbuhaler ranged from 28% to 49% of the delivered dose. The TENORETIC Tablets
systemic bioavailability is about 61% of the delivered dose.
Distribution and metabolism (Atenolol and Chlorthalidone )
Plasma protein binding is approximately 50% for formoterol
and 90% for budesonide. Volume of distribution is about 4 COMPOSITION
L/kg for formoterol and 3 L/kg for budesonide. Formoterol is Tablets containing 100 mg of Atenolol Ph. Eur. and 25 mg of
inactivated via conjugation reactions (active O-demethylated and Chlorthalidone Ph.Eur.
deformylated metabolites are formed, but they are seen mainly
as inactivated conjugates). Budesonide undergoes an extensive PHARMACEUTICAL FORM
degree (approximately 90%) of biotransformation on rst passage White, round, biconvex, lm coated tablets
The inhaler is now prepared for use, and you should not repeat
through the liver to metabolites of low glucocorticosteroid
the above procedure again. To take a dose, please continue THERAPEUTIC INDICATIONS
activity. The glucocorticosteroid activity of the major metabolites,
according to the instructions below. Hypertension.
6-beta-hydroxy-budesonide and 16-alfa-hydroxy-prednisolone, is
less than 1% of that of budesonide. There are no indications of How to use SYMBICORT TURBUHALER
any metabolic interactions or any displacement reactions between To administer one dose, simply follow the instructions below.
formoterol and budesonide. Adults
1. Unscrew and lift off the cover. A rattling sound is heard when
Elimination you unscrew the cover. One tablet daily. Most patients with hypertension will give a
satisfactory response to a single tablet daily of Tenoretic. There
The major part of a dose of formoterol is transformed by liver 2. Hold the inhaler upright with the red grip downwards .Do not
is little or no further fall in blood pressure with increased dosage
metabolism followed by renal elimination. After inhalation, 8% to hold the mouthpiece when you turn the grip. To load the inhaler
but, where necessary, another antihypertensive drug, such as a
13% of the delivered dose of formoterol is excreted unmetabolised with a dose turn the grip as far as it will go in one direction, and
vasodilator, can be added.
in the urine. Formoterol has a high systemic clearance then back again as far as it will go. It does not matter which way
you turn rst. During this procedure you will hear a click. Elderly
(approximately 1.4 L/min) and the terminal elimination half-life
averages 17 hours. 3. Breathe out. Do not breathe out through the mouthpiece. Dosage requirements are often lower in this age group.
Budesonide is eliminated via metabolism mainly catalysed by the Children
4. Place the mouthpiece gently between your teeth, close your lips
enzyme CYP3A4. The metabolites of budesonide are eliminated and inhale forcefully and deeply through the device. Do not There is no paediatric experience with Tenoretic, and for this
in urine as such or in conjugated form. Only negligible amounts of chew or bite on the mouthpiece. reason it is not recommended for use in children.
unchanged budesonide have been detected in the urine. Budesonide Renal Failure
has a high systemic clearance (approximately 1.2 L/min) and the Caution should be exercised in patients with renal failure. The dose
plasma elimination half-life after i.v. dosing averages 4 hours. should be reduced by decreasing the frequency of administration
The pharmacokinetics of budesonide or formoterol in patients (see Special warnings and precautions for use).
with renal failure is unknown. The exposure of budesonide and
formoterol may be increased in patients with liver disease. CONTRAINDICATIONS
TENORETIC should not be used in patients with any of
PRECLINICAL SAFETY DATA the following: known hypersensitivity to either component,
The toxicity observed in animal studies with budesonide and bradycardia, cardiogenic shock, hypotension, metabolic acidosis,
formoterol, given in combination or separately, were effects severe peripheral arterial circulatory disturbances, second
associated with exaggerated pharmacological activity. 5. Remove the inhaler from your mouth, before breathing out. or third degree heart block, sick sinus syndrome, untreated
In animal reproduction studies, corticosteroids such as budesonide 6. If more than one dose has been prescribed, repeat steps 2-5. phaeochromocytoma, uncontrolled heart failure.
have been shown to induce malformations (cleft palate, skeletal 7. Replace the cover by screwing it back on tightly. TENORETIC must not be given during pregnancy or
malformations). However, these animal experimental results do not lactation.
seem to be relevant in humans at the recommended doses. Animal 8. Rinse your mouth out with water after morning and evening
reproduction studies with formoterol have shown a somewhat doses. Do not swallow. SPECIAL WARNINGS AND PRECAUTIONS FOR USE
reduced fertility in male rats at high systemic exposure and NOTE! Due to its beta-blocker component TENORETIC:
implantation losses as well as decreased early postnatal survival Do not try to remove the mouthpiece since it is xed to the inhaler. - although contraindicated in uncontrolled heart failure (see
and birth weight at considerably higher systemic exposures The mouthpiece can be rotated, but do not twist it unnecessarily. Contraindications), may be used in patients whose signs of
than those reached during clinical use. However, these animal As the amount of the powder dispensed is very small, you may heart failure have been controlled. Caution must be exercised
experimental results do not seem to be relevant in humans. not be able to taste it after inhalation. However, you can still be in patients whose cardiac reserve is poor.
condent that you have inhaled the dose if you have followed the - may increase the number and duration of angina attacks in
LIST OF EXCIPIENTS
instructions. patients with Prinzmetals angina due to unopposed alpha
Lactose monohydrate (which contains milk proteins). receptor mediated coronary artery vasoconstriction. Atenolol
If you by mistake perform the loading procedure more than once
INCOMPATIBILITIES is a beta-1 selective beta-blocker; consequently the use of
before taking your dose, you will still only receive one dose. The
TENORETIC may be considered although utmost caution
Not applicable. dose indicator will, however, register all the loaded doses.
must be exercised.
SHELF-LIFE The sound heard if you shake the inhaler is not produced by the - although contraindicated in severe peripheral arterial circulatory
medication but by a drying agent. disturbances (see Contraindications), may also aggravate less
Please refer to expiry date on the outer carton.
How will I know when to replace the inhaler? severe peripheral arterial circulatory disturbances.
SPECIAL PRECAUTIONS FOR STORAGE The dose indicator tells you approximately how many doses are - due to its negative effect on conduction time, caution must be
Do not store above 30 C. Keep the container tightly closed. left in the inhaler, starting with either 60 or 120 when full. exercised if it is given to patients with rst degree heart block.
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ASTRAZENECA
SPDI
- may modify the tachycardia of hypoglycaemia. Cardiovascular: bradycardia, heart failure deterioration, postural Atenolol penetrates tissues poorly due to its low lipid solubility
- may mask the signs of thyrotoxicosis. hypotension which may be associated with syncope, cold and its concentration in brain tissue is low. Plasma protein binding
- will reduce heart rate, as a result of its pharmacological action. extremities. In susceptible patients: precipitation of heart block, is low (approximately 3%).
In the rare instances when a treated patient develops symptoms intermittent claudication may be increased if already present, Absorption of chlorthalidone following oral dosing is consistent but
which may be attributable to a slow heart rate, the dose may be Raynauds phenomenon. incomplete (approximately 60%) with peak plasma concentrations
reduced. CNS: confusion, dizziness, headache, mood changes, nightmares, occurring about 12 hours after dosing. The chlorthalidone blood
- should not be discontinued abruptly in patients suffering from psychoses and hallucinations, sleep disturbances of the type noted levels are consistent and subject to little variability. The plasma
ischaemic heart disease. with other beta-blockers. half-life is about 50 hours and the kidney is the major route of
- may cause a more severe reaction to a variety of allergens, when Gastrointestinal: dry mouth, gastrointestinal disturbances, elimination. Plasma protein binding is high (approximately 75%).
given to patients with a history of anaphylactic reaction to such elevations of transaminase levels have been seen infrequently, rare Co-administration of chlorthalidone and atenolol has little effect
allergens. Such patients may be unresponsive to the usual doses cases of hepatic toxicity including intrahepatic cholestasis have on the pharmacokinetics of either.
of adrenaline used to treat the allergic reactions. been reported, nausea (related to chlorthalidone), pancreatitis. TENORETIC is effective for at least 24 hours after a single oral
- may cause an increase in airways resistance in asthmatic patients. Haematological: leucopenia, purpura, thrombocytopenia. daily dose. This simplicity of dosing facilitates compliance by its
Atenolol is a beta-1 selective beta-blocker; consequently the use Integumentary: alopecia, dry eyes, psoriasiform skin reactions, acceptability to patients.
of TENORETIC may be considered although utmost caution exacerbation of psoriasis, skin rashes.
must be exercised. If increased airways resistance does occur, LIST OF EXCIPIENTS
Neurological: paraesthesia.
Tenoretic should be discontinued and bronchodilator therapy Maize starch, heavy magnesium carbonate, gelatine, sodium
Respiratory: bronchospasm may occur in patients with bronchial lauryl sulphate, magnesium stearate, hypromellose, glycerol, and
(e.g. salbutamol) administered if necessary.
asthma or a history of asthmatic complaints. titanium dioxide
Due to its chlorthalidone component:
Reproductive: impotence
- hypokalaemia may occur. Measurement of potassium levels STORAGE
is appropriate, especially in the older patient, those receiving Special senses: visual disturbances.
Do not store above 25 C. Protect from light and moisture.
digitalis preparations for cardiac failure, those taking an Others: fatigue; an increase in ANA (Antinuclear Antibodies) has
abnormal (low in potassium) diet or those suffering from been observed, however the clinical relevance of this is not clear SHELF LIFE
gastrointestinal complaints. Hypokalaemia may predispose to Discontinuance of TENORETIC should be considered if, Please refer to expiry date on the blister strip or outer carton.
arrhythmias in patients receiving digitalis. according to clinical judgement, the well-being of the patient is
PACK SIZE
- caution must be exercised in patients with severe renal failure adversely affected by any of the above reactions.
(see Posology and method of administration). Please refer to the outer carton for pack size.
OVERDOSE TENORETIC is a trademark of the AstraZeneca group of
- impaired glucose tolerance may occur and caution must be
exercised if chlorthalidone is administered to patients with a The symptoms of overdosage may include bradycardia, companies.
known pre-disposition to diabetes mellitus. hypotension, acute cardiac insufciency and bronchospasm. AstraZeneca 2006
- hyperuricaemia may occur. Only a minor increase in serum General treatment should include: close supervision, treatment in
uric acid usually occurs but in cases of prolonged elevation, an intensive care ward, the use of gastric lavage, activated charcoal
and a laxative to prevent absorption of any drug still present in the
TENORMIN
the concurrent use of a uricosuric agent will reverse the
hyperuricaemia. gastrointestinal tract, the use of plasma or plasma substitutes to Film-coated tablets and solution for injection
treat hypotension and shock. The possible use of haemodialysis or
INTERACTIONS
haemoperfusion may be considered.
Combined use of beta-blockers and calcium channel blockers (Atenolol)
Excessive bradycardia can be countered with atropine 1-2 mg
with negative inotropic effects e.g. verapamil, diltiazem can lead
intravenously and/or a cardiac pacemaker. If necessary, this may
to an exaggeration of these effects particularly in patients with COMPOSITION
be followed by a bolus dose of glucagon 10 mg intravenously.
impaired ventricular function and/or sino-atrial or atrio-ventricular
If required, this may be repeated or followed by an intravenous Tablets containing 25 mg( N.R), 50 mg or 100 mg of Atenolol
conduction abnormalities. This may result in severe hypotension,
infusion of glucagon 1-10 mg/hour depending on response. If Ph. Eur.
bradycardia and cardiac failure. Neither the beta-blocker nor the
no response to glucagon occurs or if glucagon is unavailable, Injection for intravenous use presented as an isotonic, citrate
calcium channel blocker should be administered intravenously
a beta-adrenoceptor stimulant such as dobutamine 2.5 to 10 buffered, aqueous solution, containing 5 mg of Atenolol Ph. Eur.
within 48 hours of discontinuing the other. micrograms/kg/minute by intravenous infusion may be given. in 10 ml.
Concomitant therapy with dihydropyridines eg. nifedipine, may Dobutamine, because of its positive inotropic effects could be
increase the risk of hypotension, and cardiac failure may occur in For excipients see List of excipients.
used to treat hypotension and acute cardiac insufciency. It is
patients with latent cardiac insufciency. likely that these doses would be inadequate to reverse the cardiac THERAPEUTIC INDICATIONS
Digitalis glycosides, in association with beta-blockers, may effects of beta-blockade if a large overdose has been taken. The i) Hypertension.
increase atrioventricular conduction time. dose of dobutamine should therefore be increased if necessary to ii) Angina pectoris.
Beta-blockers may exacerbate the rebound hypertension which achieve the required response according to the clinical condition iii) Cardiac arrhythmias.
can follow the withdrawal of clonidine. If the two drugs are co- of the patient.
iv) Myocardial infarction. Early and late intervention.
administered, the beta-blocker should be withdrawn several Bronchospasm can usually be reversed by bronchodilators.
days before discontinuing clonidine. If replacing clonidine by POSOLOGY AND METHOD OF ADMINISTRATION
Excessive diuresis should be countered by maintaining normal
beta-blocker therapy, the introduction of beta-blockers should uid and electrolyte balance. The dose must always be adjusted to individual requirements
be delayed for several days after clonidine administration has of the patients, with the lowest possible starting dosage. The
stopped. PHARMACODYNAMIC PROPERTIES following are guidelines.
Caution must be exercised when prescribing a beta-blocker with TENORETIC combines the antihypertensive activity of two Adults
Class 1 antiarrhythmic agents such as disopyramide. agents, a beta-blocker (atenolol) and a diuretic (chlorthalidone).
Hypertension
Concomitant use of sympathomimetic agents, eg adrenaline, may Atenolol is beta-1 selective (i.e. acts preferentially on beta-1
One tablet daily. Most patients respond to 100 mg daily given
counteract the effect of beta-blockers. adrenergic receptors in the heart). Selectivity decreases with
orally as a single dose. Some patients, however, will respond
increasing dose.
Concomitant use of prostaglandin synthetase inhibiting drugs (eg. to 50 mg given as a single daily dose. The effect will be fully
ibuprofen, indomethacin) may decrease the hypotensive effects of Atenolol is without intrinsic sympathomimetic and membrane established after one to two weeks. A further reduction in blood
beta-blockers. stabilising activities and, as with other beta-blockers, has negative pressure may be achieved by combining TENORMIN with
inotropic effects (and is therefore contraindicated in uncontrolled other antihypertensive agents. For example, co-administration
Preparations containing lithium should not be given with diuretics
heart failure). of TENORMIN with a diuretic, provides a highly effective and
because they may reduce its renal clearance.
As with other beta-blockers, the mode of action of atenolol in the convenient antihypertensive therapy.
Caution must be exercised when using anaesthetic agents with
treatment of hypertension is unclear. Angina
Tenoretic. The anaesthetist should be informed and the choice
of anaesthetic should be an agent with as little negative inotropic It is unlikely that any additional ancillary properties possessed by Most patients with angina pectoris will respond to 100 mg given
activity as possible. Use of beta-blockers with anaesthetic drugs S (-) atenolol, in comparison with the racemic mixture, will give orally once or 50 mg given twice daily. It is unlikely that additional
may result in attenuation of the reex tachycardia and increase rise to different therapeutic effects. benet will be gained by increasing the dose.
the risk of hypotension. Anaesthetic agents causing myocardial Chlorthalidone, a monosulfonamyl diuretic, increases excretion of Cardiac Arrhythmias
depression are best avoided. sodium and chloride. Natriuresis is accompanied by some loss of
A suitable initial dose of TENORMIN is 2.5 mg (5 ml) injected
potassium. The mechanism by which chlorthalidone reduces blood
PREGNANCY AND LACTATION intravenously over a 2.5 minute period (i.e. 1 mg/minute). This
pressure is not fully known but may be related to the excretion and
Pregnancy: TENORETIC must not be given during pregnancy. may be repeated at 5 minute intervals until a response is observed,
redistribution of body sodium.
up to a maximum dosage of 10 mg. If TENORMIN is given by
Lactation: TENORETIC must not be given during lactation. Atenolol is effective and well-tolerated in most ethnic populations. infusion, 0.15 mg/kg bodyweight may be administered over a
Black patients respond better to the combination of atenolol and 20 minute period. If required, the injection or infusion may be
EFFECT ON ABILITY TO DRIVE AND USE MACHINES
chlorthalidone, than to atenolol alone. repeated every 12 hours. Having controlled the arrhythmias with
Use is unlikely to result in any impairment of the ability of patients
The combination of atenolol with thiazide-like diuretics has been intravenous TENORMIN, a suitable oral maintenance dosage is
to drive or operate machinery. However, it should be taken into
shown to be compatible and generally more effective than either 50-100 mg daily, given as a single dose.
account that occasionally dizziness or fatigue may occur.
drug used alone.
Myocardial Infarction
UNDESIRABLE EFFECTS
PHARMACOKINETIC PROPERTIES Early intervention after acute myocardial infarction: For
TENORETIC is well tolerated. In clinical studies, the undesired
Absorption of atenolol following oral dosing is consistent patients suitable for treatment with intravenous beta-blockade
events reported are usually attributable to the pharmacological
but incomplete (approximately 40-50%) with peak plasma and presenting within 12 hours of the onset of chest pain,
actions of its components.
concentrations occurring 2-4 hours after dosing. The atenolol TENORMIN 5-10 mg should be given by slow intravenous
The following undesired events, listed by body system, have been blood levels are consistent and subject to little variability. There is injection (1 mg/minute) followed by TENORMIN 50 mg
reported with TENORETIC or either of its components: no signicant hepatic metabolism of atenolol and more than 90% orally about 15 minutes later, provided no untoward effects have
Biochemical: hyperuricaemia, hyponatraemia (related to of that absorbed reaches the systemic circulation unaltered. The occurred from the intravenous dose. This should be followed by a
chlorthalidone), hypokalaemia, impaired glucose tolerance (see plasma half-life is about 6 hours but this may rise in severe renal further 50 mg orally 12 hours after the intravenous dose and then
Special warnings and precautions for use). impairment since the kidney is the major route of elimination. 12 hours later by 100 mg orally, once daily. If bradycardia and/or
76
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ASTRAZENECA
SPDI
hypotension requiring treatment, or any other untoward effects obstructive airways disease, unless there are compelling clinical cases of hepatic toxicity including intrahepatic cholestasis have
occur, TENORMIN should be discontinued. reasons for their use. Where such reasons exist, TENORMIN been reported.
Late intervention after acute myocardial infarction: For patients may be used with caution. Occasionally, some increase in airways Haematological: purpura; thrombocytopenia.
who present some days after suffering an acute myocardial resistance may occur in asthmatic patients, however, and this may
Integumentary: alopecia; dry eyes; psoriasiform skin reactions;
infarction an oral dose of Tenormin (100 mg daily) is recommended usually be reversed by commonly used dosage of bronchodilators
exacerbation of psoriasis; skin rashes.
for long-term prophylaxis of myocardial infarction. such as salbutamol or isoprenaline.
Neurological: paraesthesia.
Elderly As with other beta-blockers, in patients with a phaeochromocytoma,
an alpha-blocker should be given concomitantly. Reproductive: impotence
Dosage requirements may be reduced, especially in patients with Respiratory: bronchospasm may occur in patients with bronchial
impaired renal function. INTERACTIONS asthma or a history of asthmatic complaints.
Children Combined use of beta-blockers and calcium channel blockers Special senses: visual disturbances.
There is no paediatric experience with TENORMIN and for this with negative inotropic effects e.g. verapamil, diltiazem can lead
Others: hypersensitivity reactions, including angioedema and
reason it is not recommended for use in children. to an exaggeration of these effects particularly in patients with
urticaria; fatigue; an increase in ANA (Antinuclear Antibodies)
impaired ventricular function and/or sino-atrial or atrio-ventricular
Renal Failure has been observed, however, the clinical relevance of this is not
conduction abnormalities. This may result in severe hypotension,
Since TENORMIN is excreted via the kidneys the dosage should clear.
bradycardia and cardiac failure. Neither the beta-blocker nor the
be reduced in cases of severe impairment of renal function. calcium channel blocker should be administered intravenously Discontinuance of the drug should be considered if, according
No signicant accumulation of TENORMIN occurs in patients within 48 hours of discontinuing the other. to clinical judgement, the well-being of the patient is adversely
who have a creatinine clearance greater than 35 ml/min/1.73 m2 affected by any of the above reactions.
Concomitant therapy with dihydropyridines e.g. nifedipine, may
(normal range is 100-150 ml/min/1.73 m2 ). increase the risk of hypotension, and cardiac failure may occur in OVERDOSE
For patients with a creatinine clearance of 15-35 ml/min/1.73 m2 patients with latent cardiac insufciency. The symptoms of overdosage may include bradycardia,
(equivalent to serum creatinine of 300-600 micromol/litre) the oral Digitalis glycosides, in association with beta-blockers, may hypotension, acute cardiac insufciency and bronchospasm.
dose should be 50 mg daily and the intravenous dose should be 10 increase atrio-ventricular conduction time.
General treatment should include: close supervision, treatment in
mg once every two days. Beta-blockers may exacerbate the rebound hypertension, which an intensive care ward, the use of gastric lavage, activated charcoal
For patients with a creatinine clearance of <15 ml/min/1.73 m2 can follow the withdrawal of clonidine. If the two drugs are and a laxative to prevent absorption of any drug still present in
(equivalent to serum creatinine of >600 micromol/litre) the oral co-administered, the beta-blocker should be withdrawn several the gastrointestinal tract, the use of plasma or plasma substitutes
dose should be 25 mg daily or 50 mg on alternate days and the days before discontinuing clonidine. If replacing clonidine by to treat hypotension and shock. The use of haemodialysis or
intravenous dose should be 10 mg once every four days. beta-blocker therapy, the introduction of beta-blockers should haemoperfusion may be considered.
Patients on haemodialysis should be given 50 mg orally after each be delayed for several days after clonidine administration has Excessive bradycardia can be countered with atropine 1-2 mg
dialysis; this should be done under hospital supervision as marked stopped. (See also prescribing information for clonidine). intravenously and/or a cardiac pacemaker. If necessary, this may
falls in blood pressure can occur. Caution must be exercised when prescribing a beta-blocker be followed by a bolus dose of glucagon 10 mg intravenously.
with Class 1 antiarrhythmic agents such as disopyramide and If required, this may be repeated or followed by an intravenous
CONTRAINDICATIONS
quinidine. infusion of glucagon 1-10 mg/hour depending on response. If no
TENORMIN, as with other beta-blockers, should not be used in response to glucagon occurs or if glucagon is unavailable, a beta-
Concomitant use of sympathomimetic agents, e.g. adrenaline, may
patients with any of the following: known hypersensitivity to the counteract the effect of beta-blockers. adrenoceptor stimulant such as dobutamine 2.5 to 10
active substance, or any of the excipients; bradycardia (<45bpm);
Concomitant use with insulin and oral antidiabetic drugs may lead micrograms/kg/minute by intravenous infusion may be given.
cardiogenic shock; hypotension; metabolic acidosis; severe
to the intensication of the blood sugar lowering effects of these Dobutamine, because of its positive inotropic effect could also
peripheral arterial circulatory disturbances; second or third degree
drugs. Symptoms of hypoglycaemia, particularly tachycardia, may be used to treat hypotension and acute cardiac insufciency. It is
heart block; sick sinus syndrome; untreated phaeochromocytoma;
be masked (see Special warnings and precautions for use). likely that these doses would be inadequate to reverse the cardiac
uncontrolled heart failure.
Concomitant use of prostaglandin synthetase inhibiting drugs (e.g. effects of beta-blocker blockade if a large overdose has been taken.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE ibuprofen, indomethacin), may decrease the hypotensive effects The dose of dobutamine should therefore be increased if necessary
Tenormin as with other beta-blockers: of beta-blockers. to achieve the required response according to the clinical condition
of the patient.
- should not be withdrawn abruptly. The dosage should be Caution must be exercised when using anaesthetic agents with
withdrawn gradually over a period of 7-14 days, to facilitate a TENORMIN. The anaesthetist should be informed and the choice Bronchospasm can usually be reversed by bronchodilators.
reduction in beta-blocker dosage. Patients should be followed of anaesthetic should be an agent with as little negative inotropic PHARMACODYNAMIC PROPERTIES
during withdrawal, especially those with ischaemic heart activity as possible. Use of beta-blockers with anaesthetic drugs Betablocking agents, plain selective, CO7A B03
disease. may result in attenuation of the reex tachycardia and increase
- when a patient is scheduled for surgery, and a decision is made the risk of hypotension. Anaesthetic agents causing myocardial Atenolol is a beta-blocker which is beta1-selective (i.e. acts
to discontinue beta-blocker therapy, this should be done at least depression are best avoided. preferentially on beta1-adrenergic receptors in the heart).
Selectivity decreases with increasing dose.
24 hours prior to the procedure. The risk-benet assessment
PREGNANCY AND LACTATION Atenolol is without intrinsic sympathomimetic and membrane
of stopping beta-blockade should be made for each patient.
If treatment is continued, an anaesthetic with little negative TENORMIN crosses the placental barrier and appears in the cord stabilising activities and as with other beta-blockers, has negative
inotropic activity should be selected to minimise the risk of blood. No studies have been performed on the use of TENORMIN inotropic effects (and is therefore contraindicated in uncontrolled
myocardial depression. The patient may be protected against in the rst trimester and the possibility of foetal injury cannot be heart failure).
vagal reactions by intravenous administration of atropine. excluded. TENORMIN has been used under close supervision for As with other beta-blockers, the mode of action of atenolol in the
the treatment of hypertension in the third trimester. Administration treatment of hypertension is unclear.
- although contraindicated in uncontrolled heart failure (see
of TENORMIN to pregnant women in the management of mild
Contraindications), may be used in patients whose signs of It is probably the action of atenolol in reducing cardiac rate and
to moderate hypertension has been associated with intra-uterine
heart failure have been controlled. Caution must be exercised contractility which makes it effective in eliminating or reducing
growth retardation.
in patients whose cardiac reserve is poor. the symptoms of patients with angina.
- may increase the number and duration of angina attacks in The use of TENORMIN in women who are, or may become,
It is unlikely that any additional ancillary properties possessed by
patients with Prinzmetals angina due to unopposed alpha- pregnant requires that the anticipated benet be weighed against
S (-) atenolol, in comparison with the racemic mixture, will give
receptor mediated coronary artery vasoconstriction. the possible risks, particularly in the rst and second trimesters,
rise to different therapeutic effects.
since beta-blockers, in general, have been associated with a
Tenormin is a beta1-selective beta-blocker; consequently, its use TENORMIN is effective and well-tolerated in most ethnic
decrease in placental perfusion which may result in intra-uterine
may be considered although utmost caution must be exercised. populations although the response may be less in black patients.
deaths, immature and premature deliveries.
- although contraindicated in severe peripheral arterial circulatory TENORMIN is effective for at least 24 hours after a single oral
There is signicant accumulation of TENORMIN in breast milk.
disturbances (see Contraindications), may also aggravate less dose. The drug facilitates compliance by its acceptability to
severe peripheral arterial circulatory disturbances. Neonates born to mothers who are receiving TENORMIN at
patients and simplicity of dosing. The narrow dose range and early
- due to its negative effect on conduction time, caution must be parturition or breast-feeding may be at risk for hypoglycemia and patient response ensure that the effect of the drug in individual
exercised if it is given to patients with rst degree heart block. bradycardia. patients is quickly demonstrated. TENORMIN is compatible with
- may mask the symptoms of hypoglycaemia, in particular, Caution should be exercised when TENORMIN is administered diuretics, other hypotensive agents and antianginal agents (see
tachycardia. during pregnancy or to a woman who is breast-feeding. Interactions). Since it acts preferentially on beta-receptors in the
- may mask the signs of thyrotoxicosis. EFFECT ON ABILITY TO DRIVE AND USE MACHINES heart, TENORMIN may, with care, be used successfully in the
- will reduce heart rate, as a result of its pharmacological action. treatment of patients with respiratory disease, who cannot tolerate
Use is unlikely to result in any impairment of the ability of patients non-selective beta-blockers.
In the rare instances when a treated patient develops symptoms to drive or operate machinery. However it should be taken into
which may be attributable to a slow heart rate and the pulse account that occasionally dizziness or fatigue may occur. Early intervention with TENORMIN in acute myocardial
rate drops to less than 50-55bpm at rest, the dose should be infarction reduces infarct size and decreases morbidity and
reduced. UNDESIRABLE EFFECTS mortality. Fewer patients with a threatened infarction progress
- may cause a more severe reaction to a variety of allergens, when TENORMIN is well tolerated. In clinical studies, the undesired to frank infarction; the incidence of ventricular arrhythmias is
given to patients with a history of anaphylactic reaction to such events reported are usually attributable to the pharmacological decreased and marked pain relief may result in reduced need of
allergens. Such patients may be unresponsive to the usual doses actions of atenolol. opiate analgesics. Early mortality is decreased. TENORMIN is
of adrenaline used to treat the allergic reactions. The following undesired events, listed by body system, have been an additional treatment to standard coronary care.
- may cause a hypersensitivity reaction including angioedema reported. PHARMACOKINETIC PROPERTIES
and urticaria Cardiovascular: bradycardia; heart failure deterioration; Following intravenous administration, the blood levels of atenolol
- should be used with caution in the elderly, starting with a lesser postural hypotension which may be associated with syncope; cold decay tri-exponentially with an elimination half-life of about
dose (see Posology and method of administration). extremities. In susceptible patients: precipitation of heart block; 6 hours. Throughout the intravenous dose range of 5-10 mg
Since TENORMIN is excreted via the kidneys, dosage should intermittent claudication; Raynauds phenomenon. the blood level prole obeys linear pharmacokinetics and beta-
be reduced in patients with a creatinine clearance of below 35ml/ CNS: confusion; dizziness; headache; mood changes; nightmares; adrenoceptor blockade is still measurable 24 hours after a 10 mg
min/1.7m2 . psychoses and hallucinations; sleep disturbances of the type noted intravenous dose.
Although cardioselective (beta1) beta-blockers may have less with other beta-blockers. Absorption of atenolol following oral dosing is consistent
effect on lung function than non-selective beta-blockers, as with all, Gastrointestinal: dry mouth, gastrointestinal disturbances, but incomplete (approximately 40-50%) with peak plasma
beta-blockers, these should be avoided in patients with reversible elevations of transaminase levels have been seen infrequently, rare concentrations occurring 2-4 hours after dosing. The atenolol
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blood levels are consistent and subject to little variability. There is Each actuation of the metered-dose valve delivers 10 mg Xylocaine EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
no signicant hepatic metabolism of atenolol and more than 90% base. It is unnecessary to dry the site prior to application. Depending on the dose, local anaesthetics may have a very mild
of that absorbed reaches the systemic circulation unaltered. The XYLOCAINE SPRAY 10% should not be used on cuffs of effect on mental function and may temporarily impair locomotion
plasma half-life is about 6 hours but this may rise in severe renal endotracheal tubes (ETT) made of plastic. and coordination.
impairment since the kidney is the major route of elimination. Otorhinolaryngology: 3 metered doses for puncture of the
Atenolol penetrates tissues poorly due to its low lipid solubility UNDESIRABLE EFFECTS
maxillary sinus or other minor surgical procedures.
and its concentration in brain tissue is low. Plasma protein binding Local reactions
- Paracentesis: 3 metered doses.
is low (approximately 3%). Local irritation at the application site has been described. Following
- During delivery: Up to 20 metered doses (200 mg lidocaine
LIST OF EXCIPIENTS base). application to laryngeal mucosa before endotracheal intubation,
reversible symptoms such as sore throat, hoarseness and loss
Tablets: Gelatin, Glycerol, Magnesium carbonate, Magnesiun - Introduction of instruments, tubes and catheters into the
of voice have been reported. The use of XYLOCAINE SPRAY
stearate, Maize starch, Hypromellose, Sodium lauryl sulphate, respiratory and digestive tract: Up to 20 metered doses (200 mg
provides surface anaesthesia during an endotracheal procedure but
TENORMIN hydroxide. lidocaine base) for procedures in pharynx, larynx and trachea.
does not prevent post-intubation soreness.
100 mg tablets only: Macrogol 300, Sunset yellow lake. During prolonged procedures up to 400 mg of lidocaine may be
administered. In addition, when combined with other lidocaine Allergic reactions
Injection: Citric acid, Sodium chloride, Sodium hydroxide, Water products, the total dose should not exceed 400 mg. With Allergic reactions (in the most severe instances anaphylactic
for injection applications mainly to the larynx, trachea and bronchi, the dose shock) to local anaesthetics of the amide type are rare (<0.1%).
INCOMPATIBILITIES should not exceed 20 metered doses (200 mg lidocaine base). Acute systemic toxicity
Compatibility with intravenous infusion uids - Dental practice: 1-5 metered doses to the mucous membranes. Lidocaine may cause acute toxic effects if high systemic levels
TENORMIN Injection is compatible with sodium chloride Debilitated or elderly patients, children over 12 years of age, occur due to rapid absorption or overdose. (See Pharmacokinetic
intravenous\infusion (0.9%w/v) and Glucose Intravenous Infusion acutely ill patients or patients with sepsis should be given doses properties and Overdose.)
BP (5% w/v). commensurate with their age, weight and physical condition.
OVERDOSE
In children less than 12 years of age the dose should not exceed 3
SHELF-LIFE mg/kg (e.g. 6 metered doses in an infant weighing 20 kg). When Acute systemic toxicity
Please refer to expiry date on the blister strip or outer carton. used mainly in the larynx and trachea the dose should be reduced Toxic reactions originate mainly in the central nervous system and
to 1.5 mg/kg. In children less than 3 years of age less concentrated the cardiovascular system.
lidocaine solutions are recommended. Central nervous system toxicity is a graded response with
TENORMIN Tablets: Do not store above 25C. Protect from
CONTRAINDICATIONS symptoms and signs of escalating severity. The rst symptoms are
light and moisture.
circumoral paraesthesia, numbness of the tongue, light-headedness,
TENORMIN Injection: Do not store above 25C. Protect from Known history of hypersensitivity to local anaesthetics of the
hyperacusis and tinnitus. Visual disturbance and muscular tremors
light. amide type or to other components of the spray solution.
are more serious and precede the onset of generalized convulsions.
PACK SIZE SPECIAL WARNINGS AND PRECAUTIONS FOR USE Unconsciousness and grand mal convulsions may follow, which
Excessive dosage or short intervals between doses, may result in may last from a few seconds to several minutes. Hypoxia and
Please refer to the outer carton for pack size.
high plasma levels and serious adverse effects. Absorption from hypercarbia occur rapidly following convulsions due to the
TENORMIN is a trademark of the AstraZeneca group of increased muscular activity, together with the interference with
mucous membranes is variable but is especially high from the
companies. normal respiration. In severe cases apnoea may occur. Acidosis
bronchial tree. Lidocaine spray should be used with caution in
patients with wounds or traumatized mucosa in the region of the increases the toxic effects of local anaesthetics.
XYLOCAINE PUMP SPRAY 10% proposed application. A damaged mucosa will permit increased Recovery is due to redistribution and metabolism of the local
Pump spray systemic absorption. The management of serious adverse reactions anaesthetic drug from the central nervous system. Recovery may be
may require the use of resuscitative equipment, oxygen and other rapid unless large amounts of the drug have been administered.
OTC resuscitative drugs. (See Overdose.) Cardiovascular effects are only seen in cases with high systemic
(Lidocaine) In paralysed patients under general anaesthesia, higher blood concentrations. Severe hypotension, bradycardia, arrhythmia and
concentrations may occur than in spontaneously breathing patients. cardiovascular collapse may be the result in such cases.
COMPOSITION Unparalysed patients are more likely to swallow a large proportion Cardiovascular toxic effects are generally preceded by signs
Active constituent: of the dose which then undergoes considerable rst-pass hepatic of toxicity in the central nervous system, unless the patient is
metabolism following absorption from the gut. receiving a general anaesthetic or is heavily sedated with drugs
1 dose XYLOCAINE PUMP SPRAY contains: Lidocaine base
10 mg. The oropharyngeal use of topical anaesthetic agents may interfere such as a benzodiazepine or barbiturate.
with swallowing and thus enhance the danger of aspiration. Treatment of acute toxicity
For excipients see List of excipients.
Numbness of the tongue or buccal mucosa may increase the
Treatment of acute toxicity should be instituted at the latest when
PHARMACEUTICAL FORM danger of biting trauma.
twitches occur. The necessary drugs and equipment should be
Cutaneous spray, solution If the dose or administration is likely to result in high blood levels, immediately available. The objectives of treatment are to maintain
The solution is a clear to almost clear, slightly pink-coloured liquid some patients require special attention to prevent potentially oxygenation, stop the convulsions and support the circulation.
with menthol and banana avour. dangerous side effects:
Oxygen must be given and, if necessary, assisted ventilation (mask
- Patients with partial or complete heart block. and bag). An anticonvulsant should be given i.v. if the convulsions
- The elderly and patients in poor general health. do not stop spontaneously in 15-20 sec. Thiopentone sodium 1-
For the prevention of pain associated with the following
- Patients with advanced liver disease or severe renal 3 mg/kg i.v. will abort the convulsions rapidly. Alternatively
procedures:
dysfunction. diazepam 0.1 mg/kg bw i.v. may be used although its action is
Otorhinolaryngology slower.
Avoid contact with the eyes.
- Puncture of the maxillary sinus and minor surgical procedures Prolonged convulsions may jeopardise the patients ventilation
Patients treated with anti-arrhythmic drugs class III (e.g.
in the oral and nasal cavity, pharynx and epipharynx. and oxygenation. If so, injection of a muscle relaxant (eg,
amiodarone) should be under close surveillance and ECG
- Paracentesis. succinylcholine 1 mg/kg bw) will facilitate ventilation, and
monitoring considered, since cardiac effects may be additive.
Obstetrics XYLOCAINE SPRAY 10% should not be used on cuffs of oxygenation can be controlled. Early endotracheal intubation
During the nal stages of delivery and before episiotomy and endotracheal tubes (ETT) made of plastic. Lidocaine base in must be considered in such situations.
perineal suturing as supplementary pain control. contact with both PVC and non-PVC cuffs of endotracheal tubes Suxamethonium will stop the muscle convulsions rapidly, but
Introduction of instruments, tubes and catheters into the may cause damage of the cuff. This damage is described as will require tracheal intubation and articial ventilation, and
respiratory and digestive tract pinholes, which may cause leakage that could lead to pressure loss should only be used by those familiar with these procedures. If
in the cuff. cardiovascular depression is evident (hypotension, bradycardia),
Provides surface anaesthesia for the oropharyngeal and tracheal
ephedrine 5-10 mg i.v. should be given and repeated, if necessary,
areas to reduce reex activity, attenuate haemodynamic responses INTERACTIONS after 2-3 min.
and facilitate insertion of the tube or the passage of instruments Lidocaine should be used with caution in patients receiving agents
during endotracheal intubation and endoscopic procedures of the Should circulatory arrest occur, immediate cardiopulmonary
structurally related to local anaesthetics, e.g. antiarrhythmics such resuscitation should be instituted. Optimal oxygenation and
airways and upper gastrointestinal tract. as mexiletin and tocainide, since the toxic effects are additive. ventilation and circulatory support as well as treatment of acidosis
Dental practice Specic interaction studies with lidocaine and anti-arrhythmic are of vital importance, since hypoxia and acidosis will increase
Before injections, dental impressions, X-ray photography, removal drugs class III (e.g. amiodarone) have not been performed, but the systemic toxicity of local anaesthetics. Adrenaline (0.1-0.2 mg
of calculus. caution is advised. as intravenous or intracardiac injections) should be given as soon
POSOLOGY AND METHOD OF ADMINISTRATION Drugs that reduce the clearance of lidocaine (eg, cimetidine or as possible and repeated, if necessary.
betablockers) may cause potentially toxic plasma concentrations Children should be given doses commensurate with their age and
XYLOCAINE SPRAY is intended for use on mucous membranes
when lidocaine is given in repeated high doses over a long time weight.
and provides efcient surface anaesthesia, which lasts for
period. Such interactions should therefore be of no clinical
approximately 10-15 minutes. The anaesthesia usually occurs PHARMACODYNAMIC PROPERTIES
importance following short term treatment with lidocaine (eg,
within 1-5 minutes, depending on the area of application.
XYLOCAINE SPRAY) at recommended doses. ATC Code: N01B B02
As with any local anaesthetic, the safety and effectiveness of
PREGNANCY AND LACTATION Pharmacotherapeutic group: Local anaesthetic
lidocaine depend on the proper dosage, the correct technique,
adequate precautions and readiness for emergencies. Pregnancy XYLOCAINE PUMP SPRAY is intended for use on mucous
membranes and provides an efcient surface anaesthesia, which
The following dosage recommendations should be regarded as a It is reasonable to assume that a large number of pregnant women
lasts for approximately 10-15 minutes. The anaesthesia usually
guide. The clinicians experience and knowledge of the patients and women of child-bearing age have been given lidocaine. No
occurs within 1-5 minutes depending on the area of application.
physical status are of importance in calculating the required dose. specic disturbances to the reproductive process have so far been
The degree of absorption from mucous membranes is variable reported, e.g. no increased incidence of malformations. PHARMACOKINETIC PROPERTIES
but especially high from the bronchial tree. Application only lactation The extent of absorption of lidocaine is dependent upon the total
to areas below the vocal cords may result in excessive plasma Like other local anaesthetics lidocaine may enter the mothers dose administered, and also upon the specic site of application
concentrations because of less transfer to the intestine and less milk, but in such small amounts that there is generally no risk of and the duration of exposure. In general, the rate of absorption
rst-pass loss. this affecting the neonate. following topical administration is most rapid after intratracheal
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and bronchial administration. Such applications may therefore Starting dose be re-evaluated. Patients who develop symptoms of heart failure
result in rapidly rising plasma concentrations, with an increased In patients with hypertension the usual recommended starting dose should continue with ZESTRIL (see Posology and method of
risk of toxic symptoms, such as convulsions. Lidocaine is well is 10 mg. Patients with a strongly activated renin-angiotensin- administration).
absorbed from the gastrointestinal tract, but undergoes extensive aldosterone system (in particular, renovascular hypertension, Renal complications of diabetes mellitus
rst-pass metabolism. salt and/or volume depletion, cardiac decompensation, or severe In normotensive insulin-dependent diabetes mellitus patients, the
The plasma protein binding is predominantly to alpha-1- hypertension) may experience an excessive blood pressure daily dose is 10mg ZESTRIL once daily which can be increased
glycoprotein. fall following the initial dose. A starting dose of 2.5-5mg is to 20mg once daily, if necessary, to achieve a sitting diastolic blood
The main elimination pathway of lidocaine is by liver metabolism. recommended in such patients and the initiation of treatment pressure below 75 mmHg. In hypertensive non-insulin-dependent
De-alkylation to monoethylglycine xylidide (MEGX) is mediated should take place under medical supervision. A lower starting diabetes mellitus patients, the dose schedule is as above to achieve
mainly by cytochrome P450 3A4. MEGX is metabolised to 2,6- dose is required in the presence of renal impairment (see Table a sitting diastolic blood pressure below 90 mmHg.
xylidine and glycine xylidide (GX). 2,6-xylidine is metabolised 1 below).
In cases of renal impairment (creatinine clearance <80ml/min),
further by CYP2A6 to 4-hydroxy-2,6-xylidine, which is the major Maintenance dose the initial ZESTRIL dosage should be adjusted according to the
metabolite in the urine (80%) and is excreted as conjugate. MEGX The usual effective maintenance dosage is 20 mg administered in patients creatine clearance (see Table 1).
has a convulsant activity equivalent to that of lidocaine, while GX a single daily dose. In general if the desired therapeutic effect
is devoid of convulsant activity. MEGX appears to occur in similar Paediatric use
cannot be achieved in a period of 2 to 4 weeks on a certain dose
plasma concentrations as the parent substance. The elimination Efcacy & safety of use in children has not been fully established.
level, the dose can be further increased. The maximum dose used
half-life of lidocaine and MEGX following an intravenous bolus Therefore, use in children is not recommended.
in long-term, controlled clinical trials was 80 mg/day.
dose are approx. 1.5-2 and 2.5 hours respectively. Use in the elderly
Diuretic-treated patients
On account of the rapid hepatic metabolism, the kinetics are In clinical studies, there was no age-related change in the efcacy
sensitive to all alterations in liver function. The half-life can Symptomatic hypotension may occur following initiation of
or safety prole of the drug. When advanced age is associated
be more than doubled in patients with impaired liver function. therapy with ZESTRIL. This is more likely in patients who are
with decrease in renal function, however, the guidelines set
Impaired renal function does not affect the kinetics, but can being treated currently with diuretics. Caution is recommended,
out in Table 1 should be used to determine the starting dose of
increase the accumulation of metabolites. therefore, since these patients may be volume and/or salt depleted.
ZESTRIL. Thereafter, the dosage should be adjusted according
If possible, the diuretic should be discontinued 2 to 3 days before
Factors such as acidosis and the use of CNS stimulants and to the blood pressure response.
beginning therapy with ZESTRIL. In hypertensive patients
depressants affect the levels of lidocaine required to produce Use in kidney transplant patients
in whom the diuretic cannot be discontinued, therapy with
systemic effects. With plasma levels from 5 to 10 mg/ml signs of There is no experience regarding the administration of ZESTRIL
ZESTRIL should be initiated with a 5 mg dose. Renal function
overdosage become apparent.
and serum potassium should be monitored. The subsequent in patients with recent kidney transplantation. Treatment with
LIST OF EXCIPIENTS dosage of ZESTRIL should be adjusted according to blood ZESTRIL is therefore not recommended.
Ethanol, Polyethylene glycol 400, Essence of banana, Menthol, pressure response. If required, diuretic therapy may be resumed Contraindications
Saccharin, Puried water. (see Special warnings and precautions for use & Interactions). - Hypersensitivity to ZESTRIL, to any of the excipients or any
Dosage adjustment in renal impairment other angiotensin-converting enzyme (ACE) inhibitor.
Dosage in patients with renal impairment should be based on - History of angioedema associated with previous ACE inhibitor
Do not store above 25C. During storage at temperatures below therapy.
creatinine clearance as outlined in Table 1 below.
8C precipitation may occur. This precipitation is dissolved when
Table 1 Dosage adjustment in renal impairment - Hereditary or idiopathic angioedema.
warming up in room-temperature.
Creatinine clearance (ml/min) Starting Dose (mg/day) - Second or third trimesters of pregnancy (see Pregnancy and
Instructions for use and handling
lactation)
The spray nozzle is already bent to its nal appearance and no less than 10 ml/min(including 2.5 mg*
further actions should be done before using the spray nozzle. patients on dialysis) SPECIAL WARNINGS AND PRECAUTIONS FOR USE
The nozzle must not be shortened, otherwise the spray function 10 - 30 ml/min 2.5 - 5 mg Symptomatic hypotension
will be destroyed. If cleaning of the nozzle is desired, the entire 31 - 80 ml/min 5 - 10 mg Symptomatic hypotension is seen rarely in uncomplicated
nozzle can be submersed in boiling water for 5 minutes. The hypertensive patients. In hypertensive patients receiving
nozzle can be autoclaved (20 minutes at 120C). * Dosage and/or frequency of administration should be adjusted ZESTRIL, hypotension is more likely to occur if the patient
depending on the blood pressure response. has been volume-depleted e.g. by diuretic therapy, dietary salt
SHELF-LIFE
The dosage may be titrated upward until blood pressure is restriction, dialysis, diarrhoea or vomiting, or has severe renin-
Please see outer pack controlled or to a maximum of 40 mg daily. dependent hypertension (see Interactions and Undesirable effects).
PACK SIZE Heart failure In patients with heart failure, with or without associated renal
Please see outer pack insufciency, symptomatic hypotension has been observed.
In patients with symptomatic heart failure, ZESTRIL should be
This is most likely to occur in those patients with more severe
XYLOCAINE is a trade mark of the Astra Zeneca group of used as adjunctive therapy to diuretics and, where appropriate,
degrees of heart failure, as reected by the use of high doses of
companies. digitalis or beta-blockers. ZESTRIL may be initiated at a starting
loop diuretics, hyponatraemia or functional renal impairment. In
dose of 2.5 mg once a day, which should be administered under
patients at increased risk of symptomatic hypotension, initiation
medical supervision to determine the initial effect on the blood
ZESTRIL 5mg, 10mg and 20mg Tablets pressure. The dose of ZESTRIL should be increased:
of therapy and dose adjustment should be closely monitored.
Similar considerations apply to patients with ischaemic heart
- By increments of no greater than 10mg or cerebrovascular disease in whom an excessive fall in blood
(Lisinopril dihydrate) - At intervals of no less than 2 weeks pressure could result in a myocardial infarction or cerebrovascular
- To the highest dose tolerated by the patient up to a maximum of accident.
COMPOSITION 35mg once daily If hypotension occurs, the patient should be placed in the supine
Each tablet contains lisinopril dihydrate equivalent to 5 mg, 10mg Dose adjustment should be based on the clinical response position and, if necessary, should receive an intravenous infusion
or 20mg of anhydrous lisinopril. of individual patients. Patients at high risk of symptomatic of normal saline. A transient hypotensive response is not a
PHARMACEUTICAL FORM hypotension e.g. patients with salt depletion with or without contraindication to further doses, which can be given usually
hyponatraemia, patients with hypovolaemia or patients who without difculty once the blood pressure has increased after
Pink, round and biconvex tablets.
have been receiving vigorous diuretic therapy should have these volume expansion.
All tablets are marked on one side with a number denoting the conditions corrected, if possible, prior to therapy with ZESTRIL.
tablet strength. In some patients with heart failure who have normal or low
Renal function and serum potassium should be monitored (see blood pressure, additional lowering of systemic blood pressure
THERAPEUTIC INDICATIONS Special warnings and precautions for use) may occur with ZESTRIL. This effect is anticipated and is not
Hypertension Acute myocardial infarction usually a reason to discontinue treatment. If hypotension becomes
Patients should receive, as appropriate, the standard recommended symptomatic, a reduction of dose or discontinuation of ZESTRIL
Treatment of hypertension
treatments such as thrombolytics, aspirin, and beta-blockers. may be necessary.
Heart failure
Intravenous or transdermal glyceryl trinitrate may be used together Hypotension in acute myocardial infarction
Treatment of symptomatic heart failure with ZESTRIL. Treatment with ZESTRIL must not be initiated in acute
Acute myocardial infarction Starting dose (rst 3 days after infarction) myocardial infarction patients who are at risk of further serious
Short-term (6 weeks) treatment of haemodynamically stable Treatment with ZESTRIL may be started within 24 hours of the haemodynamic deterioration after treatment with a vasodilator.
patients within 24 hours of an acute myocardial infarction. onset of symptoms. Treatment should not be started if systolic These are patients with systolic blood pressure of 100 mmHg
Renal complications of diabetes mellitus blood pressure is lower than 100 mmHg. The rst dose of or lower or cardiogenic shock. During the rst 3 days following
In normotensive insulin-dependent and hypertensive non- ZESTRIL is 5 mg given orally, followed by 5mg after 24 hours, the infarction, the dose should be reduced if the systolic blood
insulin-dependent diabetes mellitus patients who have incipient 10 mg after 48 hours and then 10 mg once daily. Patients with a pressure is 120 mmHg or lower. Maintenance doses should be
nephropathy characterised by microalbuminuria, ZESTRIL low systolic blood pressure (120 mmHg or less) when treatment reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure
reduces urinary albumin excretion rate (see Pharmacodynamic is started or during the rst 3 days after the infarction should is 100 mmHg or lower. If hypotension persists (systolic blood
properties). be given a lower dose - 2.5 mg orally (see Special warnings & pressure less than 90 mmHg for more than 1 hour) then ZESTRIL
precautions for use). should be withdrawn.
POSOLOGY AND METHOD OF ADMINISTRATION In cases of renal impairment (creatinine clearance <80ml/min), Aortic and mitral valve stenosis / hypertrophic cardiomyopa-
ZESTRIL should be administered orally in a single daily dose. the initial ZESTRIL dosage should be adjusted according to the thy
As with all other medication taken once daily, ZESTRIL should patients creatine clearance (see Table 1). As with other ACE inhibitors, ZESTRIL should be given with
be taken at approximately the same time each day. The absorption Maintenance dose caution to patients with mitral valve stenosis and obstruction in the
of ZESTRIL tablets is not affected by food. outow of the left ventricle such as aortic stenosis or hypertrophic
The maintenance dose is 10mg once daily. If hypotension
The dose should be individualised according to patient prole and occurs (systolic blood pressure less than or equal to 100 mmHg) cardiomyopathy.
blood pressure response (see Special warnings and precautions for a daily maintenance dose of 5 mg may be given with temporary Renal function impairment
use). reductions to 2.5 mg if needed. If prolonged hypotension occurs In cases of renal impairment (creatinine clearance <80ml/min),
Hypertension (systolic blood pressure less than 90 mmHg for more than 1 hour) the initial ZESTRIL dosage should be adjusted according to the
ZESTRIL may be used as monotherapy or in combination with ZESTRIL should be withdrawn. patients creatine clearance (see Table 1 in Posology and method
other classes of antihypertensive therapy. Treatment should continue for 6 weeks and then the patient should of administration) and then as a function of the patients response
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to treatment. Routine monitoring of potassium and creatinine is reversible after discontinuation of the ACE inhibitor. ZESTRIL Chronic administration of NSAIDs may reduce the antihypertensive
part of normal medical practice for these patients. should be used with extreme caution in patients with collagen effect of an ACE inhibitor. NSAIDs and ACE inhibitors exert an
In patients with heart failure, hypotension following the vascular disease, immunosuppresant therapy, treatment with additive effect on the increase in serum potassium and many result
initiation of therapy with ACE inhibitors may lead to some allopurinol or procainamide, or a combination of these complicating in a deterioration of renal function. These effects are usually
further impairment in renal function. Acute renal failure, usually factors, especially if there is pre-existing impaired renal function. reversible. Rarely, acute renal failure may occur, especially in
reversible, has been reported in this situation. Some of these patients developed serious infections, which in a patients with compromised renal function such as the elderly or
few instances did not respond to intensive antibiotic therapy. If dehydrated.
In some patients with bilateral renal artery stenosis or stenosis
ZESTRIL is used in such patients, periodic monitoring of white Other antihypertensive agents
of the artery to a solitary kidney, who have been treated with
blood cell counts is advised and patients should be instructed to Concomitant use of these agents may increase the hypotensive
angiotensin converting enzyme inhibitors, increases in blood urea
report any sign of infection. effects of ZESTRIL. Concomitant use with glyceryl trinitrate
and serum creatinine, usually reversible upon discontinuation
of therapy, have been seen. This is especially likely in patients Race and other nitrates, or other vasodilators, may further reduce blood
Angiotensin converting enzyme inhibitors cause a higher rate of pressure.
with renal insufciency. If renovascular hypertension is also
present there is an increased risk of severe hypotension and renal angioedema in black patients than in non-black patients. Tricyclic antidepressants/Antipsychotics/Anaesthetics
insufciency. In these patients, treatment should be started under As with other ACE inhibitors, ZESTRIL may be less effective Concomitant use of certain anaesthetic medicinal products,
close medical supervision with low doses and careful dose titration. in lowering blood pressure in black patients than in non-blacks, tricylcic antidepressants and antipsychotics with ACE inhibitors
Since treatment with diuretics may be a contributory factor to the possibly because of a higher prevalence of low-renin states in the may result in further reduction of blood pressure (see Special
above, they should be discontinued and renal function should be black hypertensive population. warnings and precautions for use).
monitored during the rst weeks of Zestril therapy. Cough Sympathomimetics
Some hypertensive patients with no apparent pre-existing renal Cough has been reported with the use of ACE inhibitors. Sympathomimetics may reduce the antihypertensive effects of
vascular disease have developed increases in blood urea and serum Characteristically, the cough is non-productive, persistent and ACE inhibitors.
creatinine, usually minor and transient, especially when ZESTRIL resolves after discontinuation of therapy. ACE inhibitor-induced Antidiabetics
has been given concomitantly with a diuretic. This is more likely cough should be considered as part of the differential diagnosis Epidemiological studies have suggested that concomitant
to occur in patients with pre-existing renal impairment. Dosage of cough. administration of ACE inhibitors and antidiabetic medicines
reduction and/or discontinuation of the diuretic and/or ZESTRIL (insulins, oral hypoglycaemic agents) may cause an increased
Surgery/Anaesthesia
may be required. blood glucose lowering effect with risk of hypoglycaemia. This
In patients undergoing major surgery or during anaesthesia
In acute myocardial infarction, treatment with ZESTRIL should phenomenom appeared to be more likely to occur during the
with agents that produce hypotension, ZESTRIL may block rst weeks of combined treatment and in patients with renal
not be initiated in patients with evidence of renal dysfunction,
angiotensin II formation secondary to compensatory renin impairment.
dened as serum creatinine concentration exceeding 177
release. If hypotension occurs and is considered to be due to this
micromol/l and/or proteinuria exceeding 500 mg/24 h. If renal Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates
mechanism, it can be corrected by volume expansion.
dysfunction develops during treatment with ZESTRIL (serum ZESTRIL may be used concomitantly with acetylsalicylic acid (at
creatinine concentration exceeding 265 micromol/l or a doubling Hyperkalaemia
cardiologic doses), thrombolytics, beta-blockers and/or nitrates.
from the pre-treatment value) then the physician should consider Elevations in serum potassium have been observed in some
withdrawal of ZESTRIL. patients treated with ACE inhibitors, including ZESTRIL. PREGNANCY AND LACTATION
Hypersensitivity/Angioedema Patients at risk for the development of hyperkalaemia include Pregnancy
those with renal insufciency, diabetes mellitus, or those using ZESTRIL should not be used during the rst trimester of
Angioedema of the face, extremities, lips, tongue, glottis and/or concomitant potassium-sparing diuretics, potassium supplements pregnancy. When pregnancy is planned or conrmed the switch
larynx has been reported rarely in patients treated with angiotensin or potassium-containing salt substitutes, or those patients taking to an alternative treatment should be initiated as soon as possible.
converting enzyme inhibitors, including ZESTRIL. This may other drugs associated with increases in serum potassium (e.g. Controlled studies with ACE inhibitors have not been done in
occur at any time during therapy. In such cases, ZESTRIL heparin). If concomitant use of the above-mentioned agents is humans, but a limited number of cases with rst trimester toxicity
should be discontinued promptly and appropriate treatment and deemed appropriate, regular monitoring of serum potassium is exposure have not appeared to manifest malformations consistent
monitoring should be instituted to ensure complete resolution recommended (see Interactions). with human foetotoxicity as described below.
of symptoms prior to dismissing the patients. Even in those
Diabetic patients ZESTRIL is contraindicated during the second and third trimester
instances where swelling of only the tongue is involved, without
In diabetic patients treated with oral antidiabetic agents or insulin, of pregnancy.
respiratory distress, patients may require prolonged observation
since treatment with antihistamines and corticosteroids may not glycaemic control should be closely monitored during the rst Prolonged ACE inhibitor exposure during the second and third
be sufcient. month of treatment with an ACE inhibitor (see Interactions). trimesters is known to induce human foetotoxicity (decreased
Lithium renal function, oligohydramnios, skull ossication retardation)
Very rarely, fatalities have been reported due to angioedema and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
associated with laryngeal oedema or tongue oedema. Patients The combination of lithium and ZESTRIL is generally not
Should exposure to ZESTRIL have occurred from the second
with involvement of the tongue, glottis or larynx, are likely to recommended (see Interactions).
trimester of pregnancy, an ultrasound check of renal function and
experience airway obstruction, especially those with a history Pregnancy and lactation the skull is recommended.
of airway surgery. In such cases emergency therapy should be Lisinopril should not be used during the rst trimester of pregnancy.
administered promptly. This may include the administration of Infants whose mothers have taken ZESTRIL should be closely
ZESTRIL is contraindicated in the second and third trimesters of observed for hypotension, oliguria and hyperkalaemia. ZESTRIL,
adrenaline and/or the maintenance of a patent airway. The patient pregnancy (see Contraindications). When pregnancy is detected, which crosses the placenta, has been removed from the neonatal
should be under close medical supervision until complete and lisinopril treatment should discontinue as soon as possible (see circulation by peritoneal dialysis with some clinical benet, and
sustained resolution of symptoms has occurred. Pregnancy and lactation). theoretically may be removed by exchange transfusion.
Angiotensin converting enzyme inhibitors cause a higher rate of Use of lisinopril is not recommended during breast-feeding. Lactation
angioedema in black patients than in non-black patients.
INTERACTIONS It is not known whether ZESTRIL is secreted in human breast
Patients with a history of angioedema unrelated to ACE inhibitor milk. Lisinopril is excreted into the milk of lactating rats. The
therapy may be at increased risk of angioedema while receiving an Diuretics
use of ZESTRIL is not recommended in women who are breast-
ACE inhibitor (See Contraindications). When a diuretic is added to the therapy of a patient receiving feeding.
Anaphylactoid reactions in haemodialysis patients ZESTRIL the antihypertensive effect is usually additive.
Anaphylactoid reactions have been reported in patients dialysed Patients already on diuretics and especially those in whom diuretic
therapy was recently instituted, may occasionally experience an When driving vehicles or operating machines it should be taken
with high ux membranes (e.g. AN 69) and treated concomitantly
excessive reduction of blood pressure when ZESTRIL is added. into account that occasionally dizziness or tiredness may occur.
with an ACE inhibitor. In these patients consideration should be
given to using a different type of dialysis membrane or different The possibility of symptomatic hypotension with ZESTRIL can UNDESIRABLE EFFECTS
class of antihypertensive agent. be minimised by discontinuing the diuretic prior to initiation of The following undesirable effects have been observed and reported
treatment with ZESTRIL (see Special warnings and precautions during treatment with ZESTRIL and other ACE inhibitors with
Anaphylactoid reactions during low-density lipoproteins
for use and Posology and method of administration). the following frequencies: Very common (10%), common (1%,
(LDL) apheresis
Potassium supplements, potassium-sparing diuretics or <10%), uncommon (0.1, <1%), rare (0.01, <0.1%), very rare
Rarely, patients receiving ACE inhibitors during low-density
potassium-containing salt substitutes (<0.01%) including isolated reports.
lipoproteins (LDL) apheresis with dextran sulphate have
experienced life-threatening anaphylactoid reactions. These Although in clinical trials, serum potassium usually remained Blood and the lymphatic system disorders:
reactions were avoided by temporarily withholding ACE inhibitor within normal limits, hyperkalaemia did occur in some patients. rare: decreases in haemoglobin, decreases in
therapy prior to each apheresis. Risk factors for the development of hyperkalaemia include renal haematocrit.
insufciency, diabetes mellitus, and concomitant use of potassium- very rare: bone marrow depression, anaemia, thrombocytopenia,
Desensitisation
sparing diuretics (e.g. spironolactone, triamterene or amiloride), leucopenia, neutropenia, agranulocytosis (see
Patients receiving ACE inhibitors during desensitisation treatment potassium supplements or potassium-containing salt substitutes. Special warnings and precautions for use), haemo
(e.g. hymenoptera venom) have sustained anaphylactoid reactions. The use of potassium supplements, potassium-sparing diuretics lytic anaemia, lymphadenopathy, autoimmune
In the same patients, these reactions have been avoided when ACE or potassium-containing salt substitutes, particularly in patients disease.
inhibitors were temporarily withheld but they have reappeared with impaired renal function, may lead to a signicant increase in Metabolism and nutrition disorders:
upon inadvertent re-administration of the medicinal product. serum potassium. If ZESTRIL is given with a potassium-losing very rare: hypoglycaemia
Hepatic failure diuretic, diuretic-induced hypokalaemia may be ameliorated. Nervous system and psychiatric disorders:
Very rarely, ACE inhibitors have been associated with a syndrome Lithium common: dizziness, headache
that starts with cholestatic jaundice and progresses to fulminant Reversible increases in serum lithium concentrations and toxicity uncommon: mood alterations, paraesthesia, vertigo, taste
necrosis and (sometimes) death. The mechanism of this syndrome have been reported during concomitant administration of lithium disturbance, sleep disturbances.
is not understood. Patients receiving ZESTRIL who develop with ACE inhibitors. Concomitant use of thiazide diuretics may rare: mental confusion
jaundice or marked elevations of hepatic enzymes should discontinue increase the risk of lithium toxicity and enhance the already Cardiac and vascular disorders:
ZESTRIL and receive appropriate medical follow-up. increased lithium toxicity with ACE inhibitors. Use of ZESTRIL common: orthostatic effects (including hypotension)
Neutropenia/Agranulocytosis with lithium is not recommended, but if the combination proves uncommon: myocardial infarction or cerebrovascular accident,
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have necessary, careful monitoring of serum lithium levels should be possibly secondary to excessive hypotension in high
been reported in patients receiving ACE inhibitors. In patients performed (see Special warnings and precautions for use). risk patients (see Special warnings and precautions
with normal renal function and no other complicating factors, Non steroidal anti-inammatory drugs (NSAIDs) including for use), palpitations , tachycardia. Raynauds phe-
neutropenia occurs rarely. Neutropenia and agranulocytosis are acetylsalicylic acid 3g/day nomenon.
80
Book_01.indd 80 6/4/2008 2:19:40 PM

ASTRAZENECA
SPDI
Respiratory, thoracic and mediastinal disorders: = 0.073) were observed. In a post-hoc analysis, the number of min. In mild to moderate renal impairment (creatinine clearance
common: cough hospitalisations for heart failure was reduced by 24% (p=0.002) 30-80 ml/min) mean AUC was increased by 13% only, while a
uncommon: rhinitis in patients treated with high-dose ZESTRIL compared with low 4.5- fold increase in mean AUC was observed in severe renal
very rare: bronchospasm, sinusitis. Allergic alveolitis/eosino dose. Symptomatic benets were similar in patients treated with impairment (creatinine clearance 5-30ml/min).
philic pneumonia. high and low doses of ZESTRIL. Lisinopril can be removed by dialysis. During 4 hours of
Gastrointestinal disorders: The results of the study showed that the overall adverse event haemodialysis, plasma lisinopril concentrations decreased on
common: diarrhoea, vomiting proles for patients treated with high or low dose Zestril were average by 60%, with a dialysis clearance between 40 and 55ml/
similar in both nature and number. Predictable events resulting min.
uncommon: nausea, abdominal pain and indigestion
from ACE inhibition, such as hypotension or altered renal function, Heart failure
rare: dry mouth
were manageable and rarely led to treatment withdrawal. Cough Patients with heart failure have a greater exposure of lisinopril
very rare: pancreatitis, intestinal angioedema, hepatitis - either was less frequent in patients treated with high dose ZESTRIL
hepatocellular or cholestatic, jaundice and hepatic when compared to healthy subjects (an increase in AUC on
compared with low dose. average of 125%), but based on the urinary recovery of lisinopril,
failure (see Special warnings and precautions for
use) In the GISSI-3 trial, which used a 2x2 factorial design to compare there is reduced absorption of approximately 16% compared to
the effects of ZESTRIL and glyceryl trinitrate given alone or healthy subjects.
Skin and subcutaneous tissue disorders:
in combination for 6 weeks versus control in 19,394, patients Elderly
uncommon: rash, pruritus
who were administered the treatment within 24 hours of an
rare: hypersensitivity/angioneuroticoedema: Older patients have higher blood levels and higher values for
acute myocardial infarction, ZESTRIL produced a statistically
angioneurotic oedema of the face, extremities, lips, the area under the plasma concentration time curve (increased
signicant risk reduction in mortality of 11% versus control
tongue, glottis, and/or larynx (see Special warnings approximately 60%) compared with younger subjects.
(2p=0.03). The risk reduction with glyceryl trinitrate was not
and precautions for use), urticaria, alopecia, signicant but the combination of ZESTRIL and glyceryl LIST OF EXCIPIENTS
psoriasis trinitrate produced a signicant risk reduction in mortality of Mannitol
very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, 17% versus control (2p=0.02). In the sub-groups of elderly (age Calcium hydrogen phosphate dihydrate
Stevens-Johnson Syndrome, erythema multiforme > 70 years) and females, pre-dened as patients at high risk of
Red iron oxide
A symptom complex has been reported which may include one mortality, signicant benet was observed for a combined endpoint
Maize starch
or more of the following: of mortality and cardiac function. The combined endpoint for all
Pregelatinised starch
fever, vasculitis, myalgia, arthralgia/arthritis, a patients, as well as the high-risk sub-groups, at 6 months also
showed signicant benet for those treated with ZESTRIL Magnesium stearate
positive antinuclear antibodies (ANA), elevated red
blood cell sedimentation rate (ESR), eosinophilia or ZESTRIL plus glyceryl trinitrate for 6 weeks, indicating a SHELF-LIFE
and leucocytosis, rash, photosensitivity or other prevention effect for ZESTRIL. As would be expected from any Please refer to expiry date on the blister strip or outer carton.
dermatological manifestations may occur. vasodilator treatment, increased incidences of hypotension and
Renal and urinary disorders: renal dysfunction were associated with Zestril treatment but these SPECIAL PRECAUTIONS FOR STORAGE
common: renal dysfunction were not associated with a proportional increase in mortality. Do not store above 30C
rare: uraemia, acute renal failure In a double-blind, randomised, multicentre trial which compared
PACK SIZE
very rare: oliguria/anuria ZESTRIL with a calcium channel blocker in 335 hypertensive
Type 2 diabetes mellitus subjects with incipient nephropathy Please refer to the outer carton for pack size.
Reproductive system and breast disorders:
characterised by microalbuminuria, ZESTRIL 10 mg to 20 mg ZESTRIL is a trade mark of the Astra Zeneca group of
uncommon: impotence companies.
administered once daily for 12 months, reduced systolic/diastolic
rare: gynaecomastia
blood pressure by 13/10 mmHg and urinary albumin excretion AstraZeneca 2003-05
General disorders and administration site conditions: rate by 40%. When compared with the calcium channel blocker,
uncommon: fatigue, asthenia which produced a similar reduction in blood pressure, those
Investigations: treated with ZESTRIL showed a signicantly greater reduction in
ZOLADEX
uncommon: increases in blood urea, increases in serum creati- urinary albumin excretion rate, providing evidence that the ACE
nine, increases in liver enzymes, hyperkalaemia. inhibitory action of ZESTRIL reduced microalbuminuria by a (Goserelin acetate)
rare: increases in serum bilirubin, hyponatraemia. direct mechanism on renal tissues in addition to its blood pressure
lowering effect. PRESENTATION
OVERDOSE
ACE is known to be present in the endothelium and increased ZOLADEX is presented as a sterile, white to cream coloured
Limited data are available for overdose in humans. Symptoms ACE activity in diabetic patients which results in the formation cylindrical depot in which goserelin acetate (equivalent to 3.6
associated with overdosage of ACE inhibitors may include
of angiotensin II and destruction of bradykinin, potentiates the mg of goserelin) is dispersed in a biodegradable matrix of lactide
hypotension, circulatory shock, electrolyte disturbance, renal
damage to the endothelium caused by hyperglycaemia. ACE glycolide co polymer. It is supplied as a single dose SafeSystem
failure, hyperventilation, tachycardia, palpitations, bradycardia,
inhibitors, including lisinopril, inhibit the formation of angiotensin syringe applicator with a protective sleeve in a sealed pouch which
dizziness, anxiety and cough.
II and breakdown of bradykinin and hence ameliorate endothelial contains a desiccant.
The recommended treatment of overdose is intravenous infusion dysfunction.
of normal saline solution. If hypotension occurs, the patient INDICATIONS
Lisinopril treatment does not affect glycaemic control as shown
should be placed in the shock position. If available, treatment i) Prostate cancer: ZOLADEX is indicated in the management
by a lack of signicant effect on levels of glycated haemoglobin
with angiotensin II and/or intravenous catecholamines may also of prostate cancer suitable for hormonal manipulation.
(HbA1c).
be considered. If ingestion is recent, take measures aimed at ii) Breast cancer: ZOLADEX is indicated in the management
eliminating ZESTRIL (e.g., emesis, gastric lavage, administration PHARMACOKINETIC PROPERTIES of breast cancer in premenopausal and perimenopausal women
of absorbents and sodium sulphate). ZESTRIL may be removed Lisinopril is an orally active non-sulphydryl-containing ACE suitable for hormonal manipulation.
from the general circulation by haemodialysis (see Special inhibitor. iii) Endometriosis: In the management of endometriosis,
warning and precautions for use). Pacemaker therapy is indicated
Absorption ZOLADEX alleviates symptoms, including
for therapy-resistant bradycardia. Vital signs, serum electrolytes
Following oral administration of lisinopril, peak serum pain, and reduces the size and number of endometrial
and creatinine concentrations should be monitored frequently.
concentrations occur within about 7 hours, although there lesions.
PHARMACODYNAMIC PROPERTIES was a trend to a small delay in time taken to reach peak serum iv) Endometrial thinning: ZOLADEX is indicated for the
Pharmacotherapeutic group: Angiotensin converting enzyme concentrations in acute myocardial infarction patients. Based prethinning of the uterine endometrium prior to endometrial
inhibitors on urinary recovery, the mean extent of absorption of lisinopril ablation or resection.
ATC code: C09AA03. is approximately 25%, with interpatient variability 6-60% over v) Uterine broids: In conjunction with iron therapy in the
the dose range studied (5-80 mg). The absolute bioavailability haematological improvement of anaemic patients with
ZESTRIL is a peptidyl dipeptidase inhibitor. It inhibits the
is reduced to approximately 16% in patients with heart failure. broids, prior to surgery.
angiotensin converting enzyme (ACE) that catalyses the conversion
Lisinopril absorption is not affected by the presence of food. vi) Assisted reproduction: Pituitary downregulation in prepara-
of angiotensin I to the vasoconstrictor peptide, angiotensin II.
Angiotensin II also stimulates aldosterone secretion by the adrenal Distribution tion for superovulation.
cortex. Inhibition of ACE results in decreased concentrations of Lisinopril does not appear to be bound to serum proteins other than
angiotensin II which results in decreased vasopressor activity and to circulation angiotensin converting enzyme (ACE). Studies in
reduced aldosterone secretion. The latter decrease may result in an rats indicate that lisinopril crosses the blood-brain barrier poorly. Adults
increase in serum potassium concentration. Elimination One 3.6 mg depot of ZOLADEX injected subcutaneously into
Whilst the mechanism through which lisinopril lowers blood the anterior abdominal wall, every 28 days.
Lisinopril does not undergo metabolism and is excreted entirely
pressure is believed to be primarily suppression of the renin- unchanged into the urine. On multiple dosing lisinopril has an Assisted reproduction: ZOLADEX 3.6mg is administered to
angiotensin-aldosterone system, lisinopril is antihypertensive downregulate the pituitary gland, as dened by serum oestradiol
effective half life of accumulation of 12.6 hours. The clearance
even in patients with low renin hypertension. ACE is identical levels similar to those observed in the early follicular phase
of lisinopril in healthy subjects is approximately 50ml/min.
to kininase II, an enzyme that degrades bradykinin. Whether (approximately 150 pmol/1). This will usually take between 7
Declining serum concentrations exhibit a prolonged terminal
increased levels of bradykinin, a potent vasodilatory peptide, and 21 days.
phase which does not contribute to drug accumulation. This
play a role in the therapeutic effects of lisinopril remains to be terminal phase probably represents saturable binding to ACE and When downregulation is achieved, superovulation (controlled
elucidated. is not proportional to dose. ovarian stimulation) with gonadotrophin is commenced. The
The effect of ZESTRIL on mortality and morbidity in heart downregulation achieved with a depot agonist is more consistent
Hepatic impairment
failure has been studied by comparing a high dose (32.5 mg or suggesting that, in some cases, there may be an increased
Impairment of hepatic function in cirrhotic patients resulted in requirement for gonadotrophin. At the appropriate stage of
35 mg once daily) with a low dose (2.5 mg or 5 mg once daily).
a decrease in lisinopril absorption (about 30% as determined by follicular development, gonadotrophin is stopped and human
In a study of 3164 patients, with a median follow up period of
urinary recovery) but an increase in exposure (approximately chorionic gonadotrophin (hCG) is administered to induce
46 months for surviving patients, high dose ZESTRIL produced
50%) compared to healthy subjects due to decreased clearance. ovulation. Treatment monitoring, oocyte retrieval and fertilisation
a 12% risk reduction in the combined endpoint of all-cause
mortality and all-cause hospitalisation (p = 0.002) and an 8% risk Renal impairment techniques are performed according to the normal practice of the
reduction in all-cause mortality and cardiovascular hospitalisation Impaired renal function decreases elimination of lisinopril, which individual clinic.
(p = 0.036) compared with low dose. Risk reductions for all-cause is excreted via the kidneys, but this decrease becomes clinically No dosage adjustment is necessary for patients with renal
mortality (8%; p = 0.128) and cardiovascular mortality (10%; p important only when the glomerular ltration rate is below 30 ml/ impairment.
81
Book_01.indd 81 6/4/2008 2:19:41 PM

ASTRAZENECA
SPDI
No dosage adjustment is necessary for patients with hepatic The use of ZOLADEX during breast feeding is not treatment every 28 days, remain suppressed at levels comparable
impairment. recommended. with those observed in postmenopausal women. This suppression
No dosage adjustment is necessary in the elderly. is associated with a response in hormone dependent breast cancer,
EFFECT ON ABILITY TO DRIVE OR OPERATE MA-
endometriosis, uterine broids and suppression of follicular
Endometriosis should be treated for a period of six months only, CHINERY
development within the ovary. It will produce endometrial thinning
since at present there are no clinical data for longer treatment There is no evidence that ZOLADEX results in impairment of and will result in amenorrhoea in the majority of patients.
periods. Repeat courses should not be given due to concern about these activities.
loss of bone mineral density. In patients receiving ZOLADEX ZOLADEX in combination with iron has been shown to induce
for the treatment of endometriosis, the addition of hormone UNDESIRABLE EFFECTS amenorrhoea and improve haemoglobin concentrations and
replacement therapy (a daily oestrogenic agent and a progestogenic General related haematological parameters in women with broids who
agent) has been shown to reduce bone mineral density loss and are anaemic. The combination produced a mean haemoglobin
Rare incidences of hypersensitivity reactions, which may include
vasomotor symptoms. some manifestations of anaphylaxis, have been reported. concentration 1g/dl above that achieved by iron therapy alone.
For use in endometrial thinning; two depots to be administered 4 Arthralgia has been reported. Non-specic paraesthesias have During treatment with LHRH analogues patients may enter the
weeks apart, with surgery timed for between zero and two weeks been reported. Skin rashes have been reported which are generally menopause. Rarely, some women do not resume menses on
after the second depot. mild, often regressing without discontinuation of therapy. cessation of therapy.
For women who are anaemic as a result of uterine broids, Changes in blood pressure, manifest as hypotension or PHARMACOKINETIC PROPERTIES
ZOLADEX 3.6mg depot with supplementary iron may be given hypertension, have been occasionally observed in patients The bioavailability of ZOLADEX is almost complete.
for up to three months before surgery. administered ZOLADEX. The changes are usually transient, Administration of a depot every four weeks ensures that effective
Children resolving either during continued therapy, or after cessation of concentrations are maintained with no tissue accumulation.
therapy with ZOLADEX. Rarely, such changes have been ZOLADEX is poorly protein bound and has a serum elimination
Zoladex is not indicated for use in children.
sufcient to require medical intervention, including withdrawal of half life of two to four hours in subjects with normal renal
For correct administration of ZOLADEX, see instructions on ZOLADEX treatment.
the instruction card. function. The half life is increased in patients with impaired renal
As with other agents in this class, very rare cases of pituitary function. For the compound given monthly in a depot formulation,
CONTRA-INDICATIONS apoplexy have been reported following initial administration. this change will have minimal effect. Hence, no change in dosing
ZOLADEX should not be given to patients with a known Occasional local reactions include mild bruising at the is necessary in these patients. There is no signicant change in
hypersensitivity to the active substance, to other LHRH analogues, subcutaneous injection site. pharmacokinetics in patients with hepatic failure.
or to any excipients of this product. Males PRECLINICAL SAFETY DATA
ZOLADEX should not be used during pregnancy or lactation. Pharmacological effects in men include hot ushes and sweating Following long term repeated dosing with ZOLADEX, an
WARNING AND PRECAUTIONS and a decrease in potency, seldom requiring withdrawal of therapy. increased incidence of benign pituitary tumours has been observed
Breast swelling and tenderness have been noted infrequently. in male rats. Whilst this nding is similar to that previously noted
ZOLADEX is not indicated for use in children as safety and
Initially, prostate cancer patients may experience a temporary in this species following surgical castration, any relevance to
efcacy have not been established in this group of patients.
increase in bone pain, which can be managed symptomatically. humans has not been established.
Males Isolated cases of ureteric obstruction and spinal cord compression
In mice, long term repeated dosing with multiples of the human
The use of ZOLADEX in men at particular risk of developing have been recorded.
dose produced histological changes in some regions of the
ureteric obstruction or spinal cord compression should be The use of LHRH agonists in men may cause a loss of bone digestive system manifested by pancreatic islet cell hyperplasia
considered carefully and the patients monitored closely during mineral density.
the rst month of therapy. If spinal cord compression or renal and a benign proliferative condition in the pyloric region of the
Females stomach, also reported as a spontaneous lesion in this species. The
impairment due to ureteric obstruction are present or develop,
specic standard treatment of these complications should be Pharmacological effects in women include hot ushes and clinical relevance of these ndings is unknown.
instituted. sweating, and a change in libido, seldom requiring withdrawal
PRECAUTIONS FOR STORAGE
of therapy. Headaches, mood changes including depression,
Females Do not store above 25C
vaginal dryness and change in breast size have been noted
The use of LHRH agonists in women may cause a loss of bone infrequently. Initially breast cancer patients may experience a INSTRUCTIONS FOR USE, HANDLING AND DISPOSAL
mineral density. Currently available ZOLADEX data indicate a temporary increase in signs and symptoms, which can be managed
mean loss of 4.6% in vertebral bone mineral density following a Use as directed by the prescriber. Use only if pouch is undamaged.
symptomatically. In women with broids, degeneration of broids
six month course of treatment with progressive recovery to a mean Use immediately after opening pouch.
may occur. Rarely, breast cancer patients with bony metastases
loss compared to baseline of 2.6% six months after cessation of have developed hypercalcaemia on initiation of therapy. Dispose of the syringe in an approved sharps collector.
treatment. In patients receiving ZOLADEX for the treatment
In Assisted Reproduction: As with other LHRH agonists, there PACK SIZE
of endometriosis, the addition of hormone replacement therapy (a
have been reports of ovarian hyperstimulation syndrome (OHSS), Please refer to the outer carton for pack size.
daily oestrogenic agent and a progestogenic agent) has been shown
associated with the use of ZOLADEX 3.6mg in combination
to reduce bone mineral density loss and vasomotor symptoms. SHELF LIFE
with gonadotrophin. It has been suggested that the downregulation
ZOLADEX should be used with caution in women with known achieved with a depot agonist may lead, in some cases, to an Please refer to expiry date on outer carton.
metabolic bone disease. increased requirement for gonadotrophin. The stimulation ZOLADEX and ZOLADEX SAFESYSTEM are trademarks of
ZOLADEX may cause an increase in uterine cervical resistance, cycle should be monitored carefully to identify patients at risk the AstraZeneca Group of Companies.
which may result in difculty in dilating the cervix. of developing OHSS because its severity and incidence may be
Currently, there are no clinical data on the effects of treating dependent on the dose regimen of gonadotrophin. Human chorionic
benign gynaecological conditions with ZOLADEX for periods gonadotrophin (hCG) should be withheld, if appropriate. B. BRAUN MELSUNGEN AG
in excess of six months. Follicular and luteal ovarian cysts have been reported to occur
Assisted Reproduction: following LHRH therapy. Most cysts are asymptomatic, non C/o Medical Supplier & Services Co. Ltd.
ZOLADEX 3.6mg should only be administered as part of a functional, varying in size and resolve spontaneously. P.O.BOX 17550, RIYADH 11494
regimen for assisted reproduction under the supervision of a OVERDOSAGE
SAUDI ARABIA
specialist experienced in the area.
There is limited experience of overdosage in humans. In cases
TEL: 01-461 6999, FAX: 01-217 3472
As with other LHRH agonists, there have been reports of ovarian where ZOLADEX has unintentionally been readministered early,
hyperstimulation syndrome (OHSS) associated with the use of or given at a higher dose, no clinically relevant adverse effects 10% W/V CALCIUM GLUCONATE
ZOLADEX 3.6mg, in combination with gonadotrophin. It has have been seen. Animal tests suggest that no effect other than
been suggested that the downregulation achieved with a depot the intended therapeutic effects on sex hormone concentrations
INJECTION
agonist may lead, in some cases, to an increased requirement and on the reproductive tract will be evident with higher doses
for gonadotrophin. The stimulation cycle should be monitored of ZOLADEX. If overdosage occurs, this should be managed
carefully to identify patients at risk of developing OHSS because symptomatically. (Calcium Gluconate, Calcium D-Saccharate
its severity and incidence may be dependent on the dose regimen Tetrahydrate)
of gonadotrophin. Human chorionic gonadotrophin (hCG) should PHARMACOLOGICAL PROPERTIES
be withheld, if appropriate. PHARMACODYNAMIC PROPERTIES COMPOSITION
It is recommended that ZOLADEX 3.6mg be used with caution Mode of action: ZOLADEX (D Ser(But)6 Azgly10 LHRH) is One ampoule (10 ml) of solution contains
in assisted reproduction regimens in patients with polycystic a synthetic analogue of naturally occurring LHRH. On chronic Active ingredients:
ovarian syndrome as follicle recruitment may be increased. administration ZOLADEX results in inhibition of pituitary LH
Calcium Gluconate for Injection 940 mg
INTERACTIONS secretion leading to a fall in serum testosterone concentrations
in males and serum oestradiol concentrations in females. This Calcium D-Saccharate Tetrahydrate 50 mg
None known
effect is reversible on discontinuation of therapy. Initially, 1 ml contains 0.23 mmol of calcium
PREGNANCY AND LACTATION ZOLADEX, like other LHRH agonists, may transiently Excipient:
Although reproductive toxicology in animals gave no evidence of increase serum testosterone concentration in men and serum Water for injections
teratogenic potential, ZOLADEX should not be used in pregnancy oestradiol concentration in women. During early treatment with
as there is a theoretical risk of abortion or foetal abnormality if ZOLADEX some women may experience vaginal bleeding PHARMACEUTICAL FORM
LHRH agonists are used during pregnancy. Potentially fertile of variable duration and intensity. Such bleeding probably Solution for injection
women should be examined carefully before treatment to exclude represents oestrogen withdrawal bleeding and is expected to stop
spontaneously. PHARMACO-THERAPEUTIC GROUP
pregnancy. Non hormonal methods of contraception should be
employed during therapy and in the case of endometriosis until In men by around 21 days after the rst depot injection testosterone Electrolyte replacement solution
menses are resumed. concentrations have fallen to within the castrate range and remain INDICATIONS
Pregnancy should be excluded before ZOLADEX 3.6mg is suppressed with continuous treatment every 28 days. This Treatment of acute symptomatic hypocalcaemia
used for assisted reproduction. The clinical data from use in this inhibition leads to prostate tumour regression and symptomatic
setting are limited but the available evidence suggests there is no improvement in the majority of patients. CONTRAINDICATIONS
causal association between ZOLADEX and any subsequent In women serum oestradiol concentrations are suppressed by 10 % W/V CALCIUM GLUCONATE INJECTION must not
abnormalities of oocyte development or pregnancy and outcome. around 21 days after the rst depot injection and, with continuous be administered in the following conditions:
82
Book_01.indd 82 6/4/2008 2:19:42 PM

B. BRAUN MELSUNGEN AG
SPDI
- Hypercalcaemia, INSTRUCTIONS FOR STORAGE / USE / HANDLING UNDESIRABLE EFFECTS
- Nephrocalcinosis, Do not store above 25 C None to be expected if the solution is used according to
- Hypercalcuria The product is supplied in single-dose containers. instructions.
- Therapy with digitalis preparations, The solution should only be used if it is clear and the container Note:
- Intoxication with digitalis preparations, Patients are advised to inform their doctor or pharmacist if they
is undamaged.
- Severe renal insufciency. notice any adverse in connection with the administration of the
product.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE 5% W/V DEXTROSE INTRAVENOUS EXPIRY DATE
10 % W/V CALCIUM GLUCONATE INJECTION should INFUSION
only be administered with particular caution in the following The product must not be used beyond the expiry date stated on
conditions: the labelling.
- Impaired renal function [Glucose (as glucose monohydrate)] INSTRUCTIONS FOR STORAGE / USE / HANDLING
- Heart diseases, Only to be used if solution is clear and container undamaged.
- Sarcoidosis (Boeck's disease) COMPOSITION
Calcium is not soluble in adipose tissue and may therefore cause 1000 ml of solution contain
10 % W/V DEXTROSE INTRAVENOUS
inltration and subsequent abscess formation. Active ingredients:
In children, 10 % W/V CALCIUM GLUCONATE INJECTION Glucose 50.0 g
INFUSION
should never be injected i.m. but only slowly i.v. (as glucose monohydrate 55.0 g)
During parenteral therapy with calcium serum calcium level and Excipients: [Glucose (as glucose monohydrate)]
urinary calcium excretion should be monitored carefully. Water for Injections
Carbohydrate content: 50.0 g/l COMPOSITION
Caloric value: 835 kJ/l = 200 kcal/l 1000 ml of solution contain
Pregnancy:
Theoretical osmolarity: 278 mOsm/l Active ingredients:
10 % W/V CALCIUM GLUCONATE INJECTION may be Titration acidity (to pH 7.4): < 0.5 mmol/l
used during pregnancy as indicated. Glucose 100.0 g
pH: 3.5 5.5
Lactation: (as glucose monohydrate 110.0 g)
PHARMACEUTICAL FORM Excipients:
10 % W/V CALCIUM GLUCONATE INJECTION may be
used during the lactation period as indicated. Solution for infusion Water for Injections
PHARMACO-THERAPEUTIC GROUP Carbohydrate content 100 g/l
INTERACTIONS
Vehicle solution Caloric value 1675 kJ/l = 400 kcal/l
Calcium increases the sensitivity of the heart to digitalis. Theoretical osmolarity 555 mOsm/l
In patients receiving digitalis preparations calcium may provoke INDICATIONS Titration acidity (to pH 7.4) < 0.5 mmol/l
cardiac arrhythmia. Vehicle solution for physico-chemically compatible electrolyte pH 3.5 5.5
Calcium and magnesium mutually antagonise their effects. concentrates and medicaments.
PHARMACEUTICAL FORM
Calcium may antagonise the effect of calcium channel blockers. CONTRAINDICATIONS Solution for infusion
Medicaments containing phosphate, oxalate, or carbonate/ - Elevated blood sugar concentration (hyperglycaemia),
bicarbonate may cause precipitation on mixing with calcium - Decreased blood potassium concentration (hypokalaemia), PHARMACO-THERAPEUTIC GROUP
gluconate solutions. Solution for energy supply
- High concentration of acid substances in blood (Acidosis)
Tetracyclines are incompatible with calcium solutions.
If it should be necessary to administer large volumes further INDICATIONS
DOSAGE contraindications can arise on account of the glucose and/or uid - Administration of glucose for energy supply,
Adults: load: - Therapy of hypoglycaemia,
- Hyperhydration, - Vehicle solution for compatible electrolyte concentrates and
As a rule, approx. 10 ml of 10 % W/V CALCIUM GLUCONATE
INJECTION are administered to adults. - Simultaneous sodium and water deciency (hypotonic medicaments.
dehydration).
Children: CONTRAINDICATIONS
Children receive, according to their age, 2 - 5 ml of 10 % W/V PRECAUTIONS FOR USE
- Elevated blood sugar concentration (hyperglycaemia),
CALCIUM GLUCONATE INJECTION. Patient monitoring should include regular checks of the blood - Decreased blood potassium concentration (hypokalaemia),
Further administration depends on the clinical situation and the glucose level, the water balance, serum electrolyte concentrations
- High concentration of acid substances in blood (Acidosis)
values obtained from the serum ionogram. - in particular serum potassium -, and acid-base balance.
- Hyperhydration,
Glucose infusions should not be administered through the - Simultaneous sodium and water deciency (hypotonic
Method of administration same infusion equipment, simultaneously with, before, or after dehydration).
Adults: administration of blood, because of the possibility of pseudo-
Slow intravenous or deeply intramuscular injection agglutination. SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Children: INTERACTIONS The solution should be administered with caution to patients with
Slow intravenous injection. increased serum osmolarity.
Because 5 % W/V GLUCOSE INTRAVENOUS INFUSION
Intravenous injection should be performed slowly; the patient has an acid pH, incompatibilities can occur on mixing with other Patient monitoring should include regular checks of the blood
should be in lying position and should be closely observed during medicaments. glucose level, depending on the prevailing metabolic condition
injection. and the administered dose.
Erythrocyte concentrates must not be suspended in 5 % W/V
Care should be taken to administer intramuscular injections GLUCOSE INTRAVENOUS INFUSION because this can lead Patient monitoring should also include regular checks of water
deeply i.m. to pseudoagglutination. balance, serum electrolyte concentrations - in particular serum
potassium -, and acid-base balance.
OVERDOSE DOSAGE Glucose infusions should not be administered through the
Symptoms: Choose a volume that yields the desired concentration of the same infusion equipment, simultaneously with, before, or after
Overdose resulting from too rapid injection may cause medicament for which 5 % W/V GLUCOSE INTRAVENOUS administration of blood, because of the possibility of pseudo-
vasodilatation, hypotension, bradycardia and arrhythmia, up to INFUSION is to be used as vehicle solution, taking also account agglutination.
cardiac arrest. of the maximum doses stated below.
Recommended daily dose INTERACTIONS
Emergency treatment, antidotes: Because 10 % W/V GLUCOSE INTRAVENOUS INFUSION
Up to 40 ml per kg body weight per day, corresponding to 2 g of
Therapy depends on the prevailing symptoms. has an acid pH, incompatibilities can occur on mixing with other
glucose. The maximum dose corresponds to the maximum daily medicaments.
Occurrence of a hypercalcaemia syndrome requires forced
diuresis. Fluid, e.g. physiological saline, must then be supplied uid intake. Erythrocyte concentrates must not be suspended in 10 % W/V
simultaneously and water and electrolyte balances should be Infusion rate GLUCOSE INTRAVENOUS INFUSION because this can lead
closely monitored. If required, calcitonin or mithramycin may be Up to 5 ml per kg BW/hour, corresponding to 0.25 g of glucose/kg to pseudo-agglutination.
given. In severe cases, haemodialysis may be performed. BW/hour. This is equivalent to a maximum drop rate of 1.7
DOSAGE
UNDESIRABLE EFFECTS drops/kg BW/minute.
The dose is to be adjusted according to the patient's actual need
Too rapid intravenous injection may provoke heat sensations, Method of administration of glucose and uid.
ushing, sweating, nausea, drop of blood pressure, and cardiac Intravenous infusion. The solution can be administered Recommended daily dose:
arrhythmia. peripherally; however, the possibility of peripheral administration
can be limited by the nature or the concentration of the dissolved Up to 40 ml per kg BW, corresponding to 4 g of glucose.
Intramuscular injection may be accompanied by painM
drug. In the presence of metabolic disorders (e.g. postoperatively or after
sensations.
injuries, hypoxia, organ insufciencies), the oxidative metabolism
If intramuscular injection is not made at adequate depth, inltration OVERDOSE of glucose may be impaired. In such situations the glucose intake
of the adipose tissue may occur with subsequent abscess formation, Symptoms should be limited to 2 - 4 g/kg BW/day
tissue induration, and necrosis.
Overdose may result in hyperhydration, electrolyte disorders, For use as vehicle solution, a volume should be chosen that yields
Reddening of skin, burning sensation or pain during intravenous hyperglycaemia, glucosuria, and hyperosmolarity of the blood (up the desired concentration of the medicament to be dissolved or
injection may indicate accidental perivascular injection that may to hyperglycaemic hyperosmotic coma). diluted.
lead to tissue necrosis. Emergency treatment, antidotes Infusion rate
EXPIRY DATE Depending on type and severity of the disorders: The maximum infusion rate is 2.5 ml per kg BW per hour,
The product must not be used beyond the expiry date stated on Cessation of infusion, administration of electrolytes, diuretics, or corresponding to 0.25 g of glucose per kg BW per hour. The
the labelling. insulin. maximum drop rate is 0.8 drops per kg BW per minute.
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Thus for a patient weighing 70 kg the maximum infusion rate is INTERACTIONS
approx. 175 ml/hour (corresponding to a maximum drop rate of 56 Because 40 % W/V GLUCOSE INTRAVENOUS INFUSIOn 50 % W/V GLUCOSE INJECTION
drops/min), resulting in a glucose intake of 17.5 g/hour. has an acid pH, it may be incompatible with other medicaments.
Method of administration Erythrocyte concentrates must not be suspended in this solution [Glucose (as glucose Monohydrate)]
Intravenous infusion. The solution can be administered because of the possibility of pseudo-agglutination.
peripherally. COMPOSITION
DOSAGE
If 10 % W/V GLUCOSE INTRAVENOUS INFUSION is used 100 ml of solution contain
as vehicle solution the possibility of peripheral infusion can be It should be noted that this solution constitutes only one component
Active substance:
limited by the nature or the concentration of the dissolved drug. of parenteral nutrition. In total parenteral nutrition, of glucose
infusions should always be combined with adequate supplies of Glucose 50.0 g
OVERDOSE amino acids, electrolytes, vitamins, essential fatty acids and trace (as glucose monohydrate, 55.0 g)
Symptoms elements. Excipients:
Overdose may cause hyperglycaemia, glucosuria, serum The dosage should be adjusted according to the individual glucose Water for injections
hyperosmolarity, possibly leading to hyperosmotic and requirements. Caloric value: 835 kJ/100 ml = 200 kcal/100 ml
hyperglycaemic coma, further hyperhydration and electrolyte Theoretical osmolarity 2770 mOsm/l
Adults: Titration acidity (to pH 7.4) < 1.5 mmol/l
disorders.
Maximum daily dose pH 3.5 5.5
Emergency treatment, antidotes
Up to 15 ml per kg body weight per day, corresponding to 6 g of PHARMACEUTICAL FORM
The primary therapy is dose reduction. Disorders of the glucose glucose per kg body weight per day.
metabolism and of the electrolyte balance can be corrected by Concentrate for solution for infusion
administration of insulin and appropriate supplementation of In the presence of metabolic disorders, e.g. postoperative/post-
traumatic stress, hypoxia, organ insufciencies, the glucose PHARMACO-THERAPEUTIC GROUP
electrolytes.
oxidation may be impaired, which may be associated with Solution for energy supply
UNDESIRABLE EFFECTS hyperglycaemia and insulin resistance and possibly with an INDICATIONS
None to be expected if the solution is used according to increased mortality. In such cases, reduction of the glucose intake
Therapy of hypoglycaemia.
instructions. to 2 4 g of glucose per kg body weight per day may be required.
Note The blood glucose level should not exceed 110 mg/100 ml (6.1 CONTRAINDICATIONS
Patients are advised to inform their doctor or pharmacist if they mmol/l). Hyperglycaemia;
notice any adverse effect in connection with the administration of Maximum infusion rate Hypokalaemia;
the product. Up to 0.62 ml, corresponding to 0.25 g of glucose, per kg body Acidosis.
weight per hour. The corresponding maximum drop rate is approx. SPECIAL WARNINGS AND PRECAUTIONS FOR USE
EXPIRY DATE
0.2 drops per kg body weight per minute. Caution should be exercised in patients with increased serum
The product must not be used beyond the expiry date stated on
the labelling. Thus for a patient weighing 70 kg the infusion rate may be up to osmolarity.
43 ml per hour or approx. 14 drops per minute, corresponding to Blood glucose concentrations should be monitored, depending on
INSTRUCTIONS FOR USE/HANDLING 17.5 g of glucose per hour. metabolic conditions and administered dose.
Only to be used if solution is clear and container undamaged. In the setting of parenteral nutrition, the total uid administration Clinical monitoring should include checks of serum electrolyte
may only exceptionally exceed 40 ml per kg body weight per day. concentrations in particular potassium and the acid-base
balance.
40 % W/V GLUCOSE INTRAVENOUS Children (from the 6th year of life onward):
Maximum daily doses: GLUCOSE INJECTIONS should not be administered through
INFUSION the same infusion equipment, simultaneously with, before, or after
The maximum daily glucose doses (taking account, however, of administration of blood, because of the possibility of pseudo-
the limitations of uid intake stated below) are: agglutination.
[Glucose (as Glucose monohydrate)] 6th 10th year: up to 10 g of glucose per kg body
INTERACTIONS
weight per day, corresponding to 25
COMPOSITION Because of its acid pH, 50 % W/V GLUCOSE INJECTION may
ml per kg body weight per day;
1000 ml of solution contain be incompatible with other medicaments.
11th 14th year: up to 8 g of glucose per kg body
Active substance: weight per day, corresponding to 20 DOSAGE
Glucose 400.0 g ml per kg body weight per day. The dosage should be adjusted according to individual requirements
(as glucose monohydrate 440.0 g) When determining the dose, care should be taken that total or the actual blood glucose concentration.
Excipients: parenteral uid administration does not exceed the following In the critically ill, the administration rate should not exceed 6
Hydrochloric acid, water for injections values. mg of glucose per kg body weight per min. Only exceptionally
the administration rate may be up to 9 mg of glucose per kg body
Carbohydrate content 400 g/l The basic uid requirements are for: weight per min.
Caloric value: 6700 kJ/l 1600 kcal/l 6th 10th year: 60 80 ml per kg body weight per Method of administration
Theoretical osmolarity 2220 mOsm/l day.
Only to be used diluted as additive to intravenous infusions in
Titration acidity (to pH 7.4) < 1 mmol/l 11th 14th year: 50 70 ml per kg body weight per order to avoid vein irritation.
pH 3.5 5.5 day.
OVERDOSE
PHARMACEUTICAL FORM During administration of carbohydrate solutions, regular blood
Overdose may cause hyperglycaemia, glucosuria, serum
Solution for infusion glucose monitoring is mandatory, irrespective of the concentration
hyperosmolarity, possibly leading to hyperosmotic and
of the solution administered.
hyperglycaemic coma, further hyperhydration and electrolyte
PHARMACO-THERAPEUTIC GROUP Method of administration disorders.
Carbohydrate solution for parenteral nutrition Intravenous use. Administer via central venous catheter The primary therapy is dose reduction. Disorders of the glucose
INDICATIONS metabolism and of the electrolyte balance can be corrected by
OVERDOSE administration of insulin and appropriate supplementation of
High-caloric energy supply when uid intake has to be
Symptoms electrolytes.
restricted
Energy supply by means of glucose Overdose may lead to hyperglycaemia, hyperosmolarity of the UNDESIRABLE EFFECTS
Carbohydrate component in parenteral nutrition serum, hyperglycaemic or hyperosmotic coma, hyperhydration,
If the product is used in accordance with the directions given, the
and electrolyte imbalances.
Therapy of hypoglycaemia occurrence of side effects is not to be expected.
Emergency treatment, antidotes Note:
CONTRAINDICATIONS
The primary therapy is dose reduction. Disorders of the glucose Patients are advised to inform their doctor or pharmacist of any
- Elevated blood sugar concentration (hyperglycaemia), requiring metabolism and of the electrolyte balance can be corrected by
more than 6 units of insulin per hour for correction adverse effect they notice in connection with the administration
administration of insulin and appropriate supplementation of of this drug.
- Decreased blood potassium concentration (hypokalaemia) electrolytes.
- High concentration of acid substances in blood (Acidosis) EXPIRY DATE
- Hyperhydration UNDESIRABLE EFFECTS The product must not be used beyond the expiry date stated on
- Simultaneous sodium and water deciency (hypotonic None to be expected if the solution is used according to the labelling.
dehydration). instructions.
INSTRUCTIONS FOR STORAGE / USE / HANDLING
Note: The product is supplied in single-dose containers. Remaining
This solution should only be administered with caution to patients Patients should inform their doctor or pharmacist if they notice contents must not be stored for later use.
with increased serum osmolarity. any adverse effect in connection with the administration of this Only to be used if solution is clear and container undamaged.
medicine.
Patient monitoring should include regular checks of the blood
glucose level, depending on the prevailing metabolic condition EXPIRY DATE 7.45 % POTASSIUM CHLORIDE
and the administered dose. The product must not be used beyond the expiry date stated on INJECTION
Patient monitoring should also include regular checks of the water the labelling.
balance, the serum electrolyte concentrations - in particular serum
potassium and the acid-base balance. INSTRUCTIONS FOR STORAGE / USE / HANDLING (Potassium Chloride)
Glucose infusions should not be administered through the The solution is supplied in single-use containers. Unused contents
same infusion equipment, simultaneously with, before, or after must be discarded and not be stored for later use. COMPOSITION
administration of blood, because of the possibility of pseudo- Only to be used if the solution is clear and the container 10 ml solution contains:
agglutination. undamaged Potassium Chloride 0.745 g
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Excipient brillation and cardiac arrest. In the ECG there are high, sharp, INTERACTIONS
Water for Injections symmetrical T-waves and, at very high potassium levels, An increase in the extracellular potassium concentration reduces
Theoretical osmolarity 2000 mOsm/l broadening of the QRS complex. The vascular effects are the effect of cardiac glycosides, a reduction increases the
hypotension and centralisation. arrythmogenic effect of cardiac glycosides.
pH 4.5 7.5
The neuromuscular symptoms encompass fatigue, weakness, states Potassium saving diuretics, aldosterone antagonists, ACE
1 ml contains 1 mmol potassium and 1 mmol chloride.
of confusion, heaviness of limbs, muscle twitching, paraesthesia, inhibitors, nonsteroid anti-inammatories and peripheral analgesics
PHARMACEUTICAL FORM and ascending paralysis. reduce the renal excretion of potassium. Severe hyperkalaemia can
Concentrate for solution for infusion Plasma potassium concentrations greater than 6.5 mmol/l are occur on simultaneous administration with potassium chloride.
dangerous, over 8 mmol/l often lethal. Severe hyperkalaemia, with adverse effect on the heart rhythm, can
PHARMACO-THERAPEUTIC GROUP also occur when suxamethonuium and potassium are administered
Emergency treatment, antidotes:
IV solution additive, electrolyte solution simultaneously.
The rst measure is immediate stop of infusion. Further corrective
INDICATIONS measures include slow intravenous administration of 10 % calcium DOSAGE
States of potassium deciency, especially if accompanied by gluconate, infusion of glucose together with insulin, increase The dosage should be adjusted according to the analysis values of
alkali excess and decreased chloride concentration in the blood of diuresis, oral or rectal administration of cation exchangers, the serum ionogram and the acid base status.
(hypochloraemic alkalosis). correction of acidosis, if necessary. The potassium decit is calculated according to the following
CONTRAINDICATIONS In cases of severe intoxication haemodialysis may be necessary. formula:
7.45 % POTASSIUM CHLORIDE INJECTION must not be mmol potassium =
UNDESIRABLE EFFECTS
administered when there are kg b.w. x 0.2 x 2 x (4.5 - current serum potassium [mmol/l]).
Administration of potassium chloride may be accompanied by
- an elevated potassium level (hyperkalaemia) nausea, acidosis, an elevated concentrations of chloride in the (Body weight x 0.2 represents the extracellular uid volume.)
- an elevated chloride level (hyperchloraemia) blood. Maximum daily dose:
- disorders that are frequently associated with hyperkalaemia Too rapid infusion may lead to heart arrhythmia. Not more than 2 - 3 mmol/kg b.w./day
such as dehydration, reduced renal excretion, Addison`s disease, Maximum infusion rate:
Adynamia episodica hereditaria (GAMSTORP`S syndrome), Note:
Patients are advised to inform their doctor or pharmacist if they Up to 20 mmol potassium per hour (corresponding to 0.3 mmol
sickle cell anaemia.
notice any adverse effect not mentioned in this leaet. potassium/kg b.w./hour) in adults.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE Method of administration
7.45 % POTASSIUM CHLORIDE INJECTION should only EXPIRY DATE
Intravenously, only diluted as an additive to infusion solutions.
be administered with caution when there is Do not use after the expiry date stated on the labelling. The potassium concentration in the infusion solution must not
- cardiac decompensation exceed 40 mmol/l. Suitable vehicle solutions are e.g. 5 % or 10 %
INSTRUCTIONS FOR STORAGE / USE / HANDLING
- simultaneous treatment with potassium-saving diuretics, glucose solutions, isotonic sodium chloride solution, Compound
Only to be used if solution is clear and container undamaged. Sodium Lactate solution, or complete electrolyte solutions.
aldosterone antagonists, ACE inhibitors or potentially
nephrotoxic medicaments (nonsteroid anti-inammatories The product is supplied in single-dose containers. Unused portions 15 % POTASSIUM CHLORIDE INJECTION should only
etc.). must be discarded. be added immediately before setting up the infusion and strictly
The administration of potassium-containing infusions must be aseptic technique should be observed. The infusion bottle should
discontinued if there are signs of renal insufciency. 15 % W/V POTASSIUM CHLORIDE then be gently shaken.
There are typical changes in the ECG when the potassium balance INJECTION As a matter of principle, infusion pumps should be used for the
is disturbed (hypo- or hyperkalaemia). However, there is no linear infusion of potassium in the setting of correction therapy.
relationship between the ECG changes and the concentration of OVERDOSE
potassium in the blood. (Potassium Chloride) Symptoms:
Clinical monitoring should include checks of the serum electrolyte
COMPOSITION Overdose may cause hyperkalaemia, in particular in the presence
levels and the acid-base balance.
of acidosis or kidney insufciency.
It must be made absolutely sure that the solution is administered 1 ml solution contains:
The symptoms of hyperkalaemia are primarily cardiovascular
intravenously, because paravenous administration may cause Potassium Chloride 150 mg disorders. There can be bradycardia, AV blockade and ventricular
tissue necrosis. Excipient brillation and cardiac arrest. In the ECG there are high, sharp,
INTERACTIONS Water for Injections symmetrical T-waves and, at very high potassium levels,
An increase in the extracellular potassium concentration reduces broadening of the QRS complex. The vascular effects are
1 ml contains 2 mmol potassium and 2 mmol chloride.
the effect of cardiac glycosides, a reduction increases the hypotension and centralisation.
Theoretical osmolarity 4022 mOsm/l
arrhythmogenic effect of cardiac glycosides. The neuromuscular symptoms encompass fatigue, weakness, states
pH 4.5 7.5 of confusion, heaviness of limbs, muscle twitching, paraesthesia,
Potassium saving diuretics, aldosterone antagonists, ACE
PHARMACEUTICAL FORM and ascending paralysis.
inhibitors, nonsteroid anti-inammatories and peripheral analgesics
reduce the renal excretion of potassium. Severe hyperkalaemia can Concentrate for solution for infusion Plasma potassium concentrations greater than 6.5 mmol/l are
occur on simultaneous administration with potassium chloride. dangerous, over 8 mmol/l often lethal.
PHARMACO-THERAPEUTIC GROUP Emergency treatment, antidotes:
Severe hyperkalaemia, with adverse effect on the heart rhythm, can
also occur when suxamethonium and potassium are administered Electrolyte replacement solutions The rst measure is immediate stop of infusion. Further corrective
simultaneously. INDICATIONS measures include slow intravenous administration of 10 % calcium
gluconate, infusion of glucose together with insulin, increase
DOSAGE States of potassium deciency, especially if accompanied by of diuresis, oral or rectal administration of cation exchangers,
The dosage should be adjusted according to the analysis values of alkali excess and decreased chloride concentration in the blood correction of acidosis, if necessary.
the serum electrolytes and the acid base status. (hypochloraemic alkalosis).
In cases of severe intoxication haemodialysis may be necessary.
The potassium decit is calculated according to the following CONTRAINDICATIONS
UNDESIRABLE EFFECTS
formula: 15 % POTASSIUM CHLORIDE INJECTION must not be Administration of potassium chloride may be accompanied by
mmol potassium = kg body weight (BW) 0.2 2 (4.5 - current administered when there are nausea, acidosis, an elevated concentrations of chloride in the
serum potassium [mmol/l]). - an elevated potassium level (hyperkalaemia) blood.
(Body weight 0.2 represents the extracellular uid volume.) - an elevated chloride level (hyperchloraemia) Too rapid infusion may lead to heart arrhythmia.
Maximum daily dose: - disorders that are frequently associated with hyperkalaemia Note:
Not more than 2 3 mmol/kg BW/day such as dehydration, reduced renal excretion, Addisons disease,
Patients are advised to inform their doctor or pharmacist of
Maximum infusion rate: Adynamia episodica hereditaria (Gamstorps syndrome), sickle
any adverse effect they experience in connection with the
Up to 20 mmol potassium per hour in adults (corresponding to 0.3 cell anaemia. administration of this drug.
mmol potassium/kg BW/hour) SPECIAL WARNINGS AND PRECAUTIONS FOR USE EXPIRY DATE
Method of administration 15 % POTASSIUM CHLORIDE INJECTION should only be Do not use after the expiry date stated on the labelling.
Intravenously, only diluted as an additive to infusion solutions. administered with caution when there is
The potassium concentration in the infusion solution must not - cardiac decompensation INSTRUCTIONS FOR STORAGE / USE / HANDLING
exceed 40 mmol/l. Suitable vehicle solutions are e.g. 5 % or 10 % - simultaneous treatment with potassium-saving diuretics, Only to be used if solution is clear and container undamaged.
glucose solutions, isotonic sodium chloride solution, Compound aldosterone antagonists, ACE inhibitors or potentially The product is supplied in single-dose containers. Unused portions
Sodium Lactate solution, or complete electrolyte solutions. nephrotoxic medicaments (nonsteroid anti-inammatories must be discarded.
7.45 % POTASSIUM CHLORIDE INJECTIONshould only etc.).
be added immediately before setting up the infusion and strictly 4.2% W/V SODIUM BICARBONATE
The administration of potassium-containing infusions must be
aseptic technique should be observed. The infusion bottle should
discontinued if there are signs of renal insufciency. INTRAVENOUS INFUSION
then be gently shaken.
There are typical changes in the ECG when the potassium balance
As a matter of principle, infusion pumps should be used for the
is disturbed (hypo- or hyperkalaemia). However, there is no linear
infusion of potassium in the setting of correction therapy. (Sodium bicarbonate)
relationship between the ECG changes and the concentration of
OVERDOSE potassium in the blood.
Symptoms: COMPOSITION
Clinical monitoring should include checks of the serum ionogram
Overdose may cause hyperkalaemia, in particular in the presence and the acid-base balance 1000 ml of solution contain:
of acidosis or kidney insufciency. It must be made absolutely sure that the solution is administered Sodium bicarbonate 42.0 g
The symptoms of hyperkalaemia are primarily cardiovascular intravenously, because paravenous administration may cause Excipients:
disorders. There can be bradycardia, AV blockade and ventricular tissue necrosis. Disodium edetate, water for Injections
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Electrolyte concentrations: monitoring of the acid-base balance and the water balance. Care It must be made absolutely sure that the solution is infused
Sodium 500 mmol/l should be taken not to exceed the maximum infusion rate stated intravenously; accidental intra-arterial infusion may cause shock
Bicarbonate 500 mmol/l below. or loss of an extremity.
Theoretical osmolarity 1000 mOsm/l Maximum daily dose: Patient monitoring should include regular checks of the acid-
Titration alkalinity (to pH 7.4) approx. 35 mmol/l According to the correction requirements. base balance, the serum electrolyte concentrations and the water
pH 7.0 - 8.5 Flow rate: balance.
Up to 1.5 mmol of sodium bicarbonate per kg body weight per Alkalisation therapy may lead to hypokalaemia.
PHARMACEUTICAL FORM
hour, corresponding to Potassium or calcium deciencies should be corrected before
Solution for infusion beginning of the alkalising therapy.
3 ml of 4.2 % W/V SODIUM BICARBONATE INTRAVENOUS
PHARMACO-THERAPEUTIC GROUP INFUSION/kg BW/h. INTERACTIONS
Solution for electrolyte substitution Method of administration Urine alkalisation by sodium bicarbonate accelerates the
INDICATIONS Intravenous infusion elimination of acid drug substances, e.g. acetylsalicylic acid, and
- Correction of metabolic acidosis; OVERDOSE delays the elimination of basic drug substances.
- Urine alkalisation in the case of intoxication with weak organic Symptoms Sodium bicarbonate may interact with gluco- and
acids, e. g. barbiturates or acetylsalicylic acid; mineralocorticoids, androgens and diuretics increasing the
Overdose may lead to alkalosis, hypernatraemia, and serum
- Urine alkalisation in order to improve the solubility of drug potassium excretion.
hyperosmolarity. When an acidosis is corrected too rapidly, esp. in
substances which are poorly soluble in neutral or acid medium, cases of concomitant respiratory disorders, the increased liberation Due to their alkaline pH, sodium bicarbonate solutions are
e. g. methotrexate, sulphonamides; of carbon dioxide may transiently aggravate cerebral acidosis. incompatible with most medicaments. In particular, they must
- Urine alkalisation in the case of haemolysis. Emergency treatment, antidotes not be administered simultaneously with solutions containing
calcium, magnesium or phosphate because of the possibility of
CONTRAINDICATIONS Therapy of alkalosis, depending on its severity: Infusion of
precipitation.
4.2% SODIUM BICARBONATE INTRAVENOUS INFUSION physiological saline, substitution of potassium; in marked alkalosis
must not be administered to patients with infusion of arginine hydrochloride or hydrochloric acid. DOSAGE
- respiratory and metabolic alkalosis, UNDESIRABLE EFFECTS The quantity of 8.4 % W/V SODIUM BICARBONATE
- hypernatraemia, INJECTION to be administered is determined by the blood gas
Administration of Sodium Bicarbonate Intravenous Infusion may
- hypokalaemia. values and is calculated according to the following formula:
lead to hypernatraemia, and serum hyperosmolarity.
# ml of 1 M (8.4 % w/v) sodium bicarbonate solution
SPECIAL WARNINGS AND PRECAUTIONS FOR USE Paravenous administration may lead to tissue necrosis.
Note = base decit x kg b.w. x 0.3
4.2 % W/V SODIUM BICARBONATE INTRAVENOUS
Patients are advised to inform their doctor or pharmacist if they (The factor 0.3 corresponds to the proportion of the extracellular
INFUSION should only be administered with particular caution
notice any adverse reaction not mentioned in this leaet. uid in relation to total body uid).
in presence of the following conditions:
hypoventilation, Example:
EXPIRY DATE
- hypocalcaemia, If in a patient of 70 kg b.w. the base decit is 5 mmol/l, then
- increased serum osmolarity, the labelling. 5 x 70 x 0,3 = 105 ml of 8.4 % W/V SODIUM BICARBONATE
- further in all situations where sodium intake must be restricted INJECTION are to be given.
like cardiac insufciency, oedema, hypertension, eclampsia, INSTRUCTIONS FOR STORAGE / USE / HANDLING Maximum daily dose
severe kidney insufciency. Only to be used if solution is clear and container undamaged. The maximum daily dose depends on the correction requirements.
Administration of 4.2 % W/V SODIUM BICARBONATE The solution is supplied in single-use containers. Unused portions Correction of metabolic acidosis should not be effected too rapidly.
INTRAVENOUS INFUSION may lead to sodium and uid of the solution must be discarded. It is advisable to start administering only half of the calculated
overload. dose and adjust further doses according to the actual results of
Correction of the acid-base status is always associated with 8.4 % W/V SODIUM BICARBONATE blood gas analysis.
shifts of the electrolyte balance. In particular, the potassium
INJECTION For urine alkalisation the dose is adjusted according to the desired
balance is affected. Alkalisation or correction of acidosis pH of the urine and administration should be accompanied by
promote the potassium inux into cells and may therefore lead to monitoring of the acid-base balance and the water balance. Care
hypokalaemia. (Sodium bicarbonate) should be taken not to exceed the maximum infusion rate stated
Patient monitoring should include regular checks of the acid- below.
base balance, the serum electrolyte concentrations and the water COMPOSITION Maximum infusion rate
balance. 100 ml of solution contain:
Up to 1.5 mmol of sodium bicarbonate per kg body weight per
Potassium or calcium deciencies should be corrected before Sodium bicarbonate 8.40 g hour, corresponding to
beginning of the alkalinising therapy. Excipient: 1.5 ml of 8.4 % W/V SODIUM BICARBONATE INJECTION/
If infused too rapidly into peripheral veins, 4.2 % W/V SODIUM Water for Injections kg b.w./h.
BICARBONATE INTRAVENOUS INFUSION may cause vein
1 ml contains 1 mmol of sodium and 1 mmol of bicarbonate. Method of administration
irritation and consecutively phlebitis or thrombosis on account of
its alkalinity. Theoretical osmolarity 2000 mOsm/l Intravenous use, as additive to large-volume parenteral solutions.
It must be made absolutely sure that the solution is infused Titration alkalinity (to pH 7.4) approx. 80 mmol/l 8.4 % W/V SODIUM BICARBONATE INJECTION should
intravenously; accidental intra-arterial infusion may cause shock pH 7.0 - 8.5 be added to the vehicle solution under strictly aseptic conditions,
or loss of an extremity. PHARMACEUTICAL FORM immediately before setting up the infusion. The container should
then be shaken gently.
INTERACTIONS Concentrate for solution for infusion
As a rule the calculated amount of sodium bicarbonate is diluted
Urine alkalisation by sodium bicarbonate accelerates the PHARMACO-THERAPEUTIC GROUP in 250 ml of a suitable vehicle solution. Larger volumes may be
elimination of acid drug substances, e.g. acetylsalicylic acid, and required in cases of uid deciency.
Solution for electrolyte substitution
delays the elimination of basic drug substances.
INDICATIONS For infusion into peripheral veins, the solution must be diluted so
Sodium bicarbonate may interact with gluco- and
as not to exceed an osmolarity of 800 mOsm/l.
mineralocorticoids, androgens and diuretics increasing the - Correction of metabolic acidosis;
potassium excretion. - Urine alkalisation in the case of intoxication with weak organic OVERDOSE
Due to their alkaline pH, sodium bicarbonate solutions are acids, e. g. barbiturates or acetylsalicylic acid; Symptoms
incompatible with most medicaments. In particular, they must - Urine alkalisation in order to improve the solubility of drug Overdose may lead to alkalosis, hypernatraemia, and serum
not be administered simultaneously with solutions containing substances which are poorly soluble in neutral or acid medium, hyperosmolarity. When an acidosis is corrected too rapidly, esp. in
calcium, magnesium or phosphate because of the possibility of e. g. methotrexate, sulphonamides; cases of concomitant respiratory disorders, the increased liberation
precipitation. - Urine alkalisation in the case of haemolysis. of carbon dioxide may transiently aggravate cerebral acidosis.
DOSAGE CONTRAINDICATIONS Emergency treatment, antidotes
The dose depends on the degree of the disorder of the acid- 8.4 % SODIUM BICARBONATE INJECTION must not be Therapy of alkalosis, depending on its severity: Infusion of
base status. According to the blood gas values the amount to be administered to patients with physiological saline, substitution of potassium; in marked alkalosis
administered is calculated applying the following formula: - respiratory and metabolic alkalosis, infusion of arginine hydrochloride or hydrochloric acid.
# ml of 0.5 M (4.2 % w/v) sodium bicarbonate solution = base - hypernatraemia, UNDESIRABLE EFFECTS
decit x kg BW x 0.3 x 2 - hypokalaemia.
Administration of 8.4 % W/V SODIUM BICARBONATE
(The factor 0.3 corresponds to the proportion of the extracellular SPECIAL WARNINGS AND PRECAUTIONS FOR USE INJECTION may lead to hypernatraemia, and serum
uid in relation to total body uid). hyperosmolarity
8.4 % W/V SODIUM BICARBONATE INJECTION should
Example: only be administered with particular caution in the presence of the If injected into peripheral veins the solution may cause vein
If in a patient of 70 kg BW the base decit is 5 mmol/l, then following conditions: irritation, phlebitis, or thrombosis.
5 x 70 x 0,3 x 2 = 210 ml of 4.2 % W/V SODIUM BICARBONATE - hypoventilation, Paravenous administration may lead to tissue necrosis.
INTRAVENOUS INFUSION are to be given. - hypercalcaemia, Note:
Correction of metabolic acidosis should not be effected too rapidly. - increased serum osmolarity,
Patients are advised to inform their doctor or pharmacist if they
It is advisable to start administering only half of the calculated - further in all situations where sodium intake must be restricted notice any adverse effect not mentioned in this leaet.
dose and adjust further doses according to the actual results of like cardiac insufciency, oedema, hypertension, eclampsia,
blood gas analysis. severe kidney insufciency. EXPIRY DATE
For urine alkalisation the dose is adjusted according to the desired Administration of 8.4 % W/V SODIUM BICARBONATE The product must not be used beyond the expiry date stated on
pH of the urine and administration should be accompanied by INJECTION may lead to sodium and uid overload. the labelling.
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INSTRUCTIONS FOR STORAGE / USE / HANDLING Note:
Only to be used if solution is clear and container undamaged. 0.9 % W/V SODIUM CHLORIDE Patients are advised to inform their doctor or pharmacist if they
The solution is supplied in single-dose containers. Solution should INTRAVENOUS INFUSION notice any adverse effect not mentioned in this leaet.
be used immediately after opening the container. Unused portions EXPIRY DATE
of the solution must be discarded. (Sodium Chloride) The product must not be used beyond the expiry date stated on
The solution is almost saturated. It should not be stored below the labelling.
room temperature. Possible crystallisation can be reversed by COMPOSITION
gently warming up the solution. INSTRUCTIONS FOR USE / HANDLING
1000 ml of solution contain
Sodium Chloride 9.0 g Only to be used if solution is clear and the container undamaged.
0.9 % W/V SODIUM CHLORIDE Excipients: GENERAL GUIDELINES ON FLUID AND ELECTROLYTE
INJECTION Water for Injections INTAKE:
Theoretical osmolarity: 308 mOsm/l A level of 30 ml of the solution per kg body weight per day only
(Sodium Chloride) Titration acidity (to pH 7.4): < 0.3 mmol/l covers the physiological basic uid requirements. Post-operatively
pH: 4.5 - 7.0 and in intensive care patients there is an increased requirement
COMPOSITION Electrolyte concentrations: for uid intake on account of the limited concentrating capacity
of the kidneys and the increased excretion of metabolites, so
100 ml of solution contain Sodium 154 mmol/l
that it is necessary to increase the uid intake to about 40 ml/kg
Active substance: Chloride 154 mmol/l
body weight per day. Additional losses (e.g. fever, diarrhoea,
Sodium Chloride 0.9 g PHARMACEUTICAL FORM stulae, vomiting etc.) must be compensated for by a still higher,
Excipient: Solution for infusion individually adapted uid intake. The actual and individual uid
Water for Injections requirement is determined by the stepwise monitoring necessary
PHARMACO-THERAPEUTIC GROUP
in every case (e.g. urine excretion, osmolarity in serum and urine,
Electrolyte concentrations: Solution for uid and electrolyte supply, vehicle solution determination of substances excreted).
Sodium 154 mmol/l
INDICATIONS The basic substitution of the most important cations sodium and
Chloride 154 mmol/l potassium amounts to approx. 1.5 3 mmol/kg body weight per
- Fluid and electrolyte substitution in hypochloraemic alkalosis;
Theoretical osmolarity: 308 mOsm/l - Chloride losses; day and 0.8 1.0 mmol/kg body weight per day respectively. The
Titration acidity: < 0.3 mmol/l - Short-term intravascular volume substitution; actual requirement during infusion therapy depends on appropriate
pH: 4.5 - 7.0 - Hypotonic dehydration; determinations of the electrolyte balance and on the laboratory
- Isotonic dehydration; monitoring of the plasma concentrations.
PHARMACEUTICAL FORM
- Vehicle solution for compatible electrolyte concentrates and Instructions for Handling the Ecoac plus Container
Solution for injection
medicaments; Instructions for Handling the Ecoac plus Container
PHARMACO-THERAPEUTIC GROUP - Externally for wound irrigation and moistening of wound
Vehicle solution dressings. 1. Gravity infusion 3. Admixture of additives
CONTRAINDICATIONS - Insert infusion Addition via
INDICATIONS
set, ll half of cannula
Solvent or diluent for compatible electrolyte concentrates or 0.9 % W/V SODIUM CHLORIDE INTRAVENOUS d r i p c h a m b e r, - Insert cannula
drugs. INFUSION must not be used in states of hyperhydration. ll infusion vertically.
CONTRAINDICATIONS SPECIAL WARNINGS AND PRECAUTIONS FOR USE tube avoiding
bubbles.
None 0.9 % W/V SODIUM CHLORIDE INTRAVENOUS
- Close air vent of
INFUSION should only be administered with caution in cases of
PRECAUTIONS FOR USE AND SPECIAL WARNINGS infusion set.
- hypokalaemia - Connect infusion
0.9 % W/V SODIUM CHLORIDE INJECTION should only be - hypernatraemia tube to cannula/
administered with particular caution to patients with - hyperchloraemia catheter.
- hypernatraemia - disorders where restriction of sodium intake is indicated, - Open clamp and
- hyperchloraemia such as cardiac insufciency, generalised oedema, pulmonary start infusion wit
oedema, hypertension, eclampsia, severe renal insufciency. air vent closed
INTERACTIONS
Patient monitoring should include regular checks of the serum
When mixing with other medicaments, possible incompatibilities 2.Pressure infusion Addition using the transfer
ionogram and the water balance.
should be considered. - Insert infusion cap (Ecoac
High infusion rates should be avoided in cases of hypertonic set. Mix)
DOSAGE dehydration because of possible increases of plasma osmolarity
- Hold container 1 Attach transfer
The quantity to be chosen depends on the desired concentration of and plasma sodium concentration.
upright. cap to the
the medicament to be dissolved. In case of pressure infusion, which may be necessary in vital container.
- Leave clamp
For the use of this solution as solvent/diluent for compatible emergencies, all air must be removed from the container and the open, expel air 2 Attach vial to
electrolyte concentrates or medicaments, the instructions for use infusion set before the solution is administered. from container the other end
relating to the medicament to be added should be observed. INTERACTIONS and ll half of (click!).
Method of administration drip chamber. 3 Transfer
When mixing with other medicaments, physical or chemical
Intravenous or subcutaneous injection. incompatibilities should be considered. - Turn container solution into the
and expel air vial containing
OVERDOSE DOSAGE from infusion the additive
Symptoms The dose is adjusted according to the patient's actual need of uid device. by pressing
and electrolytes. - Close clamp. the Ecoac
Overdose of 0.9 % W/V SODIUM CHLORIDE INJECTION
The amount to be used for irrigation or moistening depends on plus container.
may result in hypernatraemia, hyperchloraemia, hyperhydration,
actual requirements. Dissolve
hyperosmolarity of the serum, and metabolic acidosis. additive
Emergency treatment, antidotes Recommended daily dose
completely.
Immediate stop of administration, administration of diuretics Up to 40 ml/kg b.w./day, corresponding to 6 mmol of sodium/ kg Turn Ecoac
with continuous monitoring of serum electrolytes, correction of b.w./day. plus container
electrolyte and acid-base imbalances. Infusion rate with attached
Up to 5 ml/kg b.w./hour, corresponding to a maximum drop rate of vial upside
UNDESIRABLE EFFECTS down. Press
1.7 drops/kg b.w./min.
None to be expected if the product is used according to air into the vial
Method of administration until all solution
directions.
Intravenous infusion, irrigation or moistening. has been
Note
Precautions re. pressure infusion, see section "Precautions for transferred into
Patients are advised to inform their doctor or pharmacist if they Use" and gures at the end of this leaet. the Ecoac
notice any adverse reaction in connection with the administration plus container.
of this product. OVERDOSE
Symptoms
EXPIRY DATE - Place container Documentation
Overdose may result in hypernatraemia, hyperchloraemia, in pressure of addition and
The product must not be used beyond the expiry date stated on hyperhydration, and metabolic acidosis. cuff. re-sealing the
the labelling.
Emergency treatment, antidotes - Build up injection port with
INSTRUCTIONS FOR USE / HANDLING Immediate cessation of infusion, administration of diuretics pressure. ECOPIN
The solution is supplied in single-use containers. Discard unused with continuous monitoring of serum electrolytes, correction of - Open clamp 1 Insert
contents. electrolyte and treatment of acidosis. and start ECOPINinto
infusion. injection port
Use contents immediately after opening the container. UNDESIRABLE EFFECTS
2 Break off handle
Only to be used if solution is clear and the container undamaged. Administration may lead to hypernatraemia and hyperchloraemia.
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monitoring of serum electrolytes, correction of electrolyte and INTERACTIONS
5.85 % W/V SODIUM CHLORIDE acid-base imbalances. When mixing with other medicaments it should be remembered
INJECTION UNDESIRABLE EFFECTS that 0.45 % W/V SODIUM CHLORIDE AND 5 % W/V
GLUCOSE Intravenous Infusion has an acid pH which can
Administration of 5.85 % W/V SODIUM CHLORIDE
cause precipitation in the mixture.
(Sodium Chloride) INJECTION may lead to hypernatraemia and hyperchloraemia.
Too rapid infusion of solutions with high sodium concentration DOSAGE
COMPOSITION may cause acute volume overload, osmotic diuresis and diarrhoea, The dose is adjusted according to the uid, electrolyte and energy
100 ml of concentrate for solution for infusion contain further hypernatraemia and hyperchloraemia. requirements:
Active ingredient: Infusion of solutions with high sodium concentration into
MAXIMUM DOSE:
Sodium Chloride 5.85 g peripheral veins may cause vein irritation or even phlebitis.
Note: 40 ml/kg BW per day, corresponding to 2 g glucose/kg BW per
Excipient: day
Water for Injections Patients are advised to inform their doctor or pharmacist if they
notice any adverse effect not mentioned in this leaet. Infusion and drop rate:
Theoretical Osmolarity 2000 mOsm/l
Not more than 5 ml/kg BW per hour, corresponding to 0.25 g
Titration acidity (to pH 7,4) < 0.5 mmol/l EXPIRY DATE
glucose/kg BW per hour or not more than 1.7 drops/kg BW per
pH 5.0 - 7.0 The product must not be used beyond the expiry date stated on min.
1 ml contains 1 mmol of sodium and 1 mmol of chloride the labelling.
Partial coverage of energy requirements, i. e. substitution of the
PHARMACEUTICAL FORM INSTRUCTIONS FOR STORAGE / USE / HANDLING obligatory daily glucose requirements, is only possible with the
Concentrate for solution for infusion The product is supplied in single-use containers. Discard unused maximum dose stated above.
contents. For the use of this solution as vehicle solution, the instructions for
Only to be used if solution is clear and container undamaged. use relating to the medicament to be added should be observed.
Solution for electrolyte substitution
Method of administration
INDICATIONS 0.45% W/V SODIUM CHLORIDE and
- Hyponatraemia, Intravenous infusion
- Hypochloraemia,
5% W/V DEXTROSE INTRAVENOUS
OVERDOSE
- Hypotonic hyperhydration, INFUSION. Symptoms
CONTRAINDICATIONS Overdose may result in hyperhydration with increased skin tension,
5.85 % W/V SODIUM CHLORIDE INJECTION must not be (Sodium Chloride, Glucose ) venous congestion, oedema - possibly also lung or brain oedema -,
used in cases of hypokalaemia and acidbase imbalances, and hyperglycaemia.
COMPOSITION
-Hypernatraemia, Emergency treatment, antidotes Immediate cessation of
1000 ml of solution contain infusion, administration of diuretics with continuous monitoring
-Hyperchloraemia
Active ingredients: of serum electrolytes, correction of electrolyte and acid-base
SPECIAL WARNINGS AND PRECAUTIONS FOR USE imbalances, administration of insulin if necessary.
Sodium Chloride 4.5 g
5.85 % W/V SODIUM CHLORIDE INJECTION should only Glucose 50.0 g
be administered with caution in cases of UNDESIRABLE EFFECTS
(as glucose monohydrate 55.0 g) None to be expected if the solution is used according to
- Hypokalaemia,
- Disorders where restriction of sodium intake is indicated, Excipient: instructions.
such as cardiac insufciency, generalised oedema, pulmonary Water for Injections Note
oedema, hypertension, eclampsia, severe renal insufciency, Electrolyte concentrations: Patients are advised to inform their doctor or pharmacist if they
- Therapy with corticosteroids or with ACTH, Sodium 77 mmol/l notice any adverse reaction in connection with the administration
- Metabolic acidosis. Chloride 77 mmol/l of this drug.
Clinical monitoring should include checks of the serum ionogram, Carbohydrate content 50 g/l
EXPIRY DATE
the water balance, and the acid-base balance. Caloric value: 835 kJ/l 200 kcal/l
INTERACTIONS Theoretical osmolarity: 432 mOsm/l
the labelling.
During therapy with corticosteroids or ACTH there may be an Titration acidity: < 0.5 mmol/l
increased retention of sodium and chloride. pH: 3.5 5.5 INSTRUCTIONS FOR STORAGE / USE / HANDLING
Incompatibility can arise upon mixing with other medicaments. PHARMACEUTICAL FORM Do not store above 25 C
The attending doctor will decide on the use of mixed infusions. Solution for infusion Only to be used if solution is clear and the container or its closure
do not show visible signs of damage.
DOSAGE PHARMACO-THERAPEUTIC GROUP
For single use only. Discard unused contents.
The dose is adjusted according to the analytical values of the serum Solution for uid, electrolyte and carbohydrate supply
ionogram and should also be adjusted according to the analytical GENERAL GUIDELINES ON THE CARBOHYDRATE
values of the acid-base status. INDICATIONS INTAKE:
The sodium decit is calculated by the formula: - Hypertonic dehydration
The total input of carbohydrates should be restricted to 350 to 400
Sodium decit (mmol) = (Na+required - Na+actual) kg BW - Isotonic dehydration g per day under normal metabolic conditions.
0.2 - Partial coverage of energy requirements
In conditions of impaired glucose metabolism, e.g. in postoperative/
(The extracellular volume is calculated as body weight 0.2) - Vehicle solution for compatible electrolyte concentrates and
post-traumatic stress, in hypoxic states or organ insufciency, the
medicaments
Maximum daily dose daily dose should be reduced to 200 - 300 g; individual adaptation
The maximum daily dose depends on the actual need of CONTRAINDICATIONS of the dose requires adequate monitoring.
electrolytes. As a rule, the daily dose for adults is 3 - 6 mmol/kg 0.45 % W/V SODIUM CHLORIDEAND 5 % W/V The following dose limitations should be observed for the
BW, for children 3 - 5 mmol/kg BW GLUCOSE Intravenous Infusion must not be used in cases of: administration of glucose to adults:
Maximum infusion rate - hyperhydration states 0.25 g glucose/kg body weight per hour and up to 6 g/kg body
The maximum infusion rate depends on the prevailing clinical - hypotonic dehydration weight per day.
situation. - hypokalaemia
GENERAL GUIDELINES ON THE FLUID AND
Method of administration SPECIAL WARNINGS AND PRECAUTIONS FOR USE ELECTROLYTE INTAKE:
Intravenous use, only diluted by addition to a suitable infusion 0.45 % W/V SODIUM CHLORIDE AND 5 % W/V A level of 30 ml of the solution per kg body weight per day only
solution. GLUCOSE covers the physiological basic uid requirements. Post-operatively
In general, the calculated amount of sodium chloride is added to Intravenous Infusion should only be administered and in intensive care patients there is an increased requirement for
250 ml of uid. In cases of uid decit larger volumes of vehicle uidintake on account of the limited concentrating capacity
with caution in cases of
solution may be used. For infusion into peripheral veins, the
- hyponatraemia of the kidneys and the increased excretion of metabolites, so that
solution must be diluted so as not to exceed an osmolarity of 800
mOsm/l. - persistent hyperglycaemia not responding to insulin doses of up it is necessary to increase the uid intake to about 40 ml/kg body
to 6 i.u./hour weight per day.
Care should be taken to add the sodium chloride concentrate to
the infusion solution under strictly aseptic conditions immediately Clinical supervision should include checks of the serum ionogram Additional losses (e.g. fever, diarrhoea, stulae, vomiting etc.)
before setting up the infusion. After mixing the infusion bottle and the water balance. Special attention should be paid to regular must be compensated for by a still higher, individually adapted
should be gently shaken. monitoring of the serum potassium concentration. uid intake. The actual and individual uid requirement is
In post-operative and post-traumatic conditions and in conditions determined by the stepwise monitoring necessary in every case
OVERDOSE (e.g. urine excretion, osmolarity in serum and urine, determination
of impaired glucose tolerance: only administer with monitoring of
Symptoms blood glucose level. of substances excreted).
Too rapid infusion of hypertonic solutions may cause acute volume For correction of hypertonic dehydration, solutions containing The basic substitution of the most important cations sodium and
overload. Overdose may cause hyperhydration, hypernatraemia not less than 70 mmol/l of sodium should be used. The time for potassium amounts to ca. 1.5 3 mmol/kg body weight per day
and hyperchloraemia, serum hyperosmolarity, and metabolic correction should not be shorter than 48 hours. and 0.8 1.0 mmol/kg body weight per day respectively. The
acidosis. actual requirement during infusion therapy depends on appropriate
The solution should not be administered through the same infusion
Emergency treatment, antidotes equipment simultaneously, before or after an administration of determinations of the electrolyte balance and on the laboratory
Stop of infusion, administration of diuretics with continuous blood because of the possibility of pseudo-agglutination. monitoring of the plasma concentrations.
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For the use of this solution as vehicle solution, the instructions for INDICATIONS
0.9% W/V SODIUM CHLORIDE AND use relating to the medicament to be added should be observed. - Irrigation of wounds and burns;
5% W/V DEXTROSE Method of administration - Mechanical irrigation of the eyes
Intravenous Infusion Intravenous infusion - Moistening of wound tamponades, cloths and dressings;
- Rinsing and cleansing of bladder catheters;
OVERDOSE - Irrigation and cleansing in stoma care;
(Sodium Chloride, Glucose) Symptoms - Filling of respiratory air humidiers;
Overdose may result in hyperhydration, electrolyte and acid-base - Rinsing and cleansing of instruments;
COMPOSITION imbalances, hyperglycaemia, and hyperosmolarity of the serum. - Intra- and post-operative irrigation
1000 ml of solution contain (endoscopic interventions without HF current, after TUR
Active ingredients: interventions).
Immediate stop of infusion, administration of diuretics with
Sodium Chloride 9.0 g continuous monitoring of serum electrolytes, correction of CONTRAINDICATIONS
Glucose 50.0 g electrolyte and acid-base imbalances, administration of insulin if This product must not be used in electrosurgical procedures.
(as glucose monohydrate 55.0 g)
necessary.
Excipients: SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
Water for Injections UNDESIRABLE EFFECTS FOR USE
Electrolyte concentrations: Administration may lead to hypernatraemia and hyperchloraemia. Do not use for infusion
Sodium 154 mmol/l Note DOSAGE
Chloride 154 mmol/l Patients are advised to inform their doctor or pharmacist if they The required amount of uid depends on the particular situation.
Carbohydrate content 50.0 g/l notice any adverse reaction not mentioned in this leaet.
Caloric value: 835 kJ/l = 200 kcal/l OVERDOSE
Theoretical osmolarity: 586 mOsm/l EXPIRY DATE Symptoms
Titration acidity: < 0.5 mmol/l The product must not be used beyond the expiry date stated on Overdose during wound irrigation and intra operative application
pH: 3.5 5.5 the label. can lead to systemic absorption of irrigation uid, with consecutive
uid overload: hyper hydration and electrolyte disorders. This
PHARMACEUTICAL FORM INSTRUCTIONS FOR STORAGE / USE / HANDLING manifests as headache, nausea, restlessness, and disorientation. In
Solution for infusion Only to be used if solution is clear and the container or its closure severe cases, comatose states may occur.
PHARMACO-THERAPEUTIC GROUP do not show visible signs of damage. Emergency treatment, antidotes
Solution for supply of uid with electrolytes and glucose. After end of infusion, discard any remaining contents. Stop of irrigation, correction of the uid and electrolyte balance,
depending on the particular clinical situation.
INDICATIONS Do not store above 25 C.
- Fluid and electrolyte substitution in hypochloraemic alkalosis, UNDESIRABLE EFFECTS
GENERAL GUIDELINES ON THE CARBOHYDRATE
- Chloride losses, INTAKE: None known
- Hypotonic dehydration, Note:
The total input of carbohydrates should be restricted to 350 to 400
- Isotonic dehydration, g per day under normal metabolic conditions. Patients are advised to inform their doctor or pharmacist if they
- Partial coverage of energy requirements, notice any adverse effect connection with the administration of
In conditions of impaired glucose metabolism, e.g. post-aggression this product.
- Vehicle solution for compatible electrolyte concentrates and metabolism, hypoxic states or organ insufciency, the daily dose
medicaments. should be reduced to 200 - 300 g; individual adaptation of the dose EXPIRY DATE
CONTRAINDICATIONS requires adequate monitoring. The product must not be used beyond the expiry date stated on
0.9 % W/V SODIUM CHLORIDE AND 5 % W/V The following dose limitations should be observed for the the label.
GLUCOSE administration of glucose to adults: INSTRUCTIONS FOR STORAGE / USE / HANDLING
Intravenous Infusion must not be used in cases of: 0.25 g glucose/kg body weight per hour and up to 6 g/kg body Only to be used if solution is clear and the container undamaged.
- hyperhydration states, weight per day. Unused contents of an opened container must be discarded and not
- hypertonic dehydration, be stored for later use.
GENERAL GUIDELINES ON FLUID AND ELECTROLYTE
- hypokalaemia. INTAKE: Keep this product out of the reach and sight of children.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE A level of 30 ml of the solution per kg body weight per day only
0.9 % W/V SODIUM CHLORIDE AND 5 % W/V covers the physiological basic uid requirements. Post-operatively AMINOPLASMAL - 5 % E
GLUCOSE and in intensive care patients there is an increased requirement for Solution for Injection
Intravenous Infusion should only be administered uid intake on account of the limited concentrating capacity
with caution in cases of: of the kidneys and the increased excretion of metabolites, so that
- hypernatraemia, it is necessary to increase the uid intake to about 40 ml/kg body (Isoleucine, Leucine, Lysine, Hydrochloride,
- hyperchloraemia, weight per day. Methionine, Phenylalanine, Threonine, Tryp-
- disorders where restriction of sodium intake is indicated, such Additional losses (e.g. fever, diarrhoea, stulae, vomiting etc.) tophan, Valine, Arginine, Histidine, Glycine,
as cardiac insufciency, generalisedn oedema, pulmonary must be compensated for by a still higher, individually adapted uid
oedema, hypertension, eclampsia, severe renal insufciency, intake. The actual and individual uid requirement is determined
Alanine, Proline, Aspartic Acid, Asparagine
- persistent hyperglycaemia not responding to insulin doses of up by the stepwise monitoring necessary in every case (e.g. Monohydrate, Acetylcysteine, Glutamic Acid,
to 6 i.u./hour. urine excretion, osmolarity in serum and urine, determination of Ornithine Hydrochloride, Serine, Tyrosine,
Clinical supervision should include checks of the serum ionogram substances excreted). Acetyltyrosine, Sodium Acetate Trihydrate,
and the water balance. Special attention should be paid to regular The basic substitution of the most important cations sodium and
monitoring of the serum potassium level. Potassium Acetate, Magnesium Acetate
potassium amounts to ca. 1.5 3 mmol/kg body weight per day
In post-operative and post-traumatic conditions and in conditions and 0.8 1.0 mmol/kg body weight per day respectively. The Tetrahydrate, Sodium Dihydrogen Phos-
of impaired glucose tolerance: only administer with monitoring of actual requirement during infusion therapy depends on appropriate phate Dihydrate, Sodium Hydroxide, Malic
blood glucose level. determinations of the electrolyte balance and on the laboratory
The solution should not be administered through the same infusion
Acid)
monitoring of the plasma concentrations.
equipment simultaneously, before or after an administration of
COMPOSITION
blood because of the possibility of pseudo-agglutination.
0.9 % W/V SODIUM CHLORIDE 1000 ml of solution contain
Irrigation Solution Active ingredients:
See warning re. eclampsia above. Isoleucine 2.55g
INTERACTIONS Leucine 4.45g
(Sodium Chloride) Lysine Hydrochloride 3.50g
When mixing with other medicaments it should be remembered
that 0.9 % W/V SODIUM CHLORIDE AND 5 % W/V (equivalent to Lysine 2.80 g)
COMPOSITION
GLUCOSE Intravenous Infusion has an acid pH which can cause Methionine 1.90g
1000 ml of solution contain Phenylalanine 2.55g
precipitation in the mixture.
Sodium Chloride 9.0 g Threonine 2.05g
DOSAGE
Excipients: Tryptophan 0.90g
The dose is adjusted according to uid, electrolyte and energy Valine 2.40g
Water for Injections
requirements: Arginine 4.60g
Electrolyte concentrations:
Maximum dose 40 ml/kg BW per day, corresponding to 2 g Histidine 2.60g
glucose/kg BW per day Sodium 154 mmol/l
Glycine 3.95g
Infusion and drop rate: Chloride 154 mmol/l
Alanine 6.85g
Theoretical osmolarity: 308 mOsm/l
Not more than 5 ml/kg BW per hour, corresponding to 0.25 g Proline 4.45g
glucose/kg BW per hour or not more than 1.7 drops/kg BW per PHARMACEUTICAL FORM Aspartic Acid 0.65g
min. Solution for irrigation Asparagine Monohydrate 1.86g
Partial coverage of energy requirements, i. e. substitution of the (equivalent to Asparagine 1.64 g)
obligatory daily glucose requirements, is only possible with the PHARMACO-THERAPEUTIC GROUP Acetylcysteine 0.34g
maximum dose stated above. Sodium chloride solution for irrigation (equivalent to Cysteine 0.25 g)
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Glutamic Acid 2.30g For complete parenteral nutrition, administration of carbohydrates, EXPIRY DATE
Ornithine Hydrochloride 1.60g essential fatty acids, vitamins and trace elements is necessary. The product must not be used beyond the expiry date stated on
(equivalent to Ornithine 1.25 g) the labelling.
Serine 1.20g
No preclinical or clinical studies regarding the use in pregnant INSTRUCTIONS FOR STORAGE / USE / HANDLING
Tyrosine 0.30g
or breast-feeding women have been conducted with this product. Keep the container in the outer carton in order to protect the
Acetyltyrosine 0.43g On the other hand, there are no ndings suggesting that the contents from light.
(equivalent to Tyrosine 0.35 g) constituents of AMINOPLASMAL - 5 % E would be harmful to The product is supplied in single-use containers. Unused contents
Sodium Acetate Trihydrate 3.95g embryos, fetuses or pregnant women. must be discarded and should not be stored for later use.
Potassium Acetate 2.45g
Yet AMINOPLASMAL - 5 % E should be administered during The solution should not be administered if it is not clear or if the
Magnesium Acetate Tetrahydrate 0.56g pregnancy and lactation and after careful assessment of its benets container or its closure show visible signs of damage.
Sodium Dihydrogen Phosphate Dihydrate 1.40g and possible risks.
Sodium Hydroxide 0.20g
Malic Acid 1.01g
INTERACTIONS AMINOPLASMAL-10% Solution for Inf.
On account of an increased risk of microbial contamination and
Electrolyte concentrations:
physico-chemical incompatibility, it is not recommended that any (Isoleucine, Leucine, Lysine Hydrochloride,
Sodium 43mmol/l additives should be incorporated into AMINOPLASMAL - 5 %
Potassium 25mmol/l E solution. Methionine, Phenylalanine, Threonine,
Magnesium 2.6mmol/l Tryptophan, Valine, Arginine, Histidine,
Acetate 59 mmol/l DOSAGE
The daily dose is adjusted individually, according to the patients
Glycine, Alanine, Proline, Aspartic Acid,
Chloride 29 mmol/l
Dihydrogen phosphate 9.0mmol/l need of amino acids, electrolytes and uid, depending on her/his Asparagine Monohydrate, Acetylcysteine,
L-Malate 7.5mmol/l
clinical condition, i.e. her/his nutritional status and the degree of Glutamic Acid, Ornithine Hydrochloride,
catabolism. Serine, Tyrosine, Acetyltyrosine).
Total amino acids 50g/l
The infusion should be started at low doses and infusion rates,
Total nitrogen 8.0g/l
with gradual increase to the desired levels. Active ingredients
Caloric value: 835 kJ/l = 200 kcal/l
Theoretical osmolarity 590 mOsm/l When calculating the dose for paediatric patients account should Isoleucine 5.10 g
be taken of the patients hydration status. Leucine 8.90 g
Titration acidity (to pH 7.4) approx. 18 mmol/l
Daily dose: Lysine Hydrochloride 7.00 g
pH 5.0 7.5
20 40 ml/kg body weight (BW) ^;= 1.0 2.0 g of amino (equivalent to Lysine 5.60 g)
Excipients: Methionine 3.80 g
Disodium edetate, water for injections acids/kg BW,
Phenylalanine 5.10 g
^;= 1400 2800 ml for Threonine 4.10 g
PHARMACEUTICAL FORM a patient of 70 kg BW Tryptophan 1.80 g
Solution for infusion Maximum daily dose: Valine 4.80 g
PHARMACO-THERAPEUTIC GROUP 40 ml/kg BW ^;= 2.0 g of amino Arginine 9.20 g
Solution for supply of amino acids acids / kg BW, Histidine 5.20 g
^;= 140 g of amino Glycine 7.90 g
INDICATIONS Alanine 13.70 g
acids for a patient of 70
Supply of substrate for protein synthesis in the setting of parenteral Proline 8.90 g
kg BW
nutrition. Aspartic Acid 1.30 g
` ^;= 2800 ml for a
In parenteral nutrition, aminoacid infusions should always be Asparagine Monohydrate 3.72 g
patient of 70 kg BW (equivalent to Asparagine 3.27 g)
accompanied by administration of sufcient amounts of caloric
solutions, e. g. carbohydrate solutions. Maximum infusion and drop rate: Acetylcysteine 0.68 g
2.0 ml/kg BW/h ^;= 0.1 g of amino (equivalent to Cysteine 0.50 g)
CONTRAINDICATIONS
acids / kg BW/h, Glutamic Acid 4.60 g
- Life threatening unstable circulation, i. e. shock Ornithine Hydrochloride 3.20 g
^;= 45 drops/min for a
- cellular hypoxia or acidosis, (equivalent to Ornithine 2.51 g)
- acute pulmonary oedema, patient of 70 kg BW
Serine 2.40 g
- known hypersensitivity to any of the ingredients of ^;= 140 ml/h Tyrosine 0.30 g
AMINOPLASMAL - 5 % E With this dosage and infusion rate the recommended maximum Acetyltyrosine 1.23 g
This solution should not be given to new-borns or infants up to daily dose (2.0 g/kg BW) and infusion rate (0.1 g/kg BW/h) for (equivalent to Tyrosine 1.00 g)
completed 2nd year as the nutrient relations do not properly meet amino acids are not exceeded. Electrolyte concentrations
the special paediatric requirements. Children Chloride 57 mmol/l
If amino acid requirements exceed 1 g/kg BWday, account should Total amino acids 100 g/l
be taken of the maximum daily uid intake. Then, if necessary, Total nitrogen 16.0 g/l
This solution should be administered with great caution and only Caloric value 1675 kJ/l 400 kcal/l
solutions with higher amino acid concentrations should be used.
after careful consideration of its expected benets and potential Theoretical osmolarity 885 mOsm/l
risks to patients with: The dosage recommendations given here are average values for
orientation. Dosage must be adjusted individually according to the Titration acidity (to pH 7.4) < 6 mmol/l
- inborn errors of amino acid metabolism pH 5.0 7.5
patients age, development stage and disease.
- hyperhydration, Excipients
- hyperkalaemia, Daily doses for:
Disodium edetate, water for injections
- hyponatraemia, 3rd to 5th year: 30 ml/kg BW/day, corresponding to
Individual dosage regimens must be established for patients with 1.5 g amino acids/kg BW/day PHARMACEUTICAL FORM
insufciency of liver, kidneys, adrenal glands, heart or lungs. 6th to 14th year: 20 ml/kg BW/day, corresponding to Solution for infusion
Caution is to be exercised in patients with increased serum 1.0 g amino acids/kg BW/day PHARMACO-THERAPEUTIC GROUP
osmolarity Infusion rate: up to 2 ml/kg BW/h, corresponding to Solution for supply of amino acids
During parenteral therapy uid and electrolyte balance, serum 0.1 g amino acids/kg BW/h
osmolarity, acid-base balance, blood glucose and liver function INDICATIONS
Duration of use Supply of substrate for protein synthesis in the setting of parenteral
should be monitored. Type and frequency of the examinations
depend on the severity of the patients disease and clinical Amino acid solutions may be administered as long as parenteral nutrition.
condition. In particular, regular and more frequent clinical nutrition is indicated. In parenteral nutrition, aminoacid infusions should always be
examinations and laboratory tests are necessary in patients with: Method of administration accompanied by administration of sufcient amounts of caloric
- disorders of amino acid metabolism, Intravenous infusion solutions, e. g. carbohydrate solutions.
- hepatic insufciency, because of the risk of occurrence Amino acid solutions are only one component of parenteral CONTRAINDICATIONS
or worsening of neurological disorders resulting from nutrition. For complete parenteral nutrition, substrates for calorie - life threatening unstable circulation, i. e. shock
hyperammonaemia, supply, essential fatty acids, electrolytes, vitamins, and trace - cellular hypoxia or acidosis
- renal insufciency, in particular in the presence of hyperkalaemia, elements must be administered together with amino acids. This solution should not be given to new-borns or infants up to
risk factors promoting the occurrence or worsening of metabolic completed 2nd year as the nutrient relations do not properly meet
acidosis, and hyperazotaemia due to impaired renal clearance OVERDOSE
the special paediatric requirements.
- In patient s with insufciency of adrenal glands, heart or lungs, Overdose or a too rapid infusion rate may manifest in form of
the uid and electrolyte balance should frequently controlled. nausea, shivering, vomiting and renal amino acid losses. In such PRECAUTIONS FOR USE AND SPECIAL WARNINGS
During long-term administration (over several weeks) blood cell cases, the infusion should be interrupted and later continued at a This solution should be administered to patients with disorders
counts and coagulation factors should be monitored more careful. lower infusion rate. of amino acid metabolism only after careful consideration of its
expected benets and potential risks.
SPECIAL PRECAUTIONS FOR USE IN PAEDIATRICS: UNDESIRABLE EFFECTS
Electrolyte and uid imbalances, i.e. hyperhydration, hypokalae-
The dosage must be adjusted according the patients age, nutritional Provided contraindications, dosage recommendations and mia, hyponatraemia, must be corrected before administration of
status and the prevailing disease. In the case of supplementary or precautions are observed, side effects are not anticipated. this solution.
partial parenteral nutrition further protein supplying nutrients may Note: Individual dosage regimens must be established for patients with
have to be given. Patients are advised to inform their doctor or pharmacist if they hepatic and renal insufciency.
An infusion from one bottle should not be carried out over longer notice any adverse reaction in connection with the administration Caution is to be exercised in patients with increased serum
than 24 hours. of this drug. osmolarity.
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Clinical supervision should include regular checks of uid balance Lysine Monohydrate 8.93 g Method of administration
and serum electrolytes. (equivalent to Lysine 7.95 g) Intravenous infusion into a central vein.
Electrolytes are to be supplied according to actual requirements. Methionine 5.70 g Amino acid solutions are only one component of parenteral
AMINOPLASMAL- 10 % is suitable for total parenteral Phenylalanine 5.70 g nutrition. For complete parenteral nutrition, substrates for calorie
nutrition in combination with appropriate caloric solutions (fat Threonine 5.40 g supply, essential fatty acids, electrolytes, vitamins, and trace
emulsions and carbohydrate solutions). Tryptophan 2.10 g elements must be administered together with amino acids.
INTERACTIONS Valine 7.20 g
Arginine 16.05 g OVERDOSE
On account of an increased risk of microbial contamination and Too rapid infusion rate may lead to adverse reactions such
physico-chemical incompatibility, it is not recommended that any Histidine 5.25 g
Glycine 19.20 g as nausea, shivering, vomiting and renal amino acid losses.
additives should be incorporated into AMINOPLASMAL 10 Overdose may lead to amino acid intoxication, hyperhydration,
% solution. Alanine 22.35 g
hyperosmolarity, disorders of acid-base balanceand serum
Proline 7.35 g
DOSAGE electrolyte concentrations.In such cases, the infusion rate should
Aspartic Acid 7.95 g
The daily dose is adjusted individually, according to the patients be reduced or the infusion should be interrupted. Serum electrolyte
Acetylcysteine 0.50 g disorders are to be corrected.
need of amino acids and uid. (equivalent to Cysteine 0.37 g)
Adults Glutamic Acid 16.20 g UNDESIRABLE EFFECTS
Recommended dose: Serine 3.00 g Provided contraindications, dosage recommendations and
Up to 20 ml/kg body weight/day Tyrosine 0.50 g precautions are observed, adverse effects are not to be expected.
Infusion rate: Excipients: Note:
Up to 1.0 ml/kg body weight/h or (for a 70 kg patient): Sodium hydroxide, disodium edetate, water for injections Patients are advised to inform their doctor or pharmacist of
up to 25 drops/min. Total amino acids 150 g/l any adverse reaction they experience in connection with the
corresponding to approx. 70 ml/h. Total nitrogen 24.0 g/l administration of this drug.
With this dosage and ow rate the recommended maximum daily Caloric value: 2510 kJ/l = 600 kcal/l
EXPIRY DATE
dose (2.0 g/kg b.w.) and infusion rate (0.1 g/kg b.w./h) for amino Theoretical osmolarity 1290 mOsm/l
acids are not exceeded. Titration acidity (to pH 7.4) 30 mmol/l
the label.
Children pH 5.5 7.0
3rd to 5th year: INSTRUCTIONS FOR STORAGE / USE / HANDLING
PHARMACEUTICAL FORM
PROTECT FROM LIGHT.
15 ml/kg b.w./day, corresponding to 1.5 g amino acids/kg b.w./ Solution for infusion
day The product is supplied in single-dose containers. Unused contents
PHARMACO-THERAPEUTIC GROUP must be discarded and should not be stored for later use.
6th to 14th year:
Solution for supply of amino acids The solution should not be administered if it is not clear or if the
10 ml/kg b.w./day, corresponding to1.0 g amino acids/kg b.w./day
container or its closure show visible signs of damage.
Flow rate: INDICATIONS
Cool storage of the solution may lead to formation of crystals, that
up to 1 ml/kg b.w./h, corresponding to 0.1 g amino acids/kg Supply of substrate for protein synthesis in the setting of parenteral
can, however, be easily dissolved by gentle warming.
b.w./h nutrition.
Individual dosage regimens must be established for patients with In parenteral nutrition, aminoacid infusions should always be
hepatic and renal insufciency. accompanied by administration of sufcient amounts of caloric ATROPINE SULPHATE INJECTION 0.5 MG
Duration of use solutions, e. g. carbohydrate solutions. Solution for Injection
Amino acid solutions may be administered as long as parenteral CONTRAINDICATIONS
nutrition is indicated.
AMINOPLASMAL 15 % must not be used when there are (Atropine Sulphate)
- Disorders of amino acid metabolism;
Intravenous infusion into a central vein. COMPOSITION
- Acute renal failure with increased non-protein nitrogen
Amino acid solutions are only one component of parenteral concentrations in the serum; 1 ampoule (1 ml) of solution contains
nutrition. For complete parenteral nutrition, substrates for calorie
- Advanced liver disease; Active ingredient:
supply, essential fatty acids, electrolytes, vitamins, and trace
elements must be administered together with amino acids. - Acidosis; Atropine Sulphate 0.5 mg
- Hyperhydration; (as atropine sulphate monohydrate, 0.513 mg)
OVERDOSE - Hyponatraemia;
Excipients:
Overdose or a too rapid infusion rate may manifest in form of - Hypokalaemia;
nausea, shivering, vomiting and renal amino acid losses. In such Sodium Chloride, Water for Injections
- Dangerous circulation disorders (shock);
cases, the infusion should be interrupted and later continued at a
This solution should not be given to neonates, infants, and children PHARMACEUTICAL FORM
lower infusion rate.
up to the completed 2nd year as the nutrient relations do not Solution for injection
UNDESIRABLE EFFECTS properly meet the special paediatric requirements.
Provided contraindications, dosage recommendations and Precautions for use and special warnings Individual dosage
precautions are observed, adverse effects are not to be expected. Spasmolytic
regimens must be established for patients with hepatic and renal
Note: insufciency. INDICATIONS
Patients are advised to inform their doctor or pharmacist of Caution is to be exercised in patients with increased serum - Treatment of spasms and colic in the gastro-intestinal, biliary
any adverse reaction they experience in connection with the osmolarity. and urinary tracts;
administration of this drug. - Reduction of gastric or pancreatic secretion;
Clinical supervision should include regular checks of uid balance,
EXPIRY DATE serum electrolytes, blood glucose and acid-base balance. - Premedication in anaesthesia;
The product must not be used beyond the expiry date stated on Electrolytes are to be supplied according to actual requirements. - Treatment of brady-arrhythmia;
the labelling. - Antidote in poisoning with insecticides of the organophosphate
INTERACTIONS
group and with parasympathomimetics.
INSTRUCTIONS FOR STORAGE / USE / HANDLING Pharmacological interactions are not known.
Protect from light. On account of an increased risk of microbial contamination and CONTRAINDICATIONS
The product is supplied in single-dose containers. Unused contents physico-chemical incompatibility, it is not recommended that any Atropine Sulphate Injection 0.5 mg must not be used in cases of
must be discarded and should not be stored for later use. additives should be incorporated into AMINOPLASMAL 15 - congestive glaucoma,
Only to be administered if solution is clear and the container or its % solution. - enlargement of the prostate with urine retention
closure do not show visible signs of damage. Mixing or co-infusion with other nutrient solutions is possible; - mechanic obstruction in the gastro-intestinal tract,
Cool storage of the solution may lead to formation of crystals, that however, chemical and galenical compatibility must be conrmed - tachy-arrhythmia,
can, however, be easily dissolved by gentle warming. prior to mixing. - megacolon,
DOSAGE - paralytic ileus,
AMINOPLASMAL-15% The daily dose should be adjusted individually, according to - severe cerebral sclerosis,
Solution for Injection the patient's needs of amino acids and uid, or according to the - severe muscle weakness (myasthenia gravis),
prevailing metabolic situation, respectively. - hypersensitivity towards atropine,
Maximum dose: - acute lung oedema,
(Isoleucine, Leucine, Lysine Monohydrate,
13 ml/kg b.w./day, corresponding to 2 g of amino acids/kg body - gestosis,
Methionine, Phenylalanine, Threonine, weight/day. - caesarean section or during parturition.
Tryptophan, Valine, Arginine, Histidine, Infusion rate: SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Glycine, Alanine, Proline, Aspartic Acid, Up to 0.6 ml/kg b.w./h, corresponding to 0.09 g of amino acids/kg ATROPINE SULPHATE INJECTION 0.5 MG should only be
Acetylcysteine, Glutamic Acid, Serine, b.w./h or up to 0.2 drops/kg b.w./min. used with particular caution in cases of
Tyrosine) Thus, for a patient of 70 kg b.w. the infusion rate is up to 40 ml/h or - elevated temperature (hyperthermia) because atropine can
up to 14 drops/min., corresponding to 6.0 g of amino acids/h. disturb temperature regulation;
COMPOSITION Individual dosage regimens must be established for patients with - hyperthyreosis;
1000 ml of solution contain hepatic and renal insufciency. - cardiac insufciency, because tachycardia should not occur in
Active ingredients: Duration of use this condition;
Isoleucine 5.85 g Amino acid solutions may be administered as long as parenteral - mitral valve stenosis, because tachycardia should not occur in
Leucine 11.40 g nutrition is indicated. this condition;
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- recent myocardial infarction, because in this situation tachy- The dose is administered i.m. or s.c. 30 - 60 min prior to Electrolyte concentrations:
arrhythmia, up to ventricular brillation, may occur; anaesthesia, or i.v. 3 - 5 min prior to anaesthesia. A dose of 0.5 mg Sodium 131 mmol/l
- constipation. of atropine should not be exceeded. Potassium 5.4 mmol/l
Retardation of the intestinal passage following atropine Antidote Calcium 1.8 mmol/l
administration may alter the absorption of medicaments having For therapy of organophosphate poisoning the dose is adjusted Chloride 112 mmol/l
been administered shortly before or simultaneously with atropine. according to the effect of the atropine sulphate. Initially, 0.1 ml Lactate 28 mmol/l
of ATROPINE SULPHATE INJECTION 0.5 MG ( 0.05 mg
EFFECTS ON ABILITY TO DRIVE AND TO USE of atropine sulphate) per kg BW are injected i.v. Treatment is PHARMACEUTICAL FORM
MACHINES continued with the same dose every 10 - 30 min until salivation Solution for infusion
Even if used in accordance with the given directions, atropine may decreases. PHARMACO-THERAPEUTIC GROUP
affect the patient's vision and reactivity in such a manner that his In case of serious poisoning atropine sulphate should be
ability to drive a car or operate machinery is impaired. Solution for uid and electrolyte supply.
administered by continuous infusion.
PREGNANCY AND LACTATION Notice INDICATIONS
- Fluid and electrolyte substitution in conditions of undisturbed
ATROPINE should only be given to pregnant women if it has Suckling infants and patients over 65 year are especially sensitive
acid-base balance or mild acidosis;
been denitely established that its expected benets clearly to atropine. The same holds true for patients with DOWN's
syndrome. In such cases doses should be adjusted with particular - Isotonic and hypotonic dehydration;
outweigh any potential risks.
caution. - Short-term intravascular uid replacement;
ATROPINE passes the placenta and may provoke foetal
- Vehicle solution for electrolyte concentrates and compatible
bradycardia or tachycardia. Method of administration drugs.
Although only minor amounts of atropine pass into breast milk, Intravenous, intramuscular or subcutaneous injection
anticholinergic effects may appear in suckling infants. Therefore CONTRAINDICATIONS
nursing should be discontinued before use of atropine. OVERDOSE COMPOUND SODIUM LACTATE INTRAVENOUS INFU-
Symptoms SION must not be administered to patients in states of hyperhy-
INTERACTIONS dration.
Overdose of atropine sulphate will cause mydriasis, unrest,
ATROPINE sulphate must not be administered together with confusion, hallucinations, convulsions, rise of temperature SPECIAL WARNINGS AND PRECAUTIONS FOR USE
epinephrine or norepinephrine. (atropine fever), esp. in children. Severe intoxication causes COMPOUND SODIUM LACTATE INTRAVENOUS INFU-
The effects of anticholinergic drugs, e.g. amantadine, tricyclic tachycardia, shock, respiratory depression, coma, with possible SION should only be administered with particular caution in the
antidepressants, neuroleptics, antiparkinson drugs, procaine, lethal outcome. presence of the following conditions:
quinidine, may be intensied by simultaneously administered The lethal dose is about 100 mg in adults, and from 10 mg upward - Hypertonic dehydration,
atropine. in children. - Hyperkalaemia
The effect of atropine may be intensied by simultaneously Emergency treatment, antidotes - Hypernatraemia,
administered MAO inhibitors. In adults 1 - 2 mg of physostigmine and in children 0.5 mg of - Hyperchloraemia,
DOSAGE physostigmine are injected slowly i.v. or i.m. If required the - Renal insufciency with tendency to hyperkalaemia,
dose may be repeated at intervals of 1 - 2 hours. For treatment of - Disorders necessitating restriction of sodium intake, such as
Depending on the indication the following dosage guidelines
convulsions, in adults 10 - 20 mg of diazepam, and in children 1 cardiac insufciency, generalised oedema, pulmonary oedema,
should be followed: - 2 mg of diazepam are initially injected i.v. hypertension, eclampsia, severe renal insufciency
Adults Hyperthermia is treated with physical measures. Clincal monitoring should include regular checks of the serum
Spasmolysis Assisted ventilation may become necessary. ionogram and the water balance.
Up to three times 1 - 2 ml of ATROPINE SULPHATE Atropine sulphate is only poorly dialysable. In case of pressure infusion, which may be necessary in vital emer-
INJECTION 0.5 MG ( 0.5 - 1 mg of atropine sulphate) are gencies, all air must be removed from the container and the infu-
injected i.v., i.m. or s.c. for therapy of colic. UNDESIRABLE EFFECTS sion set before the solution is administered.
Reduction of gastric or pancreatic secretion Depending on the dose and the patient's individual responsiveness,
INTERACTIONS
Every 4 hours 1 ml of ATROPINE SULPHATE INJECTION the following side effects may appear after administration of
atropine: Drugs containing oxalate, phosphate, or carbonate/ bicarbonate
0.5 MG ( 0.5 mg of atropine sulphate) is injected i.v. may cause precipitation upon mixing with COMPOUND
From about 0.5 mg upward dryness of the mouth and impaired
Treatment of brady-arrhythmia SODIUM LACTATE INTRAVENOUS INFUSION.
swallowing, reduction of sweating, beginning enlargement of
1 - 3 ml of ATROPINE SULPHATE INJECTION 0.5 MG ( pupils, loss of ocular accomodation, photophobia, increase DOSAGE
0.5 - 1.5 mg of atropine sulphate) are injected i.v. of intraocular pressure, dry and reddened skin, rise of body The daily dose is adjusted according to the patient's actual need of
Premedication in anaesthesia temperature, impaired micturition, constipation after chronic uid and electrolytes.
1 - 2 ml of ATROPINE SULPHATE INJECTION 0.5 MG ingestion. Occasionally also queasiness and retrosternal pain
Maximum daily dose:
( 0.5 1 mg of atropine sulphate) are injected i.m. or s.c. 30 caused by gastro-oesophagal reux are observed.
40 ml per kg body weight per day.
60 min preoperatively or the same dose is injected i.v. 3 - 5 min After higher doses these symptoms aggravate and central nervous
preoperatively reactions appear such as disturbance of speech, vertigo, uncertain Infusion rate:
gait, muscle weakness, confusion, and excitement. The infusion rate should be adjusted according to the patient's
Antidote
Atropine may provoke acute congestive glaucoma. Longer lasting clinical condition. It should normally not exceed the following
For therapy of organophosphate poisoning the dose is adjusted values:
according to the effect of the atropine sulphate. Initially, 4 - 10 ml therapy with atropine may lead to parotitis. Patients with DOWN's
syndrome may experience marked mydriasis and tachycardia 5 ml/kg BW/hour, corresponding to about 1.7 drops/kg BW/min.
of ATROPINE SULPHATE INJECTION 0.5 MG ( 2 - 5 mg
already after low atropine doses. For the use of COMPOUND SODIUM LACTATE
of atropine sulphate) are injected i.v. Treatment is continued with
the same dose approx. every 10 min until salivation decreases. Allergic reactions to atropine may appear in the form of INTRAVENOUS INFUSION as vehicle solution, the
conjunctivitis or rash. Isolated cases of anaphylactic shock after instructions for use relating to the medicament to be added should
For therapy of muscarin or carbamate poisoning, besides other be observed.
atropine have been reported.
therapy e.g. gastrolavage or administration of carbo medicinalis,
Note Precautions re. pressure infusion, see section "Precautions for
initially 2 - 4 ml of Atropine Sulphate Injection 0.5 mg ( 1
Patients are advised to inform their doctor or pharmacist if they Use" and gures at the end of this leaet.
- 2 mg of atropine sulphate) are injected i.m. or i.v. If required
the same dosage regimen may be applied as for organophosphate notice any adverse effect not mentioned in this leaet. OVERDOSE
poisoning. EXPIRY DATE Symptoms
Children The product must not be used beyond the expiry date stated on Overdose may result in hyperhydration with increased skin
Spasmolysis the labelling. tension, venous congestion, oedema - possibly also lung or brain
In general, 0.02 ml of ATROPINE SULPHATE INJECTION oedema -, electrolyte and acid-base imbalances as well as serum
STORAGE hyperosmolarity.
0.5 MG ( 0.01 mg of atropine sulphate) per kg BW are injected
i.v. every 4 - 6 hours. A dose of 0.5 mg of atropine should not be Do not store above 25 C Emergency treatment, antidotes
exceeded. Cessation of infusion, administration of diuretics with continuous
Reduction of gastric or pancreatic secretion COMPOUND SODIUM LACTATE INTRA- monitoring of serum electrolytes, correction of electrolyte and
acid-base imbalances.
In general, 0.02 ml of ATROPINE SULPHATE INJECTION VENOUS INFUSION
0.5 MG ( 0.01 mg of atropine sulphate) per kg BW are injected UNDESIRABLE EFFECTS
i.v. every 4 - 6 hours. A dose of 0.5 mg of atropine should not be Provided the solution is administered according to the directions
exceeded. (Sodium Chloride, Sodium Lactate, Potassium given, side effects are not to be expected.
Treatment of brady-arrhythmia Chloride, Calcium Chloride Dihydrate) Note
The normal dose is 0.02 - 0.06 ml of ATROPINE SULPHATE Patients are advised to inform their doctor or pharmacist if tehy
INJECTION 0.5 MG ( 0.01 - 0.03 mg of atropine sulphate) per COMPOSITION notice any adverse effect in connection with the admnistration of
kg BW i.v. A dose of 0.5 mg of atropine should not be exceeded. 1000 ml of solution contain this medicine.
Premedication in anaesthesia Active substances: EXPIRY DATE
The dose is adjusted according to the patients' body weight: Sodium Chloride 6.00 g The product must not be used beyond the expiry date stated on
up to 3 kg: 0.2 ml ( 0.10 mg Atropine Sulphate) Sodium Lactate 3.12 g the labelling.
5 - 7 kg: 0.3 ml ( 0.15 mg Atropine Sulphate) Potassium Chloride 0.40 g
Calcium Chloride Dihydrate 0.27 g INSTRUCTIONS FOR STORAGE / USE / HANDLING
7 - 9 kg: 0.4 ml ( 0.20 mg Atropine Sulphate) Only to be used if solution is clear and the container undamaged.
Excipients:
9 - 12 kg: 0.5 ml ( 0.25 mg Atropine Sulphate) Do not store above 25 C.
12 - 16 kg: 0.6ml ( 0.30 mg Atropine Sulphate)
Theoretical osmolarity: 277 mOsm/l GENERAL GUIDELINES ON FLUID AND ELECTROLYTE
16 - 20 kg: 0.7ml ( 0.35 mg Atropine Sulphate) Titration acidity: < 1 mmol/l INTAKE:
over 20 kg: 0.8ml ( 0.40 mg Atropine Sulphate) pH: 5.0 - 7.0 30 ml/kg body weight/day is sufcient to cover the basic
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physiological uid requirements. Post-operatively and in intensive INSTRUCTIONS FOR HANDLING THE ECOBAG excessive uptake of irrigation uid into the systemic circulation.
care patients there is an increased requirement for uid intake on CONTAINER This is particularly suggested by the occurrence of non-reactive
account of the limited concentrating capacity of the kidneys and bilateral mydriasis during general anaesthesia (indicating the
6. Pressure infusion
the increased excretion of metabolites, so that it is necessary to presence of GLYCINE in the circulation) or the appearance of
- Place container in pressure cuff. any of the following symptoms: nausea, headache, sleepiness,
increase the uid intake to about 40 ml/kg body weight per day.
- Build up pressure. agitation, confusion, visual disturbances or amaurosis during
Additional losses (e.g. fever, diarrhoea, stulae, vomiting etc.)
must be compensated for by a still higher, individually adapted - Open roller clamp and start infusion. regional anaesthesia. These symptoms can also appear during the
uid intake. The actual and individual uid requirement is 7. Admixture of additives with syringe decremental phase of an intervention.
determined by the stepwise monitoring necessary in every case - Open the additive port by twisting off the Emergency treatment, antidotes
(e.g. urine excretion, osmolarity in serum and urine, determination corresponding toggle. The opened port Above-mentioned symptoms require the intervention to be stopped
of substances excreted). site is sterile. after careful haemostasis. The sodium concentration in the serum
The basic substitution of the most important cations sodium and - `Inject additive and the haematocrit should be rapidly determined and appropriate
potassium amounts to approx. 1.5 3 mmol per kg body weight per treatment of the hyperhydration and haemodilution should begin
day and 0.8 1.0 mmol per kg body weight per day respectively. 8. Admixture of additives with transfer set notably by restricting the water input and administering a diuretic
The actual requirement during infusion therapy depends on - Open medication vial and disinfect injection acting on the Henles loop.
appropriate determinations of the electrolyte balance and on the site of the vial.
UNDESIRABLE EFFECTS
laboratory monitoring of the plasma concentrations. - Attach transfer set to the vial and insert until
The most commonly observed adverse effect is the Turp syndrome
it ts rmly.
Instructions for Handling the Ecoac plus Container (water absorption with hyponatraemia). This is caused by
- In the case of evacuated vials rst attach
1. Gravity infusion 3. Admixture of additives continuous excessive uptake of irrigation uid into the circulation
transfer set to the bag. and is associated with
- Insert infusion Addition via
set, ll half of cannula 9. Admixture of additives with transfer set - Nausea;
d r i p c h a m b e r, - Insert cannula - Open the additive port by twisting off the - Neurological problems: cephalgia, sleepiness, agitation,
ll infusion vertically. corresponding toggle. The opened port site confusion, which can proceed to a potentially fatal coma or to
tube avoiding is sterile. convulsions;
bubbles. - Attach transfer set together with the vial to - Visual problems: hazy vision, temporary blindness, non-reactive
- Close air vent of infusion the additive port and insert until it ts rmly. bilateral mydriasis (symptoms of glycinaemia);
set.
- Connect infusion tube to 10. Admixture of additives with transfer set - Hyponatraemia, sometimes pronounced, reduced osmotic
cannula/catheter. - Transfer uid into the vial by repeated pressure, reduced levels of haematocrit and plasma proteins.
- Open clamp and start pressing of the bag. - Increased blood volume indicated by dyspnoea, changes of
infusion wit air vent closed - Dissolve contents completely. blood pressure or even pulmonary oedema.
2.Pressure infusion Addition using the transfer All these symptoms result from an excessive uptake of
cap (Ecoac 11. Admixture of additives with transfer set irrigation uid into the systemic circulation and indicate cellular
- Insert infusion
set. - Turn bag with attached vial upside down. hyperhydration, which can be fatal. They can appear during the
Mix)
- Transfer solution with dissolved additive from intervention or in the decremental phase.
- Hold container 1 Attach transfer
upright. cap to the the vial to the bag by pressing air into the vial. Risk factors
- After transfer is complete, remove vial and
- Leave clamp open, expel air container. - The risk increases with:
from container and ll half 2 Attach vial to the other end transfer set from the bag - Prolonged treatment with this solution (as a rule after more than
of drip chamber. (click!). 12. Admixture 60 minutes);
- Turn container and expel air 3 Transfer solution into the - Cover injection port reversibly with the - High pressure in the cavity where the operation takes place;
from infusion device. vial containing the additive Memory Cap (i.e. the twisted off toggle). - Size and number of opened venous sinuses
- Close clamp. by pressing - Large volume of absorbed uid (as a rule, when more than 1.5
the Ecoac plus litres are absorbed), as estimated by entry-exit comparison;
container. Dissolve additive - Delay in diagnosis
completely. Turn ECOPIN
GLYCINE 1.5 % W/V IRRIGATION
Note:
plus container with attached
vial upside down. Press air Patients are advised to inform their doctor or pharmacist of
(Glycine) any adverse effect they experience in connection with the
into the vial until all solution
has been transferred into the administration of this product.
COMPOSITION
ECOPIN plus container. EXPIRY DATE
1000 ml of solution contain
- Place container Documentation Active ingredient: The product must not be used beyond the expiry date stated on
in pressure of addition and the labelling.
GLYCINE 15.0 g
cuff. re-sealing the
Excipient: INSTRUCTIONS FOR STORAGE / USE / HANDLING
- Build up injection port with
ECOPIN Water for Injections Strict sterile conditions must be maintained when handling the
pressure.
irrigation solution.
- Open clamp 1 Insert PHARMACEUTICAL FORM
and start ECOPINinto Only to be used if solution is clear and the container undamaged.
Solution for irrigation
infusion. injection port Unused contents of an opened container must be discarded and not
2 Break off handle PHARMACO-THERAPEUTIC GROUP be stored for later use.
GLYCINE solution for irrigation Store this product out of the reach of children.
INSTRUCTIONS FOR HANDLING THE ECOBAG
CONTAINER INDICATIONS
- Irrigation during endoscopic examinations of body cavities; HEPARIN SODIUM INJECTION 5000 I.U./ml
1. Preparation of the container
- Check container and closure are intact. - Irrigation during urological interventions by endoscopy
involving HF current, e.g. TUR (transurethral resections),
- Check contents for clarity and discoloration
disintegration of bladder stones, interventions in the ureter, [Heparin Sodium (mucosa)]
- Open container by twisting off the
interventions in the renal pelvis etc.
corresponding toggle. COMPOSITION
- Irrigation during gynaecological interventions by endoscopy
The opened infusion port site is sterile. involving HF current; 1 ml of solution contains
(<symbol> Infusion port) - Irrigation during arthroscopy of the knee, shoulder, or other Heparin Sodium (mucosa) 5000 I.U.
(<symbol> Additive port) joints involving HF current; Excipients:
2. Gravity infusion - Postoperative irrigation
Benzyl alcohol (antimicrobial preservative), sodium chloride,
- Close air vent and roller clamp of infusion set. CONTRAINDICATIONS water for injections
- Insert infusion set. None known PHARMACEUTICAL FORM
3. Gravity infusion SPECIAL WARNINGS AND SPECIAL PRECAUTIONS Solution for injection in glass vials of 5 ml
- Fill half of drip chamber. FOR USE
- Fill infusion tube avoiding bubbles. PHARMACO-THERAPEUTIC GROUP
Do not use for infusion.
Anticoagulant
4. Gravity infusion DOSAGE
- Connect infusion tube to cannula/catheter. INDICATIONS
The required amount of uid depends on the extent and duration of Prophylaxis of thrombo-embolism;
- Start infusion, leaving air vent closed.
the intervention and on the postoperative course.
Use as anticoagulant in the therapy of acute venous and arterial
5. Pressure infusion thrombo-embolism (including early treatment of myocardial
OVERDOSE
- Insert infusion set. infarction and unstable angina pectoris);
Symptoms
- Hold container upright. Prevention of blood clotting during use of extracorporeal
During long-lasting interventions, particularly when a large venous
- Leave roller clamp open, expel air from circulation (heart-lung machine, haemodialysis)
sinus is opened, systemic uptake of irrigation uid can lead to uid
container and ll half of drip chamber.
overload with dilution hyponatraemia (hypotonic hyperhydration, CONTRAINDICATIONS
- Turn container and expel air from infusion set. corresponding to a water intoxication). HEPARIN SODIUM INJECTION 5000 I.U./ML must not be
- Close roller clamp.
Throughout the procedure, regular checks must be carried out for used in the following conditions:
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Hypersensitivity to heparin or to any of the excipients of Anticoagulatory therapy is contraindicated in conditions Adults:
HEPARIN SODIUM INJECTION 5000 I.U./ML characterised by an increased tendency to bleeding, such as Initially, 5 000 I.U. are injected intravenously as bolus, followed
Case history or acute cases of thrombocytopenia (type II) imminent abortion (see also section Contraindications). by continuous infusion of 1 000 I.U./h using an infusion pump.
caused by an allergic reaction to heparin Lactation Children:
Diseases associated with haemorrhagic diathesis, such as: Heparin is not secreted into breast milk. Daily administration Initially 50 i.u./kg body weight, subsequently 20 i.u./kg kg body
coagulopathies of high heparin doses over more than 3 months may increase weight /h
severe diseases of liver, kidneys, and pancreas the risk of osteoporosis in breast-feeding women. Continuous If continuous infusion cannot be performed, alternatively,
Diseases where there is a suspicion of vascular damage, e.g. administration of high doses of heparin should therefore not heparin may be administered by subcutaneous injection, the
ulcers in the gastro-intestinal tract exceed 3 months. daily dose being divided into 2 3 injections (e.g. 10 000 I.U.
hypertension with a diastolic blood pressure higher than 105 INTERACTIONS 12 500 I.U. every 12 hours) with careful monitoring of the
mm Hg therapeutic effect.
The following interactions should be paid attention to:
brain haemorrhage As a rule, the therapy is controlled and doses are adjusted
Clinically signicant enhancement of the heparin effect and according to the values of the activated partial thromboplastin
injuries or surgical procedures on the central nervous system
increase of the tendency to bleeding by: time (aPTT), which should be 1.5 to 2.5 times the reference
cerebral arterial aneurysm
platelet aggregation inhibitors (acetylsalicylic acid, ticlopidin, value. During continuous infusion, it is recommended to
retinopathias, bleeding into the vitreum
clopidogrel, high-dose dipyridamol), brinolytics, other determine the aPTT 1 2 hours, 6 hours, 12 hours, and 24 hours
ophthalmic surgical procedures anticoagulants (coumarin derivatives), non-steroidal anti- after start of the therapy. During subcutaneous administration
infectious bacterial endocarditis inammatory drugs (phenylbutazone, indometacine, determinations should be performed 6 hours after administration
Imminent abortion sulnpyrazone), glycoprotein-IIb/IIIa receptor blockers, high- of the second dose.
Spinal or epidural anaesthesia, lumbar puncture dose penicillin, dextrans. Treatment of venous thrombo-embolism:
Organ lesions with haemorrhagic diathesis Cytostatic drugs Initially, 5 000 I.U. are injected as bolus intravenously, followed
Because HEPARIN SODIUM INJECTION 5000 I.U./ML may enhance the effect of heparin, doxorubicin probably weakens by continuous infusion of usually 1 000 I.U./h.
contains benzyl alcohol, it must not be administered to new-borns, the heparin effect. The therapy is controlled by determination of the aPTT which
esp. to immature pre-term infants. should be 1.5 to 2.5 times the reference value. These values
Glyceryl trinitrate (nitro-glycerine), administered by
SPECIAL WARNINGS AND PRECAUTIONS FOR USE intravenous infusion, should be reached within the rst 24 hours of therapy.
Administration of Heparin Sodium Injection 5000 I.U./ml weakens the effect of heparin. After discontinuation of glyceryl Treatment should be continued for at least 4 days or until oral
should also be avoided in the following conditions: trinitrate the aPTT may rise suddenly. If heparin is administered anticoagulation is sufciently effective.
Suspected malignant tumour with risk of bleeding during nitro-glycerine infusion, close monitoring of the aPTT and Use in therapy of unstable angina pectoris or non-Q wave
Nephro- and ureterolithiasis adjustment of the heparin dose are necessary. myocardial infarction:
Chronic alcohol abuse Ascorbic acid, antihistamines, digitalis, tetracyclines, nicotine As a rule, initially 5 000 I.U. are injected intravenously as
Especially careful medical monitoring should be instituted: abuse: bolus, followed by continuous infusion of 1 000 I.U./h.
during pregnancy, esp. if heparin is to be administered over Inhibition of the heparin effect is possible. The dose is adjusted according to the values of the aPTT which
extended periods, Other drugs being bound to plasma proteins (e.g. proprano- should be 1.5 to 2.5 times the reference value. Heparin should
in elderly patients, especially elderly women, lol) be administered over 48 hours.
during medication with brinolytics, oral anticoagulants, drugs Heparin may displace these from protein binding, leading to an Adjunct therapy during thrombolysis with brin-specic
inhibiting platelet aggregation, such as acetylsalicylic acid, thrombolytic agents (e.g. r-tPA) for therapy of acute
enhancement of their effect.
ticlopidin, clopidogrel, and/or glycoprotein- IIb/IIIa receptor myocardial infarction:
Drugs that lead to an increase of the serum potassium level
blockers, Initially, 5 000 I.U. are injected intravenously as bolus, followed
should only be administered together with heparin under careful by continuous infusion of 1 000 I.U./h.
in patients receiving medicaments that raise the serum
monitoring.
potassium level. In general, serum potassium levels should The dose is adjusted according to the values of the aPTT which
be monitored in patients at risk of hyperkalaemia (e.g. due to Alkaline drug substances (tricyclic psychotropic agents, should be 1.5 to 2.5 times the reference value. Heparin should
diabetes mellitus, impaired renal function, or medicaments that antihistamines, or quinine) be administered over 48 hours.
raise the serum potassium level). Heparin forms salts with these, leading to mutual weakening of When non-brin-specic thrombolytic agents (e.g.
During therapy with heparin, i.m. injections must be avoided their effects. streptokinase) are used, alternatively 12 500 I.U. of heparin
because of the risk of haematoma. Inuence of heparin on laboratory tests: may be administered subcutaneously every 12 hours, the rst
If thrombo-embolic complications occur during therapy with Heparin may cause various laboratory tests to yield incorrect dose being given 4 hours after start of thrombolysis.
heparin, type II heparin-induced thrombocytopenia must be results, such as erythrocyte sedimentation rate, erythrocyte The exact heparin dose depends on the thrombolytic drug
considered and platelet count should be performed. resistance and complement binding tests. used; the instructions given for the thombolytic drug must be
If heparin is administered to infants, children and patients with Under heparin therapy thyroid function tests may yield incorrect followed. In any case, careful control of the coagulation status
hepatic or renal failure, close monitoring including checks of is indispensable.
results, e. g. falsely high values of T3 and T4 levels.
the coagulation status is mandatory. This also applies to the use 3) Anticoagulation during therapy or surgical procedures
DOSAGE using extra-corporal circulation
of heparin for prophylaxis of thrombo-embolism ("low-dose"
therapy). Determine the heparin dose individually for each patient. Heart-lung machine:
Patients under heparin therapy (more than 22,500 i.u./day) should The dosage depends on the actual values of blood coagulation The dosage must be determined individually, depending on the
not be exposed to the risk of injuries. parameters, type and course of the disease, the patient's response type of heart-lung machine and the duration of the operation.
to therapy, type and severity of side effects, as well as the patient's Haemodialysis:
Heparin may lead to an increase and prolongation of menorrhagia.
age and body weight. Varying sensitivity to heparin as well as
In case of unusual strong or acyclic uterine bleeding, any organic The dosage must be determined individually, depending on the
a changed heparin tolerance pattern during therapy must be
disease requiring specic treatment should be excluded by a patient's coagulation status and the type of apparatus used.
considered.
supplementary gynaecological examination.
The following dosage guidelines should be followed: Method of administration
Recommendations re. blood coagulation monitoring
1) Prophylaxis of thrombo-embolism ("low-dose" therapy) Heparin is administered by subcutaneous or intravenous injection
Heparin therapy must always be accompanied by regular controls or by intravenous infusion after dilution with a suitable vehicle
of aPTT and platelet counts. For prophylaxis of thrombo-embolism subcutaneous injection
solution.
is recommended. General dosage recommendations are as
Platelet counts should be performed Subcutaneous injection
follows:
before the beginning of the therapy with heparin, After mild skin disinfection, inject the heparin dose strictly
on the 1st day of therapy, Pre- and postoperative prophylaxis of thrombo-embolism:
subcutaneously into a loosely grasped skin fold of the abdomen,
every 3rd or 4th day during the rst three weeks of therapy, Preoperatively, 5 000 to 7 500 i.u. are injected subcutaneously 2 or the extensor side of the thigh, vertically to the longitudinal axis
and hours prior to beginning of operation; of the body, using a ne needle. Remove any drops of injection
at the end of the therapy. Postoperatively, depending on the risk of thrombosis, 5 000 solution from the exterior of the needle prior to injection, because
Heparin may affect the prothrombin time; this should be considered i.u. are injected subcutaneously every 8 to 12 hours or 7 500 heparin introduced in the puncture channel may cause supercial
when determining the dosage of coumarin derivatives. I.U. every 12 hours, until the patient can be mobilised or until haematoma or, in rare cases, hypersensitivity reactions (local
vitamin K antagonists are sufciently effective. For adjustment allergic reactions)
PREGNANCY AND LACTATION of the dosage, determinations of the coagulation status may be To avoid lymph drainage impairment in patients having undergone
Pregnancy required. lymph node resection in the abdominal or uro-genital region,
Heparin does not cross the placental barrier. Until now there are Prophylaxis of thrombo-embolism in non-surgical subcutaneous injection should be performed on the upper arm in
no reports about foetal malformations that could have been caused medicine: these patients.
by the administration of heparin during pregnancy, nor are there (e. g. in patients conned to bed over longer periods, patients Infusion
ndings from animal experiments indicating embryotoxic or particularly at risk of thrombosis or diseases with risk of For infusion the product can be diluted with the following
foetotoxic effects of heparin. thrombosis): solutions:
An increased risk of accidental abortions and stillbirths, however, Depending on the risk of thrombosis, 5 000 I.U. are injected Sodium Chloride 0.9 % w/v Intravenous Infusion
has been reported. subcutaneously every 8 to 12 hours or 7 500 I.U. every 12 Glucose 5 % or 10 % w/v Intravenous Infusion
During pregnancy, complications resulting from underlying illness hours. Sodium Chloride 0.45 % w/v and Glucose 2.5 % w/v Intravenous
and/or treatment cannot be excluded. The dosage should be adjusted according to the individual Infusion
Daily administration of high heparin doses over more than 3 risk of thrombosis and the activity of the patient's coagulation Ringer's solution.
months may increase the risk of osteoporosis in pregnant women. system; it should be determined according to the values of the Dilutions with these solutions are stable at room temperature for
Continuous administration of high doses of heparin should patient's coagulation status. 48 hours.
therefore not exceed 3 months. 2) In treatment of venous or arterial thrombo-embolism Note:
Epidural anaesthesia must not be performed in obstetrics in In the presence of clots in blood vessels continuous intravenous Because heparin is neutralized by platelet components (PF4),
pregnant women receiving anticoagulants. administration is recommended. citrated blood samples taken for the determination of coagulation
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SPDI
parameters should be centrifuged and decanted as soon as possible Vascular disorders After use of lidocaine in surgery, operative dentistry or after
to separate plasma from blood cells. Very rare (< 1:10 000 of treated patients, including isolated procedures involving the use on extended body areas, the
The duration of therapy is determined by the attending physician. cases) physician has to decide whether the patient is t for driving or
Vasospasm. operating machines.
OVERDOSE
Hepato-biliary disorders Before undertaking any local anaesthetic procedure, adequate
Symptoms replenishment of the intravascular volume should be ensured and
Very common ( 1:10 of treated patients)
Bleeding, in most cases from the skin, mucous membranes, hypovolaemia should be corrected if necessary.
wounds, in the gastro-intestinal tract, the urinary tract and the Increases of the serum concentrations of transaminases (GOT,
In the case of known allergy towards lidocaine, group allergy
genital tract (e. g. epistaxis, haematuria, melaena, haematomas, GPT), gamma-glutamyl transpeptidase, lactate dehydrogenase
towards all amide-type local anaesthetics should be considered.
pinpoint bleeding). Drop of blood pressure, decrease of the and lipase, which are, however, reversible and of no clinical
signicance. During anaesthetic procedures in the neck and head region patients
haematocrit or other symptoms may indicate concealed bleeding. are at increased risk of central nervous toxic effects of the drug.
Emergency treatment, antidotes Musculoskeletal, connective tissue and bone disorders
Prior to injection of the local anaesthetic, it must be made sure
In cases of bleeding or appearance of symptoms of concealed After prolonged administration (over months), especially after high
that all equipment for resuscitation, e.g. for intubation and for
bleeding a doctor must be consulted immediately. doses and in predisposed patients, osteoporosis may develop. Such
oxygen supply, and emergency medication for the treatment of
patients should be monitored also under prophylactic therapy.
Mild bleeding can be stopped by simply reducing the dose. toxic reactions are instantly available.
Reproductive system disorders
In cases of moderate, not life-threatening bleeding, heparin should To avoid adverse effects, attention should be paid to the
Very rare (< 1:10 000 of treated patients, including isolated following:
be discontinued.
cases)
Severe life-threatening bleeding clearly due to heparin (after Create venous access in patients at risk and when doses of
Priapism. more than 25 per cent of the maximum recommended dose are
exclusion of other causes such as deciency of coagulation factors
or consumption coagulopathy) necessitates intensive medical Administration site conditions applied by a single injection.
treatment and administration of protamine. Common (< 1:10, 1:100 of treated patients) Choose doses as low as possible.
Protamine should only be given for life-threatening haemorrhage, Local tissue reactions at the injection site, such as induration, Do not routinely use a vasoconstrictor in combination with the
because complete neutralisation of heparin will induce the redness, discoloration, and minor haematomas. local anaesthetic.
risk of thrombosis. Concomitantly, under ICU conditions, the Very rare (< 1:10 000 of treated patients, including isolated Ensure correct positioning of the patient.
patient's vital parameters must be monitored and, if necessary, cases) Perform aspirations in two directions (rotate needle).
corrected, i.e. blood transfusions, volume substitution and Calcinosis at the site of injection, mainly in patients with severe Exercise caution when injecting the local anaesthetic into
correction of haemodynamic parameters, e.g. by administration of renal failure. infected regions because of increased systemic absorption and
catecholamines, must be performed. decreased effect.
EXPIRY DATE
Protamine is a protein rich of arginine, which is used in the form Inject the local anaesthetic slowly.
of its chloride or sulphate. As a rule, 1 mg of protamine will Do not use the product beyond the expiry date stated on the label.
Monitor blood pressure, pulse, and pupil width.
neutralise 100 i.u. of heparin. The serum half life time and the INSTRUCTIONS FOR STORAGE / USE / HANDLING Observe all general and special contra-indications as well as
route of administration of heparin should be considered; thus, 90 If withdrawal of injection solution from the container is performed interactions with other medicaments.
min after intravenous administration of heparin, only half of the under aseptic conditions, a vial can be stored for up to 14 days In patients on medication with anticoagulants (e.g. heparin),
calculated amount of protamine should be given, 3 hours after after rst use. The date of rst withdrawal must be noted on the nonsteroidal anti-inammatory drugs (NSAIDs), or plasma
heparin administration, only 25 % of the calculated protamine label. substitutes, not only accidental vascular puncture during a local
dose. Overtitration with protamine may activate brinolysis and anaesthetic procedure may cause serious bleeding complications,
Suitable solutions for dilution see section Dosage, Method of
thus itself cause an increased tendency to bleeding. Too rapid administration - Infusion but generally an increased bleeding risk upon injection of local
i.v. injection of protamine may cause drop of blood pressure, anaesthetics should be considered. If necessary, in such patients
bradycardia, dyspnoea, and sensation of discomfort. Protamine Do not administer if solution shows signs of deterioration,
i.e. turbidity, precipitate or discoloration, or if the container is the partial thromboplastin time (PTT) or activated partial
is eliminated from the circulation more rapidly than heparin. The thromboplastin time (aPTT), respectively, should be determined,
damaged.
efcacy of neutralisation is to be controlled by determinations of Quicks test should be performed, and platelet count should be
thrombin time and PTT. checked. The same tests should also be performed in risk patients
Heparin is not dialysable. LIDOCAINE B. BRAUN 2 % receiving low-dose heparin for prophylaxis of thrombo-embolism.
UNDESIRABLE EFFECTS
Solution for Injection If necessary, the anticoagulant therapy should be discontinued in
sufciently early before the local anaesthetic procedure.
Blood and lymphatic system disorders
Local anaesthesia should be performed with due caution in patients
Very common ( 1 : 10 of treated patients) (Lidocaine Hydrochloride Monohydrate) receiving low-molecular heparin for prevention of thrombo-
Depending on the dose, increased incidence of bleeding, especially embolism.
COMPOSITION
bleeding from the skin, mucous membranes, wounds, in the gastro- Determination of the bleeding time is necessary in patients under
intestinal tract, the urinary tract and the genital tract. 1 ml of solution contains
medication with NSAIDs, e.g. acetylsalicylic acid, during the last
Common (< 1 : 10, 1 : 100 of treated patients) Active substance: ve days prior to epidural or spinal anaesthesia.
At the beginning of heparin therapy mild heparin-induced Lidocaine Hydrochloride Monohydrate 20 mg
thrombocytopenia not mediated by antibodies (platelet count 100 Excipients:
Lidocaine should only be used in pregnancy if there is an
000 - 150 000 per microlitre), without thrombosis. Sodium chloride, sodium hydroxide, water for injections
imperative indication. There are no controlled clinical studies on
Rare (< 1:1 000, 1:10 000 of treated patients) PHARMACEUTICAL FORM the use of lidocaine during pregnancy. Data from a limited number
Severe heparin-induced, antibody-mediated thrombocytopenia Solution for injection of exposed pregnancies do not indicate congenital effects caused
(type II thrombocytopenia), characterised by platelet counts by lidocaine. Animal studies indicated reproduction toxicity of
markedly below 100 000 per microlitre or a rapid decrease to less PHARMACO-THERAPEUTIC GROUP lidocaine.
than 50 per cent of the initial value and accompanied by arterial Local anaesthetic Lidocaine rapidly crosses the placenta. In neonates high plasma
or venous thromboses or embolism, consumption coagulopathy, INDICATIONS concentrations of lidocaine may cause central nervous depression
skin necroses at the site of injection, pinpoint bleeding (petechia), and thus a depression of the Apgar score.
Local and regional anaesthesia
and tarry stools (melaena). The anticoagulatory effect of heparin
Lidocaine in strengths above 1 % w/v is contraindicated for
may be reduced. CONTRAINDICATIONS
regional anaesthesia in obstetrics.
In patients without pre-existing hypersensitivity to heparin the LIDOCAINE B. BRAUN 2 % must not be used in cases of
Use of lidocaine for paracervical block may cause bradycardia or
decrease of the platelet count begins between 6 to 14 days after hypersensitivity towards amide-type local anaesthetics,
tachycardia in the fetus. An accidental subcutaneous injection of
commencement of the heparin therapy. In patients with existing severely disturbed cardiac conduction, lidocaine in the fetus during paracervical or perineal block may
hypersensitivity to heparin such decrease may begin already sudden heart failure (acute cardiac decompensation), cause apnoea, hypotension and convulsive ts and may thus put
after a few hours. In such cases heparin administration must be cardiogenic or hypovolaemic shock. the new-born at vital risk.
discontinued immediately. Re-exposure of the patient to parenteral It must not be used for pain relief in obstetrics.
heparin is absolutely contraindicated. Minor amounts of lidocaine are secreted into breast milk. It is
The special contra-indications for spinal and epidural anaesthesia unlikely that any risk for the suckling infant is associated with
Immune system disorders must also be observed, e. g. therapeutic doses of lidocaine administered to the mother.
Uncommon (< 1:100, 1:1 000 of treated patients) uncorrected hypovolaemia,
INTERACTIONS
Systemic allergic reactions including nausea, headache, rise of clinically relevant disorders of blood coagulation,
temperature, limb pain, urticaria, vomiting, pruritus, dyspnoea, The local anaesthetic effect is prolonged by combination with a
increased intracranial pressure. vasoconstrictor, e.g. epinephrine.
bronchospasm, and drop of blood pressure, local and general
hypersensitivity reactions such as angiooedema, transient alopecia, Safety instructions re. epidural or spinal anaesthesia, under the Administration of secale alkaloids, e.g. ergotamine, simultaneously
skin necroses. conditions of prophylaxis against thrombo-embolism, see section with epinephrine that may be combined with the local anaesthetic,
Special warnings and precautions for use. may cause marked hypotension.
Rare (< 1:1 000, 1:10 000 of treated patients)
Hypersensitivity reactions to benzyl alcohol SPECIAL WARNINGS AND PRECAUTIONS FOR USE Lidocaine should be administered with due caution to patients on
Sudden arterial hypotension may occur as a complication of medication with sedatives that also affect the function of the CNS
Very rare (< 1:10 000 of treated patients, including isolated
epidural anaesthesia, in particular in elderly patients. and therefore may alter the toxicity of the local anaesthetic. There
cases)
Lidocaine should only be used with particular caution in patients is an antagonism between the local anaesthetic and sedatives or
Anaphylactic shock especially in sensitized patients having hypnotics. The latter raise the threshold for convulsions in the
with liver or kidney diseases or with myasthenia gravis. Particular
previously received heparin. CNS.
caution should also be exercised if the local anaesthetic is to be
Endocrine disorders injected into inamed (infected) tissue. Simultaneous administration of lidocaine and aprindin may lead
Rare (< 1 : 1000, 1:10 000 of treated patients) The risk of post-spinal headache mainly occurring in adolescents to an addition of their undesirable effects. Due to the similar
Heparin may cause hypoaldosteronism, resulting in hyperkalaemia and in adults up to the age of 30 years during spinal anaesthesia chemical structure the side effects of aprindin are similar to those
and metabolic acidosis, especially in patients with impaired kidney can be markedly reduced by choosing sufciently thin injection caused by lidocaine.
function and diabetes mellitus. cannulae. Caution should be exercised in patients under medication with
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SPDI
propranolol, diltiazem, or verapamil. These medicaments reduce to the patients age and body weight. In children, only a low expected at plasma concentrations exceeding 5 10 mg/l, are
the plasma clearance of lidocaine and thus prolong its elimination strength (0.5 % w/v) of the local anaesthetic should be used. To related to the particulars of the method of administration, or to
half life, which may be associated with the risk if accumulation. achieve a complete motor block, a higher strength (1 % w/v) may pharmacodynamic or pharmacokinetic particulars. They become
Combination of different local anaesthetics may lead to additive be required. manifest in the form of both CNS symptoms and cardiovascular
effects on the cardiovascular and the central nervous system. Also for elderly patients, the doses must be calculated individually symptoms. Therefore frequency and severity of the undesirable
according to the patients age and body weight. effects are dose-dependent. They become manifest in the form
Lidocaine should be administered with caution to patients
of both CNS symptoms and cardiovascular symptoms (For CNS
simultaneously receiving cimetidine. Due to reduction of liver Method of administration
symptoms see section Overdose). In particular, the following
perfusion and inhibition of microsomal liver enzymes toxic Depending on the anaesthetic procedure, the solution is undesirable effects may be observed:
plasma levels of lidocaine may result even after normal lidocaine administered by intracutaneous, subcutaneous, or epidural
doses applied for intercostal block. Immune system disorders
injection or is injected into a circumscribed tissue area (inltration)
The effect of non-depolarising muscle relaxants is prolonged by or administered locally after appropriate puncture according to the Allergic reactions to local anaesthetics of the amide type, which
lidocaine. particular anatomical situation. can occur in the form of urticaria, oedema, bronchospasm,
respiratory distress and circulatory symptoms, are rare (in 0.01
Lidocaine B. Braun 2 % is incompatible with solutions containing Every local anaesthetic procedure should only be carried out 0.1 % of treated patients).
sodium bicarbonate and other alkaline solutions. It must therefore by personnel adequately skilled in the respective anaesthetic
not be mixed with those. technique. Nervous system disorders
As a matter of principle, for continuous anaesthesia the lower After spinal anaesthesia, transient pain in the lower extremities
DOSAGE and lower back pain is commonly observed (in 1 10 % of treated
strengths should be preferred.
As a matter of principle the smallest possible dose that produces patients). The pain may last several (up to 5) days and will resolve
adequate anaesthesia should be administered. The dosage should OVERDOSE spontaneously.
be adjusted individually according to the particulars of each case. Symptoms Rarely (in 0.01 0.1 % of treated patients), neurological
When injected into tissues with marked systemic absorption, Low toxic doses of lidocaine result in CNS stimulation; gross complications following central nervous blocks mainly
without combination with a vasoconstrictor, a single dose of overdose, producing high toxic plasma concentrations, causes spinal anaesthesia may occur such as persistent anaesthesia,
lidocaine hydrochloride monohydrate should not exceed 300 depression of the central functions. paraesthesia, paresis or plegia of the lower extremities and loss of
mg. If combined with a vasoconstrictor, 500 mg of lidocaine Two phases of lidocaine intoxication can be distinguished: sphincter control (e.g. cauda equina syndrome).
hydrochloride monohydrate per single dose should not be Cardiac disorders
a) Stimulation
exceeded.
Central nervous system: A slight increase of blood pressure, resulting from the positive
The dose should be adjusted individually for elderly patients and inotropic and chronotropic effect of lidocaine may commonly be
for children. Unpleasant perioral sensations, tongue paraesthesia, unrest,
observed (in less than 10 % but in not less than 1 % of treated
delirium, convulsions.
For the clinical uses listed below, recommendations for single patients).
doses to be administered to adolescents over 15 years and to adults Cardiovascular system:
Sudden hypotension as a manifestation of a cardiotoxic effect may
with average body weight and height are as follows: Tachycardia, hypertension, ushing be the rst sign of relative overdose.
Type of anaesthesia / Dose mg of Lidocaine b) Depression As with other local anaesthetics, precipitation of malignant
site of administration Hydrochloride H2O Central nervous system: hyperthermia cannot be excluded for lidocaine. In general,
Coma, respiratory arrest. however, the use of lidocaine is regarded to be safe in patients with
Cardiovascular system: a tendency to or a history of malignant hyperthermia, although
Supercial anaesthesia up to 15 ml 300 mg occurrence of this complication has been reported for one patient
Inltration anaesthesia up to 15 ml 300 mg Unpalpable pulse, pallor, cardiac arrest. having received lidocaine for epidural anaesthesia.
Inltration and nerve up to 15 ml 300 mg At the beginning of intoxication with local anaesthetics patients Note:
mainly show symptoms of excitation: unrest, vertigo, disturbances
conduction anaesthesia Patients should inform their doctor or pharmacist if they notice any
of hearing and vision, tingling mainly in tongue and lips,
in dentistry adverse effect that has not been mentioned in this leaet.
inarticulate speech (dysarthria). Shivering and muscular twitching
Peripheral nerve block up to 15 ml 300 mg may be signs of imminent attacks of generalized convulsion. EXPIRY DATE
Epidural anaesthesia up to 15 ml 300 mg Subconvulsive plasma levels of lidocaine often also lead to The product must not be used beyond the expiry date stated on
sleepiness and sedation. During progress of the intoxication of the labelling.
Field block up to 25 ml 500 mg
the CNS, after the convulsive phase, increasing impairment of the
In epidural anaesthesia the dosage should be adjusted according brain stem function appears in the form of respiratory depression INSTRUCTIONS FOR STORAGE / USE / HANDLING
to the patients age. The following dosages should be taken as and coma, even up to death. Only to be used if solution is clear and container undamaged.
guidance for epidural anaesthesia in the lumbar region: Sudden hypotension often is the rst sign of cardiovascular The product is supplied in single-use containers. Solution is to
Age Dosage toxicity of lidocaine. The hypotension is mainly caused by an be administered immediately after opening the container. Unused
impairment or block of cardiac impulse conduction. These toxic contents of containers once opened must be discarded.
5 years 0.5 ml per segment
effects, however, are less relevant than those on the CNS.
Emergency treatment, antidotes LIPOFUNDIN MCT/LCT 10 %
The occurrence of central nervous or cardiovascular symptoms Emulsion for Infusion
20 years 1.5 ml per segment demands immediate action:
40 years 1.3 ml per segment Discontinue administration of the local anaesthetic.
60 years 1.0 ml per segment Maintain airways open. Supply additional oxygen. If necessary (Soya-bean Oil, Medium-chain Triglycerides-
80 years 0.7 ml per segment provide articial ventilation with pure oxygen assisted Glycerol, egg lecithin, all-rac--tocopherol,
or controlled rst via mask and air bag, then intubate, if
For prolongation of anaesthesia lidocaine may be combined
necessary. The oxygen therapy must be continued until all vital
sodium oleate, water for injections Linoleic
with a vasoconstrictor, e.g. epinephrine. Addition of epinephrine acid, -Linolenic acid)
functions have returned to normal.
at a concentration of 1:100 000 to 1:200 000 has proven useful.
Monitor blood pressure, pulse and pupil width carefully.
Especially in dentistry, use of a local anaesthetic containing a COMPOSITION
vasoconstrictor may be indispensable when using substances These measures are also applicable in the case of accidental total
spinal anaesthesia, rst manifesting as unrest, whispering voice, 1000 ml of emulsion contain
with short or medium duration of the effect. However, lidocaine
with epinephrine should only be used for anaesthesia in the facial and sleepiness. The latter can proceed to unconsciousness and Soya-bean Oil 50.0 g
region (tooth, mouth, jaws). respiratory arrest. Medium-chain Triglycerides 50.0 g
Further therapeutic measures include the following: Glycerol, eegg lecithin, all-rac--tocopherol, sodium oleate, water
Doses should be reduced in patients in poor general condition or
in those with reduced protein binding capacity (resulting e.g. from If there is an acute life-threatening drop in blood pressure, for injections
renal insufciency, liver insufciency, cancer, pregnancy). immediately put the patient in recumbent position with Content of essential fatty acids:
legs elevated and administer a beta-sympathomimetic drug
In patients with renal insufciency a shorter duration of the local Linoleic acid 24.0 - 29.0 g/l
slowly intravenously (e.g. 10 20 drops of a solution of 1
anaesthetic effect has been observed. This may be attributable to -Linolenic acid 2.5 - 5.5 g/l
mg of isoprenaline in 200 ml of glucose solution per minute).
accelerated systemic absorption resulting from acidosis or from Caloric value: 4280 kJ/l = 1022 kcal/l
Additionally administer uid (e.g. electrolyte solution).
increased cardiac output per minute. Theoretical osmolarity 345 mOsm/l
When the vagal tone is increased (bradycardia), 0.5 1 mg of
Patients with liver diseases show reduced tolerance towards atropine should be given i.v. Titration acidity or alkalinity
amide-type local anaesthetics. This may be due to reduced hepatic (to pH 7.4) < 0.5 mmol/l
If there are convulsions, inject an ultra-short-acting barbiturate,
metabolism and decreased protein synthesis resulting in a lower pH 6.5 - 8.8
e.g. thiopentone (50 100 mg), or diazepam (5 10 mg), in
protein binding rate of the local anaesthetic. Dose reduction is
repeated small doses intravenously. Repeat treatment until the PHARMACEUTICAL FORM
advisable in such cases.
convulsions are controlled. If the convulsions continue inject
Patients with epilepsy should be carefully monitored for the thiopentone (250 mg) and a short acting muscle relaxant, Emulsion for infusion
occurrence of central nervous symptoms. An increased tendency intubate and provide articial respiration with 100 % oxygen. PHARMACO-THERAPEUTIC GROUP
to convulsions should be considered even with doses below It should be noted that in many cases ventilation with oxygen
maximum. In patients with MELKERSSON-ROSENTHAL Fat emulsion for calorie supply and supply of essential fatty acids
alone may be sufcient therapy when rst signs of convulsions
syndrome the incidence of allergic toxic reactions of the nervous appear. INDICATIONS
system may be increased.
In cases of suspected cardiac arrest apply all appropriate Calorie supply including a readily metabolisable fat component
The dose should be reduced in patients showing clinical signs of resuscitation procedures. (MCT);
cardiac insufciency or disorders of cardiac impulse generation Supply of essential fatty acids and uid in the setting of total
Centrally acting analeptics are contra-indicated.
and conduction. The heart function of such patients should parenteral nutrition
be monitored continuously, also beyond the end of the local UNDESIRABLE EFFECTS
anaesthetic effect. Nevertheless, local or regional nerve blockage The possible undesirable effects after administration of lidocaine CONTRAINDICATIONS
can be the anaesthetic method of choice in such patients. are largely the same as those produced by other amide-type LIPOFUNDIN MCT/LCT must not be administered in the
In children, the doses must be calculated individually according local anaesthetics. Systemic adverse effects, which are to be following conditions:
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SPDI
Severe blood coagulation disorders, states of shock and collapse, 3. Infants and pre-school children Note:
acute thrombo-embolism, fat embolism, severe septicaemia 1 - 3 g lipid per kg body weight per day, corresponding to Patients are advised to inform their doctor or pharmacist if they
accompanied by acidosis and hypoxia, acute phases of myocardial notice any adverse effect not mentioned in this leaet.
10 - 30 ml LIPOFUNDIN MCT/LCT 10 % per kg body weight
infarction and stroke, keto-acidotic coma, decompensated diabetic EXPIRY DATE
per day.
metabolism diabetic metabolism or unstable metabolism.
Infusion rate The product must not be used beyond the expiry date stated on
The administration of LIPOFUNDIN MCT/LCT is also contra- the labelling.
indicated if serum triglycerides accumulate in the following The infusion rate should be as low as possible. The infusion rate
conditions: during the rst 15 minutes of the infusion should not exceed STORAGE
Disorders of lipid metabolism, liver diseases, disorders of 0.05 0.1 g lipid per kg body weight per hour, corresponding to Do not store above 25 C
the reticulo-endothelial system, haemorrhagic necrotising 0.5 1.0 ml of emulsion per kg body weight per hour.
pancreatitis. Maximum infusion rate: LIPOFUNDIN MCT/LCT 20 %
General contra-indications for parenteral nutrition: Up to 0.15 g lipid per kg body weight per hour, corresponding to Emulsion for Infusion
Acidoses of various origin, uncorrected disturbances of the up to 1.5 ml LIPOFUNDIN MCT/LCT 10 % per kg body
electrolyte and uid balances (such as hypotonic dehydration, weight per hour.
hypokalaemia, hyperhydration), intrahepatic cholestasis. Accordingly, the drop rate should not exceed 0.5 drops per kg (Soya-bean Oil, Medium-chain Triglycerides,
SPECIAL WARNINGS AND PRECAUTIONS FOR USE body weight per minute. Glycerol, Egg Lecithin, all-rac--tocopherol,
Hypersensitivity reactions to one of the ingredients of This means that for a patient weighing 70 kg the maximum sodium oleate, water for injections, Linoleic
LIPOFUNDIN MCT/LCT, (e.g. traces of protein in soya oil or infusion rate may be approx. 100 ml/hour or 35 drops/min.
acid, -Linolenic acid)
egg lecithin), are extremely rare, however, these cannot be totally The infusion rate should be reduced in malnourished patients and
excluded for sensitised patients. Therefore particular caution in children. COMPOSITION
should be observed when LIPOFUNDIN MCT/LCT (or fat It is recommended that the infusion rate be so chosen that the 1000 ml of emulsion contain
emulsions in general) are to be administered to such patients. planned daily dose can be administered within 24 hours or not less Soya-bean Oil 100.0 g
If fat is to be administered in high doses every day there should be than 16 hours per day. Medium-chain Triglycerides 100.0 g
controls of serum triglycerides and, if necessary, of blood sugar, Duration of use Glycerol, Egg Lecithin, all-rac--tocopherol, sodium oleate, water
acid base and electrolyte status after the rst day of infusion and
The duration of administration of the fat emulsion as part of a for injections
then at suitable intervals.
complete parenteral nutrition is generally 1 - 2 weeks. If parenteral Content of essential fatty acids:
The water balance and/or body weight should be monitored daily. nutrition with lipid emulsions is further indicated, the emulsion
Linoleic acid 48.0 - 58.0 g/l
Because alterations in the blood cell counts may be symptoms of can be administered over longer periods provided appropriate
-Linolenic acid 5.0 - 11.0 g/l
overdose, monitoring of the blood cell counts is advisable. monitoring is employed.
Caloric value: 7990 kJ/l = 1908 kcal/l
In the case of patients suspected to have disturbances of lipid
METHOD OF ADMINISTRATION Theoretical osmolarity 380 mOsm/l
metabolism fasting hyperlipaemia should be excluded by
As intravenous infusion Titration acidity or alkalinity
determination of the serum triglyceride concentration. If during
Lipid emulsions are suitable for peripheral venous administration (to pH 7.4) < 0.5 mmol/l
infusion the serum triglyceride concentrations exceed 3 mmol/l in
and can also be administered separately via peripheral veins as part pH 6.5 - 8.5
adults and 1.7 mmol/l in children the infusion rate must be reduced
or the infusion must be stopped. Serum triglyceride concentrations of total parenteral nutrition. PHARMACEUTICAL FORM
exceeding above values 12 hours after the lipid infusion has been If infusion sets with in-line lters are used they must be lipid- Emulsion for infusion
stopped also indicates disturbance of lipid metabolism. permeable.
Fat administration should also be interrupted if there is a marked When lipid emulsions are to be simultaneously infused with
increase of the blood glucose concentration during fat infusion. Fat emulsion for calorie supply and supply of essential fatty acids
amino acid and carbohydrate solutions the Y- or the bypass
Using fat emulsions as the only calorie source may provoke connector should be placed as close to the patient as possible. INDICATIONS
metabolic acidosis. Simultaneous carbohydrate infusions will It should be made sure that solutions to be infused together with Calorie supply including a readily metabolisable fat component
prevent those complications. Therefore, fat infusions should LIPOFUNDIN MCT/LCT 10 % through the same tubing are (MCT);
always be accompanied by infusions of sufcient amounts of compatible with the fat emulsion. Supply of essential fatty acids and uid in the setting of total
carbohydrate containing solutions. When administering the fat emulsion from exible bags, the air parenteral nutrition
Vitamin E may have an inuence on the effect of vitamin K in the vent of the infusion set must be closed.
CONTRAINDICATIONS
synthesis of coagulation factors. Therefore, in patients receiving Only infuse emulsions having room temperature!
oral anticoagulants and suspected to have vitamin K deciency, LIPOFUNDIN MCT/LCT must not be administered in the
monitoring of the coagulation status is recommended. OVERDOSE following conditions:
Symptoms Severe blood coagulation disorders, states of shock and collapse,
PREGNANCY AND LACTATION acute thrombo-embolism, fat embolism, severe septicaemia
Overdose can cause an overload syndrome showing the
The safety of LIPOFUNDIN MCT/LCT during pregnancy and accompanied by acidosis and hypoxia, acute phases of myocardial
following symptoms: fever, headache, abdominal pain, fatigue,
lactation has not been assessed, but its use during these periods infarction and stroke, keto-acidotic coma, decompensated diabetic
hyperlipaemia, hepatomegaly with or without jaundice,
is not considered to constitute a hazard. Nevertheless, medicines metabolism or unstable metabolism.
splenomegaly, pathological liver function tests, anaemia, reduction
should not be used in pregnancy, especially during the rst The administration of LIPOFUNDIN MCT/LCT is also
of platelet counts, reduction of leucocyte counts, haemorrhage
trimester, unless the expected benet is thought to outweigh any contraindicated if serum triglycerides accumulate in the following
and tendency to haemorrhage, alterations or reductions in blood
possible risk to the foetus. conditions:
coagulation factors (as indicated by pathological values of
INTERACTIONS bleeding time, coagulation time, prothrombin time etc.). Disorders of lipid metabolism, liver diseases, disorders of
the reticulo-endothelial system, haemorrhagic necrotising
Interactions with other medicaments are not known so far. Emergency treatment, antidotes
pancreatitis.
LIPOFUNDIN MCT/LCT 10 % must not be used as vehicle Immediate cessation of infusion. Further therapy is determined General contra-indications for parenteral nutrition:
solutions for electrolyte concentrates or other medicaments. according to the individual symptoms and their severity; in some
Uncontrolled mixing with other infusion solutions should also Acidoses of various origin, uncorrected disturbances of the
circumstances it may be necessary to transfuse blood or blood
be avoided because adequate stability of the emulsion would no electrolyte and uid balances (such as hypotonic dehydration,
components.
longer be guaranteed. hypokalaemia, hyperhydration), intrahepatic cholestasis.
UNDESIRABLE EFFECTS
Combined regimes are only to be used for parenteral nutrition SPECIAL WARNINGS AND PRECAUTIONS FOR USE
after their pharmaceutical compatibility has been controlled and In very rare cases there can be acute reactions such as Hypersensitivity reactions to one of the ingredients of
guaranteed. dyspnoea, cyanosis, allergic reactions, hyperlipaemia, marked LIPOFUNDIN MCT/LCT, (e.g. traces of protein in soya oil or
hyperglycaemia, hypercoagulability, nausea, vomiting, headache, egg lecithin), are extremely rare, however, these cannot be totally
Admixture of alcohol containing injections or infusion solutions
ush, hyperthermia, hypertension or hypotension, sweating, excluded for sensitised patients. Therefore particular caution
must be strictly avoided.
shivering, drowsiness, chest and back pain during the intravenous should be observed when LIPOFUNDIN MCT/LCT (or fat
DOSAGE infusion of lipids. The infusion should be stopped in such cases. emulsions in general) are to be administered to such patients.
As a rule, depending on calorie requirements When the symptoms have disappeared and elevated serum If fat is to be administered in high doses every day there should be
1. Adults and school-age children triglyceride concentrations (or lipaemic serum turbidity) have controls of serum triglycerides and, if necessary, of blood sugar,
normalised it is generally possible to recommence the infusion at acid base and electrolyte status after the rst day of infusion and
1 - 2 g fat per kg body weight per day
a lower ow rate and/or dose. In such cases the patients should then at suitable intervals.
corresponding to be carefully monitored, particularly in the initial stages, and the The water balance and/or body weight should be monitored daily.
10 - 20 ml LIPOFUNDIN MCT/LCT 10 % per kg body weight serum triglyceride concentrations (serum turbidity) should be
Because alterations in the blood cell counts may be symptoms of
per day controlled at short intervals.
overdose, monitoring of the blood cell counts is advisable.
2. Neononates In the case of patients suspected to have disturbances of In the case of patients suspected to have disturbances of lipid
2 - 3 (max. 4) g lipid per kg body weight per day, corresponding lipid metabolism fasting hyperlipaemia (serum triglyceride metabolism fasting hyperlipaemia should be excluded by
to 20 - 30 (up to 40) ml LIPOFUNDIN MCT/LCT 10 % per kg concentrations above 3 mmol/l in adults and above 1.7 mmol/ determination of the serum triglyceride concentration. If during
body weight per day. l in children) should be excluded before the commencement infusion the serum triglyceride concentrations exceed 3 mmol/l in
The ability to eliminate triglycerides and lipids is not fully of infusion. In the presence of fasting lipaemia, the further adults and 1.7 mmol/l in children the infusion rate must be reduced
developed, particularly in the case of premature and hypotrophic administration of lipid emulsions is contraindicated. or the infusion must be stopped. Serum triglyceride concentrations
neonates, hence to dosage limits should not be exploited Hyperlipaemia (serum triglyceride concentrations above 3 mmol/ exceeding above values 12 hours after the lipid infusion has been
completely and triglyceride and fatty acids should be monitored l in adults and above 1.7 mmol/l in children) 12 hours after the stopped also indicates disturbance of lipid metabolism.
very carefully. There must not be any hyperlipaemia at the end of lipid infusion has been stopped also indicates disturbance of lipid Fat administration should also be interrupted if there is a marked
the interval between the daily infusions. metabolism. increase of the blood glucose concentration during fat infusion.
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Using fat emulsions as the only calorie source may provoke When administering the fat emulsion from exible bags, the air gynaecological infections (e. g. endometritis, after hysterectomy
metabolic acidosis. Simultaneous carbohydrate infusions will vent of the infusion set must be closed. or caesarean section, childbed fever, septic abortion);
prevent those complications. Therefore, fat infusions should Only infuse emulsions having room temperature! bone and joint infections (e. g. osteomyelitis);
always be accompanied by infusions of sufcient amounts of gas gangrene;
carbohydrate containing solutions. OVERDOSE
septicaemia with thrombophlebitis.
Vitamin E may have an inuence on the effect of vitamin K in the Symptoms
A prophylactic use is always indicated prior to operations with
synthesis of coagulation factors. Therefore, in patients receiving Overdose can cause an overload syndrome showing the a high risk of anaerobic infections (gynaecological and intra-
oral anticoagulants and suspected to have vitamin K deciency, following symptoms: fever, headache, abdominal pain, fatigue,
abdominal operations)
monitoring of the coagulation status is recommended. hyperlipaemia, hepatomegaly with or without jaundice,
splenomegaly, pathological liver function tests, anaemia, reduction CONTRAINDICATIONS
PREGNANCY AND LACTATION of platelet counts, reduction of leukocyte counts, haemorrhage In cases of hypersensitivity to metronidazole or other
The safety of LIPOFUNDIN MCT/LCT during pregnancy and and tendency to haemorrhage, alterations or reductions in blood nitroimidazole derivatives (which are, however, very rare),
lactation has not been assessed, but its use during these periods coagulation factors (as indicated by pathological values of METRONIDAZOLE INTRAVENOUS INFUSION 500 MG
is not considered to constitute a hazard. Nevertheless, medicines bleeding time, coagulation time, prothrombin time etc.). should only be given for life-threatening infections when other
should not be used in pregnancy, especially during the rst Emergency treatment, antidotes antibiotic treatment is ineffective.
trimester, unless the expected benet is thought to outweigh any
Immediate cessation of infusion. Further therapy is determined SPECIAL WARNINGS AND PRECAUTIONS FOR USE
possible risk to the foetus.
according to the individual symptoms and their severity; in some
circumstances it may be necessary to transfuse blood or blood In situations of severe liver damage, impaired haematopoiesis (e. g.
INTERACTIONS
components. granulocytopenia) or diseases of the central or peripheral nervous
Interactions with other medicaments are not known so far. system METRONIDAZOLE INTRAVENOUS INFUSION
LIPOFUNDIN MCT/LCT 20 % must not be used as vehicle Undesirable effects
500 MG should only be given if its expected benets clearly
solutions for electrolyte concentrates or other medicaments. In very rare cases there can be acute reactions such as outweigh potential hazards.
Uncontrolled mixing with other infusion solutions should also dyspnoea, cyanosis, allergic reactions, hyperlipaemia, marked
The duration of therapy with metronidazole or drugs containing
be avoided because adequate stability of the emulsion would no hyperglycaemia, hypercoagulability, nausea, vomiting, headache,
other nitroimidazoles should not exceed 10 days. Only in
longer be guaranteed. ush, hyperthermia, hypertension or hypotension, sweating,
individual cases and if clearly needed, the treatment period may
Combined regimes are only to be used for parenteral nutrition shivering, drowsiness, chest and back pain during the intravenous
be extended.
after their pharmaceutical compatibility has been controlled and infusion of lipids. The infusion should be stopped in such cases.
When the symptoms have disappeared and elevated serum Repeat therapy should be restricted as much as possible and to
guaranteed. specic elective cases only. This limitation must be observed
triglyceride concentrations (or lipaemic serum turbidity) have
Admixture of alcohol containing injections or infusion solutions strictly because the possibility of metronidazole developing
normalised it is generally possible to recommence the infusion at
must be strictly avoided. mutagenic activity cannot be safely excluded and because in
a lower ow rate and/or dose. In such cases the patients should
DOSAGE be carefully monitored, particularly in the initial stages, and the animal experiments an increase of the incidence of certain tumours
serum triglyceride concentrations (serum turbidity) should be has been noted.
As a rule, depending on calorie requirements
controlled at short intervals. EFFECTS ON ABILITY TO DRIVE AND TO USE
1. Adults and school-age children
In the case of patients suspected to have disturbances of MACHINES:
1 - 2 g fat per kg body weight per day corresponding to 5 - 10 lipid metabolism fasting hyperlipaemia (serum triglyceride
ml LIPOFUNDIN MCT/LCT 20 % per kg body weight per Even when used as directed, metronidazole may alter reactivity so
concentrations above 3 mmol/l in adults and above 1.7 mmol/ far that the ability to drive or to use machinery is impaired. This
day l in children) should be excluded before the commencement holds true to a still higher degree at the beginning of treatment or
2. Neonates of infusion. In the presence of fasting lipaemia, the further in combination with alcohol intake.
2 - 3 (max. 4) g lipid per kg body weight per day, corresponding administration of lipid emulsions is contra-indicated.
to 10 - 15 (up to 20) ml LIPOFUNDIN MCT/LCT 20 % per Hyperlipaemia (serum triglyceride concentrations above 3 mmol/ PREGNANCY AND LACTATION
kg body weight per day. l in adults and above 1.7 mmol/l in children) 12 hours after the Although there are no conclusive data indicating that metronidazole
The ability to eliminate triglycerides and lipids is not fully lipid infusion has been stopped also indicates disturbance of lipid could be embryo- or fetotoxic, METRONIDAZOLE
developed, particularly in the case of premature and hypotrophic metabolism. INTRAVENOUS INFUSION 500 MG should only be given
neonates, hence to dosage limits should not be exploited Note: for life-threatening infections during pregnancy and the lactation
completely and triglyceride and fatty acids should be monitored period.
Patients are advised to inform their doctor or pharmacist if they
very carefully. There must not be any hyperlipaemia at the end notice any adverse effect not mentioned in this leaet.. Since metronidazole is secreted into breastmilk, nursing is to
of the interval between the daily infusions. be interrupted during therapy. After cessation of therapy with
3. Infants and pre-school children EXPIRY DATE metronidazole, nursing should not be resumed before another
1 - 3 g lipid per kg body weight per day, corresponding to The product must not be used beyond the expiry date stated on 2 - 3 days because of the prolonged serum half-life time of
the labelling. metronidazole.
5 - 15 ml LIPOFUNDIN MCT/LCT 20 % per kg body
weight per day. STORAGE INTERACTIONS
Infusion rate Do not store above 25 C Metronidazole / alcohol
The infusion rate should be as low as possible. The infusion rate Intake of alcoholic beverages must be avoided during
during the rst 15 minutes of the infusion should not exceed 0.05 METRONIDAZOLE INTRAVENOUS metronidazole therapy since adverse reactions such as dizziness
0.1 g lipid per kg body weight per hour, corresponding to 0.25 and vomiting may be the consequence (disulram-like effect).
0.5 ml of emulsion per kg body weight per hour.
INFUSION 500 MG Simultaneous administration of disulram may cause states of
confusion.
Maximum infusion rate:
(Metronidazole) Metronidazole / anticoagulants
Up to 0.15 g lipid per kg body weight per hour, corresponding to
Metronidazole may affect the serum concentration of anticoagulants.
up to 0.75 ml LIPOFUNDIN MCT/LCT 20 % per kg body
COMPOSITION In patients receiving such medicaments the anticoagulant dosage
weight per hour.
100 ml of solution contain regimen must be re-adjusted, if necessary, because metronidazole
Accordingly, the drop rate should not exceed 0.25 drops per kg has a synergetic effect on anticoagulant drugs
body weight per minute. Metronidazole 500 mg
Metronidazole / lithium
This means that for a patient weighing 70 kg the maximum Excipients:
Caution is to be exercised when metronidazole is administered
infusion rate may be approx. 50 ml/hour or 18 drops/min. Sodium chloride, disodium hydrogen phosphate dodecahydrate,
simultaneously with lithium salts, because under metronidazole
The infusion rate should be reduced in malnourished patients and citric acid monohydrate, water for injections
therapy raised serum concentrations of lithium have been
in children. Electrolyte content per 100 ml: observed.
It is recommended that the infusion rate be so chosen that the Sodium 14 mmol Metronidazole / anticonvulsive drugs
planned daily dose can be administered within 24 hours or not less Chloride 13 mmol
The efcacy of metronidazole is reduced when barbiturates or
than 16 hours per day.
PHARMACEUTICAL FORM phenytoin are administered simultaneously.
Duration of use
Solution for infusion Metronidazole / cimetidine
The duration of administration of the fat emulsion as part of a
PHARMACO-THERAPEUTIC GROUP Concurrently administered cimetidine may reduce the elimination
complete parenteral nutrition is generally 1 - 2 weeks. If parenteral
of metronidazole in isolated cases and subsequently lead to
nutrition with lipid emulsions is further indicated, the emulsion can Anti-infective drug
increased metronidazole concentrations in the serum.
be administered over longer periods, accompanied by appropriate
INDICATIONS Inuence on laboratory tests
monitoring.
Treatment and prophylaxis of infections that are or may be due to Metronidazole interferes with the spectrophotometric determination
METHOD OF ADMINISTRATION anaerobic bacteria. of SGOT resulting in decreased values.
As intravenous infusion The treatment is effective in cases of:
DOSAGE
Lipid emulsions are suitable for peripheral venous administration infections of the central nervous system (e. g. brain abscess,
and can also be administered separately via peripheral veins as part meningitis); The following dosage guidelines should be followed:
of total parenteral nutrition. infections of the respiratory tract (e. g. necrotising pneumonia, Adults and children over 12 years
If infusion sets with in-line lters are used they must be lipid- aspiration pneumonia, lung abscess); On the 1st day of therapy, every 6 - 8 hours 500 mg of
permeable. infections in the ear-nose-throat region (e. g. PLAUT-VINCENT metronidazole (corresponding to 100 ml of METRONIDAZOLE
When lipid emulsions are to be simultaneously infused with amino angina) and infections of teeth, mouth and jaws; INTRAVENOUS INFUSION 500 MG), up to max 2.0 g per
acid and carbohydrate solutions the Y- or the bypass connector endocarditis; day.
should be placed as close to the patient as possible. It should be infections in the G.I. tract and the abdominal area, e.g. On the 2nd and the following days, every 12 hours 500 mg
made sure that solutions to be infused together with Lipofundin peritonitis, liver abscess, postoperative infections after colonic of metronidazole, i. e. 1.0 g of metronidazole per day. Only
MCT/LCT 20 % through the same tubing are compatible with the and rectal surgery, purulent diseases in the abdominal and exceptionally, if clearly indicated, the maintenance dose may be
fat emulsion. pelvic cavities; increased to 1.5 g per day.
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For preoperative prophylaxis of infection a single dose of 0.5 - 1.0 Osmolality [mOsm/kg] 920 920 920
(2.0 g max.) of metronidazole should be given immediately prior NUTRIFLEX LIPID PERI
pH 5.0 - 6.0 5.0 - 6.0 5.0 - 6.0
to the beginning of the operation Emulsion for infusion
Children under 12 years Electrolyte content (mmol)
Every 8 hours 7 - 10 mg of metronidazole per kg B.W., Sodium 50 75 100
corresponding to a daily dose of 20 - 30 mg of metronidazole per (Glucose monohydrate, Sodium dihydrogen Potassium 30 45 60
kg b.w. phosphate dehydrate, Zinc acetate Magnesium 3.0 4.5 6.0
Duration of therapy: dehydrate, Soya-bean oil, Medium-chain Calcium 3.0 4.5 6.0
As a rule, the treatment period is 5 to 7 days (see also Special Zinc 0.03 0.045 0.06
triglycerides, Isoleucine, Leucine, Lysine
warnings and precautions for use" above). Chloride 48 72 96
hydrochloride, Methionine, Phenylalanine, Acetate 40 60 80
METHOD OF ADMINISTRATION
Threonine, Tryptophan, Valine, Arginine, Phosphate 7.5 11.25 15
Intravenous infusion.
The contents of one bottle are to be infused slowly i.v., i. e. 100 ml
Histidin hydrochloride monohydrate, Excipients:
max. over not less than 20 minutes, but normally over one hour. Alanine, Aspartic acid, Glutamic acid, Citric acid monohydrate, egg lecithin, glycerol, sodium oleate,
METRONIDAZOLE INTRAVENOUS INFUSION 500 MG Glycine, Proline, Serine, Sodium hydroxide, water for injections
can also be diluted before administration, adding the drug to an Sodium chloride, Sodium acetate trihydrate, PHARMACEUTICAL FORM
i.v. vehicle solution such as 0.9 % sodium chloride or 5 % glucose
infusion solution. Potassium acetate, Magnesium acetate Emulsion for intravenous infusion in three-chamber bags
containing 1250 ml, 1875 ml(N.R) and 2500 ml.
Simultaneously prescribed antibiotics are to be administered tetrahydrate, Calcium chloride dehydrate)
separately. PHARMACO-THERAPEUIC GROUP
COMPOSITION Emulsion for intravenous supply of amino acids, carbohydrates,
OVERDOSE
The ready to use emulsion for infusion contains after mixing of the fat and electrolytes.
There is no specic treatment for gross overdose of metronidazole. contents of the individual chambers:
If required, metronidazole can be effectively eliminated by INDICATIONS
Active ingredients
haemodialysis. Supply of the daily requirement of energy, essential fatty acids,
- from the upper, in 1250 ml in 1875 ml in 2500 ml
amino acids, electrolytes and uids during parenteral nutrition for
UNDESIRABLE EFFECTS left chamber (N.R)
patients with mild to moderately severe catabolism when oral or
Effects on the gastro-intestinal tract Glucose monohydrate 88.0 g 132.0 g 176.0 g
enteral nutrition is impossible, insufcient or contraindicated.
Occasionally, metallic taste, eructation with bitter taste, furry equivalent to 80.0 g 120.0 g 160.0 g
anhydrous glucose CONTRAINDICATIONS
tongue, glossitis and stomatitis, epigastric pressure, nausea,
Sodium dihydrogen 1.170g 1.755g 2.340g This product must not be administered in the following
vomiting, loss of appetite, and diarrhoea may occur.
phosphate dihydrate conditions
In very rare cases of severe persistent diarrhoea during and after
Zinc acetate dihydrate 6.625mg 9.9mg 13.2mg - disturbances of amino acid metabolism,
therapy the attending doctor should be informed, because those
- disturbances of lipid metabolism,
symptoms may be caused by pseudomembraneous colitis, which - from the upper, in 1250 ml in 1875 ml in2500 ml
requires immediate treatment. In those cases administration of - hyperkalaemia; hyponatraemia,
right chamber
METRONIDAZOLE INTRAVENOUS INFUSION 500 MG - unstable metabolism (e.g. severe postaggression syndrome,
Soya-bean oil 25.0 g 37.5 g 50.0 g
is to be discontinued and appropriate therapy (e. g. vancomycin, unstabilized diabetic metabolic situation, coma of unknown
Medium-chain 25.0 g 37.5 g 50.0 g
orally 4 times 250 mg per day) must be instituted. Peristalsis origin),
triglycerides
inhibiting drugs are contraindicated. - hyperglycaemia not responding to insulin doses of up to 6 units
Effects on liver and pancreas from the lower in 1250 ml in 1875 ml in2500 ml insulin/hour,
chamber - acidosis,
Rarely, disorders of liver function (e. g. raised serum levels
Isoleucine 2.34g 3.51 g 4.68 g - intrahepatic cholestasis,
of transaminases and bilirubin) may occur; sporadically:
pancreatitis. Leucine 3.13 g 4.70 g 6.26 g - severe hepatic insufciency,
Lysine hydrochloride 2.84 g 4.26 g 5.68 g - severe renal insufciency,
Symptoms of hypersensitivity
eq. to Lysine 2.26 g 3.39 g 4.52 g - manifest cardiac insufciency,
Occasionally, skin affections (e. g. pruritus, urticaria) and drug
Methionine 1.96 g 2.94 g 3.92 g - aggravating haemorrhagic diatheses,
fever may appear.
Phenylalanine 3.51 g 5.27 g 7.02 g - acute phases of cardiac infarction and stroke,
Severe acute hypersensitivity reactions (i. e. anaphylactic reactions, Threonine 1.82 g 2.73 g 3.64 g - acute thrombo-embolic events, lipid embolism.
up to anaphylactic shock) may occur, but these are very rare. Such
Tryptophan 0.57 g 0.86 g 1.14 g - known hypersensitivity to egg or soya-bean protein or to any of
reactions necessitate immediate therapeutic intervention.
Valine 2.60 g 3.90 g 5.20 g the ingredients
Effects on central and peripheral nervous system Arginine 2.70 g 4.05 g 5.40 g On account of its composition NUTRIFLEX LIPID PERI
Occasionally, headache, vertigo, somnolence or insomnia, states Histidin hydrochloride 1.69 g 2.54 g 3.38 g should not be used for neonates, infants and children under 2 years
of confusion, irritability, depression, and ataxia may be observed. monohydrate of age.
Also occasionally, during administration of METRONIDAZOLE eq. to Histidine 1.25 g 1.88 g 2.50 g
General contra-indications to parenteral nutrition are:
INTRAVENOUS INFUSION 500 MG, peripheral nervous Alanine 4.85 g 7.28 g 9.70 g
- unstable circulatory status with vital threat (states of collapse
disorders (neuropathia) and seizures have been observed. The Aspartic acid 1.50 g 2.25 g 3.00 g and shock),
former become manifest as paresthesia, furry sensation, and Glutamic acid 3.50 g 5.25 g 7.00 g
tingling in the extremities. In such cases the attending doctor - inadequate cellular oxygen supply,
Glycine 1.65 g 2.48 g 3.30 g
should be informed immediately. - states of hyperhydration,
Proline 3.40 g 5.10 g 6.80 g
Effects on blood and blood cell counts - disturbances of the electrolyte and uid balance, acute
Serine 3.00 g 4.50 g 6.00 g
pulmonary oedema, decompensated cardiac insufciency
During therapy with METRONIDAZOLE INTRAVENOUS Sodium hydroxide 0.800 g 1.200 g 1.600 g
INFUSION 500 MG, decreases of leukocyte and platelet Sodium chloride 1.081 g 1.622 g 2.162 g PREGNANCY AND LACTATION
counts (leukopenia, granulocytopenia, in isolated cases even Sodium acetate 0.544 g 0.816 g 1.088 g NUTRIFLEX LIPID PERI should only be used in pregnancy if
up to agranulocytosis, and thrombocytopenia) have been seen trihydrate there is an imperative indication. This medicine manufactured with
occasionally. Therefore, under prolonged administration regular Potassium acetate 2.943 g 4.415 g 5.886 g soya-bean oil contains phytosterols in concentrations that could
monitoring of the blood cell counts is mandatory. Magnesium acetate 0.644 g 0.966 g 1.288 g lead to disturbances of fertility, according to results of testing of
Effects on kidneys and bladder tetrahydrate the puried substance in animal experiments. At present there are
Dysuria, cystitis, and urinary incontinence are very rare Calcium chloride 0.441 g 0.662 g 0.882 g no studies available making a risk-benet assessment possible
occurrences. dihydrate with regard to effects on the embryo or the fetus.
Other effects Breast-feeding is not recommended if women need parenteral
Amino acid content [g] 40 60 80 nutrition in that time.
Occasionally, darkened urine (due to a metabolite of metronidazole) Total nitrogen [g] 5.7 8.6 11.4
may be observed; rare side effects are genital superinfections with content SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
candida, weakness, and blurred vision. Carbohydrate [g] 80 120 160 FOR USE
Local reactions content Caution should be exercised in cases of increased serum
After intravenous administration, vein irritations (up to Lipid content [g] 50 75 100 osmolarity.
thrombophlebitis) may occur. Energy in the As for all large-volume infusion solutions NUTRIFLEX LIPID
Note: form of lipid [kJ/(kcal)] 1990 (475) 2985 (715) 3980 (950) PERI should be administered with caution to patients with impaired
Energy in the cardiac or renal function. Disturbances of the uid, electrolyte or
Patients should inform their doctor or pharmacist if they notice any
from of acid-base balance, e.g. hyperhydration, hyperkalaemia, acidosis,
adverse effect that has not been mentioned in this leaet.
carbohydrate [kJ/(kcal)] 1340 (320) 2010 (480) 2680 (640) should be corrected before the start of infusion. Too rapid infusion
EXPIRY DATE Energy in the can lead to uid overload with pathological serum electrolyte
Do not use the product beyond the expiry date stated on the label. from of concentrations, hyperhydration and pulmonary oedema.
amino acids [kJ/(kcal)] 670 (160) 1005 (240) 1340 (320) The serum triglyceride concentration should be monitored when
STORAGE Non-protein infusing NUTRIFLEX LIPID PERI. Fasting lipaemia should
Keep container in the outer carton. energy [kJ/(kcal)] 3330 (795) 4995 (1195) 6660 (1590) be excluded in patients with suspected disturbances of lipid
Do not store above 25 C. Total energy [kJ/(kcal)] 4000 (955) 6000 (1435) 8000 (1910) metabolism before starting infusion. The administration of lipids
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SPDI
is contra-indicated if there is fasting lipaemia. The presence of METHOD OF ADMINISTRATION
hypertriglyceridaemia 12 hours after lipid administration also For intravenous infusion. Especially suitable for infusion into NUTRIFLEX LIPID PLUS
indicates a disturbance of lipid metabolism peripheral veins. Emulsion for infusion
NUTRIFLEX LIPID PERI should be administered cautiously Preparation of the mixed solution:
to patients with disturbances of lipid metabolism, e.g. renal Remove the bag from its protective pack and proceed as follows:
insufciency, diabetes mellitus, pancreatitis, impaired hepatic (Glucose monohydrate, Sodium dihydrogen
open out the bag and lay on a solid surface
function, , hypothyroidism (with hypertriglyceridemia) and sepsis.
If NUTRIFLEX LIPID PERIis given to patients with these open the peel seals to the two upper chambers by using pressure phosphate dehydrate, Zinc acetate dehydrate.
conditions, close monitoring of serum triglycerides is mandatory. with both hands Soya-bean oil, Medium-chain triglycerides,
Any sign or symptom of anaphylactic reaction (such as fever, briey mix the contents of the bag together Isoleucine, Leucine, Lysine hydrochloride,
shivering, rash or dyspnoea) should lead to immediate interruption Preparation for infusion: Methionine, Phenylalanine, Threonine,
of the infusion. fold the two empty chambers backwards
Tryptophan Valine, Arginine, Histidine
Depending on the patients metabolic condition, occasional hang the mixing bag on the infusion stand by the centre hanging
hypertriglyceridaemia or increases of the blood glucose loop hydrochloride monohydrate, Alanine,,
concentration may occur.. If the plasma triglyceride concentration remove the protective cap from the run-out port and carry out Aspartic acid, Glutamic acid, Glycine
rises to more than 3 mmol/l during administration of lipid it is infusion using the normal technique (aminoacetic acid), Proline, Serine, Sodium
recommended that the infusion rate should be reduced. Should Duration of use hydroxide, Sodium chloride, Sodium acetate
the plasma triglyceride concentration remain above 3 mmol/l the
The duration of treatment for the indications stated should not trihydrate, Potassium acetate, Magnesium
administration should be stopped until the level normalizes.
exceed 7 days.
A dose reduction or interruption of administration is also indicated acetate tetrahydrate, Calcium chloride
if the blood glucose concentration rises to more than 14 mmol/l OVERDOSE dehydrate)
(250 mg/dl) when administering the lipid. Overdose of NUTRIFLEX LIPID PERI is not to be expected
As with all solutions containing carbohydrates the administration on proper administration. COMPOSITION
of NUTRIFLEX LIPID PERI can lead to hyperglycaemia. Symptoms of uid and electrolyte overdose The ready to use emulsion for infusion contains after mixing of the
The blood glucose level should be monitored. If there is Hypotonic hyperhydration, electrolyte imbalance and pulmonary contents of the individual chambers:
hyperglycaemia the rate of infusion should be reduced or insulin oedema. Active ingredients
should be administered. Symptoms of amino acid overdose: - from the upper,
Intravenous infusion of amino acids is accompanied by increased Renal amino acid losses with consecutive amino acid imbalances, left chamber in 1250 ml in 1875 ml in 2500 ml
urinary excretion of the trace elements, especially copper and, in sickness, vomiting and shivering. Glucose monohydrate 165.0g 247.5g 330.0g
particular, zinc. This should be considered in the dosing of trace
Symptoms of glucose overdose: = anhydrous glucose 150.0g 225.0g 300.0g
elements, especially during long-term intravenous nutrition.
Hyperglycaemia, glucosuria, dehydration, hyperosmolality, Sodium dihydrogen
NUTRIFLEX LIPID PERI should not be given simultaneously
hyperglycaemic and hyperosmolar coma.
with blood in the same infusion set due to the risk of phosphate dihydrate 2.340g 3.510g 4.680g
pseudoagglutination. Symptoms of fat overdose:
Zinc acetate dihydrate 6.580 mg 9.870 mg 13.160mg
Moreover controls of the serum ionogramme, the water balance, Lipid overdose may lead to the overload syndrome, characterised
the acid-base balance and during long-term administration - (for example) by fever, headache, abdominal pain, fatigue, - from the upper, right
of blood cell counts, coagulation status and hepatic function are hyperlipaemia, hepatomegaly with or without jaundice,
chamber in 1250 ml in 1875 ml in2500 ml
necessary. splenomegaly, pathological disturbances of liver function,
anaemia, reduction in platelet count, reduction in white cell count, Soya-bean oil 25.0 g 37.5 g 50.0 g
The fat content may interfere with certain laboratory measurements Medium-chain
haemorrhagic diathesis and haemorrhage, alteration or depression
(e.g. bilirubin, lactate dehydrogenase, oxygen saturation). if blood
of blood coagulation factors (bleeding time, coagulation time, triglycerides 25.0 g 37.5 g 50.0 g
is sampled before fat has been adequately cleared from the blood
prothrombin time etc.). The plasma triglyceride concentration
stream.
should not exceed 3 mmol/l during infusion. - from the lower
Substitution of electrolytes, vitamins and trace elements may be
Emergency treatment, antidotes: chamber in 1250 ml in 1875 ml in2500 ml
necessary as required.
Immediate cessation of infusion is indicated for overdose. Further Isoleucine 2.82g 4.23 g 5.64 g
As NUTRIFLEX LIPID PERI contains zinc and magnesium,
therapeutic measures depend on the particular symptoms and Leucine 3.76g 5.64 g 7.52 g
care should be taken when it is coadministered with solutions their severity. When infusion is recommenced after the symptoms
containing these elements. Lysine hydrochloride 3.41g 5.12 g 6.82 g
have declined it is recommended that the infusion rate be raised
As with all intravenous solutions strict aseptic precautions are gradually with monitoring at frequent intervals. = Lysine 2.73g 4.10 g 5.46 g
necessary for the infusion of NUTRIFLEX LIPID PERI. Methionine 2.35g 3.53 g 4.70 g
UNDESIRABLE EFFECTS
NUTRIFLEX LIPID PERI is a preparation of complex Phenylalanine 4.21g 6.32 g 8.42g
composition. It is, therefore, strongly advisable not to add other Possible early reactions on the administration of lipid emulsions
are: slight increase in temperature, ush, cold feeling, shivering, Threonine 2.18g 3.27 g 4.36 g
solutions.
loss of appetite, nausea, vomiting, respiratory distress, headache, Tryptophan 0.68g 1.02 g 1.36 g
INTERACTIONS pain in the back, bones, chest and lumbar region, fall or increase Valine 3.12g 4.68 g 6.24 g
Some drugs, like insulin, may interfere with the bodys lipase in blood pressure (hypotension, hypertension), hypersensitivity Arginine 3.24g 4.86 g 6.48 g
system. This kind of interaction seems, however, to be of only reactions (e.g. anaphylactic reactions, dermal eruptions).
Histidine hydrochloride
limited clinical importance. Hot ushes or bluish discoloration of the skin due to reduced
oxygen content of the blood (cyanosis) can occur as side effects. monohydrate 2.03g 3.05 g 4.06 g
Heparin given in clinical doses causes a transient release of
lipoprotein lipase into the circulation. This may result initially If these side effects occur the infusion should be discontinued or, = Histidine 1.50g 2.25 g 3.00 g
in increased plasma lipolysis followed by a transient decrease in if appropriate, the infusion should be continued at a lower dose Alanine 5.82g 8.73 g 11.64 g
triglyceride clearance. level. Aspartic acid 1.80g 2.70 g 3.60 g
Soya-bean oil has a neutral content of vitamin K1. This may Attention should be paid to the possibility of an overloading Glutamic acid 4.21g 6.32 g 8.42 g
interfere with the therapeutic effect of coumarin derivatives which syndrome This can occur as a result of individually varying,
Glycine
should be closely monitored in patients treated with such drugs. genetically determined metabolic conditions and can occur at
different rates and after differing doses depending on previous (aminoacetic acid) 1.98g 2.97 g 3.96 g
DOSAGE
disorders. Proline 4.08g 6.12 g 8.16 g
The dosage is adapted to the individual patients requirements.
Overloading syndrome is associated with the following symptoms: Serine 3.60g 5.40 g 7.20 g
The maximum daily dose is 40 ml per kg body weight, enlargement of the liver (hepatomegaly) with and without Sodium hydroxide 0.976g 1.464 g 1.952 g
corresponding to jaundice (icterus), enlargement of the spleen (splenomegaly), fatty Sodium chloride 0.503g 0.755 g 1.006 g
- 1.28 g amino acids /kg body weight per day inltration of the organs, pathological hepatic function parameters,
Sodium acetate
- 2.56 g glucose /kg body weight per day anaemia, reduction of white cell count (leucopenia), reduction of
platelet count (thrombocytopenia), a tendency to haemorrhage and trihydrate 0.277g 0.416 g 0.554 g
- 1.6 g fat /kg body weight per day
haemorrhages, alterations or reduction in the blood coagulation Potassium acetate 3.434g 5.151 g 6.868 g
It is recommended that NUTRIFLEX LIPID PERI be
factors (bleeding time, coagulation time, prothrombin time etc.), Magnesium acetate
administered continuously. A stepwise increase of the infusion rate
fever, hyperlipaemia, headache, stomache ache, fatigue.
over the rst 30 minutes up to the desired infusion rate avoids tetrahydrate 0.858g 1.287 g 1.716 g
possible complications. If signs of vein wall irritation, phlebitis, or thrombophlebitis occur,
Calcium chloride
change of the infusion site should be considered.
The maximum infusion rate is 2.5 ml/kg body weight per hour, dihydrate 0.588 g 0.882 g 1.176 g
corresponding to Please inform your doctor or pharmacist if you notice any
undesirable effect that is not mentioned in this leaet.
- 0.08 g amino acids /kg body weight per hour Amino acid content [g] 48 72 96
- 0.16 g glucose /kg body weight per hour INSTRUCTIONS FOR STORAGE / USE / HANDLING Total nitrogen
- 0.1 g fat /kg body weight per hour Do not use after the product has passed the expiry date. content [g] 6.8 10.2 13.6
For a patient weighing 70 kg this corresponds to an infusion rate The emulsion is to be used immediately after mixing. It can be Carbohydrate
of 175 ml/ kg body weight per hour. The amount of amino acid stored at 2 8 C over 4 days, plus 48 hours at 25 C.
content [g] 150 225 300
administered is then 5.6 g/hour, of glucose 11.2 g/hour and of lipid Protect from light and do not store above 25C.
Lipid content [g] 50 75 100
7 g/ hour. Do not freeze! If accidentally frozen, discard the bag.
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SPDI
Amino acid content [g] 48 72 96 could lead to disturbances of fertility, according to results of The maximum daily dose is 40 ml/kg body weight, corresponding to
testing of the puried substance in animal experiments. At present 1.54 g amino acids /kg body weight per day,
Total nitrogen
there are no studies available making a risk-benet assessment 4.8 g glucose /kg body weight per day,
content [g] 6.8 10.2 13.6 possible with regard to effects on the embryo or the fetus. 1.6 g fat /kg body weight per day.
Carbohydrate Breast-feeding is not recommended if women need parenteral It is recommended that NUTRIFLEX LIPID PLUS be
content [g] 150 225 300 nutrition in that time. administered continuously. A stepwise increase of the infusion rate
Lipid content [g] 50 75 100 over the rst 30 minutes up to the desired infusion rate helps to
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
FOR USE avoid complications.
Energy in the
Caution should be exercised in cases of increased serum The maximum rate of infusion is 2.0 ml/kg body weight per hour,
form of lipid [kJ/(kcal)] 1990 (475) 2985 (715) 3980 (950) corresponding to
osmolarity
Energy in the 0.08 g amino acids /kg body weight per hour,
As for all large-volume infusion solutions NUTRIFLEX LIPID
from of 0.24 g glucose /kg body weight per hour,
PLUS should be administered with caution to patients with impaired
carbohydrate [kJ/(kcal)] 2510 (600) 3765 (900) 5020 (1200) cardiac or renal function. Disturbances of the uid, electrolyte or 0.08 g fat /kg body weight per hour.
Energy in the acid-base balance, e.g. hyperhydration, hyperkalaemia, acidosis, For a patient weighing 70 kg this corresponds to an infusion rate
from of should be corrected before the start of infusion. Too rapid infusion of 140 ml/kg body weight per hour. The amount of amino acid
can lead to uid overload with pathological serum electrolyte administered is then 5.4 g/hour, of glucose 16.8 g/hour and of lipid
amino acids [kJ/(kcal)] 800 (190) 1200 (285) 1600 (380)
concentrations, hyperhydration and pulmonary oedema. 5.6 g/hour.
Non-protein
The serum triglyceride concentration should be monitored when In general, it is recommended that the maximum amount of energy
energy [kJ/(kcal)] 4500 (1075) 6750 (1615) 9000 (2155) should not exceed 40 kcal/kg BW and day. If specially indicated
infusing NUTRIFLEX LIPID PLUS. Fasting lipaemia should
Total energy [kJ/(kcal)] 5300 (1265) 7950 (1900) 10600 be excluded in patients with suspected disturbances of lipid e.g. for burned patients higher dosage is possible.
(2530) metabolism before starting infusion. The administration of lipids Method of administration
is contraindicated if there is fasting lipaemia. The presence of The ready-to-use emulsion is infused into a central vein.
Osmolality [mOsm/kg] 1540 1540 1540
hypertriglyceridaemia 12 hours after lipid administration also Preparation of the mixed solution:
pH 5.0 - 6.0 5.0 - 6.0 5.0 - 6.0 indicates a disturbance of lipid metabolism.
Remove the bag from its protective pack and proceed as follows:
NUTRIFLEX LIPID PLUS should be administered cautiously open out the bag and lay on a solid surface
Electrolyte content (mmol)
to patients with disturbances of lipid metabolism, e.g. renal open the peel seals to the two upper chambers by using pressure
Sodium 50.0 75.0 100.0
insufciency, diabetes mellitus, pancreatitis, impaired liver with both hands
Potassium 35.0 52.5 70.0 function, hypothyroidism (with hypertriglyceridemia) and sepsis.
briey mix the contents of the bag together
Magnesium 4.0 6.0 8.0 If NUTRIFLEX LIPID PLUS is given to patients with these
conditions, close monitoring of serum triglycerides is mandatory. Preparation for infusion:
Calcium 4.0 6.0 8.0
fold the two empty chambers backwards
Zinc 0.03 0.045 0.06 Any sign or symptom of anaphylactic reaction (such as fever,
hang the mixing bag on the infusion stand by the centre hanging
Chloride 45.0 67.5 90.0 shivering, rash or dyspnoea) should lead to immediate interruption
loop
of the infusion.
Acetate 45.0 67.5 90.0 remove the protective cap from the run-out port and carry out
Depending on the patients metabolic condition, occasional infusion using the normal technique
Phosphate 15.0 22.5 30.0
hypertriglyceridaemia or increases of the blood glucose
concentration may occur. If the plasma triglyceride concentration Duration of use
Excipients:
rises to more than 3 mmol/l during administration of lipid it is The duration of treatment for the indications stated is not limited.
Citric acid monohydrate, egg lecithin, glycerol, sodium oleate,
recommended that the infusion rate should be reduced. Should During long-term administration of NUTRIFLEX LIPID
water for injections
the plasma triglyceride concentration remain above 3 mmol/l the PLUS it is necessary to supply appropriate replacement of trace
PHARMACEUTICAL FORM administration should be stopped until the level normalizes. elements and vitamins.
Emulsion for intravenous infusion in three-chamber bags A dose reduction or interruption of administration is also indicated OVERDOSE
containing 1250 ml, 1875 ml or 2500 ml. if the blood glucose concentration rises to more than 14 mmol/l Overdose of NUTRIFLEX LIPID PLUS is not to be expected
PHARMACO-THERAPEUTIC GROUP (250 mg/dl) when administering the lipid. on proper administration.
Emulsion for intravenous supply of amino acids, carbohydrates, As with all solutions containing carbohydrates the administration Symptoms of uid and electrolyte overdose
fat and electrolytes. of NUTRIFLEX LIPID PLUS can lead to hyperglycaemia. Hypotonic hyperhydration, electrolyte imbalance and pulmonary
The blood glucose level should be monitored. If there is oedema.
INDICATIONS hyperglycaemia the rate of infusion should be reduced or insulin
Symptoms of amino acid overdose:
Supply of the daily requirement of energy, essential fatty acids, should be administered.
amino acids, electrolytes and uids during parenteral nutrition for Renal amino acid losses with consecutive amino acid imbalances,
Intravenous infusion of amino acids is accompanied by increased
patients with mild to moderately severe catabolism when oral or sickness, vomiting and shivering.
urinary excretion of the trace elements, especially copper and, in
enteral nutrition is impossible, insufcient or contraindicated. particular, zinc. This should be considered in the dosing of trace Symptoms of glucose overdose:
elements, especially during long-term intravenous nutrition. Hyperglycaemia, glucosuria, dehydration, hyperosmolality,
CONTRAINDICATIONS
NUTRIFLEX LIPID PLUS should not be given simultaneously hyperglycaemic and hyperosmolar coma.
This product must not be administered in the following
with blood in the same infusion set due to the risk of Symptoms of fat overdose:
conditions
- disturbances of amino acid metabolism, pseudoagglutination. Lipid overdose may lead to the overload syndrome, characterised
Moreover controls of the serum ionogramme, the water balance, (for example) by fever, headache, abdominal pain, fatigue,
- disturbances of lipid metabolism,
the acid-base balance and during long-term administration - hyperlipaemia, hepatomegaly with or without jaundice,
- hyperkalaemia; hyponatraemia, splenomegaly, pathological disturbances of liver function,
of blood cell counts, coagulation status and hepatic function are
- unstable metabolism (e.g. severe postaggression syndrome, anaemia, reduction in platelet count, reduction in white cell count,
necessary.
unstabilized diabetic metabolic situation, coma of unknown haemorrhagic diathesis and haemorrhage, alteration or depression
origin), The fat content may interfere with certain laboratory measurements
of blood coagulation factors (bleeding time, coagulation time,
- hyperglycaemia not responding to insulin doses of up to 6 units (e.g. bilirubin, lactate dehydrogenase, oxygen saturation). if blood prothrombin time etc.). The plasma triglyceride concentration
insulin/hour, is sampled before fat has been adequately cleared from the blood should not exceed 3 mmol/l during infusion.
- acidosis, stream.
- intrahepatic cholestasis, Substitution of electrolytes, vitamins and trace elements may be
Immediate stop of infusion is indicated in the case of overdose.
- severe hepatic insufciency, necessary as required.
Further therapeutic measures depend on the particular symptoms
- severe renal insufciency, As NUTRIFLEX LIPID PLUScontains zinc and magnesium, and their severity. When infusion is recommenced after the
- manifest cardiac insufciency, care should be taken when it is co-administered with solutions symptoms have declined it is recommended that the infusion rate
containing these elements. be raised gradually with monitoring at frequent intervals.
- aggravating haemorrhagic diatheses,
- acute phases of cardiac infarction and stroke, As with all intravenous solutions strict aseptic precautions are
UNDESIRABLE EFFECTS
necessary for the infusion ofNUTRIFLEX LIPID PLUS.
- acute event of thrombo-embolism, lipid embolism, Possible early reactions on the administration of lipid emulsions
known hypersensitivity to egg or soy protein or to any of the NUTRIFLEX LIPID PLUS is a preparation of complex
are: slight increase in temperature, ush, cold feeling, shivering,
ingredients. composition. It is, therefore, strongly advisable not to add other
loss of appetite, nausea, vomiting, respiratory distress, headache,
solutions.
On account of its composition NUTRIFLEX LIPID PLUS backache, bone pain, pain in the chest and lumbar region, fall
should not be used for neonates, infants and children under 2 years INTERACTIONS or increase in blood pressure (hypotension, hypertension),
of age. Some drugs, like insulin, may interfere with the bodys lipase hypersensitivity reactions (e.g. anaphylactic reactions, dermal
General contraindications to parenteral nutrition are: system. This kind of interaction seems, however, to be of only eruptions).
- unstable circulatory status with vital threat (states of collapse limited clinical importance. Hot ushes or bluish discoloration of the skin due to reduced
and shock), oxygen content of the blood (cyanosis) can occur as side effects.
Heparin given in clinical doses causes a transient release of
- inadequate cellular oxygen supply, lipoprotein lipase into the circulation. This may result initially If these side effects occur the infusion should be discontinued or,
- states of hyperhydration, in increased plasma lipolysis followed by a transient decrease in if appropriate, the infusion should be continued at a lower dose
- disturbances of the electrolyte and uid balance, triglyceride clearance. level.
- acute pulmonary oedema, decompensated cardiac Soya-bean oil has a natural content of vitamin K1. This may Attention should be paid to the possibility of an overloading
insufciency. interfere with the therapeutic effect of coumarin derivatives which syndrome This can occur as a result of individually varying,
should be closely monitored in patients treated with such drugs. genetically determined metabolic conditions and can occur at
PREGNANCY AND LACTATION different rates and after differing doses depending on previous
NUTRIFLEX LIPID PLUS should only be used in pregnancy DOSAGE disorders.
if there is an imperative indication. This medicine manufactured The dosage is adjusted according to the patients individual Overloading syndrome is associated with the following symptoms:
with soya-bean oil contains phytosterols in concentrations that requirements. enlargement of the liver (hepatomegaly) with or without jaundice
101
Book_01.indd 101 6/4/2008 2:19:53 PM

SPDI
(icterus), enlargement of the spleen (splenomegaly), fatty When carrying out phosphate substitution as a part of parental Drug interactions (see above) or suddenly occurring acidosis,
inltration of organs, pathological hepatic function parameters, nutrition account should be taken of the fact that various solutions acute impairment of renal function or other conditions may lead
anaemia, reduction of white cell count (leucopenia), reduction of used for parenteral nutrition (including lipid emulsions) already to sudden hyperkalaemia.
platelet count (thrombocytopenia), a tendency to haemorrhage and contain phosphate. Note
haemorrhages, alterations or reduction in the blood coagulation
PREGNANCY AND LACTATION Patients should inform their doctor or pharmacist if they notice any
factors (bleeding time, coagulation time, prothrombin time etc.),
Reports of damaging effects during pregnancy and lactation are adverse reaction not mentioned in this leaet.
fever, hyperlipaemia, headache, abdominal pain, fatigue.
not known. EXPIRY DATE
Please inform your doctor or pharmacist if you notice any
undesirable effect that is not mentioned in this leaet. INTERACTIONS The product must not be used beyond the expiry date stated on
EXPIRY DATE An increase of the intracellular potassium concentration weakens the labelling.
The product must not be used beyond the expiry date stated on the effect of cardiac glycosides, a decrease of the intracellular INSTRUCTIONS FOR STORAGE / USE / HANDLING
the labelling. potassium concentration increases the arrhythmogenic effect of
cardiac glycosides. The product is supplied in single-dose containers. Discard unused
INSTRUCTIONS FOR STORAGE / USE / HANDLING contents of a container once opened.
Potassium saving diuretics, aldosterone antagonists, ACE
Do not use after the product beyond the expiry date stated on the inhibitors, non-steroid anti-inammatory drugs and peripheral
labelling. analgesics reduce the renal potassium excretion. Potassium
adminstration simultaneously with those drugs may result in
BAXTER
The emulsion is to be used immediately after mixing. It can be
stored for 4 day at 2 8 C plus 48 hours at 25 C. severe hyperkalaemia. P.O BOX 246968, RIYADH 11312
Protect from light and do not store above 25 C. Marked hyperkalaemia, which may affect heart rhythm, may AL ASHA ST., RABWAH SQ.
Do not freeze! If accidentally frozen, discard the bag! also result from simultaneous administration of potassium and SAUDI ARABIA
suxamethonium. TEL: 01-2914348, FAX: 01-291 4238
POTASSIUM PHOSPHATES INJECTION is incompatible
POTASSIUM PHOSPHATES INJECTION with solutions containing calcium and magnesium.
DEXTROSE INJECTION, USP
DOSAGE
The dose is adjusted according to the actual basic or correction
(Dipotassium phosphate, Potassium dihydro- requirements, according to the analytical values of the serum (Dextrose Hydrous)
gen phosphate) ionogramme.
DESCRIPTION
Daily dose
COMPOSITION DEXTROSE INJECTION, USP is a sterile, nonpyrogenic
In the setting of parenteral nutrition the basic phosphate
One ampoule (= 20 ml) ml of solution contains solution for uid replenishment and caloric supply in single
requirement in adults is 0.2 0.5 mmol/kg BW/day, corresponding
Active ingredients: dose containers for intravenous administration. It contains no
to 0.3 0.8 ml/kg BW.
antimicrobial agents. Composition, osmolarity, pH, and caloric
Dipotassium phosphate 1.394 g In therapy of severe hypophosphataemia the dose is adjusted content are shown in Table 1.
Potassium dihydrogen phosphate 0.544 g according to the serum phosphate concentration. Then higher
amounts than those stated above may be needed. Table 1
1 ml contains 1 mmol potassium and 0.6 mmol phosphate
Size * Dextrose Osmolarity pH Caloric
Excipients: Per 0.6 mmol phosphate 1 mmol of potassium is administered.
(mL) Hydrous, (mOsmol/L) Content
Water for injections The maximum daily dose of potassium is 2 3 mmol/kg BW
USP (g/L) (calc.) (kcal/L)
Maximum infusion rate
PHARMACEUTICAL FORM 5% 25(N.R) 50 252 4.0 170
The infusion rate is limited by the potassium content of the
Concentrate for solution for infusion Dextrose Quad pack (3.2
solution. The maximum infusion rate is 20 mmol of potassium per
PHARMACO-THERAPEUTIC GROUP hour, that is 0.3 mmol of potassium per kg BW/ hour. Injection, 50 to 6.5)
USP Single pack
Electrolyte concentrate Method of administration
Quad pack
INDICATIONS Intravenous infusion, only to be administered diluted as an
Multi pack
additive to infusion solutions. The concentration of phosphate in
Substitution of phosphate in intensive-care patients in situations 100
the infusion solution must not exceed 24 mmol/l (corresponding to
of simultaneously existing potassium and phosphate deciency, Single pack
40 mmol of potassium/l).
with close monitoring of the serum potassium and phosphate Quad pack
concentrations. POTASSIUM PHOSPHATES INJECTION is to be added to
the vehicle solution with strict sterile precautions immediately Multi pack
CONTRAINDICATIONS before the infusion is set up. The infusion bottle should then be 150
POTASSIUM PHOSPHATES INJECTION must not be shaken gently. 250
administered in cases of Vehicle solutions should be free of calcium and magnesium. 500
- Hyperphosphataemia, Suitable solutions are e.g. 5 % glucose solution or isotonic sodium 1000
- Hyperkalaemia, chloride solution. If sodium intake must be limited, only sodium- 10% 250 100 505 4.0 340
- Disturbance of renal function, free vehicle solutions are to be used. Dextrose 500 (3.2 to
- Disorders that are frequently associated with hyperkalaemia Infusion should be carried out continuously. Use of infusion Injection, 1000 6.5)
such as dehydration, limited renal excretion. Addison's disease, pumps is advisable. USP
Adynamia episodica hereditaria (Gamstorp's syndrome), sickle Particular care should be taken to ensure that infusion is strictly
cell anaemia, *HO
intravenous, because paravenous administration can lead to
- Therapy with potassium saving diuretics. tissue necroses and to indurations and chalky deposits in the D
- Hypocalcaemia subcutaneous tissue. DH OH H2O
POTASSIUM PHOSPHATES INJECTION is not suitable for HO
OVERDOSE
treatment of acid-base imbalances. DH
Symptoms
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS D-Glucose monohydrate
Overdose can lead to hyperkalaemia and hyperphosphataemia.
FOR USE The VIAFLEX plastic container is fabricated from a specially
Hyperkalaemia is mainly characterized by cardiovascular
POTASSIUM PHOSPHATES INJECTION should only formulated polyvinyl chloride (PL 146 Plastic). The amount
disorders, i. e. bradycardia, AV block, ventricular brillation
be administered with particular caution in cases of cardiac of water that can permeate from inside the container into the
and diastolic cardiac arrest. In the ECG, high sharp symmetric
decompensation. t-waves, and, if serum potassium concentrations are very high, overwrap is insufcient to affect the solution signicantly.
Administration should be discontinued if there are signs of renal QRS broadening are observable. The circulatory disorders are Solutions in contact with the plastic container can leach out
insufciency. hypotension and centralisation. certain of its chemical components in very small amounts within
Digitalis toxicity is increased in situations of hypokalaemia. the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up
The neuromuscular symptoms encompass fatigue, states of
to 5 parts per million. However, the safety of the plastic has been
Disturbances of the potassium balance, i.e. hyper- or hypokalaemia, confusion, heaviness of limbs, muscle twitching, paraesthesia,
conrmed in tests in animals according to USP biological test for
lead to typical alterations in the ECG. There is, however, no linear ascending paralysis.
plastic containers as well as by tissue culture toxicity studies.
relationship between the ECG alterations and the potassium Plasma potassium concentrations of 6.5 mmol/l or more are
concentration in serum. dangerous, concentrations above 8 mmol/l often lethal. CLINICAL PHARMACOLOGY
Since high levels of phosphate administration can cause Hyperphosphataemia may lead to renal damage as a result of DEXTROSE INJECTION, USP has value as a source of water
hypocalcaemia and metastatic calcications, the ionized calcium the precipitation of calcium phosphate (nephrocalcinosis), the and calories. It is capable of inducing diuresis depending on the
and phosphate should be monitored regularly if daily phosphate precipitation of calcium phosphate in other tissues (e.g. skin, clinical condition of the patient.
substitution exceeds 50 mmol. cornea, lungs), and to hypocalcaemia.
The serum ionogramme should be monitored at regular intervals INDICATIONS AND USAGE
When performing phosphate substitution over longer periods DEXTROSE INJECTION, USP is indicated as a source of water
Therapy of hyperkalaemia: and calories.
(several weeks) the plasma phosphate concentration and the
Immediate discontinuation of infusion, slow intravenous
amount of phosphate excreted in 24 hour urine should be CONTRAINDICATIONS
administration of 10 % w/v calcium gluconate, glucose infusions
monitored weekly.
together with insulin, increase of diuresis or ion exchangers Solutions containing dextrose may be contraindicated in patients
When high doses of phosphate are administered it can be necessary administered orally or rectally, correction of acidosis if necessary. with known allergy to corn or corn products.
to administer calcium simultaneously. The calcium must be
In cases of massive overdose haemodialysis may be necessary.
administered by a separate route. WARNINGS
Since per 0.6 mol phosphate the solution contains 1 mol of UNDESIRABLE EFFECTS DEXTROSE INJECTION, USP should not be administered
potassium the potassium concentration should be taken into Nausea and, during too rapid infusion, cardiac arrhythmia may simultaneously with blood through the same administration set
account when calculating the electrolyte balance. occur. because of the possibility of pseudoagglutination or hemolysis.
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Book_01.indd 102 6/4/2008 2:19:54 PM

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SPDI
The intravenous administration of these solutions can cause uid Code Size (mL) NDC Product Name The structural formula of Dextrose Hydrous, USP is :
and/or solute overloading resulting in dilution of serum electrolyte 25(N.R) HO
concentrations, overhydration, congested states, or pulmonary 2B0162 250 0338-0023-02 10% Dextrose Injection,
edema. The risk of dilutive states is inversely proportional to the USP
electrolyte concentrations of the injections. The risk of solute O
2B0163 500 0338-0023-03
overload causing congested states with peripheral and pulmonary OH OHH2O
edema is directly proportional to the electrolyte concentrations of 2B0164 1000 0338-0023-04
the injections. Exposure of pharmaceutical products to heat should be minimized. HO
Excessive administration of dextrose injections may result in Avoid excessive heat. It is recommended the product be stored at OH
signicant hypokalemia. room temperature (25C/77F); brief exposure up to 40C/104F Dextrose Hydrous :
In very low birth weight infants, excessive or rapid administration does not adversely affect the product. (O-Glucose monohydrate)
of dextrose injection may result in increased serum osmolality and DIRECTIONS FOR USE OF VIAFLEX PLASTIC The VIAFLEX plastic container is fabricated from a specially
possible intracerebral hemorrhage. CONTAINER formulated polyvinyl choloride (PL 146 Plastic). Exposure to
PRECAUTIONS Warning: temperatures above 25C/77F during transport and storage will
Clinical evaluation and periodic laboratory determinations Do not use plastic containers in series connections. Such use lead to minor losses in moisture content. Higher temperatures lead
are necessary to monitor changes in uid balance, electrolyte could result in air embolism due to residual air being drawn from to greater losses. It is unlikely that these minor losses will lead
concentrations and acid base balance during prolonged parenteral the primary container before administration of the uid from the to clinically signicant changes within the expiration period. The
therapy or whenever the condition of the patient warrants such secondary container is completed. amount of water that can permeate from inside the container into
evaluation. To Open the overwrap is insufcient to affect the solution signicantly.
DEXTROSE INJECTION, USP should be used with caution in Tear overwrap down side at slit and remove solution container. Solutions in contact with the plastic container can leach out
patients with overt subclinical diabetes mellitus. Some opacity of the plastic due to moisture absorption during the certain of its chemical components in very small amounts within
sterilization process may be observed. This is normal and does the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up
Pregnancy to 5 parts per million. However, the safety of the plastic has been
not affect the solution quality or safety. The opacity will diminish
Teratogenic Effects conrmed in tests in animals according to USP biological tests for
gradually. Check for minute leaks by squeezing inner bag rmly.
Pregnancy Category C If leaks are found, discard solution as sterility may be impaired. If plastic containers as well as tissue culture toxicity studies.
Animal reproduction studies have not been conducted with supplemental medication is desired, follow To Add Medication CLINICAL PHARMACOLOGY
Dextrose Injection, USP. It is also not known whether Dextrose directions below.
DEXTROSE INJECTIONS, USP have value as a source of water
Injection, USP can cause fetal harm when administered to a Preparation for Administration and calories. They are capable of inducing diuresis depending on
pregnant woman or can affect reproduction capacity. Dextrose 1. Suspend container from eyelet support. the clinical condition of the patient.
Injection, USP should be given to a pregnant woman only if 2. Remove plastic protector from outlet port at bottom of
clearly needed. container. INDICATIONS AND USAGE
Pediatric Use 3. Attach administration set. Refer to complete directions Dextrose Injections, USP are indicated as a caloric component in
Dextrose is safe and effective for the stated indications in pediatric accompanying set. a parenteral nutrition regimen. They are used with an appropriate
patients (see Indications and Usage). As reported in the literature, To Add Medication protein (nitrogen) source in the prevention of nitrogen loss or in the
the dosage selection and constant infusion rate of intravenous treatment of negative nitrogen balance in patients where: (1) the
Warning: Additives may be incompatible.
dextrose must be selected with caution in pediatric patients, alimentary tract cannot or should not be used, (2) gastrointestinal
particularly neonates and low birth weight infants, because of To add medication before solution administration absorption of protein is impaired, or (3) metabolic requirements
the increased risk of hyperglycemia/hypoglycemia. Frequent 1 Prepare medication site. for protein are substantially increased, as with extensive burns.
monitoring of serum glucose concentrations is required when 2 Using syringe with 19 to 22 gauge needle, puncture resealable
medication port and inject. CONTRAINDICATIONS
dextrose is prescribed to pediatric patients, particularly neonates
and low birth weight infants. 3 Mix solution and medication thoroughly. For high density The infusion of hypertonic dextrose injections is contraindicated in
medication such as potassium chloride, squeeze ports while patients having intracranial or intraspinal hemorrhage, in patients
Do not administer unless solution is clear and seal is intact.
ports are upright and mix thoroughly. who are severely dehydrated, in patients who are anuric, and in
ADVERSE REACTIONS To add medication during solution administration patients in hepatic coma.
Reactions which may occur because of the injection or the 1 Close clamp on the set. Solutions containing dextrose may be contraindicated in patients
technique of administration include febrile response, infection 2 Prepare medication site. with known allergy to corn or corn products.
at the site of injection, venous thrombosis or phlebitis extending 3 Using syringe with 19 to 22 gauge needle, puncture resealable WARNINGS
from the site of injection, extravasation and hypervolemia. medication port and inject. These injections are for compounding only, not for direct
If an adverse reaction does occur, discontinue the infusion, evaluate 4 Remove container from IV pole and/or turn to an upright infusion.
the patient, institute appropriate therapeutic countermeasures position.
and save the remainder of the uid for examination if deemed Dilute before use to a concentration which will, when administered
5 Evacuate both ports by squeezing them while container is in the with an amino acid (nitrogen) source, result in an appropriate
necessary. upright position.
calorie to gram of nitrogen ratio and which has an osmolarity
DOSAGE AND ADMINISTRATION 6 Mix solution and medication thoroughly. consistent with the route of administration.
As directed by a physician. Dosage is dependent upon the age, 7 Return container to in-use position and continue
Unless appropriately diluted, the infusion of hypertonic dextrose
weight and clinical condition of the patient as well as laboratory administration.
injection into a peripheral vein may result in vein irritation, vein
determinations. damage, and thrombosis. Strongly hypertonic nutrient solutions
Parenteral drug products should be inspected visually for particulate DEXTROSE INJECTION USP should only be administered through an indwelling intravenous
matter and discoloration prior to administration whenever solution 50% AND 70%. catheter with the tip located in a large central vein such as the
and container permit. superior vena cava.
All injections in VIAFLEX plastic containers are intended for In very low birth weight infants, excessive or rapid administration
intravenous administration using sterile equipment. (Dextrose Hydrous) of dextrose injection may result in increased serum osmolality and
Additives may be incompatible. Complete information is not possible intracerebral hemorrhage.
available. DESCRIPTION WARNING:
Those additives known to be incompatible should not be used. DEXTROSE INJECTIONS, USP are sterile, nonpyrogenic This product contains aluminum that may be toxic. Aluminum
Consult with pharmacist, if available. If, in the informed judgment hypertonic solutions for uid replenishment and caloric supply in may reach toxic levels with prolonged parenteral administration
of the physician, it is deemed advisable to introduce additives, Pharmacy Bulk Package. A Pharmacy Bulk Package is a container if kidney function is impaired. Premature neonates are particularly
use aseptic technique. Mix thoroughly when additives have been of sterile preparation for parenteral use that contains many single at risk because their kidneys are immature, and they require large
introduced. Do not store solutions containing additives. doses. The contents are intended for use in a pharmacy admixture amounts of calcium and phosphate solutions, which contain
program and are restricted to the preparation of admixtures for aluminum.
HOW SUPPLIED intravenous infusion. They contain no antimicrobial agents.
Composition, osmolarity, pH, and caloric content are shown Research indicates that patients with impaired kidney function,
DEXTROSE INJECTION, USP in VIAFLEX plastic container
below. including premature neonates, who receive parenteral levels of
is available as follows:
aluminum at greater than 4 to 5 g/kg/day accumulate aluminum
Code Size (mL) NDC Product Name Table 1
at levels associated with central nervous system and bone toxicity.
25(N.R) Composition How Supplied Tissue loading may occur at even lower rates of administration.
2B0080 Quad pack 0338-0017-10 5% Dextrose Injection,
Caloric Content (kcal/L)
Dextrose Hydrous, USP
Size, code, NDC Administration by central venous catheter should be used only
USP by those familiar with this technique and its complications.
(mOsmol/L) (calc.)
50
PRECAUTIONS
2B0086 Single pack 0338-0017-41 5% Dextrose Injection,
2000 mL unit Administration of hypertonic dextrose and amino acid solutions
Osmolarity
USP
via central venous catheter may be associated with complications
2B0081 Quad pack 0338-0017-11
which can be prevented or minimized by careful attention to
(g/L)
2B0088 Multi pack 0338-0017-31

pH
all aspects of the procedure. This includes attention to solution

100 preparation, administration and patient monitoring.
2B0087 Single pack 0338-0017-48 5% Dextrose Injection, 50%
Dextrose 4.0 2B0256 It is essential that carefully prepared protocol, based upon
2B0082 Quad pack 0338-0017-18 USP NDC 0338- current medical practice, be followed, preferably by an
Injection, 500 2520 (3.2 to 1710
2B0089 Multi pack 0338-0017-38 USP 6.5) 0031-06 experienced team.
2B0061 150 0338-0017-01 70% The package insert of the protein (nitrogen) source should be
4.0 2B0296
2B0062 250 0338-0017-02 Dextose consulted for dosage and all precautionary information.
700 3530 (3.2 to 2390 NDC 0338-
2B0063 500 0338-0017-03 Injection, 6.5) 0719-06 Clinical evaluation and periodic laboratory determinations
2B0064 1000 0338-0017-04 USP are necessary to monitor changes in uid balance, electrolyte
103
Book_01.indd 103 6/4/2008 2:19:55 PM

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concentration, and acid base balance during prolonged parenteral 4. Attach solution transfer set. Refer to complete directions Trough levels should be measured in order to adjust the dose
therapy or whenever the conditions of the patient warrants such accompanying set. .and dosage interval
evaluation. Note: The closure shall be penetrated only one time with a Replacement therapy in myeloma or chronic lymphocytic
Care should be taken to avoid circulatory overload, particularly in suitable sterile transfer device or dispensing set which allows leukaemia with severe secondary hypogammaglobulinemia
patients with cardiac insufciency. measured dispensing of the contents. and recurrent infections; replacement therapy in children
5. The VIAFLEX plastic container should not be written on with AIDS and recurrent infections:
Caution must be exercised in the administration of these injections
to patients receiving corticosteroids or corticotropin. directly since ink migration has not been investigated. Afx The recommended dose is 0.20.4 g/kg BW every three to four
accompanying label for date and time of entry notation. weeks to obtain IgG trough level of at least 46 g/l.
These injections should be used with caution in patients with overt
6. Once container closure has been penetrated, withdrawal of Idiopathic Thrombocytopenic Purpura (ITP):
or subclinical diabetes mellitus.
contents should be completed without delay. After initial For the treatment of an acute episode, 0.81 g/kg BW on day
Drug product contains no more than 25 g//L of aluminum. one, which may be repeated once within 3 days, or 0.4 g/kg BW
entry, maintain contents at room temperature (25C/77F) and
Carcinogenesis, Mutagenesis, Impairment of Fertility: dispense within 4 hours. daily for two to ve days. The treatment can be repeated if a
Studies with 50% and 70% Dextrose Injection, USP have not been relapse occurs.
performed to evaluate carcinogenic potential, mutagenic potential, HOW SUPPLIED Guillain Barr syndrome:
or effects on fertility. See Table 1. 0.4 g/kg BW/day for 5 consecutive days. Experience in children
Pregnancy: Exposure of pharmaceutical products to heat should be minimized. is limited.
Teratogenic Effects Avoid excessive heat. Protect from freezing. It is recommended Kawasaki Disease:
the product be stored at room temperature (25C/77F). 1.62 g/kg BW should be administered in divided doses over
Pregnancy Category C
twoto ve days or 1.62 g/kg BW as a single dose. Patients
Animal reproduction studies have not been conducted with should receive concomitant treatment with acetylsalicylic acid.
Dextrose Injections, USP. It is also not known whether Dextrose ENDOBULIN S/D 50 mg/ml Allogeneic Bone Marrow Transplantation:
Injections, USP can cause fetal harm when administered to a Powder and solvent for solution for infusion Human normal immunoglobulin treatment is used as part of the
pregnant woman or can affect reproduction capacity. Dextrose conditioning regimen and after the transplant.For the treatment
Injections, USP should be given to a pregnant woman only if of infections and prophylaxis of graft versus host disease,
clearly needed. (Human normal immunoglobulin) dosage is individually tailored. The starting dose is normally
Nursing Mothers: 0.5 g/kg BW/week, starting seven days before transplantation
Caution should be exercised when 50% and 70% Dextrose NAME OF THE MEDICINAL PRODUCT and for up to 3 months after transplantation. In case of persistent
Injection, USP is administered to a nursing woman. ENDOBULIN S/D 50 mg/ml lack of antibody production, dosage of 0.5 g/kg BW/month is
Pediatric Use: recommended until the antibody level returns to normal.The
Powder and solvent for solution for infusion
dosage recommendations are summarised in the following
Dextrose is safe and effective for the stated indications in pediatric QUALITATIVE AND QUANTITATIVE COMPOSITION table:
patients (see Indications and Usage). As reported in the literature,
Human normal immunoglobulin (IVIg) Indication Dose Frequency Of Injections
the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, ENDOBULIN S/D is presented as powder and solvent for solution Replacement therapy - starting dose:
for infusion containing 500 mg (1000 mg(N.R), 2500 mg, 5000 in primary 0.4-0.8 g/kg BW
particularly neonates and low birth weight infants, because of
mg, 10000 mg human normal immunoglobulin G (IgG) per vial. immunodeciency - thereafter: every 2-4 weeks to obtain
the increased risk of hyperglycemia/hypoglycemia. Frequent
0.2 - 0.8 g/kg BW lgG trough level of at least
monitoring of serum glucose concentrations is required when When reconstituted with the amount of Sterilised Water for 4-6 g/1
dextrose is prescribed to pediatric patients, particularly neonates Injections accompanying ENDOBULIN S/D, 1 ml of reconstituted Replacement 0.2-1.4 g/kg BW every 3-4 weeks to obtain
and low birth weight infants. Because of their hypertonicity, ENDOBULIN S/D contains about 51 mg protein of which at least therapy in secondary lgG trough level of at least
50% and 70% Dextrose Injections must be diluted prior to 95% is immunodeciency 4-6 g/1
administration. Immunoglobulin G (IgG). Children with AIDS 0.2-0.4 g/kg VBW every 3-4 weeks
ADVERSE REACTIONS Distribution of IgG subclasses: IgG1 5080% Immunomodulation:
Too rapid infusion of a hypertonic dextrose solution may result IgG2 2050% Idiopathic
IgG3 <0.50% Thrombocytopenic 0.8-1 g/kg BW on day 1, possibly
in diuresis, hyperglycemia, glycosuria, and hyperosmolar coma.
IgG4 130% Purpura repeated once within
Continual clinical monitoring of the patient is necessary in order to 3 days
identify and initiate measures for these clinical conditions. Maximum IgA content: 0.1% (0.05 mg/ml)
or
Reactions which may occur because of the solution or the technique For excipients, see Pharmaceutical Particulars 0.4 g/kg BW/day for 2-5 days
of administration include febrile response, infection at the site of Guillain Barre
PHARMACEUTICAL FORM
injection, venous thrombosis or phlebitis extending from the site Syndrome 0.4 g/kg BW/day for 5 conssecutive days
Powder and solvent for solution for intravenous infusion. Dawasaki Disease 1.6-2 g/kg BW in several doses for
of injection, extravasation and hypervolemia.
ENDOBULIN S/D is a lyophilized, white to off-white powder or 2-5 days in association
If an adverse reaction does occur discontinue the infusion, evaluate with acetylsalicylic acid
friable
the patient, institute appropriate therapeutic countermeasures, or
and save the remainder of the uid for examination if deemed substance.
1.6-2 g/kg BW as a Single dose in associa
necessary. CLINICAL PARTICULARS tion with acetylsalicylic
Therapeutic Indications acid
Allogeneic bone
Following suitable admixture of prescribed drugs, the dosage Replacement therapy in:
marrow
is usually dependent upon age, weight and clinical condition of Primary immunodeciency syndromes (PID) such as: transplantation
the patient as well as laboratory determinations. See directions - congenital agammaglobulinemia - treatment of 0.5 g/kg BW every week from day
accompanying drugs. ohypogammaglobulinemia infections and - 7 up to 3 months after
Parenteral drug products should be inspected visually for particulate - common variable immunodeciency prophylaxis of transplantation
matter and discoloration prior to administration whenever solution - severe combined immunodeciencies graft versus host
and container permit. disease
- Wiskott Aldrich syndrome.
- persistent lack of 0.5 g/kg BW every month until antibody
Do not administer unless solution is clear and seal is intact. Myeloma or chronic lymphocytic leukaemia with severe antibody levels return to normal
Use of a nal lter is recommended during administration of all secondary hypogammaglobulinemia and recurrent infections. production
parenteral solutions where possible. Children with congenital AIDS and recurrent infections.
Immunomodulation Method of administration
50% and 70% Dextrose Injection, USP in the Pharmacy
Bulk Package is intended for use in the preparation of sterile, Idiopathic thrombocytopenic purpura (ITP) in children or adults During the rst 30 minutes, ENDOBULIN S/D is administered
intravenous admixtures. Additives may be incompatible with the athigh risk of bleeding or prior to surgery to correct the platelet intravenously at an initial rate of 0.5 ml/kg BW/hour. If well
uid withdrawn from this container. Complete information is not count. tolerated, the rate of administration may gradually be increased to
available. Those additives known to be incompatible should not be Guillain Barr Syndrome a maximum of approximately 8 ml/kg BW/hour for the remainder
used. Consult with pharmacist, if available. When compounding of the infusion.
Kawasaki Disease
admixtures, use aseptic technique. Mix thoroughly. Do not store In adults, if well tolerated, the rates of subsequent infusions may
Allogeneic bone marrow transplantation
any unused portion of the 50% and 70% Dextrose Injection, USP. be increased to a maximum of 15 ml/kg BW/hour.
Posology and method of administration
DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTRAINDICATIONS
Posology
PHARMACY BULK PACKAGE CONTAINER Hypersensitivity to any of the components.
The dose and dosage regimen is dependent on the indication.
To Open Hypersensitivity to homologous immunoglobulins, especially in
In replacement therapy the dosage may need to be individualised very rare cases of IgA deciency, when the patient has antibodies
Tear overpouch at slit and remove solution container. Some opacity for each patient depending on the pharmacokinetic and clinical
of the plastic due to moisture absorption during the sterilization againstIgA.
response.
process may be observed. This is normal and does not affect the SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
solution quality or safety. The opacity will diminish gradually. The following dosage regimens are given as a guideline.
FOR USE
Check for minute leaks by squeezing inner bag rmly. If leaks are Replacement therapy in primary immunodeciency
syndromes: Certain severe adverse drug reactions may be related to the rate
found, discard solution as sterility may be impaired. of infusion.
The dosage regimen should achieve a trough level of IgG
For compounding only, not for direct infusion. The recommended infusion rate given under Method of Ad
(measured before the next infusion) of at least 46 g/l. Three
Preparation for Admixing to six months are required after the initiation of therapy for ministration must be closely followed. Patients must be closely
1. The Pharmacy Bulk Package is to be used only in a suitable equilibration to occur. The recommended starting dose is 0.4 monitored and carefully observed for any symptoms throughout
work area such as a laminar ow hood (or an equivalent clean 0.8 g/kg body weight (BW) followed by 0.2 g/kg BW every the infusion period.
air compounding area). three weeks. Certain adverse reactions may occur more frequently
2. Suspend container from eyelet support. The dose required to achieve a trough level of 6 g/l is of the - In case of high rate of infusion,
3. Remove plastic protector from outlet port at bottom of order of 0.20.8 g/kg BW/month. The dosage interval when - In patients with hypo- or agammaglobulinemia with or without
container. steady state has been reached varies from 24 weeks. IgA deciency;
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- In patients who receive human normal immunoglobulin 6 weeks and up to 3 months the efcacy of live attenu ated virus PHARMACOLOGICAL PROPERTIES
for the rst time or, in rare cases,when the human normal vaccines such as measles, rubella, mumps and varicella. After Pharmacodynamic Properties
immunoglobulin product is switched or when there has been a administration of this product, an interval of 3 months should Pharmacotherapeutic group: immune sera and immunoglobulins:
long interval since the previous infusion. elapse before vaccination with live attenuated virus vaccines. In
immunoglobulins, normal human, for intravenous administration,
True hypersensitivity reactions are rare. They can occur in the very the case of measles, this impairment may persist for up to 1 year.
ATC code: J06BA02.
seldom cases of IgA deciency with anti-IgA antibodies. Rarely, Therefore patients receiving measles vaccine should have their
human normal immunoglobulin can induce a fall in blood pressure antibody status checked. ENDOBULIN S/D contains mainly functionally intact
with anaphylactic reaction, even in patients who had tolerated immunoglobulin G (IgG) with a broad spectrum of antibodies
Interference with serological testing against infectious agents.
previous treatment with human normal immunoglobulin.
Potential complications can often be avoided by ensuring: After infusion of human normal immunoglobulin the transitory In compliance with the Ph.Eur. ENDOBULIN S/D contains speci
rise of the various passively transferred antibodies in the patients ic antibodies* against Diphtheria toxin and against Measles at a
- that patients are not sensitive to human normal immunoglobulin
blood may result in misleading positive results in serological concentration being at least three times that in the initial plasma
by rst injecting the product slowly (0.008 ml/kg/min);
testing. Passive transmission of antibodies to erythrocyte antigens,
- that patients are carefully monitored for any symptoms pool.
e.g. A, B, D may interfere with some serological tests for red
throughout the infusion period. In particular, patients naive Hepatitis B surface antibody: not less than 0.5 I.U./g protein
cell allo-antibodies (e.g. Coombs test), reticulocyte count and
to human normal immunoglobulin, patients switched from an ENDOBULIN S/D contains the immunoglobulin G antibodies
haptoglobin.
alternative IVIg product or when there has been a long interval present in the normal population. It is usually prepared from
since the previous infusion should be monitored during the rst Pregnancy and lactation
pooled plasma from not fewer than 1000 donations. It has a
infusion and for the rst hour after the rst infusion, in order The safety of ENDOBULIN S/D for use in human pregnancy distribution of immunoglobulin G subclasses closely proportional
to detect potential adverse signs. All other patients should be has not been established in controlled clinical trials and therefore to that in native human plasma with the exception of IgG3, which
observed for at least 20 minutes after administration. should only be given with caution to pregnant women and breast- is present only in traces.
- that the glucose content (1 g/g of IgG) is taken into account in feeding mothers. Clinical experience with immunoglobulins Adequate doses of this medicinal product may restore abnormally
case of latent diabetes (where transient glycosuria could appear), suggests that no harmful effects on the course of pregnancy, or on
diabetes, or in patients on a low sugar diet. The administration low immunoglobulin G levels to the normal range.
the fetus and the neonate are to be expected.
of high doses of ENDOBULIN S/D to diabetics may result in Due to the special manufacturing procedure the antibody
Immunoglobulins are excreted into the milk and may contribute to
transient elevations of serum glucose levels. spectrum, the half-life, and all biological functions that depend on
the transfer of protective antibodies to the neonate.
There is clinical evidence of an association between IVIg intact (native) antibodies like opsonisation and neutralisation of
Effects on Ability to Drive and Use Machines pathogens are maintained.
administration and thromboembolic events such as myocardial
infarction, stroke, pulmonary embolism and deep vein thromboses No effects on ability to drive and use machines have been The mechanism of action in indications other than replacement
which is assumed to be related to a relative increase in blood observed. therapy is not fully elucidated, but includes immunomodulatory
viscosity through the high inux of immunoglobulin in at-risk Undesirable effects effects.
patients. Caution should be exercised in prescribing and infusing With human normal Immunoglobulins for Intravenous Pharmacokinetic properties
IVIg in obese patients and in patients with pre-existing risk factors administration, adverse reactions such as chills, headache, fever, ENDOBULIN S/D is immediately and completely bioavailable
for thrombotic events such as advanced age, hypertension, diabetes vomiting, allergic reactions, nausea, arthralgia, low blood pressure in the recipients circulation after intravenous administration. It
mellitus and a history of vascular disease or thrombotic episodes, and moderate low back pain may occur occasionally. is distributed relatively rapidly between plasma and extravascular
patients with acquired or inherited thrombophilic disorders,
Rarely human normal Immunoglobulins may cause a sudden uid, after approximately 3 5 days equilibrium is reached
patients with prolonged periods of immobilisation, severely
fall in blood pressure and, in isolated cases, anaphylactic shock, between the intraand extravascular compartments.
hypovolemic patients, patients with diseases which increase
blood viscosity. Cases of acute renal failure have been reported even when the patient has shown no hypersensitivity to previous The half-life of ENDOBULIN S/D is 3 weeks for specic
in patients receiving IVIg therapy. In most cases, risk factors have administration. antibodies.
been identied, such as pre-existing renal insufciency, diabetes Cases of reversible aseptic meningitis, isolated cases of reversible This half-life may vary from patient to patient, in particular in
mellitus, hypovolemia, overweight, concomitant nephrotoxic haemolytic anaemia/haemolysis and rare cases of transient primary Immunodeciency.
medicinal products, or age over 65. cutaneous reactions, have been observed with human normal IgG and IgG-complexes are broken down in cells of the reticul
In case of renal impairment, IVIg discontinuation should be immunoglobulin. Increase in serum creatinine level and/or acute endothelial system.
considered. renal failure have been observed. Pharmaceutical particulars
While the reports of renal dysfunction and acute renal failure Very rarely thromboembolic reactions such as myocardial List of excipients
have been associated with the use of many of the licensed IVIg infarction, stroke, pulmonary embolism, deep vein thrombosis
Powder: Sodium Chloride Glucose
products, those containing sucrose as a stabiliser accounted for have been observed.
a disproportionate share of the total number. In patients at risk, Solvent: Sterilised Water for Injections
With ENDOBULIN S/D, the adverse reactions reported in
the use of IVIg products that do not contain sucrose may be Incompatibilities
the listing hereafter are based on reports from post-marketing
considered. ENDOBULIN S/D must not be mixed with other medicinal
experience. Their frequency has been evaluated by using the
ENDOBULIN S/D does not contain sucrose. following criteria: very common (>1/10), common (>1/100, <1/ proucts, except those mentioned in Instructions for Use and
In patients at risk for acute renal failure or thromboembolic adverse 10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000) Hadling and Disposal.
reactions, IVIg products should be administered at the minimum and very rare (<1/10,000). Shelf-life
rate of infusion and dose practicable. ENDOBULIN S/D must not be used beyond the expiry date
The Incidence rate for the adverse reactions reported below is
In all patients, IVIg administration requires: rare: indicated on the label.
- adequate hydration prior to the initiation of the infusion Immune system disorders: allergic reactions Chemical and physical in-use stability of reconstituted
of IVIg ENDOBULIN S/D has been demonstrated for 24 hours at room
General disorders and administration site conditions: chills
- monitoring of urine output temperature. From a microbiological point of view the product
- monitoring of serum creatinine levels The incidence rate for the adverse reactions reported below is very should be used immediately unless the method of reconstitution
rare: precludes the risk of microbial contamination.
- avoidance of concomitant use of loop diuretics.
In case of adverse reaction, either the rate of administration Blood and lymphatic system disorders: reversible haemolytic Special precautions for storage
must be reduced or the infusion stopped. The treatment required anaemia
Store in a refrigerator (+ 2 to + 8C).
depends on the nature and severity of the side effect. 0705472_N1_V4 2 09.05.2006, 11:54:23 Uhr
Do not freeze, the solvent vial might break.
In case of shock, standard medical treatment for shock should be Immune system disorders: anaphylactic shock, hypersensitivity
Keep vial in the outer carton in order to protect from light.
implemented.ENDOBULIN S/D is made from human plasma. reaction.
Keep out of the reach and sight of children.
Standard measures to prevent infections resulting from the use Nervous system disorders: dizziness, dysaesthesia, headache,
of medicinal products prepared from human blood or plasma Nature and contents of container
convulsions, restlessness
include selection of donors, screening of individual donations and All powder presentations come in hydrolytic type II glass vials.
Cardiac disorders: Tachycardia.
plasma pools for specic markers of infection and the inclusion Solvent presentation of 10 ml comes in hydrolytic type I glass vals
of effective manufacturing steps for the inactivation/removal of Vascular disorders: ushing, hypertension, hypotension,
and all other solvent presentations (20 ml(N.R), 50 ml, 100 ml, and
viruses. Despite this, when medicinal products prepared from thromboticevent.
200 ml) in hydrolytic type II glass vials. Powder and solvent vials
human blood or plasma are administered, the possibility of Respiratory, thoracic and mediastinal disorders: cough, are closed with halogenobutyl rubber stoppers.
transmitting infective agents cannot be totally excluded. This also dyspnoea, respiratory disorder. ENDOBULIN S/D is available in pack sizes of: ENDOBULIN
applies to unknown or emerging virusesand other pathogens. Gastrointestinal disorders: nausea, vomiting. S/D 500 mg: Each pack contains one product vial, one solvent vial
The measures taken are considered effective for enveloped viruses Skin and subcutaneous tissue disorders: erythema, pruritus, (10 ml Sterilised Water for Injections), one transfer needle, one
such as HIV, HBV and HCV, and for the non-enveloped viruses rash, transient cutaneous reaction. aeration needle and one lter needle.
HAV and parvovirus B19.
Musculoskeletal and connective tissue disorders: arthralgia, ENDOBULIN S/D 1000 mg(N.R): Each pack contains one product
There is reassuring clinical experience regarding the lack of vial, one solvent vial (20 ml Sterilised Water for Injections), one
low back pain.
hepatitis A or parvovirus B19 transmission with immunoglobulins transfer needle, one aeration needle and one lter needle.
and it is also assumed that the antibody content makes an important General disorders and administration site conditions: fever,
malaise, oedema. ENDOBULIN S/D 2500 mg: Each pack contains one product
contribution to the viral safety.
vial, one solvent vial (50 ml Sterilised Water for Injections),
It is strongly recommended that every time that ENDOBULIN In many cases the adverse reactions as listed above can be avoided one transfer spike, one infusion set and one plastic suspender.
S/D is administered to a patient, the name and batch number of by slowing the infusion rate. ENDOBULIN S/D 5000 mg: Each pack contains one product
the product are recorded in order to maintain a link between the For safety with respect to transmissible agents see Special vial, one solvent vial (100 ml Sterilised Water for Injections), one
patient and the batch of the product. Warnings and Special Precautions for Use. transfer spike, one infusion set and one plastic suspender.
Interaction With Other Medicinal Products and Other Forms Overdose ENDOBULIN S/D 10000 mg: Each pack contains one product
of Interactions. Overdose may lead to uid overload and hyperviscosity, vial, one solvent vial (200 ml Sterilised Water for Injections), one
Live attenuated virus vaccines particularly in patients at risk, including elderly patients or patients transfer spike, one infusion set and one plastic suspender.
Immunoglobulin administration may impair for a period of at least with renal Impair ment. Certain pack sizes may not be marketed in all countries.
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Instructions for Use and Handling and Disposal Patients with a weakened immune system, e.g. those with diabetes
ENDOBULIN S/D is to be reconstituted only immediately before ENDOXAN mellitus, chronic hepatic or renal impairments, also require close
administration. For reconstitution of ENDOBULIN S/D use observation.
ase tic technique. Total dissolution should be obtained within a Should a cystitis in connection with micro- or macrohaematuria
(Cyclophosphamide)
few minutes. Warming at a maximum temperature of 37C and appear during treatment with ENDOXAN, ENDOXAN
agitating gently will shorten the time needed for dissolution. therapy has to be interrupted until normalization.
COMPOSITION
Usually the solution is clear or slightly opalescent. Do not use Leukocyte controls must be conducted regularly during treatment:
solutions which are cloudy or have deposits. The reconstituted ENDOXAN 200 MG
at intervals of 5-7 days when starting treatment and every 2
product should be inspected visually for particulate matter and dis 1 Injection vial of ENDOXAN 200 MG contains:
days if the counts drop below 3000/mm3. Daily controls may be
coloration prior to administration. 213.8 mg cyclophosphamide monohydrate (equivalent to 200 mg necessary under certain circumstances. In patients receiving long-
The product should be brought to room or body temperature before anhydrous cyclophosphamide) as the active ingredient. term treatment, controls every two weeks are usually sufcient. If
use. signs of myelosuppression become evident, it is recommended to
ENDOXAN 500 MG.
Any unused product or waste material should be disposed of in check the red blood count and the platelet count (see 4.2). Urinary
1 Injection vial of ENDOXAN 200 MG contains:
accordance with local require ments. ENDOBULIN S/D 500 mg sediment should also be checked regularly for the presence of
and 1000 mg: Reconstitution of the lyo philized powder: 534.5 mg cyclophosphamide monohydrate (equivalent to 500 mg erythrocytes.
anhydrous cyclophosphamide) as the active ingredient.
1. Remove protective caps from the concentrate and solvent vials
(g. A) and cleanse the rubber stoppers of both vials ENDOXAN 1 g
with germicidal solution. Due to the possibility of side effects when cyclophosphamide is
1 Injection vial of ENDOXAN 1 g contains: administered, e.g. nausea, vomiting which may result in circulatory
2. Twist and remove the protective covering from one of the
1.069 g cyclophosphamide monohydrate (equivalent to 1 g insufciencies, the physician should individually decide on the
ends of the enclosed transfer needle and insert the exposed
anhydrous cyclophosphamide) as the active ingredient. patients ability to participate in trafc or to operate machinery.
end through the rubber stopper of the solvent vial (g. B and
g. C). 1 ENDOXAN sugar-coated tablet contains: INTERACTION WITH OTHER MEDICAMENTS AND
3. Remove the protective covering from the other end of the 53.5 mg cyclophosphamide monohydrate (equivalent to 50 mg OTHER FORMS OF INTERACTION
transfer needle. Do not touch the exposed end. anhydrous cyclophosphamide) as the active ingredient. The blood glucose-lowering effect of sulfonyl ureas may
4. Invert the transfer needle with the attached solvent vial over List of excipients be intensied, as well as the myelosuppressive action when
the concentrate vial and insert the free end of the transfer allopurinol or hydrochlorothiazide is administered concomitantly.
Calcium carbonate, calcium monohydrogen phosphate, carmellose
needle vertically through the center of the rubber stopper of
sodium, gelatine, glycerol, lactose, maize starch, magnesium Prior or concurrent treatment with phenobarbital, phenytoin,
the concentrate vial (g. D). The solvent will be drawn into the
stearate, macrogol, montan glycol wax, polysorbate, polyvidone, benzodiazepines or chloral hydrate involves the possibility of
concentrate vial by vacuum.
saccharose, silicone dioxide, talcum, titanium dioxide. microsomal liver enzyme induction.
5. Disconnect the two vials by removing the solvent vial with
PHARMACEUTICAL FORM Since cyclophosphamide shows immunosuppressive effects, the
the attached transfer needle from the concentrate vial (g. E).
Accelerate dissolution by gently and regularly agitating the patient can be expected to exhibit a diminished response to any
ENDOXAN 200 mg/500 mg/1 g, injection vials: Powder for
concentrate vial. Do not shake the vial! vaccination; injection with activated vaccines may be accompanied
solution for i.v. injection
by vaccine-induced infection.
6. After complete reconstitution of the lyophilized substance, ENDOXAN: Sugar-coated tablet for oral use
insert the enclosed aeration needle (g. F), and any foam will If depolarizing muscle relaxants (e.g. succinylcholine halogenide)
collapse. Remove the aeration needle. INDICATIONS are applied concurrently, a prolonged apnoea may result from a
7. Draw the clear solution into the syringe through the enclosed ENDOXAN is used within a combination chemotherapy regimen reduced pseudocholinesterase concentration.
lter or as monotherapy in Leukaemias: acute or chronic lymphocytic Concomitant administration of chloramphenicol leads to a
* determined by an International Standard or Reference and myelogenous leukaemias . prolonged half-life of cyclophosphamide and to a delayed
Preparation needle (g. G). Malignant lymphomas: Hodgkins disease, non-Hodgkins metabolization.
lymphomas, plasmacytoma. Anthracyclines and pentostatin treatment may intensify the
Metastasizing and non-metastasizing malignant solid tumours: potential cardiotoxicity of cyclophosphamide. An intensication
ovarian cancer, testicular cancer, breast cancer, small cell lung of the cardiotoxic effect may also occur after previous radiotherapy
cancer, neuroblastoma, Ewings sarcoma. of the cardiac region.
Progressive autoimmune diseases: e.g. rheumatoid arthritis, Concomitant administration of indomethacin should be performed
psoriatic arthropathy, systemic lupus erythematosus, scleroderma, very carefully, since an acute water intoxication has been reported
g. A g. B g. C g. D g. E g. F g. G systemic vasculitides (e.g. with nephrotic syndrome), certain types in a single case.
of glomerulonephritis (e.g. with nephrotic syndrome), myasthenia In general, patients receiving treatment with cyclophosphamide
ENDOBULIN S/D 2500 mg, 5000 mg and 10,000 mg:
gravis, autoimmune haemolytic anaemia, cold agglutinin diseases. should abstain from drinking alcoholic beverages.
Reconstitution of the lyophilized powder: Immunosuppressive treatment in organ transplantations. Because grapefruit contains a compound that may impair the
1. Remove protective caps from the concentrate and solvent vials activation of cyclophosphamide and thereby its efcacy,
and cleanse the rubber stoppers of both vials with germicidal CONTRAINDICATIONS
solution. ENDOXAN should not be used in patients with the patient must not eat any grapefruit or drink grapefruit juice.
2. Remove the protective covering from one of the ends of the known hypersensitivity to cyclophosphamide POSOLOGY AND METHOD OF ADMINISTRATION
enclosed transfer spike (g. 1) and insert the exposed end Severely impaired bone-marrow function (particular in patients ENDOXAN should only be administered by experienced
vertically through the center of the rubber stopper of the solvent who have been pre-treated with cytotoxic agents and/or oncologists.
vial. Press down rmly so that the transfer spike ts snugly radiotherapy) The dosage must be adapted to each patient individually.
against the solvent vial. (g. 2) Caution: Failure to use center of Inammation of the bladder (cystitis)
stopper may result in dislodging the stopper. Unless otherwise prescribed the following dosages are
urinary outow obstructions recommended:
3. Remove the protective covering from the other end of the
transfer spike. Do not touch the exposed end. active infections ENDOXAN 200 mg/500 mg/1 g, injection vials:
4. Hold concentrate vial rmly and at an angle of approximately for use during pregnancy and lactation see separate note for continuous treatment in adults and children 3 to 6 mg/kg
45 degrees. Invert the solvent vial with the transfer spike at an body weight daily (equivalent to 120 to 240 mg/m2 body
angle complementary to the concentrate vial (approximately 45 surface).
degrees) and rmly insert the transfer spike into the concentrate Treatment with cyclophosphamide can cause genotype anomalies for intermittent treatment 10 to 15 mg/kg body weight
vial through the center of the rubber stopper (g. 3). The solvent in men and women. (equivalent to 400 to 600 mg/m2 body surface) at intervals of 2
will be drawn into the concentrate vial by vacuum. In a vital indication during the rst trimester of pregnancy a to 5 days.
Note: Invert the solvent vial with attached transfer spike rapidly medical consultation regarding abortion is absolutely necessary. for high-dose intermittent treatment, e.g. 20 to 40 mg/kg body
into the concentrate vial in order to avoid loss of solvent. After the 1st trimester of pregnancy, if therapy cannot be weight (equivalent to 800 to 1600 mg/m2 body surface) and
Caution: Failure to use center of stopper may result in dislodging delayed and the patient wishes to continue with her pregnancy, higher doses (e.g. for conditioning prior to bone-marrow
the stopper and loss of vacuum. chemotherapy may be undertaken after informing the patient of transplantation) at intervals of 21 to 28 days.
5. Disconnect the two vials by removing the solvent vial with the the minor but possible risk of teratogenic effects.
Preparation of the solution
attached transfer spike from the concentrate vial. Accelerate Woman should not become pregnant during treatment. Should
dissolution by gently and regularly agitating the concentrate they still conceive during treatment, they should seek genetic To prepare a solution for injection, the respective amount of
vial (g. 4). Do not shake the vial! consultation. physiological saline is added to the dry substance:
6. Administer the solution directly using the enclosed infusion set As cyclophosphamide is passing into the breast milk, mothers ENDOXAN vial 200 mg 500 mg 1g
with lter. must not breast feed during treatment. Dry substance 213.8 mg 534.5 mg 1069.0mg
Men to be treated with ENDOXAN should be informed about equivalent to
sperm preservation before treatment. Cyclophosphamide, 200 mg 500 mg 1g
The duration of contraception in men and women after the end anhydrous
of chemotherapy depends on the prognosis of the primary disease Physiological saline 10 ml 25 ml 50 ml
and on the intensity of the parents desire for a child.
The substance dissolves readily if the vials are vigorously shaken
g. 1 g. 2 g. 3 g. 4 SPECIAL WARNINGS AND SPECIAL PRECAUTIONS after addition of the solvent. If the substance fails to dissolve
In case other devices than those supplied with ENDOBULIN S/ FOR USE immediately and completely, it is advisable to allow the vial to
D are used, it has to be ensured that an adequate lter is used to Before starting treatment, it is necessary to exclude or correct any stand for a few minutes.
prevent administration of rubber particles cut from the stoppers obstructions of the efferent urinary tract, cystitis, infections and The solution is suitable for intravenous administration which
(danger of microembolism). If a concentration of less than 5% electrolyte imbalances. preferably should be conducted as an infusion. For shortterm
ENDOBULIN S/D is desired, the 5% solution may be diluted In general, ENDOXAN like all other cytostatics should be used intravenous infusion, the prepared ENDOXAN solution is added
with isotonic saline solution. with care in weakened or elderly patients and in patients who have to Ringers solution, saline or dextrose solution for a total volume
ENDOBULIN S/D is a trademark of Baxter AG had previous radiotherapy. of e.g. 500 ml.
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The duration of infusion may range from 30 minutes to 2 hours, More severe myelosuppression is to be expected in patients who Inammation of the skin and mucosa
depending on the volume. have been pre-treated with chemo- and/or radiotherapy and in Hypersensitivity reactions accompanied by fever, extending to
ENDOXAN, Sugar-coated tablets: patients with renal impairment. shock in isolated cases
For continuous therapy 1-4 tablets (50-200 mg) daily; if necessary, A combination treatment with other myelosuppressive agents Transient blurred vision and attacks of dizziness
more tablets may be taken. may require dose adjustments. Please refer to the relevant tables Acute pancreatitis may occur in isolated cases
The dose recommendations given mainly apply to the treatment on dose adjustment of cytotoxic drugs to the blood counts at the In very rare cases (< 0.01%) severe reactions e.g. Stevens
with cyclophosphamide as a monotherapy. In combination with beginning of the cycle and the nadir-adjusted dosage of cytostatic Johnson Syndrome and toxic epidermal necrolysis have been
other cytostatics of similar toxicity, a dose reduction or extension agents. reported
of the therapy-free intervals may be necessary. Gastrointestinal tract Note:
Recommendations for dose reduction in patients with Gastrointestinal side effects, such as nausea and vomiting, are There are certain complications, such as thromboembolism, DIC
myelosuppression dose-dependent adverse reactions. Moderate to severe forms occur (disseminated intravascular coagulation), or haemolytic uraemic
Leukocyte count [l] Platelet count [l] in around 50% of patients. Anorexia, diarrhoea, constipation and syndrome (HUS), that may also be induced by the underlying
Dosage
inammatory conditions of the mucosa (mucositis), ranging from disease, but that might occur with an increased frequency under
>100 000 100 % of the stomatitis to ulcerations, occur with a rarer frequency. There have
>4000 chemotherapy that includes ENDOXAN.
planned dose been isolated reports of haemorrhagic colitis.
50 % of the Attention should be paid to timely administration of antiemetics
4000 - 2500 100 000 - 50 000
planned dose Kidney and efferent urinary tract and to meticulous oral hygiene.
<50 000 Adjustment until After their excretion in the urine, metabolites of cyclophosphamide Regular blood counts are indicated during treatment: Intervals of 5
<2500
values normalize cause changes in the efferent urinary tract and especially in - 7 days at initial therapy, intervals of 2 days in case the leucocyte
or specic decision the bladder. Haemorrhagic cystitis, microhaematuria and counts decreases to <3000 per mm3, possibly daily. Checks every
is made macrohaematuria are the most common dosedependent 2 weeks are generally sufcient in case of long-term therapy. The
complications of a therapy with ENDOXAN and mandate urinary sediment should be checked regularly on erythrocytes.
Recommendations for dose adjustment in patients with hepatic
interruption of treatment. Cystitis is initially abacterial, secondary
and renal insufciency. INCOMPATIBILITIES
bacterial colonisation may follow. There have been isolated
Severe hepatic- or renal insufciency requires a dose reduction. A reports of haemorrhagic cystitis resulting in death. Oedema of the Benzyl alcohol containing solutions can reduce the stability of
dose reduction of 25% for serum bilirubin from 3.1 to 5 mg/100 bladder wall, suburethral bleeding, interstitial inammations with cyclophosphamide.
ml and of 50% for a glomerular ltration rate below 10 ml/minute brosis and a potential for sclerosis of the bladder wall have also
is recommended. Cyclophosphamide is dialysable. PHARMACOLOGICAL PROPERTIES
been observed.
ENDOXAN 200 mg/500 mg/1 g, injection vials. Renal lesions (in particular with a history of impaired renal
Pharmacodynamic properties
Duration of therapy and intervals will depend on the indication, function) are a rare side-effect after high doses. Cyclophosphamide is a cytostatic from the group of oxaza-
the applied combination chemotherapy schedule, the patients phosphorines and is chemically related to nitrogen mustard.
general state of health, the laboratory parameters and the recovery Remark:
Cyclophosphamide is inactive in vitro and is activated by
of blood cell counts. Treatment with UROMITEXAN or strong hydration can microsomal enzymes in the liver to 4-hydroxycyclophosphamide,
Attention should be paid to adequate hydration as well as to the markedly reduce the frequency and severity of these urotoxic
which is in equilibrium with its tautomere aldophosphamide. The
administration of the Uroprotector UROMITEXAN. sideeffects.
cytotoxic action of cyclophosphamide is based on an interaction
ENDOXAN, sugar-coated tablets. Genital tract between its alkylating metabolites and DNA. This alkylation
ENDOXAN sugar-coated tablets should be administered in the By virtue of its alkylating mode of action, cyclophosphamide results in breaks and linking of the DNA strands and DNA-protein
morning. During or immediately after the administration adequate can be assumed to cause partially irreversible disturbances of cross-links. In the cell cycle, passage through the G2 phase is
amounts of uid should be ingested. It is important to ensure that spermatogenesis and the resulting azoospermia or persistent retarded. The cytotoxic action is not specic to the cell cycle
the patient empties his/her bladder at regular intervals. oligospermia. Ovulation disorders, that sometimes take an phase, but is specic to the cell cycle.
Duration of therapy and intervals will depend on the indication, irreversible course, with the resulting amenorrhoea and lower Cross-resistance, particularly with structurally related cytostatics
the applied combination chemotherapy schedule, the patients levels of female sex hormones occur with a rarer frequency. like ifosfamide as well as other alkylating agents, cannot be ruled
general state of health, the laboratory parameters and the recovery liver out.
of blood cell counts. Pharmacokinetic properties
Rare cases of disturbances of hepatic function have been reported
INSTRUCTIONS FOR USE AND HANDLING that are reected by an increase in the corresponding laboratory Cyclophosphamide is almost completely absorbed from the gastro-
The handling and preparation of ENDOXAN should always be test values (SGOT, SGPT, gamma-GT, alkaline phosphatase and intestinal tract. In man, single intravenous injections of labelled
in accordance with the safety precautions used for handling bilirubin). cyclophosphamide are followed within 24 hours by a profound
of cytotoxic agents. Veno-occlusive disease (VOD) is observed in approx. 15-50 % of fall in the plasma concentrations of cyclophosphamide and its
the patients receiving high-dose cyclophosphamide in combination metabolites, though detectable levels may persist in the plasma for
OVERDOSE with busulfan or whole-body irradiation during allogenic bone up to 72 hours.
Since no specic antidote for cyclophosphamide is known, great marrow transplantation. By contrast, VOD is only rarely observed Cyclophosphamide is inactive in vitro and is activated in vivo.
caution is advised each time it is used. Cyclophosphamide can be in patients with aplastic anaemia who are receiving high dose The mean serum half-life of cyclophosphamide is 7 hours for
dialysed. Therefore, rapid haemodialysis is indicated when treating cyclophosphamide alone. The syndrome typically develops 1-3 adults and 4 hours for children.
any suicidal or accidental overdose or intoxication. A dialysis weeks after the transplantation and is characterized by sudden
clearance of 78 ml/min was calculated from the concentration Cyclophosphamide and its metabolites are mainly excreted by the
weight gain, hepatomegaly, ascites and hyperbilirubinaemia.
of non-metabolised cyclophosphamide in the dialysate (normal Hepatic encephalopathy may also develop. kidneys.
renal clearance is around 5 - 11 ml/min). A second working group Known risk factors predisposing a patient to the development of The blood levels after i.v. and oral doses being bioequivalent.
reported a value of 194 ml/min. After 6 hours of dialysis, 72 %
VOD are pre-existing disturbances of hepatic function, hepatotoxic STORAGE AND STABILITY NOTE
of the dose of cyclophosphamide administered was found in the
drug therapy concurrently with high-dose (chemo)therapy and ENDOXAN must not be stored above +25 C.
dialysate.
especially when the alkylating agent busulfan is an element of the
In the case of overdose, myelosuppression, mostly leukocytopenia, conditioning therapy. The reconstituted solution should be used within 24 hours after
is to be expected, among other reactions. The severity and duration preparation (do not store above +8 C).
Cardiovascular and pulmonary systems:
of the myelosuppression depends on the extent of the overdose. Do not use ENDOXAN after the expiry date given on the
Frequent checks of the blood count and monitoring of the patient In isolated cases, pneumonitis, interstitial pneumonia extending to
package.
are necessary. If neutropenia develops, infection prophylaxis must chronic interstitial pulmonary brosis may develop.
During transport or storage of ENDOXAN injection vials,
be given and Infections must be treated adequately with antibiotics. The occurrence of a secondary cardiomyopathy induced by
temperature inuences can lead to melting of the active ingredient
If thrombocytopenia develops, thrombocyte replacement should be cytostatic agents and manifesting as arrhythmias, EKG changes
cyclophosphamide. Vials containing melted substance can easily
ensured according to need. It is essential that cystitis prophylaxis and LVEF (e.g. myocardial infarction) has been reported, especially
be visually differentiated from those containing the Intact active
with UROMITEXAN (mesna) be undertaken to avoid any following the administration of high doses of cyclophosphamide
ingredient: melted cyclophosphamide is a clear or yellowish
urotoxic effects. (120-240 mg/kg of body weight). Furthermore, there is evidence
viscous liquid (usually found as connected phase or in droplets in
that the cardiotoxic effect of cyclophosphamide may be enhanced
REMARK the affected vials). Do not use injection vials with melted content.
in patients who have received previous radiation treatment of
If a cyclophosphamide solution is inadvertently administered the heart region and adjuvant treatment with anthracyclines or Keep drugs out of childrens reach!
by paravenous injection, there is usually no danger of cytostatic pentostatin. In this context, bear in mind that regular electrolyte
tissue damage since such damage is not expected before PACK SIZES
controls are necessary and that special caution is advised in
cyclophosphamide has been bioactivated in the liver. If paravasation Vials of 200 mg 1(N.R) and 10
patients with pre-existing heart disease.
should occur, nevertheless stop the infusion immediately and Vial of 500 mg 1
aspirate the paravasate with the cannula in place, irrigate the area Secondary tumours
Vial of 1 g 1
with saline solution and immobilize the extremity. As with cytotoxic therapy in general, treatment with
Sugar-coated tablets 50, 200(N.R), 500(N.R), 1.000(N.R).
UNDESIRABLE EFFECTS cyclophosphamide involves the risk of secondary tumours and their
precursors as late sequelae. The risk of developing urinary tract Hospital packs
Patients on ENDOXAN therapy may experience the following Not all pack sizes may be marketed.
cancer as well as myelodysplastic alterations partly progressing
dose-dependent side-effects which are reversible in most cases:
to acute leukaemias is increased. Animal studies prove that the
Blood and bone marrow risk of bladder cancer can be markedly reduced by an adequate EXTRANEAL
Depending on the dose given, different degrees of myelosuppression administration of UROMITEXAN.
may occur, involving leukocytopenia, thrombocytopenia and Other adverse effects
anaemia. It can commonly be expected that leukocytopenia (Icodextrin)
Alopecia, a frequent side-effect, is reversible in general. Cases of
with and without fever and the risk of secondary (sometimes
life-threatening) infections will occur, and thrombocytopenia pigment changes of the palms, nger nails and the soles have also
been reported. COMPOSITION
associated with the higher risk of a bleeding event. The leukocyte
In addition, the following side-effects were observed: What are the active substances?
and platelet nadirs are usually reached in week 1 and 2 of treatment.
They usually recover within 3 to 4 weeks after the initiation of SIADH (syndrome of inappropriate secretion of antidiuretic EXTRANEAL is a sterile solution for intra-peritoneal
treatment. Anaemia will usually not develop until after several hormone, Schwartz-Bartter syndrome) with hyponatraemia and administration:
treatment cycles. water retention Electrolyte solution content per 1000ml:
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Icodextrin 75g/L Sodium 133 mmol/L Signicant losses of protein, amino acids and water-soluble Fall in blood pressure, feeling light headed or dizzy, muscle
Sodium vitamins may occur during peritoneal dialysis. Replacement cramp or thirst,
5.4g/L
Chloride Calcium 1.75 mmol/L therapy should be prescribed as necessary by your physician. Loss of appetite, nausea, vomiting, dyspepsia,
Sodium 4.5g/L Serum electrolyte concentrations (particularly bicarbonate sodium Bleeding, weakness, fainting, tiredness or headache,
Lactate Magnesium 0.25 mmol/L and chloride), blood chemistry and haematological factors should EXTRANEAL associated Skin reactions. including rashes
Calcium 0.257g/L be evaluated periodically by your physician. If you have diabetes, and pruritus are generally mild or moderate in severity.
Chloride Chloride 96 mmol/L blood glucose levels should be monitored and the dosage of insulin Occasionally, rashes have been associated with exfoliation, in
Magnesium 0.051g/L or other treatment for hyperglycaemia should be adjusted by your this event and depending on severity, EXTRANEAL could be
Chloride Lactate 40 mmol/L
physician. It should be noted that EXTRANEAL may interfere withdrawn at least temporarily by your doctor.
Theoretical
with the measurement of blood glucose by certain testing kits. A What measures are to be taken if side effects occur?
osmolarity 284 (milliosmoles per litre)
Theoretical falsely high glucose might be found. If you need to test your blood
Should any of the above listed side effects occur, immediately
osmolality 301 (milliosmoles per kg) glucose, your physician will advise you on which kit to use.
inform you physician. If you notice any unwanted effects not
In case of doubt on the above precautions, you should not hesitate mentioned in this leaet or if you are unsure about the effect of
pH = 5 to 6 to consult your physician or pharmacist. this product, please inform your physician or pharmacist.
COMPOSITION IN FULL SPECIAL WARNINGS OVERDOSE
What else does EXTRANEAL contain? What do you have to consider during pregnancy and while What to do if you use too much EXTRANEAL
EXTRANEAL also contains: breast-feeding?
You should not use more than one bag of EXTRANEAL per
- Water for Injections EXTRANEAL is not recommended during pregnancy or while 24 hours. If you have repetitively used more than one bag per
- Sodium hydroxide or hydrochloric acid to adjust pH. breast-feeding. Women of childbearing potential should be 24 hours, you should consult a physician as it may affect levels
treated with EXTRANEAL only when adequate contraceptive of Icodextrin metabolites in your blood. The physician will
PHARMACEUTICAL FORM AND PHARMACO- precautions have been taken. ultimately decide if any corrective treatment is necessary.
THERAPEUTIC GROUP
What needs to be taken into consideration for children?
What is EXTRANEAL? SPECIAL PRECAUTIONS FOR STORAGE
EXTRANEAL is not recommended in children.
EXTRANEAL is a sterile peritoneal dialysis uid containing How should EXTRANEAL be stored?
What else needs to be taken into consideration?
Icodextrin as the active ingredient at a concentration of 7.5%, in EXTRANEAL has a shelf life of 2 years. Do not use the product
an electrolyte solution. There are other conditions which may make the use of after expiry date shown on the carton and product label.
EXTRANEAL unsuitable for you, for example conditions
EXTRANEAL is a solution for intra-peritoneal administration Do not store above 30C. Do not use unless the solution is clear
affecting your nutrition, breathing or if you have a potassium
only. It should not be used for intravenous administration. and the container undamaged.
deciency. EXTRANEAL should not be used if you have acute
EXTRANEAL is presented in exible PVC containers and is renal failure. Keep out of reach of children. Any unused portion of dialysis
available in the following bag sizes: 1.5(N.R), 2.0 and 2.5 litres solution in a bag should be discarded.
and in the following pack sizes: 6 x 1.5 litres, 5 x 2.0 litres and 4 INTERACTIONS WITH OTHER MEDICAMENTS AND
OTHER FORMS OF INTERACTION
x 2.5 litres.(N.R) HOLOXAN Dry substance for Injection
What other products can EXTRANEAL effect?
PROPERTIES
The effect of treatment with cardiac glycosides may be affected if
Solution
How does EXTRANEAL work? taken whilst using EXTRANEAL. Plasma levels of potassium and
Icodextrin is a starch-derived glucose polymer which acts as an calcium must therefore be carefully checked by your physician. In (Ifosfamide)
osmotic agent when administered intraperitoneally for continuous the event of abnormal levels, appropriate actions should be taken.
ambulatory peritoneal dialysis (CAPD). EXTRANEAL produces COMPOSITION:
sustained ultraltration over a period up to 12 hours in CAPD, with OTHER FORMS OF INTERACTION
a reduction in caloric load compared to 3.86% glucose solutions, EXTRANEAL interfere with the measurement of blood glucose 1 vial HOLOXAN HOLOXAN HOLOXAN HOLOXAN
but with similar volume of ultraltrate. some blood glucose testing kits. A falsely high glucose might be 200 mg (N.R) 500 mg 1g 2g
found. contains:
INCOMPATIBILITIES Ifosfamide 200 mg 500 mg 1g 2g
Why use EXTRANEAL?
Is EXTRANEAL incompatible with any other medicines? as dry substance for preparing an injectable solution.
EXTRANEAL is recommended as a once daily replacement
for a single glucose exchange as part of a CAPD or automated There are no known problems with compatibility of EXTRANEAL
and other medicines. INDICATIONS:
peritoneal dialysis (APD) regimen for the treatment of chronic
Drug compatibility must be checked before admixture. In addition, HOLOXAN is to be administered exclusively by physicians with
renal failure, particularly for patients who have lost ultraltration
the pH and salts of the solution must be taken into account. experience in oncology. It is indicated in inoperable malignant
on glucose solutions, because it can extend time on CAPD therapy
tumours that are sensitive to ifosfamide, e.g. bronchial carcinoma,
in such patients. A range of antibiotics including vancomycin, cephazolin, ovarian carcinoma, testicular tumours, soft-tissue sarcoma, breast
EXTRANEAL is a prescription only medicine, prescribed by ampicillin/ucloxacillin, ceftazidime, gentamicin, amphotericin, cancer, pancreatic carcinoma, hypernephroma, endometrial
your physician for you personally, and you should not pass it on and insulin have shown no evidence of incompatibility with carcinoma, malignant lymphomas.
to others. EXTRANEAL.
Special remark:
CONTRA INDICATIONS POSOLOGY AND METHOD OF ADMINISTRATION Should during treatment with HOLOXAN a cystitis in
When should you not use EXTRANEAL? How and when should you use EXTRANEAL? connection with macro- or microhaematuria appear,
EXTRANEAL should not be used if you have a known allergy to Your physician will decide on the dosage of EXTRANEAL. HOLOXAN therapy has to be interrupted until normalization.
starch based polymers or an icodextrin intolerance, or if you have EXTRANEAL is recommended for use during the longest dwell
CONTRAINDICATIONS:
a glycogen storage disease. period, i.e. in CAPD usually overnight and in APD for the long
daytime dwell. HOLOXAN is contraindicated in cases of
EXTRANEAL should also not be used if you have a history
- known hypersensitivity to ifosfamide
of abdominal surgery in the month preceding commencement Adults: By intraperitoneal administration limited to a single
exchange in each 24 hour-period, as part of a CAPD or APD - severely depressed bone-marrow function (especially in patients
of therapy or if you are suffering from abdominal stulae (non-
regimen. previously treated with cytotoxic agents or radiotherapy)
healing weeping wounds), tumours, open wounds, hernia or other
conditions affecting your abdomen. - active infections
Elderly: As for Adults
- impaired renal function and/or obstructions of the urine ow
PRECAUTIONS FOR USE Children: Not recommended for use in children (less than 18
years). - cystitis
What precautions have to be taken?
- pregnancy (see special comments)
EXTRANEAL is for intraperitoneal administration only. The volume to be instilled should be given over a period of
approximately 10 to 20 minutes at a rate which the patient nds - lactation
To change the dialysis bag, it is of vital importance that you
comfortable. For adult patients of normal body size the instilled REMARKS:
carefully follow the steps which have been shown to you during
volume should not exceed 2.0 litres. Before starting treatment, it is necessary to exclude or correct
training, and that you make sure that all the connecting parts
remain completely clean to reduce the possibility of infection. For larger patients, a ll volume of 2.5 L may be used. any obstruction of the efferent urinary tract, cystitis, infections
Do not administer unless the solution is clear and the container If this causes abdominal tension a 1.5 litre volume should be used. and electrolyte imbalances. In general, HOLOXAN, like other
undamaged. The recommended dwell time is between 6 and 12 hours in CAPD cytostatics, should be used with care in weakened or elderly
and 14-16 hours in APD. Drainage of the uid is by gravity at patients and in patients who have had previous radiotherapy.
To reduce discomfort on administration, the solution should be
a rate comfortable for the patient. The drained uid should be Patients with a weakened immune system, e.g. those with diabetes
warmed in the oversealed bag to a temperature of 37C prior to inspected for the presence of brin or cloudiness, signs that may mellitus, chronic hepatic and renal impairments, also require
use. This should be done using dry heat, ideally using a warming indicate the presence of infection or aseptic peritonitis. special care. Patients with brain metastases, cerebral symptoms
plate specially designed for the purpose. Hot water should not
UNDESIRABLE EFFECTS and /or deteriorated renal function must be kept under close
be used to warm the bag in order to avoid contamination of
observation.
connectors. What side effects may EXTRANEAL cause?
Use during pregnancy and lactation
An accurate uid balance record must be kept and your body weight Peritoneal dialysis may cause some undesirable effects in addition
should be carefully monitored to avoid over- and underhydration, to its benecial effects. Contact your doctor if you experience any In a vital indication during the rst trimester of pregnancy a
which may have severe consequences particularly in the elderly of the following or if you notice any other effects: medical consultation regarding abortion is absolutely necessary.
patients, including congestive heart failure, volume depletion, Cloudy efuent, high temperature, feeling sick, stomach pain or After the 1st trimester of pregnancy, if therapy cannot be
shock and neurological symptoms. shivering/u-like symptoms, delayed and the patient wishes to continue with her pregnancy,
An aseptic technique should be observed throughout the bag Redness, puss, swelling or pain around the exit site of your chemotherapy may be undertaken after informing the patient of
change procedure. catheter, catheter blockage, the minor but possible risk of teratogenic effects.
The drained uid should be inspected for the presence of brin constipation, intestinal obstruction, Shoulder pain, hernia of the Mothers must not breast feed during treatment with
or cloudiness, which may indicate the presence of brin or abdominal cavity, HOLOXAN.
cloudiness, which may indicate the presence of infection or aseptic Swollen ankles or legs, puffy eyes, shortness of breath or chest Contraceptive measures
peritonitis. pain, Ifosfamide can cause congenital anomalies. Conception during
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treatment is not advisable. Men to be treated with HOLOXAN drugs. The most common symptom of encephalopathy is In analogy with cyclophosphamide, the following interactions
should be informed about sperm preservation before treatment. drowsiness which can progress to somnolence and coma. Other seem possible:
Women should not become pregnant during treatment. Should symptoms can be weakness, forgetfulness, depressive psychoses, - The myelosuppressive action may be enhanced by the concurrent
they still conceive during treatment, they should seek genetic disorientation, restlessness, confusion, hallucinations, cerebellar administration of allopurinol or hydrochlorothiazide.
consultation. The duration of contraception after the end of symptoms, incontinence and convulsions. - The effect and the toxicity may be enhanced by the concurrent
chemotherapy depends on the prognosis of the primary disease and The encephalopathies are usually reversible and disappear administration of chlorpromazin, triiodothyronine or aldehyde
on the intensity of the parents desire for a child. The possibility of spontaneously within a few days after the last ifosfamide dehydrogenase inhibitors such as disulram.
a genetic consultation should be used. administration. Severe courses are rare, and deaths were only seen - The treatment may increase the hypoglycaemic actions of
SIDE-EFFECTS: in isolated cases and in connection with very high doses of the sulfonylureas.
drug. With a fractionated dose-regimen, encephalopathies are less
Patients on HOLOXAN therapy may experience the following - Prior or concurrent treatment with phenobarbital, phenytoin
frequent and less severe. or chloral hydrate involves the possibilit of microsomal liver
side-effects:
Myelosuppression: Remarks: enzyme induction and thus a faster metabolism of ifosfamide.
Due to the CNS-toxicity of ifosfamide, patients must be carefully - The treatment may increase the muscle-relaxant effect of
Different degrees of myelosuppression (leucocytopenia,
thrombocytopenia and anaemia) can occur, depending on the monitored. In the event of encephalopathy, ifosfamide treatment suxamethonium.
has to be discontinued and must not be resumed. In case of DOSAGE AND ADMINISTRATION:
dose. Frequently leucocytopenia with the risk of life-threatening
ifosfamide induced encephalopathy, drugs acting on the CNS (e.g.,
infections and thrombocytopenia with the risk of bleeding have to The treatment should only be administered by an experienced
antiemetics, tranquilizers, narcotics or antihistamines) should be
be taken into consideration. The lowest leucocyte and thrombocyte oncologist. The dosage must be adapted to each patient
discontinued if possible, or used with special caution.
counts normally occur one to two weeks after start of treatment individually. In single-drug therapy of adults, the most common
and recover within 3 to 4 weeks. Anaemia usually occurs after Other adverse effects: treatment is based on fractionated doses. In the absence of
several cycles of treatment. A combination treatment with other Nausea and vomiting are dose-dependent side-effects. Moderate individual prescriptions, the following recommendations may
myelosuppressive agents may require dose adjustments. Single to severe forms can be seen in about 50% of the cases. Another serve as a guideline.
high-dose treatment leads more frequently to leucocytopenia than frequent side-effect is reversible alopecia which occurs in up to In general, HOLOXAN is given intravenously in divided doses
fractionated dose-regimen. In pretreated (chemotherapy and/or 100% of patients, depending on dosage and duration of treatment. of 1.22.4 g/m2 body surface (up to 60 mg/kg of body weight)
radiotherapy) patients or patients with renal function impairment, Because of its alkylating mechanism of action, HOLOXAN daily for 5 consecutive days (the duration of these infusions is
a more severe myelosuppression can be expected. With ifosfamide can cause partly irreversible impairment of spermatogenesis with about 30120 minutes, depending on the volume). HOLOXAN
as with other cytostatics, blood counts have to be taken before resulting azoospermia or persistent oligospermia, respectively may also be given in a single high dose, usually as a 24-hours-
each chemotherapy cycle as well as during the intervals between less frequently irreversible ovulation disturbances with resulting prolonged infusion. The dosage is generally 5 g/m2 body surface
cycles. amenorrhea and reduced levels of female sex hormones. (125 mg/kg body weight) and should not exceed more than 8 g/m2
Depending on the blood picture, appropriate dose adaptations (see Additionally, there can occur: body surface (200 mg/kg body weight) per cycle.
table) should be made. - In isolated cases chronic interstitial pulmonary brosis. Toxic- A single high dose may cause higher haemato-, uro-, nephro- and
Remark: Guidelines for dose reduction in myelosuppression allergic pulmonary oedema was reported in one single case. CNS toxicity.
Leucocyte Count Thrombocyte Count - In isolated cases SIADH (syndrome of inadequate ADH- Care should be taken to ensure that the ifosfamide concentration of
> 4000 > 100 000 100% of planned dose secretion, Schwartz-Bartter-syndrome) with hyponatremia and the solution does not exceed 4 percent.
water retention. Hypokalemia was reported in one single case.
4000 2500 100 000 50 000 50% of planned dose In combination-therapy with other cytostatics, the dose should be
- In isolated cases acute pancreatitis
< 2500 < 50 000 postponement until adapted to the type of therapeutic scheme.
- In rare cases inammation of the skin and mucous membrane
normalisation or Remarks:
- In rare cases hypersensitivity reactions, in isolated cases with
individual decision Because of its urotoxicity, ifosfamide should as a matter of
fever and progressing to shock
- In rare cases blurred vision and episodes of dizziness principle be used in combination with mesna. Other toxicities
Urotoxicity and nephrotoxicity:
and the therapeutic effects of ifosfamide will not be inuenced
Haemorrhagic cystitis (macro- and microhaematuria) is a frequent, An increase in liver enzymes and/or in the bilirubin level can also
by mesna.
dose-dependent complication of ifosfamide. occur occasionally. Anorexia, diarrhea, constipation, phlebitis or
pyrexia may more seldom be seen. Polyneuropathy, pneumonitis, Should cystitis with micro- and macrohaematuria develop during
Remark: therapy, the treatment should be discontinued until the patient has
Fractionated dosing, adequate hydration, maintenance of uid impaired vision or an increased reaction to radiation were isolated
recovered.
balance and particularly concomitant treatment with mesna seen. There have been isolated reports of supraventricular or
ventricular arrhythmias, ST-T segment changes and heart failure Because the cytostatic effect of ifosfamide occurs only after
(UROMITEXAN) can markedly reduce the frequency and activation in the liver, there is no danger of injuring the tissue in
severity of haemorraghic cystitis. after very high doses of ifosfamide and/or after pretreatment
or concomitant treatment with anthracyclines. In this context, the case of paravenous injections.
Disorders of glomerular renal function with an increase in serum it is again necessary to stress the need for regular electrolyte Administration and duration of treatment:
creatinine, a decrease in creatinineclearance and proteinuria can monitoring and special caution when treating patients with history
occasionally occur, or more frequently disorders of tubular renal The therapy cycles may be repeated every 34 weeks. The
of heart disease. As with cytotoxic therapy in general, especially intervals will depend on the blood count and on the recovery from
function with hyperaminoaciduria, phosphaturia, acidosis or with alkylating agents, treatment with ifosfamide involves the risk
proteinuria. Severe nephropathies are rare. any adverse reactions or side-effects.
of secondary tumours as late sequelae.
Possible risk factors for disorders of glomerular renal function The administration of uroprotection with mesna
are high doses of the drug and additional treatment with PRECAUTIONS: (UROPROTECTOR, UROMITEXAN) as directed, should
platinum containing drugs. Risk factors for disorders of tubular The following measures and/or tests are indicated in order to limit be maintained.
renal function are previous nephrectomy, additional treatment or alleviate adverse reactions: Regular blood counts, regular checks of renal function and regular
with platinum containing drugs or concomitant irradiation of - Timely administration of antiemetics, urinalysis including urinary sediment are necessary.
the abdomen with inclusion of the kidneys or the remaining - Regular blood counts, Timely administration of antiemetics is indicated, and the additional
kidney. Caution is advisable when potentially nephrotoxic drugs - Regular checks of renal function parameters, inuences on the CNS in combination with HOLOXAN should
such as aminoglycosides, acyclovir or amphotericin B are used - Regular check of urinalysis and urinary sediment. be taken into consideration.
concomitantly.
In cases of hepatic or renal impairment before the start of therapy, PREPARATION OF THE SOLUTION:
These drugs do not potentiate the tubular kidney disorder, but may the use of HOLOXAN has to be individually weighed for each
cause further deterioration of glomerular function. The handling of HOLOXAN should always be in accordance
patient. It is recommended that patients under HOLOXAN
with the safety precautions used for the handling of cytotoxic
In rare cases, patients with chronic tubular kidney disorder may therapy are monitored more frequently.
agents.
develop Fanconis syndrome resulting in rickets or, in adults, The blood sugar level should be checked regularly in diabetics in
osteomalacia. Predisposing factors are high cumulative doses To prepare a 4% isotonic solution ready for injection, water for
order to modify the antidiabetic therapy on time.
of the drug and young age (particularly younger than 3 years). injection is added to the dry substance in the following amounts:
It is essential to ensure adequate diuresis.
Glomerular and tubular kidney function must therefore be HOLOXAN 200 mg 500 mg 1g 2g
evaluated and checked before start of therapy, during and after Fever and/or severe leucopenia require prophylactic administration
of antibiotics and/or antimycotics. Water for 5 ml 13 ml 25 ml 50 ml
therapy.
Attention should be paid to meticulous oral hygiene. Injection
During long-term treatment with ifosfamide, sufcient diuresis
and regular control of renal function is necessary. This applies Effects on ability to drive and use machines: The substance dissolves readily if the vials are vigorously shaken
especially to children. In case of beginning nephropathy, HOLOXAN may affect a subjects ability to drive a motor for 0.5 to 1 min after addition of the water for injection. If the
irreversible kidney damage has to be expected if treatment with vehicle or to operate machinery. This may occur either directly substance fails to dissolve immediately and completely, it is
ifosfamide is continued. A careful risk-benet evaluation is by induced encephalopathy or indirectly as a result of nausea and advisable to allow the solution to stand for a few minutes. The
required. vomiting, especially when CNS-active drugs or alcohol are taken prepared solution can be kept for up to approx.
Caution is required in unilaterally nephrectomized patients, in concomitantly. 24 hours if stored at a temperature not exceeding +8 C
patients with impaired renal function and in patients pretreated INTERACTIONS WITH OTHER DRUGS: (refrigerator). The HOLOXAN solution for short-term
with nephrotoxic drugs (e.g. cisplatin). In these patients frequency intravenous infusion (approx. 30120 min) is prepared by diluting
Myelotoxicity can be increased as a result of interaction with other
and intensity of myelotoxicity, nephro- and cerebral toxicity are the above solution with 250 ml Ringers solution or 5% glucose
cytostatics or radiation. Ifosfamide may intensify skin reactions
increased. solution or physiological saline. For longer infusions over one to
due to irradiation.
two hours, dilution is recommended with 500 ml Ringers solution
Central nervous system: The prior or concurrent administration of nephrotoxic agents like or 5% glucose solution or physiological saline. For continuous
In 1020% of cases, encephalopathy occurs and develops within cisplatin, aminoglycosides, acyclovir or amphotericin B may 24-hour infusions of high-dose HOLOXAN, the prepared
a few hours up to a few days after start of treatment. Risk-factors enhance the nephrotoxic effect of ifosfamide and consequently HOLOXAN solution, e.g., 5 g/m2, must be diluted to 3 litres
are a poor state of health, impaired renal function (creatinine > 1.5 haematotoxic and neurotoxic (CNS) effects as well. Because of with 5% glucose solution and/or physiological saline.
mg/dl), pre-treatment with nephrotoxic drugs (e.g. cisplatin) and the immunosuppressive effect of ifosfamide, an impaired response
post-renal obstructions (e.g. pelvic tumors). to the respective vaccine may occur. Vaccination injury can be SPECIAL REMARK:
Other possible risk-factors are old age, a history of alcohol abuse, caused by live-virus vaccinations. Because of its alkylating action, ifosfamide is a mutagenic and
decreased levels of serum albumin or hydrogen carbonate, hepatic The concurrent use of ifosfamide may increase the anticoagulant also a potential carcinogenic substance. Contact with the skin and
dysfunction or concurrent high dose treatment with antiemetic effect of warfarin and thus raise the risk of haemorrhages. mucous membranes should therefore be avoided.
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STABILITY NOTE: Driving and using machines HUMAN ALBUMIN 200 g/l BAXTER should be
HOLOXAN should not be stored above +25 C! There is no reason to believe that the medicine will affect your administered by the intravenous route, infusing the package
ability to drive or use machines. contents directly or it can also be diluted in an isotonic
HOLOXAN should not be used after the expiry date stated on
solution (e.g. 5 % glucose or 0.9% sodium chloride).
the package. 3. HOW TO USE HUMAN ALBUMIN 200 g/l BAXTER HUMAN ALBUMIN 200 g/l BAXTER should not be
The reconstituted solution should be used within 24 hours after HUMAN ALBUMIN 200 g/l BAXTER is a medicine for diluted with water for injection, since this could cause
preparation (do not store above + 8C!). hospital use. It will therefore be administered in a hospital by hemolysis in the recipient of the product.
STORE DRUGS OUT OF CHILDRENS REACH ! appropriate health care personnel. Your doctor will establish the Solutions should be clear, slightly viscous, almost colourless,
amount of product to be administered, the frequency of dosing yellow, amber or green. Solutions that are turbid or showing
PRESENTATION: and the duration of treatment based on your specic condition. sediments should not be used, since this could be an
200 mg vials : Packs of 10 vials(N.R) indication that the protein is unstable or the solution has
If you take more HUMAN ALBUMIN 200 g/l BAXTER
500 mg vials : Packs of 1 vial been contaminated. Once the package has been opened, its
than you should
Packs of 10 vials(N.R) contents must be used immediately.
1g vials : Packs of 1 If you may have got more HUMAN ALBUMIN 200 g/l
BAXTER than you should consult your doctor or pharmacist Infusion is performed by the intravenous route using a
Packs of 10 vials(N.R)
immediately. disposable sterile and pyrogen-free infusion set. Before
2g vials : Packs of 1
inserting the infusion set in the cap, this should be
Packs of 10 vials(N.R) If you experience: headache, difculties in breathing or
disinfected with an appropriate antiseptic. Once the infusion
HOLOXAN is available on prescription only increased blood pressure, please tell your doctor.
set is attached to the vial, the contents should be perfused
4. POSSIBLE SIDE EFFECTS immediately. Unused solutions should be adequately
HUMAN ALBUMIN 200 g/l BAXTER Like all medicines, HUMAN ALBUMIN 200 g/l BAXTER discarded.
can cause side effects, although not everybody gets them. The infusion rate should be adjusted according to the
20% Solution for Infusion individual circumstances and the indication.
Very common in more than 1 in 10 patients treated
In plasma exchange the infusion rate should be adjusted to
Common in less than 1 in 10, but more than
the rate of removal.
(Human albumin) 1 in 100 patients treated
If large volumes are administered, the product should be
Uncommon in less than 1 in 100, but more than
warmed to room temperature before use.
1 in 1000 patients treated
1. WHAT HUMAN ALBUMIN 200 g/l BAXTER IS AND When concentrated albumin is administered, adequate
Rare in less than 1 in 1000, but more than
WHAT IT IS USED FOR hydration of the patient must be ensured. Patients should be
1 in 10 000 patients treated
This medicine is a plasma protein and belongs to the Very rare in less than 1 in 10 000 patients adequately monitored to prevent circulatory overload and
pharmacotherapeutic group of plasma substitutes and plasma treated, including isolated cases overhydration.
protein fractions. Plasma is the uid in which blood cells are When albumin is administered, the electrolyte balance of
suspended. Very the patient should be monitored and, if required, appropriate
common Common Uncommon Rare Very rare measures should be taken to restore or maintain it.
The medicine is used for restoration and maintenance of
circulating blood volume in medical conditions where there is Immune anaphy- Adequate replacement of other blood components
not enough blood volume, and use of a colloid is appropriate. system lactic (coagulation factors, electrolytes, platelets and erythrocytes)
disorders shock must be ensured.
The choice of albumin rather than an articial substitute will
depend on the clinical situation of the individual patient, based Gastroint- nausea For safety reasons, the batch number of HUMAN ALBUMIN
on ofcial recommendations. estinal (feeling 200 g/l BAXTER administered should be recorded.
disorders sick) Human albumin must not be mixed with other medicinal
2. BEFORE YOU USE HUMAN ALBUMIN 200 g/l products (except the recommended diluents such as 5 %
BAXTER Skin and
subcutan- ushing, glucose or 0.9% sodium chloride), whole blood and packed
Do not useHUMAN ALBUMIN200 g/l BAXTER skin red cells.
eous
If you are allergic (hypersensitive ) to human albumin or tissue dis- rash Hypervolaemia may occur if the dosage and rate of infusion
any of the other ingredients of HUMAN ALBUMIN 200 g/l orders are too high. At the rst clinical signs of cardiovascular
BAXTER . overload (headache, dyspnoea, jugular vein congestion), or
General
Take special care with HUMAN ALBUMIN 200 g/l fever increased blood pressure, raised central venous pressure,
disorders
BAXTER and pulmonary oedema, the infusion should be stopped
and
If you have allergic reactions, since the infusion will have to immediately and the patients haemodynamic parameters
administ-
be stopped by your doctor or nurse. In case of shock, standard carefully monitored.
ration
medical treatment for shock should be implemened. site
If you have: conditions PARTOBULIN SDF Solution for Injection
- decompensated heart failure
The rare side effects disappear quickly when the
- high blood pressure infusion rate is decreased or stopped. (Human anti-D immunoglobulin)
- esophageal varices (swelled veins in the esophagus) If an anaphylactic shock (severe allergic reactions)
- pulmonary oedema (uid on the lungs) may occur the infusion should be stopped immediately NAME OF THE MEDICINAL PRODUCT
- a tendency to spontaneous bleeding and accurate treatment initiated. PARTOBULIN SDF
- severe anemia (lack of red blood cells) If any of the side effects gets serious, or if you notice Human anti-D immunoglobulin for intramuscular use
- no urine formation any side effects not listed in this leaet, please tell
Inform your doctor so that he/she can take appropriate your doctor or pharmacist. QUALITATIVE AND QUANTITATIVE COMPOSITION
precautions. 1 preloaded syringe of PARTOBULIN SDF (1 ml) contains:
5. HOW TO STORE HUMAN ALBUMIN 200 g/l BAXTER
When medicines are made from human blood or plasma, certain active ingredients
Keep HUMAN ALBUMIN 200 g/l BAXTER out of the reach
steps are put in place to prevent infections being passed on to anti-D antibody 250 micrograms = 1250 IU
and sight of children.
patients. These include careful selection of blood and plasma
Do not use HUMAN ALBUMIN200 g/l BAXTER after the human protein 100 170 mg/ml
donors to make sure those at risk of carrying infections are
excluded, and the testing of each donation and pools of plasma expiry date which is stated on the label. The expiry date refers (of which at least 90% is immunoglobulin)
for signs of virus/infections. Manufacturers of these products to the last day of that month. 1 preloaded syringe of PARTOBULIN SDF (1.32 ml)
also include steps in the processing of the blood or plasma Do not store above 25C. contains:(N.R)
that can inactivate or remove viruses. Despite these measures, Do not freeze. active ingredients
when medicines prepared from human blood or plasma are anti-D antibody 330 micrograms = 1650 IU
Keep the glass vial in the outer carton in order to protect from
administered, the possibility of passing on infection cannot be
light. human protein 100 170 mg/ml
totally excluded. This also applies to any unknown or emerging
viruses or other types of infections. Once the package has been opened, the contents must be used (of which at least 90% is immunoglobulin)
immediately. The amount of anti-D immunoglobulin contained in
There are no reports of virus infections with albumin
manufactured to European Pharmacopoeia specications by Do not use HUMAN ALBUMIN 200 g/l BAXTER if you PARTOBULIN SDF is determined according to the method
established processes. notice the solution is turbid or has deposits. described in the European Pharmacopoeia.
It is strongly recommended that every time you receive a dose 6. FURTHER INFORMATION For excipients, see Pharmaceutical Particulars.
of HUMAN ALBUMIN 200 g/l BAXTER the name and batch WhatHUMAN ALBUMIN 200 g/l BAXTER contains PHARMACEUTICAL FORM
number of the product are recorded in order to maintain a record
The active substance is: human albumin. Human anti-D immunoglobulin for intramuscular use is supplied
of the batches used.
Every 100 ml contain 20 g of total protein, of which at least in a liquid form. The solution comes in preloaded syringes.
Using other medicines
95% is human albumin. CLINICAL PARTICULARS
Please inform your doctor or pharmacist if you are taking, or
you have recently taken any other medicines, even those not The other ingredients are: Sodium ions, sodium caprylate, Therapeutic indications
prescribed. sodium acetyltryptophanate.
Prevention of Rh(D) immunization in Rh(D) negative women
No specic interactions of HUMAN ALBUMIN 200 g/l What HUMAN ALBUMIN 200 g/l BAXTER looks like and
Pregnancy/delivery of a Rh(D)-positive baby.
BAXTER with other medicinal products are known. the contents of the pack
Abortion/threatened abortion, ectopic pregnancy or hydatidiform
Pregnancy and breast-feeding It is a clear, slightly viscous liquid; it is almost colourless, mole
yellow, amber or green. It is a sterile solution for infusion for Transplacental hemorrhage (TPH) resulting from antepartum
Inform your doctor or pharmacist before using the medicine if
you are or could be pregnant or if you are breast-feeding. Your intravenous use in 50 ml or 100 ml (N.R)glass vials. hemorrhage (APH), amniocentesis, chorionic biopsy or
doctor will decide if you can use HUMAN ALBUMIN 200 g/l The following information is intended for medical or healthcare obstetric manipulative procedure e.g. external version, or
BAXTER during pregnancy or breast-feeding. professionals only: abdominal trauma.
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SPDI
Treatment of Rh(D) negative persons after incompatible infective agentsm cannot be totally excluded. This also applies to Nature and contents of container
transfusions of Rh(D) positive blood or erythrocyte concentrate. pathogens of unknown nature. The risk of transmission of infective PARTOBULIN SDF is supplied in preloaded syringes containing
Posology and method of administration agents is however reduced by: single doses of either 1 ml (250 micrograms = 1250 IU) or 1.32 ml
Posology selection of donors by a medical interview and screening (330 micrograms = 1650 IU).
of individual donations and plasma pools for HBSAg and Instructions for use and handling and disposal
Postpartum prophylaxis:
antibodies to HIV and HCV.
The recommended standard dose ranges between 200 micrograms The product should be brought to room or body temperature before
testing of plasma pools for genomic material of HBV, HCV and use. Usually the solution is clear or slightly opalescent. Do not use
(1000 IU) and 330 micrograms (1650 IU) and should be given to HIV-1 and -2. solutions that are turbid or have deposits.
the mother as soon as possible after delivery, at the latest within virus inactivation/removal procedures included in the
72 hours. Any unused product or waste material should be disposed of in
production process that have been validated using target and/or
lf a large feto-maternal hemorrhage is suspected, its extent should accordance with local requirements.
model viruses. These procedures are considered effective for
be deter mined by a suitable method and additional doses of anti-D HIV-1 and -2, HBV, HCV, HAV, and parvovirus B19. PARTOBULIN is a trademark of Baxter AG, V,enna, Austria.
should be administered as indicated. In the interest of patients, it is recommended that, whenever
Antepartum and postpartum prophylaxis: possible, every time that PARTOBULIN SDF is administered to RECOMBINATE 250 IU/10 ml,
200 330 micrograms (1000 1650 IU) in week 28 of pregnancy; them, the name and batch number of the product is registered.
in certain cases, earlier initiation of prophylaxis is possible if
Powder and solvent for solution for injection.
Interactions with other medicinal products and other forms
medically justied. of inter -actions RECOMBINATE 500 IU/10 ml,
If the newborn is Rh(D) positive, a further dose of 200 330 Active immunization with live virus vaccines (e.g. measles, mumps
micrograms (1000 1650 IU) should be administered to the mother
or rubella) should be postponed until 3 months after the last adminis
within 72 hours after delivery. tration of anti-D immunoglobulin, as the efcacy of the live virus RECOMBINATE 1000 IU/10 ml,
Ectopic pregnancy, hydatic mole, abortion: vaccine may be impaired. lf anti-D immunoglobulin needs to be
adminis tered within 24 weeks of a live virus vaccination, then
Before week 12 of pregnancy:
the efcacy of such a vaccination may be impaired.
120 150 micrograms (600 750 IU) is recommended within 72
hours after the event. After injection of immunoglobulin the transitory rise of the various
passively transferred antibodies in the patients blood may result in
[Octocog alfa (recombinant, coagulation
After week 12 of pregnancy:
misleading positive results in serological testing. factor)]
250330 micrograms (1250 1650 IU) are recommended within
The results of blood typing and antibody testing including the
72 hours after the event. 1.NAME OF THE MEDICINAL PRODUCT
Coombs or antiglobulin test, are signicantly affected by the
Amniocentesis, chorionic biopsy: adminis tration of anti-D immunoglobulin. RECOMBINATE 250 IU/ 10 ml, powder and solvent for solution
250 330 micrograms (12501650 IU) are recommended within Pregnancy and lactation for injection
72 hours after the event. RECOMBINATE 500 IU/ 10 ml, powder and solvent for solution
Anti-D immunoglobulin has been used in pregnant women for
Macrotransfusion: many years. No harmful effects on the course of pregnancy, the for injection
10 25 micrograms (50 125 IU) per ml of inltrated fetal Rh(D) fetus, or the neonate are known. RECOMBINATE 1000 IU/ 10 ml, powder and solvent for
positive erythrocytes. Effects on ability to drive and use machines solution for injection
Rh(D) incompatible blood or erythrocyte transfusion: No effects on ability to drive and use machines have been 2.QUALITATIVE AND QUANTITATIVE COMPOSITION
In case of a whole blood transfusion, the volume of Rh(D) positive observed. RECOMBINATE 250 IU, is presented as a lyophilised powder
whole blood administered is multiplied by the hematocrit of the Undesirable effects for solution for injection, containing nominally 250 IU octocog
donor unit giving the volume of red blood cells transfused. For
Local pain or tenderness may occur at the injection site. To a large alfa, recombinant, coagulation factor VIII per vial.
every 10 ml of Rh(D) positive red blood cells transfused, the
patient should receive a single dose of 250 micrograms (1250 IU), extent, this can be prevented by dividing higher doses (>5 ml) over The product contains approximately 25 IU/ml octocog alfa,
but within 72 hours after the event. several injection sites. recombinant coagulation factor VIII when reconstituted with 10
Occasionally fever, malaise, headache, cutaneous reactions ml of sterile water for injections.
Treatment should be given (without preceding exchange
transfusion) only if the transfused Rh(D) positive blood represents and chills occur. In rare cases: nausea, vomiting, hypotension, RECOMBINATE 500 IU, is presented as a lyophilised powder
less than 20% of the circulating red cells. tachycardia, and allergic or anaphylactic type reactions, including for solution for injection, containing nominally 500 IU octocog
dyspnoea and shock, are reported, even when the patient has alfa, recombinant, coagulation factor VIII per vial.
shown no hyper sensi tivi ty to previous administration. The product contains approximately 50 IU/ml octocog alfa,
PARTOBULIN SDF is to be administered slowly by deep intra
For information on viral safety see Special warnings. recombinant coagulation factor VIII when reconstituted with 10
muscular injection.
Overdose ml of sterile water for injections.
In case of hemorrhagic disorders where intramuscular injections
No data are available on overdosage. Patients with incompatible RECOMBINATE 1000 IU, is presented as a lyophilised powder
arecontra indicated, PARTOBULIN SDF may be administered
transfusion who receive an overdose of anti-D immunoglobulin, for solution for injection, containing nominally 1000 IU octocog
sub cutaneously. Care ful manual pressure with a compress should
should be monitored clinically and by biological parameters, alfa, recombinant, coagulation factor VIII per vial.
be applied to the site after injection.
because of the risk of hemolytic reaction. The product contains approximately 100 IU/ml octocog alfa,
If large total doses (> 5 ml) are required, it is advisable to
In other Rh(D)-negative individuals overdosage should not lead to recombinant coagulation factor VIII when reconstituted with 10
administer them in divided doses at different sites, but within 72
more frequent or more severe undesirable effects than the normal ml of sterile water for injections.
hours after the event.
dose. The potency is determined using the one-stage clotting assay
CONTRAINDICATIONS against the FDA Mega Standard calibrated to the WHO Standard.
PHARMACOLOGICAL PROPERTIES
Hypersensitivity to any of the components. The specic activity of Recombinate is approximately 4000 - 8000
Pharmacodynamic properties
The product is not intended for use in Rh(D) positive individuals. IU/mg protein.
Pharmacotherapeutic group: immune sera and immunoglobulins:
Special warnings and special precautions for use RECOMBINATE contains recombinant coagulation factor VIII
Anti-D (Rh) immunoglobulin. ATC code: J06BB01.
(INN: octocog alfa). Octocog alfa (recombinant coagulation
Special precautions Anti-D immunoglobulin contains specic antibodies (IgG) against factor VIII) is a puried protein consisting of 2332 amino acids.
The product must not be given intravenously (risk of shock). the D (Rh0) antigen of human erythrocytes. It has an amino acid sequence that is comparable to factor VIII,
In the case of postpartum use, the product is intended for maternal Pharmacokinetic properties and post-translational modications that are similar to the plasma
adminis tration. It should not be given to the newborn infant. Measurable levels of antibodies are obtained at least 24 hours after derived molecule. RECOMBINANT coagulation factor VIII
Patients should be observed for at least 20 minutes after intramuscular injection. Peak serum levels are usually achieved 2 is a glycoprotein that is expressed by genetically engineered
administration of PARTOBULIN SDF. to 3 days after administration. mammalian cells derived from a Chinese hamster ovary cell line.
If hypersensitivity reactions occur during administration The half-life in the circulation of individuals with normal IgG For a full list of excipients, see section 6.1
of PARTOBULIN SDF, the injection should be stopped levels is 3 to 4 weeks. 3.PHARMACEUTICAL FORM
immediately. IgG and IgG-complexes are broken down in cells of the Powder and solvent for solution for injection.
True hypersensitivity reactions are rare but allergic type responses reticuloendothelial
to Anti-D immunoglobulins may occur. Patients should be system. 4.CLINICAL PARTICULARS
informed of signs of hypersensitivity reactions including hives, 4.1Therapeutic indications
generalized urticaria, tightness of the chest, wheezing, hypotension PHARMACEUTICAL PARTICULARS
Treatment and prophylaxis of bleeding in patients with Hemophilia
and anaphylaxis. The treatment required depends on the nature and List of excipients A (congenital Factor VIII deciency).
severity of the side effect. Minor reactions may be controlled by Polyethylene Glycol
antihistamines. In case of shock, the current medical standards for This product does not contain von Willebrand factor and is
Glycine therefore not indicated in von Willebrands disease.
shock treatment are to be observed.
Sodium Chloride 4.2Posology and method of administration
PARTOBULIN SDF contains a small quantity of IgA. Although
anti-D immuno globulin has been used successfully to treat selected Incompatibilities 4.2.1Posology
IgA decient individuals, the attending physician must weigh the This medicinal product must not be mixed with other medicinal The dosage and duration of the substitution therapy depends on the
benet against the potential risks of hypersensitivity reactions. products and is to be administered as a separate injection. severity of the disorder of the hemostatic function, on the location
Individuals decient in IgA have a potential for development of Shelf-life and extent of bleeding episodes and on the clinical condition of the
IgA antibodies and anaphylactic reactions after administration of patient. The treatment should be carried out in collaboration with
PARTOBULIN SDF must not be used beyond the expiry date
blood components containing IgA. a physician with experience in bleeding disorders and a laboratory
indicated on the label.
Patients with incompatible transfusion, who receive anti-D with the capacity to measure plasma AHF concentration.
Special precautions for storage
immunoglobulin, should be monitored clinically and by biological The expected in vivo peak increase in Recombinate level expressed
parameters, because of the risk of hemolytic reaction. Store at +2C +8C. as IU/dL of plasma or % (percent) of normal can be estimated by
Special warnings Protect from light. multiplying the dose administered per kg body weight IU/kg) by
When medicinal products prepared from human blood or plasma Do not freeze. two.
are administered, infectious diseases due to transmission of Store out of reach of children. The method calculation is illustrated in the following examples.
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Expected % Factor VIII increase = Each vial of Recombinate is labelled with the Antihemophilic The following table provides the frequency of patients with
# units administered x 2% / IU / kg Factor (Recombinant), Recombinate activity expressed in IU adverse drug reactions in clinical trials; Within each frequency
body weight (kg) per vial. grouping, undesirable effects are presented in order of decreasing
This potency assignment is referenced to the World Health seriousness.
Example for a 70 kg adult: 1750 IU x 2% / IU / kg = ~50%
Organization International Standard for Factor VIIIC Frequency has been evaluated using the following criteria: very
70 kg Concentrate. Experiments have shown that, to achieve accurate common (>1/10), common (>1/100, <1/10), uncommon (>1/1 000,
or activity levels, such a potency assay should be conducted using <1/100), rare (>1/10 000, <1/1 000), and very rare (<1/10 000).
Dosage required (IU): plastic test tubes and pipettes as well as substrate containing
Frequency of Clinical Adverse Drug Reactions (ADRs) for
Body weight (kg) x desired % Factor VIII increase normal levels of von Willebrand Factor.
RECOMBINATE
2% / IU / kg Patients should be monitored for the development of factor VIII
MedDRA MedDRA N u m - N u m - P e r - Percent Fre-
inhibitors. If the expected factor VIII activity plasma levels are
Example for a 40 kg child: 40 kg x 70% = 1400 IU not attained, or if bleeding is not controlled with an appropriate
System Preferred ber of ber of cent of Total quency
Organ Term Events S u b - of Infus-
2% / IU / kg dose, an assay should be performed to determine if a factor VIII
inhibitor is present. In patients with high levels of inhibitor, factor Class jects E v a l - ions2
The careful control of the substitution therapy is especially uable
important in cases of major surgery or life threatening hemorrhages. VIII therapy may not be effective and other therapeutic options
should be considered. Management of such patients should be Subj-
Although dosage can be estimated by the calculation above, it ects1
is strongly recommended that whenever possible, appropriate directed by physicians with experience in the care of patients with
haemophilia. G a s t r o - Nausea 1 1 0.48 0.004 uncom-
laboratory tests including serial AHF assays be performed on
intestinal mon
the patients plasma at suitable intervals to assure that adequate See also 4.4.
disorders
AHF levels have been reached and are maintained. If the patients 4.2.2 Method of administration
plasma AHF fails to reach expected levels or if bleeding is not General Chills 4 3 1.43 0.015 common
The preparation is to be administered intravenously after disorders Fatigue 1 1 0.48 0.004 uncom-
controlled after adequate dosage, the presence of inhibitor should reconstitution with the provided diluent (see also Instructions for
be suspected. By performing appropriate laboratory procedures, and ad- mon
Use/Handling sections). It is recommended that administration ministra- Pyrexia
the presence of an inhibitor can be demonstrated and quantied in commence within three hours after reconstitution. The 1 1 0.48 0.004 uncom-
terms of AHF International Units neutralized by each ml of plasma tion site mon
reconstituted material should not be refrigerated. The preparation condi-
(Bethesda Units) or by the total estimated plasma volume. If the can be administered at a rate of up to 10 ml per minute. The pulse
inhibitor is present at levels less than 10 Bethesda Units per ml, tions
rate should be determined before and during administration of
administration of additional AHF may neutralize the inhibitor. Infections Ear 1 1 0.48 0.004 uncom-
Recombinate. Should a signicant increase occur, reducing the
Thereafter, the administration of additional AHF International and infes- infection mon
rate of administration or temporarily interrupting the injection
Units should elicit the predicted response. The control of AHF tations
usually allows the symptoms to disappear promptly. (See sections
levels by laboratory assay is necessary in this situation. Inhibitor Investi- Acoustic 1 1 0.48 0.004 uncom-
4.4 and 4.8)
titers above 10 Bethesda Units per ml may make hemostasis gations stimula- mon
control with AHF either impossible or impractical because of the 4.3 Contraindications tion tests
very large dose required. Hypersensitivity to the active substance or to any of the excipients. abnormal
Recombinate is appropriate for the use in children of all ages, Known allergic reaction to bovine, mouse or hamster protein. Muscu- Pain in 1 1 0.48 0.004 uncom-
including the newborn (Safety and efcacy studies have been 4.4 Special warnings and precautions for use loskeletal extremity mon
performed in both previously treated and previously untreated Severe allergic reactions to Recombinate have been reported. and con-
children). Patients with known hypersensitivity to mouse bovine or hamster nective
The following dosage schedule provided in Table I may be used proteins should be treated with caution. Severe allergic reactions tissue
as a guide for adults and children. The amount to be administered to Recombinate are a contraindication (See section 4.3). If allergic disorders
and the frequency of application should always be oriented to the or anaphylactic reactions occur, the injection/infusion should be Nervous Dizziness 1 1 0.48 0.004 uncom-
clinical effectiveness in the individual case. stopped immediately. Facilities for the appropriate treatment of system mon
shock should be available. disorders Tremor 1 1 0.48 0.004 uncom
Recombinate may also be administered for prophylaxis (short
If plasma AHF levels fail to reach expected levels or if bleeding is mon
or long term) of bleeding, as determined by the physician on an
not controlled after adequate dosage, appropriate laboratory test to Respira- Pharyngo- 1 1 0.48 0.004 uncom-
individual basis.
detect the presence of inhibitor should be performed. tory, laryngeal mon
Table I: Dosage Schedule thoracic pain
4.5 Interactions with other medicinal products and other
Hemorrhage and me-
forms of interaction
Degree of Required peak post- Frequency of infusion diastinal
No interactions with other medicinal products have been disorders
hemorrhage infusion AHF activity observed.
in the blood (as % of Skin and Hyperhy- 1 1 0.48 0.004 uncom-
4.6 Pregnancy and lactation subcu- drosis
normal or IU/dL mon
Animal reproduction studies have not been conducted with factor taneous Pruritus 1 1 0.48 0.004 uncom-
plasma) VIII. Based on the rare occurrence of haemophilia A in women, tissue mon
Early 20-40 Begin infusion every experience regarding the use of factor VIII during pregnancy and disorders
hemarthrosis 12 to 24 hours for breast-feeding is not available. Therefore, factor VIII should be Rash 2 2 0.95 0.008 uncom-
or muscle one-three days until used during pregnancy and lactation only if clearly indicated. mon
bleed or oral the bleeding episode Rash 1 1 0.48 0.004 uncom-
4.7 Effects on ability to drive and use machines maculo-
bleed as indicated by pain is mon
resolved or healing is No effects on ability to drive and use machines have been papular
observed.
achieved. Vascular Epistaxis 11 1 0.48 0.042 uncom-
More extensive 30-60 Repeat infusion every 4.8 Undesirable effects disorders mon
hemarthrosis, 12 to 24 hours for As with the administration of any protein, adverse reactions may Flushing 2 2 0.95 0.008 uncom-
muscle blood, usually three days or be encountered with the use of recombinant Antihemophilic mon
or hematoma more until pain and Factor (rAHF) preparations. Adverse reactions occurring after Haema- 1 1 0.48 0.004 uncom-
disability are resolved infusion of rAHF have been reported in clinical studies to include: toma mon
Life threatening 60-100 Repeat infusion every nausea, ushing, mild fatigue, rash, hematoma, diaphoresis, chills, Hypoten- 1 1 0.48 0.004 uncom-
bleeds such 8 to 24 hours until shaking, fever, leg pain, cold hands and feet, sore throat, ear sion mon
as intracranial threat is resolved. infection and failed hearing test, epistaxis and pallor. Sporadically,
adverse events resembling allergic-type hypersensitivity have been Pallor 1 1 0.48 0.004 uncom-
bleed, throat mon
bleed, severe reported in patients receiving commercial Recombinate. Allergic
Peripheral 1 1 0.48 0.004 uncom-
type symptoms may include hives, urticaria, rash, dyspnea, cough,
abdominal coldness mon
chest tightness, wheezing, hypotension and anaphylaxis.
bleed
Patients should be informed of the early signs of hypersensitivity 1Number of evaluable subjects experiencing the event/total number
Surgery
Type of operation reactions and therefore should be advised to discontinue use of the of evaluable subjects [% relative to 210, the total number of unique
product and contact their physician if these symptoms occur. subjects who received at least one infusion of Recombinate]
Minor surgery, 30-60 A single infusion plus
Caution is advised in patients with known allergic reactions to 2Number of times the event was experienced/total number of
including tooth oral antibrinolytic
extraction therapy within one constituents of the preparation (See sections 4.3 and 4.4). infusions [% relative to 25,915, the total number of infusions of
hour is sufcient in The formation of neutralizing antibodies, inhibitors, to Factor Recombinate]
approximately 70% of VIII is a known complication in the management of individuals In the spontaneous, post-marketing database, there have been
cases. Every 24 hours, with Hemophilia A. These inhibitors are invariably IgG reports of cyanosis, tachycardia, vomiting, abdominal discomfort,
at least 1 day, until immunoglobulins directed against the Factor VIII procoagulant anaphylactic shock, hypersensitivity, syncope, headache, skin
healing is achieved. activity, which are expressed as Bethesda Units (B.U.) per ml of exfoliation and inhibitor to FVIII.
Major surgery 80-100 plasma.
Repeat infusion 4.9 Overdose
every 8 to 24 hours The risk of developing inhibitors is correlated to the exposure
(pre and post- No symptoms of overdose are known.
depending on state of to Antihemophilic Factor VIII, this risk being highest within
operative) the rst 20 exposure days. The reported incidence of inhibitory
healing. 5 PHARMACOLOGICAL PROPERTIES
antibodies in patients with severe hemophilia A who are at high 5.1 Pharmacodynamic properties
This represents peak AHF activity for patients with the expected risk for inhibitor development (i.e., previously untreated patients)
mean half-life for Factor VIII. If considered necessary, is estimated in studies to be 31% for Recombinate, which is within Pharmacotherapeutic Group: antihemorrhagics: blood coagula-
peak activity should be measured within one-half hour after the reported range for plasma derived AHF. Patients treated with tion factor VIII. ATC code: B02BD02.
administration. For patients with relatively short half-lifes for Recombinate should be carefully monitored for the development The factor VIII/von Willebrand factor complex consists of two
Factor VIII it may be necessary to increase the dosage and/or of inhibitory antibodies by appropriate clinical observations and molecules (factor VIII and von Willebrand factor) with different
frequency of administration. laboratory tests. physiological functions.
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When infused into a haemophiliac patient, factor VIII binds to von 6.3 Shelf-life
Willebrand factor in the patients circulation. Two years. Within the two years period, the product may be stored RENAMIN Injection
Activated factor VIII acts as a cofactor for activated factor IX, at 15 25C prior to use for up to six months. After reconstitution,
accelerating the conversion of factor X to activated factor X. Recombinate should be administered within three hours.
(Amino Acid)
Activated factor X converts prothrombin into thrombin. Thrombin 6.4 Special precautions for storage
then converts brinogen into brin and a clot can be formed. Store in a refrigerator (2C 8C). DESCRIPTION
Haemophilia A is a sex-linked hereditary disorder of blood
coagulation due to decreased levels of factor VIII:C and results Do not freeze. RENAMIN (Amino Acid) Injection is a sterile, nonpyrogenic,
Do not return to refrigeration following storage at 15-25C hypertonic solution of essential and nonessential amino acids in a
in profuse bleeding into joints, muscles or internal organs, either
Pharmacy Bulk Package. A Pharmacy Bulk Package is a container
spontaneously or as a result of accidental or surgical trauma. By Do not refrigerate after reconstitution.
of a sterile preparation for parenteral use that contains many single
replacement therapy the plasma levels of factor VIII are increased, 6.5 Nature and contents of container doses. The contents are intended for use in a pharmacy admixture
thereby enabling a temporary correction of the factor deciency
Each package of Recombinate contains: program and are restricted to the preparation of admixtures for
and correction of the bleeding tendencies.
The powder is provided in a vial (type I glass) with rubber stopper intravenous infusion.
Recombinate has been studied in 71 previously untreated children
+ 10 ml of solvent in vial (type I glass) with rubber stopper + Each 100 mL of RENAMIN (Amino Acid) Injection
(PUPs). Median age of the cohort at the time of rst Recombinate
Baxject (for needleless reconstitution) + one sterile single-use contains:
infusion was 10 months (range: 2 days to 50 months. The product
plastic syringe + one sterile mini-infusions set. Amino Acids 6.5 g
was well tolerated and not associated with signicant short-term
adverse effects. Its clinical efcacy was comparable to other full- Pack size of 1 Total Nitrogen 1g
length FVIII molecules in both the treatment of acute haemorrhage 6.6 Special precautions for disposal pH
and for surgical prophylaxis (10 subjects had undergone surgical The preparation is to be administered intravenously after (pH adjusted with
interventions). Long-term follow-up of the cohort revealed an reconstitution with the provided Sterilised Water for Injections.
incidence of product-related adverse events of 0.86/1000 infusions, Glacial acetic acid) 6.0 (5.0 to 7.0)
The disposable plastic syringe provided with the product should
none serious or life-threatening. be used. Essential Amino Acids
5.2 Pharmacokinetic properties - Use within three hours after reconstitution.
Valine C5H11NO2 820 mg
Pharmacokinetic studies on 69 previously treated patients revealed - Do not refrigerate preparation after reconstitution.
the circulating mean half-life for Recombinate to be 14.6 4.9 - Any unused product or waste material should be disposed of in Leucine C6H13NO2 600 mg
hours (n=67), which was not statistically signicantly different accordance with local requirements. Isoleucine C6H13NO2 500 mg
from plasma-derived Antihemophilic Factor (Human), HemolM - The solution should be clear or slightly opalescent. Do not Methionine C5H11NO2S 500 mg
, (pdAHF). The mean half-life of HemolM was 14.7 5.1 hours use solutions that are cloudy or have deposits. Reconstituted Phenylalanine C9H11NO2 490 mg
(n=61). The actual baseline recovery observed with Recombinate products should be inspected visually for particulate matter and Lysine (added as the
after infusion of a 50 IU/kg dose was 123.9 47.7 IU/dl (n=23), discoloration prior to administration.
which is signicantly higher than the actual HemolM baseline hydrochloride salt) C6H14N2O2 450 mg
recovery of 101.7 31.6 IU/dl (n=61). However, the calculated RECONSTITUTION: USE ASEPTIC TECHNIQUE Histidine C6H9N3O2 420 mg
ratio of actual to expected recovery (i.e., 2% increment in Factor 1. Bring Recombinate (powder) and Sterilised Water for Injections, Threonine C4H9NO3 380 mg
VIII activity 1 IU rAHF/kg body weight) with Recombinate (121.2 (solvent) to 15-25C.
Tryptophan C11H12N2O2 160 mg
48.9%) is similar to that of HemolM (123.4 16.4%) 2. Remove caps from powder and solvent vials.
A total of 494 recovery studies were obtained from 68 previously 3. Cleanse stoppers with germicidal solution. Nonessential Amino Acids
untreated patients. Two hundred and twelve recovery studies were 4. Open the package of Baxject device by peeling away the paper Arginine C6H14N4O2 630 mg
performed when the patients were being treated for bleeds with a lid without touching the inside (Fig. a). Alanine C3H7NO2 560 mg
mean SD actual recovery of 70.0 37.9 IU/dL (N=208), four 5. Do not remove the device from the package. Turn the package
Proline C5H9NO2 350 mg
recoveries omitted from analysis as outliers). The high variability over and insert the plastic spike through the solvent stopper.
is due to the wide range of actual dose given, 13.8 to 103.2 IU/kg Grip the package at its edge and pull the package off Baxject Glycine C2H5NO2 300 mg
(mean SD of 36.0 16.2 and median of 30.2 IU/kg). To account (Fig. b). Serine C3H7NO3 300 mg
for the variable dosing levels, the actual/predicted recovery ratios 6. With Baxject attached to the diluent vial invert the system so Tyrosine - C9H11NO3 40 mg
were calculated, resulting in a mean of 1.0 0.3. that the solvent vial is on top of the device.
A total of 68 recovery studies were performed when the patients 7. Insert the other plastic spike through Recombinate stopper. The Anion Prole per Liter*
were receiving a follow-up infusion for continued treatment of a vacuum will draw the solvent into Recombinate vial (Fig. c). Acetate (1) 60 mEq
pre-existing bleed. The actual FVIII recovery level was corrected 8. Swirl gently until all material is dissolved. Be sure that Chloride (2) 31 mEq
for the pre-infusion FVIII level. The mean SD actual recovery Recombinate is completely dissolved; otherwise active material * Balanced by ions from amino acids
was 88.6 38.2 IU/dL (N= 66) with two recoveries omitted from will not pass through the device lter.
the analysis as outliers). Again, the wide range of actual doses (1) derived from pH adjustment with
given, 18.5 to 85.7 IU/kg (mean SD of 38.6 15.9 and median ADMINISTRATION: USE ASEPTIC TECHNIQUE glacial acetic acid
of 32.1 IU/kg) results in substantial variation in the recovery levels It is recommended that administration commence within three (2) contributed by the Lysine
observed. The mean SD actual/predicted recovery ratio was 1.0 hours after reconstitution. The reconstituted material should not
Hydrochloride
0.3 with a median of 1.0. be refrigerated. Parenteral drug products should be inspected
for particulate matter and discoloration prior to administration, 3 mEq/L sodium bisulte added as stabilizer
A total of 214 recovery studies were performed when patients were
whenever solution and container permit. A colourless to faintly Osmolarity (calc.) 600 mOs
in stable state resulting in a mean actual recovery of 71.6 29.7
yellow appearance is acceptable for Recombinate. mol/L
IU/dL (N= 209) with ve recoveries omitted from the analysis as
outliers). The doses given ranged from 10.4 to 68.1 IU/kg (mean 1. Turn Baxject handle down (towards Recombinate concentrate
vial), remove the cap attached to the handle (Fig d). CLINICAL PHARMACOLOGY
SD of 38.0 12.7 and median of 36.1 IU/kg). The mean SD
2. Draw air into the syringe by pulling the plunger back, connect RENAMIN (Amino Acid) Injection provides biologically
actual/predicted recovery ratio was 1.0 0.3.
the syringe to Baxject, and inject air into the concentrate vial utilizable source material for protein synthesis when used with
5.3 Preclinical safety data appropriate calorie sources (such as hypertonic dextrose or fat
(Fig. e).
Recombinate acts like the endogenous factor VIII. Doses several emulsion), electrolytes, vitamins and minerals.
3. While keeping the syringe plunger in place, invert the system
times the recommended human dosage per kilogram body weight As a concentrated source of essential amino acids,
(with concentrate vial on top). Draw the concentrate into the
show no toxic effects on laboratory animals. Recombinate was RENAMIN(Amino Acid) Injection provides maximal protein
syringe by pulling the plunger back slowly (Fig. f).
tested for mutagenicity at doses considerably exceeding plasma intake with low volume administration. The essential amino
4. Turn BaxJect handle back to its original position (facing side
concentrations of AHF in vitro and at doses up to ten times the acids are included as approximately 60% w/w of total amino
way) and disconnect the syringe.
expected maximum clinical dose in vivo, and did not cause reverse acids. Each 250 mL unit of this injection meets or exceeds the
mutations, chromosomal aberrations, or an increase in micronuclei 5. Attach administration set to the syringe. Inject intravenously.
recommended daily intake of essential amino acids. Nonessential
in bone marrow polychromatic erythrocytes. Since clinical The preparation can be administered at a rate of up to 10
amino acids have been included to meet requirements established
experience provides no evidence for tumorigenic and mutagenic ml per minute. The pulse rate should be determined before
in investigations of acute and chronic renal failure patients fed
effects, long term studies in animals to evaluate carcinogenic and during administration of Recombinate. Should a
parenterally. The 40% w/w of nonessential amino acids includes
potential are not considered imperative. signicant increase occur, reducing the rate of administration
histidine (considered an essential amino acid in renal failure),
or temporarily interrupting the injection usually allows the arginine, and other nonessential amino acids as additional sources
6. PHARMACEUTICAL PARTICULARS symptoms to disappear promptly. (See sections 4.4 and 4.8.) of nitrogen that have been shown to enhance nitrogen balance and
6.1 List of excipients weight gain.
Fig. a Fig. b Fig. c
Powder:
INDICATIONS AND USAGE
Human Albumin Solution
RENAMIN (Amino Acid) Injection is indicated as an adjunct
Sodium Chloride in the offsetting of nitrogen loss or in the treatment of negative
Histidine nitrogen balance in potentially reversible renal decompensation
Macrogol 3350 when the alimentary tract cannot or should not be used;
Calcium Chloride Dihydrate gastrointestinal absorption of protein is impaired; or metabolic
requirements for protein are substantially increased, as with
Solvent: extensive burns.
Fig. d Fig. e Fig. f
CONTRAINDICATIONS
6.2 Incompatibilities
Severe uncorrected electrolyte and acid base imbalance.
Recombinate should not be mixed with other medicinal products.
Severe liver disease or hepatic coma.
Only the provided infusion sets should be used because treatment
failure can occur as a consequence of human coagulation Hyperammonemia.
factor VIII adsorption to the internal surfaces of some infusion Hypersensitivity to one or more amino acids.
equipment. Decreased circulating blood volume.
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WARNINGS Nursing Mothers: Fat emulsion coadministration should be considered when
This injection is for compounding only, not for direct It is not known whether this drug is excreted in human milk. prolonged (more than 5 days) parenteral nutrition is required in
Infusion. Because many drugs are excreted in human milk, and because order to prevent essential fatty acid deciency (EFAD). Serum
of the potential for adverse reactions, e.g., hyperammonemia in lipids should be monitored for evidence of EFAD in patients
Proper administration of RENAMIN (Amino Acid) Injection
nursing infants, caution should be exercised when RENAMIN maintained on fat free TPN.
requires a knowledge of uid and electrolyte balance and nutrition
as well as clinical expertise in recognition and treatment of the (Amino Acid) Injection is administered to a nursing mother. Adult:
complications which may occur. Pediatric Use: The total daily dose of RENAMIN (Amino Acid) Injection
Administration of amino acid solutions to a patient with hepatic Safety and effectiveness of RENAMIN (Amino Acid) Injection depends on the patients metabolic requirement and clinical
insufciency may result in serum amino acid imbalances, have not been established by adequate and well-controlled studies response. The determination of nitrogen balance and accurate
hyperammonemia, stupor and coma. in pediatric patients. daily body weights, corrected for uid balance, are probably the
Geriatric Use: best means of assessing individual nitrogen requirements.
Hyperammonemia is of special signicance in infants. This
Clinical studies of RENAMIN (Amino Acid) Injection did Nutritional management of renal decompensation includes
reaction appears to be related to a deciency of the urea cycle
not include sufcient numbers of subjects aged 65 and over to providing sufcient amino acid and caloric support for protein
amino acids of genetic or product origin. It is essential that blood
determine whether they respond differently from other younger synthesis while not exceeding renal capacity for excretion of
ammonia be measured frequently in infants.
subjects. Other reported clinical experience has not identied metabolic wastes. A dosage of 2.5 to 5.0 grams of nitrogen per day
This injection has no added electrolytes. Clinically signicant with adequate calories will maintain nitrogen equilibrium in most
hypocalcemia, hypophosphatemia or hypomagnesemia may occur. differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, patients with uremia. If more nitrogen and calories are required,
Electrolyte replacement may become necessary. higher dosages may be administered, provided great care is taken
usually starting at the low end of the dosing range, reecting the
Contains sodium bisulte, a sulte that may cause allergic-type greater frequency of decreased hepatic, renal, or cardiac function, to avoid exceeding limits of uid intake or glucose tolerance.
reactions including anaphylactic symptoms and life-threatening or and of concomitant disease or drug therapy. Dosage should be guided by uid, glucose and nitrogen tolerances,
less severe asthmatic episodes in certain susceptible people. The as well as metabolic and clinical responses. The rate of increase
overall prevalence of sulte sensitivity in the general population SPECIAL PRECAUTIONS in blood urea nitrogen concentration generally diminishes when
is unknown and probably low. Sulte sensitivity is seen more Administration of amino acid solutions and other nutrients via infusion of amino acids is accompanied by adequate calories.
frequently in asthmatic than in nonasthmatic people. central or peripheral venous catheter may be associated with However, excessive intake of protein or increased protein
This injection should not be administered simultaneously with complications which can be prevented or minimized by careful catabolism may alter this response.
blood through the same infusion set because of the possibility of attention to all aspects of the procedure. This includes attention to The usual daily dose ranges from 250 to 500 mL of RenAmin
pseudoagglutination. solution preparation, administration and patient monitoring. It is (Amino Acid) Injection equivalent to 2.5 to 5.0 grams of nitrogen
essential that a carefully prepared protocol, based on current in 16.2 to 32.5 grams of amino acids.
RENAMIN (Amino Acid) Injection does not replace dialysis medical practices, be followed, preferably by an experienced
and conventional supportive therapy in patients with renal failure. team. Adequate calories should be administered simultaneously.
WARNING: This product contains aluminum that may be toxic. Although a detailed discussion of the complications is beyond the Patients receiving RENAMIN (Amino Acid) Injection should
Aluminum may reach toxic levels with prolonged parenteral scope of this insert, the following summary lists those based on be monitored carefully and their electrolyte requirements
current literature: individualized. Electrolyte supplementation may be required. This
administration if kidney function is impaired. Premature neonates
injection contains approximately 60 mEq acetate and 31 mEq
are particularly at risk because their kidneys are immature, and Technical: chloride.
they require large amounts of calcium and phosphate solutions, The placement of a central venous catheter should be regarded as a
which contain aluminum. Electrolyte (phosphorous, potassium and magnesium)
surgical procedure. The physician should be fully acquainted with concentrations usually fall during administration of RENAMIN
Research indicates that patients with impaired kidney function, various techniques of catheter insertion as well as recognition and (Amino Acid) Injection. Particular care should be taken in the
including premature neonates, who receive parenteral levels of treatment of complications. For details of techniques and placement
presence of cardiac arrhythmias or digitalis toxicity to assure that
aluminum at greater than 4 to 5 g/kg/day accumulate aluminum sites consult the medical literature. X-ray is the best means of
these electrolytes are supplemented when necessary.
at levels associated with central nervous system and bone toxicity. verifying catheter placement. Complications known to occur
Tissue loading may occur at even lower rates of administration. from the placement of central venous catheters are pneumothorax, Children:
hemothorax, hydrothorax, artery puncture and transection, injury Pediatric requirements vary depending upon growth, nutritional
PRECAUTIONS to the brachial plexus, malposition of the catheter, formulation of state and degree of renal insufciency. A dosage of 0.5 to 1.0 gram
It is essential to provide adequate calories concurrently if arteriovenous stula, phlebitis, thrombosis, cardiac arrhythmia of amino acids per kilogram body weight per day will meet the
parenterally administered amino acids are to be retained by the and catheter embolus. requirements of the majority of pediatric patients. Initial daily
body and utilized for protein synthesis. Concentrated dextrose Septic: dosage should be low and increased slowly. More than one gram
solutions are an effective source of such calories. of essential amino acids per kilogram of body weight per day is
The constant risk of sepsis is present during administration of
With the administration of RENAMIN (Amino Acid) Injection not recommended. The total volume of nutritional solution, and
parenteral nutrition solution. Since contaminated solutions and
in combination with highly concentrated dextrose solutions, the rate at which it is administered, will vary with the childs
infusion catheters are potential sources of infection, it is imperative
hyperglycemia, glycosuria and hyperosmolar syndrome may age, nutritional and growth state, as well as the degree of renal
that the preparation of the solution and the placement and care of
result. Blood and urine glucose should be monitored on a routine failure. See Special Precautions in Pediatric Patients for additional
catheters be accomplished under controlled aseptic conditions. If
basis in patients receiving this therapy. information.
fever develops, the solution, its delivery system and the site of the
Sudden cessation in administration of a concentrated dextrose indwelling catheter should be changed. Maintenance vitamins, additional electrolytes and trace elements
solution may result in insulin reaction due to continued should be administered as required.
Metabolic:
endogenous insulin production. Parenteral nutrition mixtures Central Vein Administration:
The following metabolic complications have been reported:
should be withdrawn slowly. metabolic acidosis, hypophosphatemia, alkalosis, hyperglycemia Hypertonic mixtures of amino acids and dextrose may be
Electrolytes may be added to RENAMIN (Amino Acid) and glycosuria, osmotic diuresis and dehydration, rebound administered safely by continuous infusion through a central vein
Injection as dictated by the patients electrolyte prole. hypoglycemia, elevated liver enzymes, hypo- and hypervitaminosis, catheter with the tip located in the vena cava. In addition to meeting
electrolyte imbalances and hyperammonemia. Frequent clinical nitrogen needs, the administration rate is governed, especially
Strongly hypertonic nutrient solutions should be administered
evaluation and laboratory determinations are necessary, especially during the rst few days of therapy, by the patients tolerance
through an indwelling intravenous catheter with the tip located in
during the rst few days of therapy, to prevent or minimize these to dextrose. Daily intake of amino acids and dextrose should be
the superior vena cava.
complications. increased gradually to the maximum required dose as indicated by
Care should be taken to avoid excess uid accumulation, frequent determinations of urine and blood sugar levels.
particularly in patients with renal disease, pulmonary insufciency Special Precautions in Patients with Renal Insufciency
Uremic patients frequently are glucose intolerant. Provision of
and heart disease. Frequent laboratory studies are necessary in patients with renal
adequate calories in the form of hypertonic dextrose may require
insufciency. In renal failure, hyperglycemia may not be reected
During amino acid administration in the absence of supporting the administration of exogenous insulin to prevent hyperglycemia
by glycosuria. Blood glucose must be determined frequently, often
carbohydrate metabolism, an accumulation of ketone bodies in and glycosuria.
every six hours to guide dosage of dextrose, and insulin should be
the blood often occurs. Correction of ketonemia usually can be Parenteral nutrition may be started at lower administration rates
given, if required.
accomplished by administering some carbohydrates. and with infusates containing lower concentrations of dextrose;
Special Precautions in Pediatric Patients
Drug product contains no more than 25 g/L of aluminum. dextrose content and rate may be gradually increased to estimated
RENAMIN (Amino Acid) Injection should be used with special caloric needs as the patients glucose tolerance increases. The
Laboratory Tests caution in pediatric patients with acute renal failure, especially patients uid, nitrogen and glucose tolerance should be the
Frequent clinical evaluation and laboratory determinations low birth weight infants. Laboratory and clinical monitoring of determining factor of the rate of administration.
are necessary for proper monitoring during administration. pediatric patients, especially those who are nutritionally depleted,
must be extensive and frequent. See Children section under Sudden cessation in administration of concentrated dextrose
Studies should include blood urea nitrogen, blood sugar, serum
Dosage and Administration for additional information. Frequent solutions may result in insulin reactions due to continued
proteins, kidney and liver function tests, electrolytes, acid-base
monitoring of blood glucose is required in low birth weight or endogenous insulin production. Such solutions should be with
balance, hemogram, carbon dioxide combining power or content,
septic infants, as hypertonic dextrose infusion involves a greater drawn slowly.
serum osmolarities, blood cultures and blood ammonia levels.
Circulating blood volume should be determined, if indicated. risk of hyperglycemia in such patients. Peripheral Vein Administration:
Carcinogenesis, Mutagenesis, Impairment of Fertility: ADVERSE REACTIONS For patients requiring parenteral nutrition in whom the central
Studies with RENAMIN (Amino Acid) Injection have not See Warnings and Precautions vein route is not indicated, this injection can be mixed with low
been performed to evaluate carcinogenesis potential, mutagenic concentration dextrose solutions and administered by peripheral
Adverse effects include metabolic, electrolyte, acid-base and uid
potential, or effects on fertility. vein with fat emulsions.
imbalances unless special care with monitoring and corrective
Pregnancy: management is maintained during RENAMIN (Amino Acid) Intravenous fat emulsions provide approximately 1.1 kcal/
injection administration. ml(10%) or 2.0 kcal/mL (20%) and may be administered along
Teratogenic Effects with amino acid-dextrose solutions through a short Y-connector
Pregnancy Category C. Infusion of any hypertonic solution can result in local inammatory
near the infusion site to supplement caloric intake. Fat, however,
reactions. Policies and procedures should be established for the
Animal reproduction studies have not been conducted with should not be the sole caloric intake since studies have indicated
recognition and management of such reactions.
RENAMIN (Amino Acid) Injection. It is also not known whether that glucose is more nitrogen sparing in the stressed patient.
RENAMIN (Amino Acid) Injection can cause fetal harm when DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate
administered to a pregnant woman or can affect reproduction If a patient is unable to take oral nourishment for a prolonged matter and discoloration prior to administration whenever solution
capacity. RENAMIN (Amino Acid) Injection should be given period of time, institution of total parenteral nutrition (TPN) with and container permit. Use of a nal lter is recommended during
to a pregnant woman only if clearly needed. exogenous calories should be considered. administration of all parenteral solutions where possible.
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Do not use unless solution is clear and vacuum is present. Unit with ethanol, ether, chloroform, and benzene, and it is slightly 270 ppm for one hour. Sporadic single cell necrosis of proximal
must be used with a vented set or a nonvented set with a vented soluble in water. SEVOFLURANE is stable when stored under tubule cells has been reported at a concentration of 114 ppm after
spike adapter. normal room lighting conditions according to instructions. No a 3-hour exposure to Compound A in rats. The LC50 reported at
RENAMIN (Amino Acid) Injection in the Pharmacy Bulk discernible degradation of sevourane occurs in the presence of 1 hour is 1050-1090 ppm (male-female) and, at 3 hours, 350-490
Package is intended for use in the preparation of sterile, strong acids or heat. When in contact with alkaline CO2 absorbents ppm (male-female).
intravenous admixtures. Additives may be incompatible with the (e.g. Baralyme and to a lesser extent soda lime) within the An experiment was performed comparing SEVOFLURANE plus
uid withdrawn from this container. Complete information is not anesthesia machine, SEVOFLURANE can undergo degradation 75 or 100 ppm Compound A with an active control to evaluate the
available. Those additives known to be incompatible should not be under certain conditions. Degradation of SEVOFLURANE potential nephrotoxicity of Compound A in non-human primates.
used. Consult with pharmacist, if available. When compounding is minimal, and degradants are either undetectable or present in A single 8-hour exposure of SEVOFLURANE in the presence
admixtures, use aseptic technique. Mix thoroughly. Do not store non-toxic amounts when used as directed with fresh absorbents. of Compound A produced single-cell renal tubular degeneration
any unused portion of RENAMIN (Amino Acid) Injection. SEVOFLURANE degradation and subsequent degradant and single-cell necrosis in cynomolgus monkeys. These changes
formation are enhanced by increasing absorbent temperature are consistent with the increased urinary protein, glucose level
Solutions should be used promptly after mixing. Any storage
increased SEVOFLURANE concentration, decreased fresh gas and enzymic activity noted on days one and three on the clinical
should be under refrigeration and limited to a brief period of time,
ow and desiccated CO2 absorbents (especially with potassium pathology evaluation. This nephrotoxicity produced by Compound
preferably less than 24 hours.
hydroxide containing absorbents e.g. Baralyme). A is dose and duration of exposure dependent.
DIRECTIONS FOR USE OF THE PHARMACY BULK SEVOFLURANE alkaline degradation occurs by two pathways. At a fresh gas ow rate of 1 L/min, mean maximum concentrations
PACKAGE CONTAINER The rst results from the loss of hydrogen uoride with the of Compound A in the anesthesia circuit in clinical settings are
For compounding only, not for direct infusion. formation of pentauoroisopropenyl uoromethyl ether, (PIFE, approximately 20 ppm (0.002%) with soda lime and 30 ppm
1. The Pharmacy Bulk Package is to be used only in a suitable C4H2F6O), also known as Compound A, and trace amounts (0.003%) with Baralyme in adult patients; mean maximum
work area such as a laminar ow hood (or an equivalent clean of pentauoromethoxy isopropyl uoromethyl ether, (PMFE, concentrations in pediatric patients with soda lime are about half
air compounding area). C5H6F6O), also known as Compound B. The second pathway for those found in adults. The highest concentration observed in a
2. Remove outer seal and metal disc. degradation of sevourane, which occurs primarily in the presence single patient with Baralyme was 61 ppm (0.0061%) and 32 ppm
3. Swab surface of stopper using approved technique. of desiccated CO2 absorbents, is discussed later. (0.0032%) with soda lime. The levels of Compound A at which
4. Insert vented connector of solution transfer set and suspend In the rst pathway, the deuorination pathway, the production of toxicity occurs in humans is not known.
unit. Refer to directions accompanying set. degradants in the anesthesia circuit results from the extraction of The second pathway for degradation of SEVOFLURANE occurs
Note: The closure shall be penetrated only one time with a the acidic proton in the presence of a strong base (KOH and/or primarily in the presence of desiccated CO2 absorbents and leads
suitable sterile transfer device or dispensing set which allows NaOH) forming an alkene (Compound A) from SEVOFLURANE to the dissociation of sevourane into hexauoroisopropanol
measured dispensing of the contents. similar to formation of 2-bromo-2-chloro-1,1-diuoro ethylene (HFIP) and formaldehyde. HFIP is inactive, non-genotoxic,
(BCDFE) from halothane. Laboratory simulations have shown rapidly glucuronidated and cleared by the liver. Formaldehyde
5. Once container closure has been penetrated, withdrawal of
that the concentration of these degradants is inversely correlated is present during normal metabolic processes. Upon exposure
contents should be completed without delay. After initial
with the fresh gas ow rate (See Figure 1). to a highly desiccated absorbent, formaldehyde can further
dispense within 4 hours. degrade into methanol and formate. Formate can contribute to the
formation of carbon monoxide in the presence of high temperature
HOW SUPPLIED that can be associated with desiccated BARALYME. Methanol
RENAMIN (Amino Acid) Injection is available in glass can react with Compound A to form the methoxy addition product
Pharmacy Bulk Packages as follows: Compound B. Compound B can undergo further HF elimination
2A6222 250 mL NDC 0338-0471-02 to form Compounds C, D, and E.
2A6223 500 mL NDC 0338-0471-03 SEVOFLURANE degradants were observed in the respiratory
circuit of an experimental anesthesia machine using desiccated
Exposure of pharmaceutical products to heat should be minimized. CO2 absorbents and maximum sevourane concentrations
Avoid excessive heat. Protect from freezing. It is recommended the (8%) for extended periods of time (2 hours). Concentrations
product be stored at room temperature (25C/77F): brief exposure of formaldehyde observed with desiccated soda lime in this
up to 40C does not adversely affect the product, Protect from light experimental anesthesia respiratory circuit were consistent
Since the reaction of carbon dioxide with absorbents is exothermic,
until immediately prior to use. with levels that could potentially result in respiratory irritation.
the temperature increase will be determined by quantities of
CO2 absorbed, which in turn will depend on fresh gas ow in Although KOH containing CO2 absorbents are no longer
the anesthesia circle system, metabolic status of the patient, and commercially available, in the laboratory experiments, exposure
SEVOFLURANE of SEVOFLURANE to the desiccated KOH containing CO2
ventilation. The relationship of temperature produced by varying
Volatile Liquid for Inhalation levels of CO2 and Compound A production is illustrated in the absorbent, Baralyme, resulted in the detection of substantially
following in vitro simulation where CO2 was added to a circle greater degradant levels.
absorber system.
(Sevourane) CLINICAL PHARMACOLOGY
SEVOFLURANE is an inhalational anesthetic agent for use in
DESCRIPTION induction and maintenance of general anesthesia. Minimum
SEVOFLURANE, volatile liquid for inhalation, a nonammable alveolar concentration (MAC) of SEVOFLURANE in oxygen for
and nonexplosive liquid administered by vaporization, is a a 40-year-old adult is 2.1%. The MAC of sevourane decreases
halogenated general inhalation anesthetic drug. SEVOFLURANE with age (see DOSAGE AND ADMINISTRATION for details).
is uoromethyl 2,2,2,-triuoro-1-(triuoromethyl) ethyl ether and Pharmacokinetics
its structural formula is: UPTAKE AND DISTRIBUTION
F 3C
Solubility
Because of the low solubility of sevourane in blood (blood/gas
H C OCH2F
partition coefcient @ 37C = 0.63-0.69), a minimal amount of
sevourane is required to be dissolved in the blood before the
alveolar partial pressure is in equilibrium with the arterial partial
F3C pressure. Therefore there is a rapid rate of increase in the alveolar
Compound A concentration in a circle absorber system increases (end-tidal) concentration (FA) toward the inspired concentration
SEVOFLURANE, Physical Constants are: as a function of increasing CO2 absorbent temperature and (FI) during induction.
composition (Baralyme producing higher levels than soda lime),
Molecular weight 200.05 Induction of Anesthesia
increased body temperature, and increased minute ventilation,
Boiling point at 760 mm Hg 58.6C and decreasing fresh gas ow rates. It has been reported that In a study in which seven healthy male volunteers were
Specic gravity at 20C 1.520 - 1.525 the concentration of Compound A increases signicantly with administered 70% N2O/30% O2 for 30 minutes followed by 1.0%
prolonged dehydration of Baralyme. Compound A exposure in SEVOFLURANE and 0.6% isourane for another 30 minutes the
Vapor pressure in mm Hg 157 mm Hg at 20C
patients also has been shown to rise with increased sevourane FA/FI ratio was greater for SEVOFLURANE than isourane at all
197 mm Hg at 25C time points. The time for the concentration in the alveoli to reach
concentrations and duration of anesthesia. In a clinical study in
317 mm Hg at 36C which sevourane was administered to patients under low ow 50% of the inspired concentration was 4-8 minutes for isourane
Distribution Partition Coefcients at 37C: conditions for 2 hours at ow rates of 1 Liter/minute, Compound and approximately 1 minute for sevourane.
Blood/Gas 0.63 - 0.69 A levels were measured in an effort to determine the relationship FA/FI data from this study were compared with FA/FI data of
between MAC hours and Compound A levels produced. The other halogenated anesthetic agents from another study. When all
Water/Gas 0.36
relationship between Compound A levels and sevourane exposure data were normalized to isourane, the uptake and distribution of
Olive Oil/Gas 47 - 54 are shown in Figure 2a. sevourane was shown to be faster than isourane and halothane,
Brain/Gas 1.15 but slower than desurane. The results are depicted in Figure 3.
Mean Component/Gas Partition Coefcients at 25C for
Polymers Used Commonly in Medical Applications:
Conductive rubber 14.0
Butyl rubber 7.7
Polyvinylchloride 17.4
Polyethylene 1.3
SEVOFLURANE is nonammable and nonexplosive as dened
by the requirements of International Electrotechnical Commission
601-2-13.
SEVOFLURANE is a clear, colorless, liquid containing no
additives. SEVOFLURANE is not corrosive to stainless steel, Compound A has been shown to be nephrotoxic in rats after
brass, aluminum, nickel-plated brass, chrome-plated brass or exposures that have varied in duration from one to three hours.
copper beryllium. SEVOFLURANE is nonpungent. It is miscible No histopathologic change was seen at a concentration of up to
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Recovery from Anesthesia Table 3: Recovery Variables for Evaluable Adult Patients in
The low solubility of SEVOFLURANE facilitates rapid Two Comparative Studies: Sevourane versus Isourane
elimination via the lungs. The rate of elimination is quantied Time to Parameter: Sevourane Isourane Mean
as the rate of change of the alveolar (end-tidal) concentration (min) Mean SEM SEM
following termination of anesthesia (FA), relative to the last
alveolar concentration (Fa0) measured immediately before Emergence 7.7 0.3 (n=395) 9.1 0.3 (n=348)
discontinuance of the anesthetic. In the healthy volunteer study Response to command 8.1 0.3 (n=395) 9.7 0.3 (n=345)
described above, rate of elimination of SEVOFLURANE was First analgesia 42.7 3.0 (n=269) 52.9 4.2 (n=228)
similar compared with desurane, but faster compared with either
halothane or isourane. These results are depicted in Figure 4. Eligible for recovery
discharge 87.6 5.3 (n=244) 79.1 5.2 (n=252)
Fluoride Concentrations After Repeat Exposure and in Special
Populations n = number of patients with recording of recovery events.
Fluoride concentrations have been measured after single, Table 4: Meta-Analyses for Induction and Emergence
extended, and repeat exposure to sevourane in normal surgical Variables for Evaluable Adult Patients in Comparative
and special patient populations, and pharmacokinetic parameters Studies: Sevourane versus Propofol
were determined.
Parameter No. of Sevourane Propofol
Compared with healthy individuals, the uoride ion half-life was Studies Mean SEM Mean SEM
prolonged in patients with renal impairment, but not in the elderly. Mean
A study in 8 patients with hepatic impairment suggests a slight maintenance 3 1.0 MAChr 0.8 7.2 mg/kg/hr 2.6
prolongation of the half-life. The mean half-life in patients with anesthesia exposure (n=259) (n=258)
renal impairment averaged approximately 33 hours (range 21-61
Time to induction: 1 3.1 0.18* 2.2 0.18**
hours) as compared to a mean of approximately 21 hours (range
(min) (n=93) (n=93)
10-48 hours) in normal healthy individuals. The mean half-life in
the elderly (greater than 65 years) approximated 24 hours (range Time to emergence: 3 8.6 0.57 11.0 0.57
Yasuda N, Lockhart S, Eger EI II, et al: Comparison of kinetics 18-72 hours). The mean half-life in individuals with hepatic (min) (n=255) (n=260)
of SEVOFLURANE and isourane in humans. Anesth Analg impairment was 23 hours (range 16-47 hours). Mean maximal Time to respond to
72:316, 1991. uoride values (Cmax) determined in individual studies of special command: 3 9.9 0.60 12.1 0.60
Protein Binding populations are displayed below. (min) (n=257) (n=260)
The effects of SEVOFLURANE on the displacement of drugs Table 1: Fluoride Ion Estimates in Special Populations Time to rst analgesia: 3 43.8 3.79 57.9 3.68
from serum and tissue proteins have not been investigated. Other Following Administration of Sevourane (min) (n=177) (n=179)
uorinated volatile anesthetics have been shown to displace drugs Dose Cmax Time to eligibility for
from serum and tissue proteins in vitro. The clinical signicance of n Age (yr) Duration (hr) (MAChr) (M) recovery discharge: 3 116.0 4.15 115.6 3.98
this is unknown. Clinical studies have shown no untoward effects PEDIATRIC (min) (n=257) (n=261)
when SEVOFLURANE is administered to patients taking drugs
PATIENTS
that are highly bound and have a small volume of distribution (e.g., *Propofol induction of one sevourane group = mean of 178.8
phenytoin). Anesthetic
Sevourane-O2 76 0 - 11 0.8 1.1 12.6 mg 72.5 SD (n=165)
Metabolism **Propofol induction of all propofol groups = mean of 170.2 mg
Sevourane-O2 40 1 - 11 2.2 3.0 16.0
SEVOFLURANE is metabolized by cytochrome P450 2E1, to Sevourane/N2O 25 5 - 13 1.9 2.4 21.3 60.6 SD (n=245)
hexauoroisopropanol (HFIP) with release of inorganic uoride n = number of patients with recording of events.
Sevourane/N2O 42 0 - 18 2.4 2.2 18.4
and CO2 . Once formed HFIP is rapidly conjugated with glucuronic
acid and eliminated as a urinary metabolite. No other metabolic Sevourane/N2O 40 1 - 11 2.0 2.6 15.5 CARDIOVASCULAR EFFECTS
pathways for sevourane have been identied. In vivo metabolism ELDERLY 33 65 - 93 2.6 1.4 25.6 SEVOFLURANE was studied in 14 healthy volunteers (18-
studies suggest that approximately 5% of the sevourane dose RENAL 21 29 - 83 2.5 1.0 26.1 35 years old) comparing SEVOFLURANE-O2 (Sevo/O2) to
may be metabolized. HEPATIC 8 42 - 79 3.6 2.2 30.6 sevourane-N2O/O2 (Sevo/N2O/O2) during 7 hours of anesthesia.
Cytochrome P450 2E1 is the principal isoform identied for OBESE 35 24 - 73 3.0 1.7 38.0 During controlled ventilation, hemodynamic parameters measured
sevourane metabolism and this may be induced by chronic n = number of patients studied. are shown in Figures 7-10:
exposure to isoniazid and ethanol. This is similar to the
metabolism of isourane and enurane and is distinct from that of PHARMACODYNAMICS
methoxyurane which is metabolized via a variety of cytochrome Changes in the depth of sevourane anesthesia rapidly follow
P450 isoforms. The metabolism of sevourane is not inducible changes in the inspired concentration.
by barbiturates. As shown in Figure 5, inorganic uoride
In the sevourane clinical program, the following recovery
concentrations peak within 2 hours of the end of sevourane
variables were evaluated:
anesthesia and return to baseline concentrations within 48 hours
post-anesthesia in the majority of cases (67%). The rapid and 1. Time to events measured from the end of study drug:
extensive pulmonary elimination of sevourane minimizes the Time to removal of the endotracheal tube (extubation time)
amount of anesthetic available for metabolism. Time required for the patient to open his/her eyes on verbal
command (emergence time)
Time to respond to simple command (e.g., squeeze my
hand) or demonstrates purposeful movement (response to
command time, orientation time)
2. Recovery of cognitive function and motor coordination was
evaluated based on:
Psychomotor performance tests (Digit Symbol Substitution
Test [DSST], Treiger Dot Test)
The results of subjective (Visual Analog Scale [VAS])
and objective (objective pain-discomfort scale [OPDS])
measurements
Time to administration of the rst post-anesthesia analgesic
Cousins M.J., Greenstein L.R., Hitt B.A., et al: Metabolism and medication
renal effects of enurane in man. Anesthesiology 44:44; 1976* Assessments of post-anesthesia patient status
and Sevo-93-044+. 3. Other recovery times were:
Legend: Time to achieve an Aldrete Score of 8
Pre-Anesth. = Pre-anesthesia Time required for the patient to be eligible for discharge from
The recovery area, per standard criteria at site
Elimination
Time when the patient was eligible for discharge from the
Up to 3.5% of the sevourane dose appears in the urine as inorganic hospital
uoride. Studies on uoride indicate that up to 50% of uoride
Time when the patient was able to sit up or stand without
clearance is nonrenal (via uoride being taken up into bone).
dizziness
PHARMACOKINETICS OF FLUORIDE ION Some of these variables are summarized as follows:
Fluoride ion concentrations are inuenced by the duration Table 2: Induction and Recovery Variables for Evaluable
of anesthesia, the concentration of sevourane administered, Pediatric Patients in Two Comparative Studies: Sevourane
and the composition of the anesthetic gas mixture. In studies versus Halothane
where anesthesia was maintained purely with sevourane for
Time to End-Point Sevourane Halothane
periods ranging from 1 to 6 hours, peak uoride concentrations
ranged between 12 M and 90 M. As shown in Figure 6, peak (min) Mean SEM Mean SEM
concentrations occur within 2 hours of the end of anesthesia and Induction 2.0 0.2 (n=294) 2.7 0.2 (n=252)
are less than 25 M (475 ng/mL) for the majority of the population Emergence 11.3 0.7 (n=293) 15.8 0.8 (n=252)
after 10 hours. The half-life is in the range of 15-23 hours.
Response to command 13.7 1.0 (n=271) 19.3 1.1 (n=230)
It has been reported that following administration of
methoxyurane, serum inorganic uoride concentrations >50 M First analgesia 52.2 8.5 (n=216) 67.6 10.6 (n=150)
were correlated with the development of vasopressin-resistant, Eligible for recovery
polyuric, renal failure. In clinical trials with sevourane, there discharge 76.5 2.0 (n=292) 81.1 1.9 (n=246)
were no reports of toxicity associated with elevated uoride ion
n = number of patients with recording of events.
levels.
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Inpatient Surgery opioids in a multicenter study of 273 patients undergoing CABG
SEVOFLURANE was compared to isourane and propofol surgery. Anesthesia was induced with midazolam (0.1-0.3 mg/
for maintenance of anesthesia supplemented with N2O in two kg); vecuronium (0.1-0.2 mg/kg), and fentanyl (5-15 mcg/kg).
multicenter studies involving 741 adult ASA Class I, II or III (18- Both isourane and sevourane were administered at loss of
92 years of age) patients. Shorter times to emergence, command consciousness in doses of 1.0 MAC and titrated until the beginning
response, and rst post-anesthesia analgesia (statistically of cardiopulmonary bypass to a maximum of 2.0 MAC. The total
signicant) were observed with sevourane compared to isourane dose of fentanyl did not exceed 25 mcg/kg. The average MAC
and propofol. dose was 0.49 for SEVOFLURANE and 0.53 for isourane.
Table 7: Recovery Parameters in Two Inpatient Surgery Studies: There were no signicant differences in hemodynamics,
cardioactive drug use, or ischemia incidence between the two
Least Squares Mean SEM
groups. Outcome was also equivalent. In this small multicenter
Sevou- Isourane/ Sevou- Propofol/ study, SEVOFLURANE appears to be as effective and as safe as
rane/N2O N2O rane/N2O N2O isourane for supplementation of opioid anesthesia for coronary
Mean 1.27 1.58 1.43 7.0 bypass grafting.
Maintenance MAChr MAChr MAChr mg/kg/hr Non-Cardiac Surgery Patients at Risk for Myocardial
Anesthesia 0.05 0.06 0.94 2.9(n=92) Ischemia
SEVOFLURANE is a dose-related cardiac depressant. Exposure SD (n=271) (n=282) (n=93) SEVOFLURANE-N2O was compared to isourane-N2O for
Sevourane does not produce increases in heart rate at doses less Time to 11.0 0.6 16.4 0.6 8.8 1.2 13.2 1.2 maintenance of anesthesia in a multicenter study in 214 patients,
than 2 MAC. Emergence (n=270) (n=281) (n=92) (n=92) age 40-87 years who were at mild-to-moderate risk for myocardial
A study investigating the epinephrine induced arrhythmogenic (min) ischemia and were undergoing elective non-cardiac surgery.
effect of SEVOFLURANE versus isourane in adult patients Time to 12.8 0.7 18.4 0.7 11.0 1.20 14.4 1.21 Forty-six percent (46%) of the operations were cardiovascular,
undergoing transsphenoidal hypophysectomy demonstrated that Respond to with the remainder evenly divided between gastrointestinal and
the threshold dose of epinephrine (i.e., the dose at which the rst (n=270) (n=281) (n=92) (n=91)
Commands musculoskeletal and small numbers of other surgical procedures.
sign of arrhythmia was observed) producing multiple ventricular The average duration of surgery was less than 2 hours. Anesthesia
(min)
arrhythmias was 5 mcg/kg with both sevourane and isourane.
induction usually was performed with thiopental (2-5 mg/kg)
Consequently, the interaction of sevourane with epinephrine Time to First 46.1 3.0 55.4 3.2 37.8 3.3 49.2 3.3
and fentanyl (1-5 mcg/kg). Vecuronium (0.1-0.2 mg/kg) was
appears to be equal to that seen with isourane. Analgesia (n=233) (n=242) (n=82) (n=79) also administered to facilitate intubation, muscle relaxation or
Clinical Trials (min)
immobility during surgery. The average MAC dose was 0.49 for
SEVOFLURANE was administered to a total of 3185 patients Time to 139.2 165.9 148.4 8.9 141.4 8.9 both anesthetics. There was no signicant difference between the
prior to sevourane NDA submission. The types of patients are Eligibility 15.6 16.3 (n=92) (n=92) anesthetic regimens for intraoperative hemodynamics, cardioactive
summarized as follows: for (n=268) (n=282) drug use, or ischemic incidents, although only 83 patients in the
Table 5: Patients Receiving Sevourane in Clinical Trials Discharge sevourane group and 85 patients in the isourane group were
Type of Patients Number Studied from successfully monitored for ischemia. The outcome was also
Recovery equivalent in terms of adverse events, death, and postoperative
ADULT 2223
Area (min) myocardial infarction. Within the limits of this small multicenter
Cesarean Delivery 29
n = number of patients with recording of recovery events. study in patients at mild-to-moderate risk for myocardial ischemia,
Cardiovascular and patients at sevourane was a satisfactory equivalent to isourane in providing
risk of myocardial ischemia 246 PEDIATRIC ANESTHESIA
supplemental inhalation anesthesia to intravenous drugs.
Neurosurgical 22 The concentration of sevourane required for maintenance
of general anesthesia is age-dependent (see DOSAGE AND CESAREAN SECTION
Hepatic impairment 8
ADMINISTRATION). SEVOFLURANE or halothane was SEVOFLURANE (n=29) was compared to isourane (n=27) in
Renal impairment 35 used to anesthetize 1620 pediatric patients aged 1 day to 18 years, ASA Class I or II patients for the maintenance of anesthesia during
PEDIATRIC 962 and ASA physical status I or II (948 sevourane, 672 halothane). cesarean section. Newborn evaluations and recovery events were
Clinical experience with these patients is described below. In one study involving 90 infants and children, there were no recorded. With both anesthetics, Apgar scores averaged 8 and 9 at
clinically signicant decreases in heart rate compared to awake 1 and 5 minutes, respectively.
ADULT ANESTHESIA values at 1 MAC. Systolic blood pressure decreased 15-20% in Use of SEVOFLURANE as part of general anesthesia for
The efcacy of SEVOFLURANE in comparison to isourane, comparison to awake values following administration of 1 MAC elective cesarean section produced no untoward effects in mother
enurane, and propofol was investigated in 3 outpatient and 25 SEVOFLURANE; however, clinically signicant hypotension or neonate. SEVOFLURANE and isourane demonstrated
inpatient studies involving 3591 adult patients. Sevourane was requiring immediate intervention did not occur. Overall incidences equivalent recovery characteristics. There was no difference
found to be comparable to isourane, enurane, and propofol for the of bradycardia [more than 20 beats/min lower than normal (80 between SEVOFLURANE and isourane with regard to
maintenance of anesthesia in adult patients. Patients administered beats/min)] in comparative studies was 3% for sevourane and the effect on the newborn, as assessed by Apgar Score and
SEVOFLURANE showed shorter times (statistically signicant) 7% for halothane. Patients who received SEVOFLURANE had
to some recovery events (extubation, response to command, and Neurological and Adaptive Capacity Score (average=29.5). The
slightly faster emergence times (12 vs. 19 minutes), and a higher safety of SEVOFLURANE in labor and vaginal delivery has not
orientation) than patients who received isourane or propofol.
incidence of post-anesthesia agitation (14% vs. 10%). been evaluated.
Mask Induction
SEVOFLURANE (n=91) was compared to halothane (n=89) in
SEVOFLURANE has a nonpungent odor and does not cause NEUROSURGERY
a single-center study for elective repair or palliation of congenital
respiratory irritability. Sevourane is suitable for mask induction Three studies compared SEVOFLURANE to isourane for
heart disease. The patients ranged in age from 9 days to 11.8 years
in adults. In 196 patients, mask induction was smooth and rapid, maintenance of anesthesia during neurosurgical procedures. In a
with an ASA physical status of II, III, and IV (18%, 68%, and
with complications occurring with the following frequencies: study of 20 patients, there was no difference between sevourane
cough, 6%; breathholding, 6%; agitation, 6%; laryngospasm, 5%. 13% respectively). No signicant differences were demonstrated
between treatment groups with respect to the primary outcome and isourane with regard to recovery from anesthesia. In 2
Ambulatory Surgery studies, a total of 22 patients with intracranial pressure (ICP)
measures: cardiovascular decompensation and severe arterial
SEVOFLURANE was compared to isourane and propofol for desaturation. Adverse event data was limited to the study outcome monitors received either SEVOFLURANE or isourane. There
maintenance of anesthesia supplemented with N2O in two studies variables collected during surgery and before institution of was no difference between SEVOFLURANE and isourane with
involving 786 adult (18-84 years of age) ASA Class I, II, or III cardiopulmonary bypass. regard to ICP response to inhalation of 0.5, 1.0, and 1.5 MAC
patients. Shorter times to emergence and response to commands inspired concentrations of volatile agent during N2O-O2-fentanyl
(statistically signicant) were observed with sevourane compared Mask Induction anesthesia. During progressive hyperventilation from PaCO2 =
to isourane and propofol. SEVOFLURANE has a nonpungent odor and is suitable for mask 40 to PaCO2 = 30, ICP response to hypocarbia was preserved
Table 6: Recovery Parameters in Two Outpatient Surgery Studies: induction in pediatric patients. In controlled pediatric studies in with sevourane at both 0.5 and 1.0 MAC concentrations. In
Least Squares Mean SEM which mask induction was performed, the incidence of induction patients at risk for elevations of ICP, SEVOFLURANE should
Sevou- Isourane/ Sevou- Propofol/ events is shown below (see ADVERSE REACTIONS). be administered cautiously in conjunction with ICP-reducing
rane/N2O N2O rane/N2O N 2O Table 8: Incidence of Pediatric Induction Events maneuvers such as hyperventilation.
Mean Sevourane (n=836) Halothane (n=660) HEPATIC IMPAIRMENT
Maintenance 0.64 0.03 0.66 0.03 0.8 0.5 7.3 2.3 Agitation 14% 11% A multicenter study (2 sites) compared the safety of sevourane
Anesthesia MAChr MAChr MAChr mg/kg/hr
Cough 6% 10% and isourane in 16 patients with mild-to-moderate hepatic
Exposure (n=245) (n=249) (n=166) (n=166)
Breathholding 5% 6% impairment utilizing the lidocaine MEGX assay for assessment
SD
Time to 9.3 0.3 Secretions 3% 3% of hepatocellular function. All patients received intravenous
8.2 0.4 8.30.7 10.4 0.7
Emergence (n=251) propofol (1-3 mg/kg) or thiopental (2-7 mg/kg) for induction
(n=246) (n=137) (n=142) Laryngospasm 2% 2%
(min) and succinylcholine, vecuronium, or atracurium for intubation.
Bronchospasm <1% 0% Sevourane or isourane was administered in either 100% O2
Time to 8.5 0.4 9.8 0.4 9.1 0.7 11.5 0.7
Respond to or up to 70% N2O/O2. Neither drug adversely affected hepatic
(n=246) (n=248) (n=139) (n=143) n = number of patients.
Commands function. No serum inorganic uoride level exceeded 45 M/L,
Ambulatory Surgery but sevourane patients had prolonged terminal disposition of
(min)
SEVOFLURANE (n=518) was compared to halothane (n=382) uoride, as evidenced by longer inorganic uoride half-life than
Time to First 45.9 4.7 59.1 6.0 46.1 5.4 60.0 4.7
for the maintenance of anesthesia in pediatric outpatients. All patients with normal hepatic function (23 hours vs. 10-48 hours).
Analgesia (n=160) (n=252) (n=83) (n=88)
patients received N2O and many received fentanyl, midazolam,
(min) RENAL IMPAIRMENT
bupivacaine, or lidocaine. The time to eligibility for discharge
Time to 87.6 5.3 79.1 5.2 103.1 3.8 105.1 3.7 from post-anesthesia care units was similar between agents SEVOFLURANE was evaluated in renally impaired patients
Eligibility (n=244) (n=252) (n=139) (n=143) (see CLINICAL PHARMACOLOGY and ADVERSE with baseline serum creatinine >1.5 mg/dL. Fourteen patients
for Discharge REACTIONS). who received SEVOFLURANE were compared with 12 patients
from who received isourane. In another study, 21 patients who
Recovery CARDIOVASCULAR SURGERY
received SEVOFLURANE were compared with 20 patients who
Area (min) Coronary Artery Bypass Graft (CABG) Surgery received enurane. Creatinine levels increased in 7% of patients
n = number of patients with recording of recovery events. SEVOFLURANE was compared to isourane as an adjunct with who received SEVOFLURANE, 8% of patients who received
117
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isourane, and 10% of patients who received enurane. Because or symptoms of muscle rigidity or hypermetabolic state. Early Desiccated CO2 Absorbents
of the small number of patients with renal insufciency (baseline and aggressive intervention to treat the hyperkalemia and resistant An exothermic reaction occurs when sevourane is exposed to
serum creatinine greater than 1.5 mg/dL) studied, the safety of arrythmias is recommended; as is subsequent evaluation for latent CO2 absorbents. This reaction is increased when the CO2absorbent
sevourane administration in this group has not yet been fully neuromuscular disease. becomes desiccated, such as after an extended period of dry gas
established. Therefore, SEVOFLURANE should be used with ow through the CO2 absorbent canisters. Rare cases of extreme
PRECAUTIONS
caution in patients with renal insufciency (see WARNINGS). heat, smoke, and/or spontaneous re in the anesthesia breathing
During the maintenance of anesthesia, increasing the concentration circuit have been reported during sevourane use in conjunction
INDICATIONS AND USAGE of sevourane produces dose-dependent decreases in blood with the use of desiccated CO2 absorbent, specically those
SEVOFLURANE is indicated for induction and maintenance of pressure. Due toSEVOFLURANEs insolubility in blood, these containing potassium hydroxide (e.g. Baralyme). KOH containing
general anesthesia in adult and pediatric patients for inpatient and hemodynamic changes may occur more rapidly than with other CO2 absorbents are not recommended for use with sevourane.
outpatient surgery. volatile anesthetics. Excessive decreases in blood pressure or An unusually delayed rise or unexpected decline of inspired
SEVOFLURANE should be administered only by persons respiratory depression may be related to depth of anesthesia and sevourane concentration compared to the vaporizer setting may
trained in the administration of general anesthesia. Facilities may be corrected by decreasing the inspired concentration of be associated with excessive heating of the CO2 absorbent and
for maintenance of a patent airway, articial ventilation, oxygen SEVOFLURANE. chemical breakdown of sevourane.
enrichment, and circulatory resuscitation must be immediately Rare cases of seizures have been reported in association with As with other inhalational anesthetics, degradation and production
available. Since level of anesthesia may be altered rapidly, sevourane use (see PRECAUTIONS, Pediatric Use and of degradation products can occur when SEVOFLURANE is
only vaporizers producing predictable concentrations of ADVERSE REACTIONS). exposed to desiccated absorbents. When a clinician suspects that
SEVOFLURANE should be used. the CO2 absorbent may be desiccated, it should be replaced. The
The recovery from general anesthesia should be assessed carefully
color indicator of most CO2 absorbents may not change upon
CONTRAINDICATIONS before a patient is discharged from the post-anesthesia care unit.
desiccation. Therefore, the lack of signicant color change should
SEVOFLURANE can cause malignant hyperthermia. It should Drug Interactions not be taken as an assurance of adequate hydration. CO2absorbents
not be used in patients with known sensitivity to sevourane or to In clinical trials, no signicant adverse reactions occurred with should be replaced routinely regardless of the state of the color
other halogenated agents nor in patients with known or suspected other drugs commonly used in the perioperative period, including: indicator.
susceptibility to malignant hyperthermia. central nervous system depressants, autonomic drugs, skeletal Carcinogenesis, Mutagenesis, Impairment of Fertility
muscle relaxants, anti-infective agents, hormones and synthetic Studies on carcinogenesis have not been performed for either
WARNINGS
substitutes, blood derivatives, and cardiovascular drugs. SEVOFLURANE or Compound A. No mutagenic effect
Although data from controlled clinical studies at low ow rates of SEVOFLURANE was noted in the Ames test, mouse
are limited, ndings taken from patient and animal studies suggest INTRAVENOUS ANESTHETICS:
micronucleus test, mouse lymphoma mutagenicity assay, human
that there is a potential for renal injury which is presumed due SEVOFLURANE administration is compatible with barbiturates, lymphocyte culture assay, mammalian cell transformation assay,
to Compound A. Animal and human studies demonstrate that propofol, and other commonly used intravenous anesthetics. 32P DNA adduct assay, and no chromosomal aberrations were
sevourane administered for more than 2 MAChours and at fresh BENZODIAZEPINES AND OPIOIDS: induced in cultured mammalian cells.
gas ow rates of <2 L/min may be associated with proteinuria and Similarly, no mutagenic effect of Compound A was noted in the
Benzodiazepines and opioids would be expected to decrease the
glycosuria. Ames test, the Chinese hamster chromosomal aberration assay and
MAC of sevourane in the same manner as with other inhalational
While a level of Compound A exposure at which clinical anesthetics. SEVOFLURANE administration is compatible the in vivo mouse micronucleus assay. However, positive responses
nephrotoxicity might be expected to occur has not been established, with benzodiazepines and opioids as commonly used in surgical were observed in the human lymphocyte chromosome aberration
it is prudent to consider all of the factors leading to Compound A practice. assay. These responses were seen only at high concentrations and
exposure in humans, especially duration of exposure, fresh gas in the absence of metabolic activation (human S-9).
ow rate, and concentration of sevourane. During sevourane NITROUS OXIDE: Pregnancy Category B: Reproduction studies have been
anesthesia the clinician should adjust inspired concentration and As with other halogenated volatile anesthetics, the anesthetic performed in rats and rabbits at doses up to 1 MAC (minimum
fresh gas ow rate to minimize exposure to Compound A. To requirement for SEVOFLURANE is decreased when alveolar concentration) without CO2 absorbent and have revealed
minimize exposure to Compound A, sevourane exposure should administered in combination with nitrous oxide. Using 50% N2O, no evidence of impaired fertility or harm to the fetus due to
not exceed 2 MAChours at ow rates of 1 to <2 L/min. Fresh gas the MAC equivalent dose requirement is reduced approximately SEVOFLURANE at 0.3 MAC, the highest nontoxic dose.
ow rates <1 L/min are not recommended. 50% in adults, and approximately 25% in pediatric patients (see Developmental and reproductive toxicity studies of sevourane
Because clinical experience in administering sevourane to DOSAGE AND ADMINISTRATION). in animals in the presence of strong alkalies (i.e., degradation of
patients with renal insufciency (creatinine >1.5 mg/dL) is limited, SEVOFLURANE and production of Compound A) have not been
NEUROMUSCULAR BLOCKING AGENTS: conducted. There are no adequate and well-controlled studies in
its safety in these patients has not been established.
As is the case with other volatile anesthetics, SEVOFLURANE pregnant women. Because animal reproduction studies are not
SEVOFLURANE may be associated with glycosuria and increases both the intensity and duration of neuromuscular always predictive of human response, SEVOFLURANE should
proteinuria when used for long procedures at low ow rates. The blockade induced by nondepolarizing muscle relaxants. When be used during pregnancy only if clearly needed.
safety of low ow sevourane on renal function was evaluated used to supplement alfentanil-N2O anesthesia, sevourane and Labor and Delivery: SEVOFLURANE has been used as part
in patients with normal preoperative renal function. One study isourane equally potentiate neuromuscular block induced with of general anesthesia for elective cesarean section in 29 women.
compared sevourane (N=98) to an active control (N=90) pancuronium, vecuronium or atracurium. Therefore, during There were no untoward effects in mother or neonate. (See
administered for 2 hours at a fresh gas ow rate of 1 Liter/minute. SEVOFLURANE anesthesia, the dosage adjustments for these CLINICAL PHARMACOLOGY, Clinical Trials.) The safety
Per study dened criteria (Hou et al.) one patient in the sevourane muscle relaxants are similar to those required with isourane. of sevourane in labor and delivery has not been demonstrated.
group developed elevations of creatinine, in addition to glycosuria
Potentiation of neuromuscular blocking agents requires Nursing Mothers: The concentrations of sevourane in milk
and proteinuria. This patient received SEVOFLURANE at fresh
equilibration of muscle with delivered partial pressure of are probably of no clinical importance 24 hours after anesthesia.
gas ow rates of 800 mL/minute. Using these same criteria, Because of rapid washout, sevourane concentrations in milk
there were no patients in the active control group who developed SEVOFLURANE. Reduced doses of neuromuscular blocking
agents during induction of anesthesia may result in delayed onset are predicted to be below those found with many other volatile
treatment emergent elevations in serum creatinine. anesthetics.
of conditions suitable for endotracheal intubation or inadequate
SEVOFLURANE may present an increased risk in patients with muscle relaxation. Geriatric Use
known sensitivity to volatile halogenated anesthetic agents. KOH
Among available nondepolarizing agents, only vecuronium, MAC decreases with increasing age. The average concentration
containing CO2 absorbents are not recommended for use with
pancuronium and atracurium interactions have been studied of sevourane to achieve MAC in an 80 year old is approximately
SEVOFLURANE. 50% of that required in a 20 year old.
during SEVOFLURANE anesthesia. In the absence of specic
Malignant Hyperthermia Pediatric Use
guidelines:
In susceptible individuals, potent inhalation anesthetic agents, Induction and maintenance of general anesthesia with
1. For endotracheal intubation, do not reduce the dose of
including sevourane, may trigger a skeletal muscle hypermetabolic SEVOFLURANE have been established in controlled clinical
nondepolarizing muscle relaxants.
state leading to high oxygen demand and the clinical syndrome trials in pediatric patients aged 1 to 18 years (see Clinical Trials
known as malignant hyperthermia. In clinical trials, one case of 2. During maintenance of anesthesia, the required dose
and ADVERSE REACTIONS). Sevourane has a nonpungent
malignant hyperthermia was reported. In genetically susceptible of nondepolarizing muscle relaxants is likely to be
odor and is suitable for mask induction in pediatric patients.
pigs, sevourane induced malignant hyperthermia. The clinical reduced compared to that during N2O/opioid anesthesia.
Administration of supplemental doses of muscle relaxants The concentration of SEVOFLURANE required for maintenance
syndrome is signaled by hypercapnia, and may include muscle of general anesthesia is age dependent. When used in combination
rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or should be guided by the response to nerve stimulation. The
effect of SEVOFLURANE on the duration of depolarizing with nitrous oxide, the MAC equivalent dose of sevourane should
unstable blood pressure. Some of these nonspecic signs may be reduced in pediatric patients. MAC in premature infants has not
also appear during light anesthesia, acute hypoxia, hypercapnia, neuromuscular blockade induced by succinylcholine has not
been determined. (See PRECAUTIONS, Drug Interactions and
and hypovolemia. been studied.
DOSAGE AND ADMINISTRATION for recommendations in
Treatment of malignant hyperthermia includes discontinuation Hepatic Function pediatric patients 1 day of age and older.)
of triggering agents, administration of intravenous dantrolene Results of evaluations of laboratory parameters (e.g., ALT, The use of SEVOFLURANE has been associated with seizures
sodium, and application of supportive therapy. (Consult AST, alkaline phosphatase, and total bilirubin, etc.), as well as (see PRECAUTIONS and ADVERSE REACTIONS). The
prescribing information for dantrolene sodium intravenous for investigator-reported incidence of adverse events relating to liver majority of these have occurred in children and young adults
additional information on patient management.) Renal failure may function, demonstrate that SEVOFLURANE can be administered starting from 2 months of age, most of whom had no predisposing
appear later, and urine ow should be monitored and sustained if to patients with normal or mild-to-moderately impaired hepatic risk factors. Clinical judgement should be exercised when using
possible. function. However, patients with severe hepatic dysfunction were sevourane in patients who may be at risk for seizures.
Perioperative Hyperkalemia not investigated.
ADVERSE REACTIONS
Use of inhaled anesthetic agents has been associated with rare Occasional cases of transient changes in postoperative hepatic
Adverse events are derived from controlled clinical trials
increases in serum potassium levels that have resulted in cardiac function tests were reported with both SEVOFLURANE and conducted in the United States, Canada, and Europe. The
arrhythmias and death in pediatric patients during postoperative reference agents. SEVOFLURANE was found to be comparable reference drugs were isourane, enurane, and propofol in adults
period. Patients with latent as well as overt neuromuscular to isourane with regard to these changes in hepatic function. and halothane in pediatric patients. The studies were conducted
disease, particularly Duchenne muscular dystrophy, appear to Very rare cases of mild, moderate and severe post-operative using a variety of premedications, other anesthetics, and surgical
be most vulnerable. Concomitant use of succinylcholine has hepatic dysfunction or hepatitis with or without jaundice procedures of varying length. Most adverse events reported
been associated with most, but not all, of these cases. These have been reported from postmarketing experiences. Clinical were mild and transient, and may reect the surgical procedures,
patients also experienced signicant elevations in serum creatine judgement should be exercised when SEVOFLURANE is used patient characteristics (including disease) and/or medications
kinase levels and, in some cases, changes in urine consistent in patients with underlying hepatic conditions or under treatment administered.
with myoglobinuria. Despite the similarity in presentation to with drugs known to cause hepatic dysfunction (see ADVERSE Of the 5182 patients enrolled in the clinical trials, 2906 were
malignant hyperthermia, none of these patients exhibited signs REACTIONS). exposed to SEVOFLURANE, including 118 adults and 507
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pediatric patients who underwent mask induction. Each patient volatile anesthetic agents, including sevourane. However, the HOW SUPPLIED
was counted once for each type of adverse event. Adverse events actual incidence and relationship of sevourane to these events SEVOFLURANE, Volatile Liquid for Inhalation, is available as:
reported in patients in clinical trials and considered to be possibly cannot be established with certainty.
NDC 10019-651-64 - Aluminum bottle containing 250 ml
or probably related to SEVOFLURANE are presented within each Laboratory Findings sevourane.
body system in order of decreasing frequency in the following
Transient elevations in glucose, liver function tests, and white
listings. One case of malignant hyperthermia was reported in pre- SAFETY AND HANDLING
blood cell count may occur as with use of other anesthetic agents.
registration clinical trials. OCCUPATIONAL CAUTION
Adverse Events During the Induction Period (from onset of OVERDOSAGE
There is no specic work exposure limit established for
anesthesia by mask induction to surgical incision) Incidence In the event of overdosage, or what may appear to be overdosage, SEVOFLURANE. However, the National Institute for
>1% the following action should be taken: discontinue administration Occupational Safety and Health has recommended an 8 hour time-
Adult Patients (N = 118) of SEVOFLURANE, maintain a patent airway, initiate assisted weighted average limit of 2 ppm for halogenated anesthetic agents
Cardiovascular: Bradycardia 5%, Hypotension 4%, or controlled ventilation with oxygen, and maintain adequate in general (0.5 ppm when coupled with exposure to N2O).
Tachycardia 2% cardiovascular function.
Nervous System: Agitation 7% STORAGE
Respiratory System: Laryngospasm 8%, Airway obstruction Store at controlled room temperature 15-30C (59-86F) [see
The concentration of SEVOFLURANE being delivered from
8%, Breathholding 5%, Cough USP].
a vaporizer during anesthesia should be known. This may be
Increased 5% accomplished by using a vaporizer calibrated specically for The bottle cap should be replaced securely after each use of
Pediatric Patients (N = 507) SEVOFLURANE. The administration of general anesthesia must sevourane.
Cardiovascular: Tachycardia 6%, Hypotension 4% be individualized based on the patients response.
Nervous System: Agitation 15% Replacement of Dessicated CO2 Absorbents 10% TRAVASOL Amino Acid Injection
Respiratory System: Breathholding 5%, Cough Increased When a clinician suspects that the CO2 absorbent may be In Viaflex Plastic Container
5%, Laryngospasm 3%, Apnea 2% desiccated, it should be replaced. The exothermic reaction that
Digestive System: Increased salivation 2% occurs with SEVOFLURANE and CO2 absorbents is increased
Adverse Events During Maintenance and Emergence Periods, when the CO2 absorbent becomes desiccated, such as after an (Essential and Nonessential amino acids)
Incidence >1% (N = 2906) extended period of dry gas ow through the CO2 absorbent
Body as a whole: Fever 1%, Shivering 6%, Hypother canisters (see PRECAUTIONS). DESCRIPTION
mia 1%, Movement 1%, Headache Pre-anesthetic Medication 10% TRAVASOL (Amino Acid) Injection is a sterile,
1% No specic premedication is either indicated or contraindicated nonpyrogenic hypertonic solution of essential and nonessential
Cardiovascular: Hypotension 11%, Hypertension 2%, with SEVOFLURANE. The decision as to whether or not amino acids in a Pharmacy Bulk Package. A Pharmacy Bulk
Bradycardia 5%, Tachycardia 2% to premedicate and the choice of premedication is left to the Package is a container of a sterile preparation for parenteral use
Nervous System: Somnolence 9%, Agitation 9%, discretion of the anesthesiologist. that contains many sngle doses. The contents are intended for
Dizziness 4%, Increased salivation Induction: use in a pharmacy admixture program and are restricted to the
4% SEVOFLURANE has a nonpungent odor and does not cause preparation of admixtures for intravenous infusion.
Digestive System: Nausea 25%, Vomiting 18% respiratory irritability; it is suitable for mask induction in pediatrics The Viaex plastic container is fabricated from a specially
Respiratory System: Cough increased 11%, Breathholding and adults. formulated polyvinyl chloride (PL 146 Plastic). Exposure to
2%, Laryngospasm 2% Maintenance: temperatures above 25C/77F during transport and storage will
Adverse Events, All Patients in Clinical Trials (N = 2906), All lead to minor losses in moisture content. Higher temperatures lead
Surgical levels of anesthesia can usually be achieved with
Anesthetic Periods, Incidence <1% (reported in 3 or more concentrations of 0.5-3% SEVOFLURANE with or without to greater losses. It is unlikely that these minor losses will lead
patients) the concomitant use of nitrous oxide. SEVOFLURANE can be to clinically signicant changes within the expiration period. The
Body as a whole: Asthenia, Pain administered with any type of anesthesia circuit. amount of water that can permeate from inside the container into
Cardiovascular: Arrhythmia, Ventricular Extrasysto the overwrap is insufcient to affect the solution signicantly.
Table 9: MAC Values for Adults and Pediatric Patients
les,Supraventricular Extrasystoles, Solutions in contact with the plastic container can leach out
According to Age
Complete AV Block, Bigeminy, Hem certain of its chemical components in very small amounts within
Age of Patient Sevourane Sevourane in 65% the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up
orrhage, Inverted T Wave, Atrial Fi (years) in Oxygen N2O/35% O2 to 5 parts per million; however, the safety of the plastic has been
brillation, Atrial Arrhythmia, Second
0 - 1 months # 3.3% conrmed in tests in animals according to USP biological test for
Degree AV Block, Syncope, S-T De plastic containers as well as by tissue culture toxicity studies.
1 - <6 months 3.0%
pressed
Nervous System: Crying, Nervousness, Confusion, 6 months - <3 years 2.8% 2.0%@ Amino acids 10 g
Hypertonia, Dry Mouth, Insomnia 3 - 12 2.5%
Total nitrogen 1.65 g
Respiratory System: Sputum Increased, Apnea, Hypoxia, 25 2.6% 1.4%
Wheezing, Bronchospasm, 40 2.1% 1.1% pH 6.0 (5.0 to 7.0)
Hyperventilation, Pharyngitis, Hiccup, 60 1.7% 0.9%
Hypoventilation, Dyspnea, Stridor 80 1.4% 0.7% (pH adjusted with glacial acetic acid and may have been adjusted
Metabolism and Nutrition: Increases in LDH, AST, ALT, BUN, with sodium hydroxide.)
Alkaline Phosphatase, Creatinine, # Neonates are full-term gestational age. MAC in premature Essential Amino Acids
Bilirubinemia, Glycosuria, Fluorosis, infants has not been determined.
Leucine - C6H13NO2 730 mg
Albuminuria, Hypophosphatemia, @ In 1 - <3 year old pediatric patients, 60% N2O/40% O2 was Isoleucine - C6H13NO2 600mg
Acidosis, Hyperglycemia used.
Lysine (added as the
Hemic and Directions for Filling Vaporizers
hydrochloride salt) - C6H14N202 580mg
Lymphatic System: Leucocytosis, Thrombocytopenia Sevourane is provided with a keyed bottle collar and should be
Valine - C5H11N02 580mg
Skin and Special Senses: Amblyopia, Pruritus, Taste Perver lled only into vaporizers designed for use with sevourane using
Phenylalanine - C9H11N02 560mg
sion, Rash, Conjunctivitis a keyed adaptor.
Histidine - C6H9N302 480mg
Urogenital: Urination Impaired, Urine 1. Remove the overseal and cap from the anesthetic bottle and
ensure that the bottle neck is not damaged. Threonine - C4H9N03 420mg
Abnormality, Urinary Retention,
2. Place the large end of the adaptor over the collar, aligning the Methionine - C5H11N02S 400mg
Oliguria
holes in the adaptor with the tabs on the collar, and tighten Tryptophan - C11H12N202 180mg
See WARNINGS for information regarding malignant
hyperthermia. securely. The color of the adaptor must match the color of Nonessential amino acids
the collar for the adaptor to index properly. Alanine - C3H7N02 2.07mg
Adverse Events During Post-Marketing Experience: Post-
marketing reports indicate that sevourane use has been associated 3. Attach the other end of the adaptor to the lling port of the Arginine - C6H14N402 1.15mg
with seizures. The majority of cases were in children and young vaporizer in accordance with the vaporizer manufacturers Glycine - C2h5N02 1.03mg
adults, most of whom had no medical history of seizures. Several instructions and ll the vaporizer. Proline - C5H9N02 680mg
cases reported no concomitant medications, and at least one case 4. Disconnect the adaptor from the vaporizer and allow any Serine - C3H7N03 500mg
was conrmed by EEG. Although many cases were single seizures excess sevourane to drain back into the bottle before Tyrosine - C9H11N03 40mg
that resolved spontaneously or after treatment, cases of multiple disconnecting the adaptor from the bottle.
Anion proles per liter*
seizures have also been reported. Seizures have occurred during, 5. Replace the cap securely on the bottle.
or soon after SEVOFLURANE induction, during emergence, and Acetate (1) 88mEq
during post-operative recovery up to a day following anesthesia. Chloride (2) 40mEq
Vaporizer Port *Balanced by ions from amino acids.
Rare cases of malignant hyperthermia (see CONTRAINDICA-
TIONS and WARNINGS) and allergic reactions, such as rash, (1) derived from pH adjustment with glacial acetic acid
urticaria, pruritis, bronchospasm, anaphylactic or anaphylactoid (2) contributed by the lysine hydrochloride
reactions (see CONTRAINDICATIONS) have been reported. Osmolarity (Calc.) 99m 0smol/L
Very rare cases of mild, moderate and severe post-operative
hepatic dysfunction or hepatitis with or without jaundice have Keyed adaptor CLINICAL PHARMACOLOGY
been reported. Histological evidence was not provided for any of 10% TRAVASOL (Amino Acid) Injection administrated via
the reported hepatitis cases. In most of these cases, patients had central vein will provide biologically utilizable source material for
underlying hepatic conditions or were under treatment with drugs protein synthesis when used with concentrated calorie sources (such
known to cause hepatic dysfunction. Most of the reported events as hypertonic dextrose or fat emulsion), electrolytes, vitamins, and
were transient and resolved spontaneously (see PRECAUTIONS). minerals. Administered peripherally after appropriate dilution or
In addition, there have been rare post-marketing reports of hepatic with minimal calorie supplementation (such as 5% dextrose), it
Collar
failure and hepatic necrosis associated with the use of potent enhances the conservation of body protein.
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INDICATIONS AND USAGE Sudden cessation in administration of a concentrated dextrose parenteral nutrition solutions. Since contaminated solutions and
10% TRAVASOL (Amino Acid) Injection is indicated as an solution may result in insulin reaction due to continued infusion catheters are potential sources of infection, it is imperative
adjunct in the offsetting of nitrogen loss or in the treatment of endogenous insulin production. Parenteral nutrition mixtures that the preparation of the solution and the placement and care of
negative nitrogen balance in patients where: (1) the alimentary should be withdrawn slowly. catheters be accomplished under controlled aseptic conditions. If
tract cannot or should not be used, (2) gastrointestinal absorption Electrolytes may be added to this injection as dictated by the fever develops, the solution, its delivery system and the site of the
of protein is impaired, or (3) metabolic requirements for protein patients electrolyte prole. indwelling catheter should be changed.
are substantially increased, as with extensive burns. The metabolizable acetate anion and amino acid prole in this Solutions ideally should be prepared in the hospital pharmacy
Central Vein Administration: injection were designed to minimize or prevent occurrences under a laminar ow hood. The key factor in their preparation is
Central vein infusion should be considered when amino acid of hyperchloremic metabolic acidosis and hyperammonemia. careful aseptic technique to avoid inadvertent touch contamination
solutions are to be admixed with hypertonic dextrose to promote However, the physician should be aware of appropriate during mixing of solutions and addition of other nutrients.
protein synthesis such as for hypercatabolic or depleted patients or countermeasures if they become necessary. Metabolic:
those requiring long term parenteral nutrition. Strongly hypertonic nutrient solutions should be administered The following metabolic complications have been reported:
Peripheral Vein Administration: through an indwelling intravenous catheter with the tip located in metabolic acidosis, hypophosphatemia, alkalosis, hyperglycemia
the superior vena cava. and glycosuria, osmotic diuresis and dehydration, rebound
For patients in whom the central vein route is not indicated, amino
acid solutions diluted with low dextrose concentrations may be Because of its antianabolic activity, concurrent administration hypoglycemia, elevated liver enzymes, hypo and hyper vitaminosis,
infused by peripheral vein when supplemented with or without fat of tetracycline may reduce the protein-sparing effects of infused electrolyte imbalances and hyperammonemia. Frequent clinical
amino acids. evaluation and laboratory determinations are necessary, especially
emulsion.
Care should be taken to avoid excess uid accumulation, during the rst few days of therapy, to prevent or minimize these
Protein-sparing:
particularly in patients with renal disease, pulmonary insufciency complications.
Dilute amino acid solutions for peripheral administration may and heart disease.
be Used In Patients Who Exemplify No Clinically Signicant ADVERSE REACTIONS
During protein-sparing therapy in the absence of supporting
Protein Malnutrition. The Purpose Of The Solution Is To Replace See Warnings and Special Precautions.
carbohydrate metabolism, an accumulation of ketone bodies in
Protein Losses Which Occur In Relation To An Intercurrent Infusion of any hypertonic solution can result in local inammatory
the blood often occurs. Correction of ketonemia usually can be
Phenomenon Which Is Known Or suspected to be productive of reactions. Policies and procedures should be established for the
accomplished by administering some carbohydrates.Protein-
a protein losscondition for a short or moderate period of time. recognition and management of such reactions.
sparing therapy is useful for periods up to 10 to 12 days. Patients
proteinsparing can be achieved by peripheral infusion of amino
requiring nutritional support thereafter should be placed on oral OVERDOSAGE
acid Solutions with or without dextrose.
or parenteral regimens that employ adequate nonprotein calorie
See Contraindications and Warnings
CONTRAINDICATIONS components.
Hypersensitivity to one or more amino acids severe liver disease or Drug product contains no more than 25 g/L of aluminum. DOSAGE AND ADMINISTRATION
hepatic coma anuria solutions with or without dextrose. LABORATORY TESTS If a patient is unable to take enteral nourishment for a prolonged
Frequent clinical evaluation and laboratory determinations period of time, institution of total parenteral nutrition (TPN) with
WARNINGS exogenous calories should be considered.
are necessary for proper monitoring during administration.
This injection is for compounding only, not for direct
Studies should include blood sugar, serum proteins, kidney and The total daily dose of 10% TRAVASOL (Amino Acid) Injection
infusion.
liver function tests, electrolytes, hemogram, carbon dioxide depends on the patients metabolic requirement and clinical
Caution should be exercised when admixing 10% TRAVASOL response. The determination of nitrogen balance and accurate
combining power or content, serum osmolarities, blood cultures
(amino acid) injection. Studies have shown that admixtures of daily body weights, corrected for uid balance, are probably the
and blood ammonia levels.
travasol (amino acid) injection, 10% and 20% travamulsion best means of assessing individual nitrogen requirements.
intravenous fat emulsion injection and high concentration dextrose Carcinogenesis, Mutagenesis, Impairment of Fertility:
Recommended Dietary Allowances* of protein range from
injection (10 to 70%), from baxter healthcare corporation, are Studies with 10% TRAVASOL (Amino Acid) Injection have
approximately 0.75 g/kg of body weight for adults to 1.68 g/
stable over short periods of time. These solutions should be not been performed to evaluate carcinogenic potential, mutagenic
kg for infants. It must be recognized, however, that protein as
used promptly after admixing. Any storage should be under potential, or effects on fertility.
well as caloric requirements in traumatized or malnourished
refrigeration and limited to a brief period of time, preferably less PREGNANCY: patients may be increased substantially. Daily amino acid doses
than 24 hours. Reference should be made to travamulsion injection
Teratogenic Effects of approximately 1.0 to 1.5 g/kg of body weight for adults with
and high concentration dextrose injection from baxter healthcare
Pregnancy Category C. adequate calories are generally sufcient to satisfy protein needs
corporation package inserts for detailed information on each
and promote positive nitrogen balance.
component. Animal reproduction studies have not been conducted with 10%
TRAVASOL (Amino Acid) Injection. It is also not known For the initial treatment of trauma or protein calorie malnutrition,
Proper administration of this injection requires knowledge of uid
whether 10% TRAVASOL (Amino Acid) Injection can cause higher doses of protein with corresponding quantities of
and electrolyte balance and nutrition as well as clinical expertise in
fetal harm when administered to a pregnant woman or can carbohydrate will be necessary to promote adequate patient
recognition and treatment of the complications which may occur.
affect reproduction capacity. 10% TRAVASOL (Amino Acid) response to therapy. The severity of the illness being treated is
Administration of amino acid solutions to a patient with hepatic the primary consideration in determining proper dose level. Such
Injection should be given to a pregnant woman only if clearly
insufciency may result in serum amino acid imbalances, higher doses, especially in infants, must be accompanied by more
needed.
hyperammonemia, stupor and coma. frequent laboratory evaluation.
Hyperammonemia is of special signicance in infants. This NURSING MOTHERS:
For protein-sparing in well-nourished patients not receiving
reaction appears to be related to a deciency of the urea cycle Caution should be exercised when 10% TRAVASOL (Amino signicant additional calories, amino acid dosages of 1.0 to 1.7
amino acids of genetic or product origin. It is essential that blood Acid)Injection is administered to a nursing woman. g/kg/day reduce nitrogen losses and spare body protein. If daily
ammonia be measured frequently in infants. increases in BUN in the range of 10 to 15 mg% for more than
PEDIATRIC USE:
Conservative doses of this injection should be given to patients three days should occur, then protein-sparing therapy should be
Safety and effectiveness of 10% TRAVASOL (Amino
with known or suspected hepatic dysfunction. Should symptoms of discontinued and a regimen with full nonprotein calorie substrates
Acid) Injection in pediatric patients have not been established
hyperammonemia develop, administration should be discontinued should be adopted.
by adequate and well-controlled studies. However, the use of
and the patients clinical status reevaluated. Care should be exercised to insure the maintenance of proper levels
amino acid injections in pediatric patients as an adjunct in the
Administration of amino acid solutions in the presence of impaired offsetting of nitrogen loss or in the treatment of negative nitrogen of serum potassium. Quantities of 60 to 180 mEq of potassium
renal function presents special issues associated with retention of balance is referenced in the medical literature. See Dosage and per day have been used with adequate clinical effect. It may be
electrolytes. Administration. necessary to add quantities of this electrolyte to this injection,
This injection should not be administered simultaneously with depending primarily on the amount of carbohydrate administered
SPECIAL PRECAUTIONS to and metabolized by the patient.
blood through the same infusion set because of the possibility of
pseudoagglutination. Administration of amino acid solutions and other nutrients via This injection provides a concentrated source of amino acids to
central or peripheral venous catheter may be associated with meet the protein requirements of patients that are uid restricted
Warning: This product contains aluminum that may be toxic.
complications which can be prevented or minimized by careful (e.g., renal failure). Acceptable total daily administration volumes
Aluminum may reach toxic levels with prolonged parenteral
attention to all aspects of the procedure. This includes attention to are dependent upon the uid balance requirements of the patient.
administration if kidney function is impaired. Premature neonates
solution preparation, administration and patient monitoring. It is Extreme care should be given to prevent uctuations of blood
are particularly at risk because their kidneys are immature, and
essential that a carefully prepared protocol, based on current
they require large amounts of calcium and phosphate solutions, osmolarity and serum electrolyte concentrations. Frequent and
medical practices, be followed, preferably by an experienced
which contain aluminum. careful monitoring is mandatory when uid restricted patients are
team.
Research indicates that patients with impaired kidney function, receiving intravenous nutrition.
Although a detailed discussion of the complications is beyond the
including premature neonates, who receive parenteral levels of Patients receiving this injection should be monitored (carefully)
scope of this insert, the following summary lists those based on
aluminum at greater than 4 to 5 g/kg/day accumulate aluminum and their electrolyte requirements individualized.
current literature:
at levels associated with central nervous system and bone toxicity. Total daily uid requirements can be met beyond the volume of
Technical:
Tissue loading may occur at even lower rates of administration. amino acid solutions by supplementing with noncarbohydrate or
The placement of a central venous catheter should be regarded as a carbohydrate-containing electrolyte solutions.
Administration by central venous catheter should be used only
surgical procedure. The physician should be fully acquainted with
by those familiar with this technique and its complications. Maintenance vitamins, additional electrolytes and trace elements
various techniques of catheter insertion as well as recognition and
should be administered as required.
PRECAUTIONS treatment of complications. For details of techniques and placement
sites consult the medical literature. X-ray is the best means of Fat emulsion coadministration should be considered when
It is essential to provide adequate calories concurrently if
verifying catheter placement. Complications known to occur prolonged parenteral nutrition (more than 5 days) is required in
parenterally administered amino acids are to be retained by the
from the placement of central venous catheters are pneumothorax, order to prevent essential fatty acid deciency (EFAD). Serum
body and utilized for protein synthesis. Concentrated dextrose
solutions are an effective source of such calories. hemothorax, hydrothorax, artery puncture and transection, injury lipids should be monitored for evidence of EFAD in patients
to the brachial plexus, malposition of the catheter, formation of maintained on fat free total parenteral nutrition.
With the administration of 10% TRAVASOL (Amino Acid)
arterio-venous stula, phlebitis, thrombosis, cardiac arrhythmia Pediatric Use:
injection in combination with highly concentrated dextrose
and catheter embolus.
solutions, hyperglycemia, glycosuria and hyperosmolar syndrome Use of 10% TRAVASOL (Amino Acid) Injection in pediatric
may result. Blood and urine glucose should be monitored on a Septic: patients is governed by the same considerations that affect the use
routine basis in patients receiving this therapy. The constant risk of sepsis is present during administration of of any amino acid solution in pediatrics. The amount administered
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is dosed on the basis of grams of amino acids/kg of body weight/ 4. Attach solution transfer set. Refer to complete directions
e.g. Day 1 Day 2 Day 3 Day 4
day. Two to three g/kg of body weight for infants with adequate accompanying set. Note: The closure shall be penetrated only
calories are generally sufcient to satisfy protein needs and one time with a suitable sterile transfer device or dispensing set 0 hrs 0-24 0-24 0-24 24 hrs 2 hrs 6 hrs
promote positive nitrogen balance. Solutions administered by which allows measured dispensing of the contents. hrs hrs hrs
peripheral vein should not exceed twice normal serum osmolarity 5. Viaex containers should not be written on directly since ink Mitoxana 2g/m2 2g/m2 2g/m2
(718 mOsmol/L). migration has not been investigated. Afx accompanying label i n f u - infu- i n f u -
Central Vein Administration: for date and time of entry, sion sion sion
Hypertonic mixtures of amino acids and dextrose may be 6. Once container closure has been penetrated, withdrawal of Uromi- 0.4g/ 2g/m2 2g/m2 2g/m2 0.8g/ 0.8g/ 0.8g/
administered safely by continuous infusion through a central vein
contents should be completed without delay. After initial texan m 2 m2 m2 m2
catheter with the tip located in the vena cava. In addition to meeting i.v. i n f u - infu- infu- po po po
dispense within 4 hours.
nitrogen needs, the administration rate is governed, especially sion sion sion
during the rst few days of therapy, by the patients tolerance HOW SUPPLIED
to dextrose. Daily intake of amino acids and dextrose should be Higher doses of mesna can be given if urothelial toxicity occurs.
10% TRAVASOL (Amino Acid) Injection is available in
increased gradually to the maximum required dose as indicated by Viaexplastic Pharmacy Bulk Package containers as follow Elderly:
frequent determinations of urine and blood sugar levels. below. No specic information on the use of this product in the elderly
In many patients, provision of adequate calories in the form of is available. Clinical trials have included patients over 65 years
1B6623 500 mL NDC 0338-0644-
hypertonic dextrose may require the administration of exogenous and no adverse reactions specic to this age group have been
insulin to prevent hyperglycemia and glycosuria. 031B6623 1000 mL NDC 0338-0644- reported.
Parenteral nutrition may be started with infusates containing Children:
041B6626 2000 mL NDC 0338-0644-06
lower concentrations of dextrose; dextrose content may be Due to increased micturition, children may require shorter intervals
gradually increased to estimated caloric needs as the patients Exposure of pharmaceutical products to heat should be between doses and/or an increased number of individual doses.
glucose tolerance increases. Sudden cessation in administration minimized. Avoid excessive heat. High risk patients:
of concentrated dextrose solution may result in insulin reaction Protect from freezing. It is recommended the product be stored at
Those who have had previous irradiation of the small pelvis,
due to continued endogenous insulin production. Such solutions room temperature (25C/77F).
occurrence of cystitis during previous cyclophosphamide,
should be withdrawn slowly. Do not remove container from overpouch until ready to use. ifosfamide or trofosfamide therapy, history of urinary tract
Peripheral Vein Administration: Do not use if overpouch has been previously opened or damaged. lesions, may also require shorter intervals between doses and/or an
For patients requiring parenteral nutrition in whom the central increased number of doses.
vein route is not indicated, this injection can be mixed with low
concentration dextrose solutions and administered by peripheral
UROMITEXAN Tablets CONTRAINDICATIONS, WARNINGS ETC.
vein in conjunction with or without fat emulsions. In pediatric Contra-indications:
patients, the nal solution should not exceed twice normal serum Known hypersensitivity to mesna or any thiol containing
osmolarity (718 mOsmol/L).
[Mesna (sodium 2-mercaptoethanesulphonate)] compounds.
Intravenous fat emulsions provide approximately 1.1 kcal/mL Use in pregnancy and lactation:
PRESENTATION
(10%) or 2.0 kcal/mL (20%) and may be administered along with Pregnancy and lactation are contra-indicated for cytostatic
amino acid-dextrose solutions by means of a short Y-connector White, oblong biconvex lm-coated tablets with a notch on one treatment, and consequently UROMITEXAN is not likely to be
near the infusion site to supplement caloric intake. Fat, however, side and either M4 or M6 on the other, containing 400 mg and 600 used under these circumstances.
should not be the sole caloric intake since studies have indicated mg of mesna (sodium 2-mercaptoethanesulphonate).
Should an individual patient be undergoing oxazaphosphorine
that glucose is more nitrogen sparing in the stressed patient. INDICATIONS: therapy during pregnancy then UROMITEXAN should be
Protein-sparing: For the prophylaxis of urothelial toxicity including haemorrhagic administered to this patient.
For well-nourished patients who require short-term parenteral cystitis, microhaematuria and macrohaematuria in patients treated Animal studies have shown no evidence of embryotoxic or
support, 10% TRAVASOL (Amino Acid) Injection can be with ifosfamide and cyclophosphamide, in doses considered to be teratogenic effects of UROMITEXAN.
administered peripherally with or without carbohydrate calories. urotoxic. Precautions:
Such infusates can be prepared by dilution of this injection DOSAGE AND ADMINISTRATION As mesna counteracts only the urotoxic side-effects of
with Sterile Water for Injection or 5% Dextrose Injection to
Sufcient mesna must be given to protect the patient adequately oxazaphosphorines, other side-effects of cytotoxic therapy e.g.
prepare isotonic or slightly hypertonic solutions which may be
from the urotoxic effects of the oxazaphosphorine. The duration myelosuppression, nausea, vomiting, alopecia, may still be
administered by peripheral vein.
of mesna treatment should equal that of the oxazaphosphorine expected. No other interaction between mesna and these alkylating
Depending upon the clinical condition of the patient, approximately treatment plus the time taken for the urinary concentration of agents has been demonstrated.
3 liters of solution may be administered per 24 hour period. When oxazaphosphorine metabolites to fall to non-toxic levels. This Oral mesna should be replaced by i.v. mesna in patients
used postoperatively, the therapy should begin with 1000 mL on usually occurs within 8-12 hours after the end of oxazaphosphorine experiencing vomiting.
the rst postoperative day. Thereafter, the dose may be increased treatment but may vary depending on the scheduling of The prevention of urotoxicity with UROMITEXAN tablets
to 3000 mL per day. oxazaphosphorine. When calculating the dose of mesna the should only be undertaken after medical guidance and careful
Parenteral drug products should be inspected visually for particulate quantity should be rounded down to the nearest whole tablet.
consideration of the risks and benets.
matter and discoloration prior to administration whenever solution Urinary output should be maintained at 100 ml/hr (as required
for oxazaphosphorine treatment) and the urine monitored for Interactions:
and container permit. Use of a nal lter is recommended during
administration of all parenteral solutions where possible. haematuria and proteinuria throughout the treatment period. There are no known in-vivo interactions of mesna with other
Compared with intravenous administration, overall availability of agents. There is no interaction with food.
Do not administer unless solution is clear and seal is intact.
mesna in urine after oral administration is approximately 50%; and Side effects:
A slight yellow color does not alter the quality and efcacy of
the product. the onset of urinary excretion is delayed by up to 2 hours and is Because patients receive potent cytotoxic agents concurrently,
more prolonged than following intravenous dosing. the side-effect prole of mesna is difcult to dene. However, in
10% TRAVASOL (Amino Acid) Injection in the Pharmacy
For intermittent oxazaphosphorine therapy: oral mesna 40% healthy volunteers the following side effects occurred at single
Bulk Package is intended for use in the preparation of sterile,
(w/w) of the oxazaphosphorine dose should be given 2 hours doses of 60-70 mg/kg per day: nausea, vomiting, colic, diarrhoea,
intravenous admixtures. Additives may be incompatible with the
prior to the oxazaphosphorine dose, and repeated after 2 and at headache, fatigue, limb and joint pains, depression, irritability,
uid withdrawn from this container. Complete information is not
6 hours. lack of energy, rash, hypotension and tachycardia.
available. Those additives known to be incompatible should not be
used. Consult with pharmacist, if available. When compounding Alternatively, an initial intravenous dose of mesna (20% (w/w) of In rare cases, pseudoallergic reactions (rash, pruritus, blistering
admixtures, use aseptic technique. Mix thoroughly. Do not the oxazaphosphorine dose can be given with the cytotoxic dose, of skin and mucous membranes, urticarial oedema, sudden
store any unused portion of 10% TRAVASOL (Amino Acid) additional oral mesna 40% (w/w) of the oxazaphosphorine dose hypotension, tachycardia and a transient rise of liver transaminases)
Injection. should then be given at 2 and 6 hours. have been reported. These pseudoallergic reactions appear to be
e.g. -2 hrs 0 hrs 2 hrs 6 hrs more common in patients with autoimmune disorders.
Any storage should be under refrigeration and limited to a brief
period of time, preferably less than 24 hours. Endoxana/ 1 g iv Overdosage:
Mitoxana Healthy volunteers given single bolus doses of 70 mg/kg mesna
DIRECTIONS FOR USE OF VIAFLEX PLASTIC showed no evidence of major toxic side-effects.
PHARMACY BULK PACKAGE CONTAINER Uromitexan 400 mg po 400 mg po 400 mg po
200 mg i.v. 400 mg po 400 mg po A specic antidote to mesna is not known.
To Open
Further information
Tear overpouch down side at slit and remove solution container. Following 24-hour infusion of ifosfamide and mesna: the rst There is evidence that the long term urothelial toxicity of the
Some opacity of the plastic due to moisture absorption during the oral mesna dose of 40% (w/w) of the ifosfamide dose is given oxazaphosphorines can be almost totally prevented by the
sterilization process may be observed. This is normal and does as the infusion is stopped, and the same dose is repeated after 2 concurrent administration of mesna in the appropriate dosage.
not affect the solution quality or safety. The opacity will diminish and 6 hours. Mesna only exerts this protective effect on the urinary tract
gradually. Check for minute leaks by squeezing inner bag rmly. If
e.g. 0 hrs 0-24 hrs 24 hrs 26 hrs 30 hrs and other precautionary measures recommended for the use of
leaks are found, discard solution as sterility may be impaired.
Mitoxana 5g/m2 oxazaphosphorine are not affected and should continue to be
For compounding only, not for direct infusion. used.
infusion
Preparation for Admixing A false positive test for urinary ketones (eg Rotheras test,
Uromitexan 1 g/m2 5g/m2 2g/m2 2g/m2 2g/m2
1. The Pharmacy Bulk Package is to be used only in a suitable N-Multistix reagent strip) may arise in patients treated with
work area such as a laminar ow hood (or an equivalent clean i.v. infusion po po po
mesna. The colour is red-violet rather than violet and it will fade
air compounding area). Following long-term infusion: the rst oral mesna dose should immediately on the addition of glacial acetic acid.
2. Suspend container from eyelet support. be 40% (w/w) of the ifosfamide dose taken in the FINAL 24 A false positive or false negative reaction in the dipstick test for
3. Remove plastic protector from outlet port at bottom of HOURS, and is given as the infusion is stopped and the same erythrocytes in the urine of patients treated with mesna may occur,
container. dose repeated at 2 and 6 hours. therefore use of urinary microscopy is recommended.
121
Book_01.indd 121 6/4/2008 2:20:08 PM

BAXTER
SPDI
PACKAGE QUANTITIES 160% of the oxazaphosphorine dose. It is recommended that after - are in cardiovascular shock;
Ten tablets in a blister strip. administration of 20% UROMITEXAN (related to the total - have severe narrowing of the blood vessel leading from the
Pack size - 10 tablets, 20 tablets(N.R), 50 tablets(N.R) dose of oxazaphosphorine) at time zero the remaining calculated heart to the main artery (high-grade aortic stenosis);
dose should be given continuously i.v. over a period of 24 hours - have unstable angina pectoris;
Product licence numbers
with a perfusor. Alternatively an intermittent bolus injection is - have suffered an acute myocardial infarction (heart attack) in
400 mg lm-coated tablets possible: For adults 3 x 40% (at times 0, 4, 8 hours) or 4 x 40% the last 4 weeks.
600 mg lm-coated tablets (at times 0, 3, 6, 9 hours) respectively. For children due to more - are taking rifampicin (a tuberculosis drug) at the same time;
frequent micturition, the bolus injections should always be given - are hypersensitive to nifedipine or any of the other ingredients;
UROMITEXAN 400 mg in 3-hour intervals (e.g. 20% at times 0, 1, 3, 6, 9, 12 hours).
- are pregnant or breast-feeding.
Instead of a bolus injection, short infusions of 15 minutes duration
are possible. When should you consult a doctor before taking
(Mesna) ADALAT 10?
With continuous infusions of ifosfamide (HOLOXAN), it has
Described below are cases in which you should only take
been shown to be of benet to give UROMITEXAN at time
UROPROTECTOR ADALAT 10 under certain circumstances and with particular
zero following the initial 20 % bolus injection (start of infusion,
caution. Please consult your doctor in these cases. You should
COMPOSITION: time 0), followed by infusion to up to 100 % of the ifosfamide
also consult your doctor if these details applied to you in the
4 ml injection solution contains mesna 400 mg Other constituents: dose, and to continue uroprotection for a further 6 to 12 hours after
past.
sodium edetate, sodium hydroxide, water for injections. termination of the ifosfamide infusion.
Particularly careful medical supervision is required in patients
Example of UROMITEXAN administration with a 24-hour
INDICATIONS: who
ifosfamide infusion:
Prevention of urothelial toxicity due to oxazaphosphorines - have extremely low blood pressure (systolic blood pressure
(Holoxan, Endoxan, Ixoten). Hours (time) 0 24 30 36 lower than 90 mmHg)
UROMITEXAN should always be given in tumour therapy Ifosfamide dose g/m2 body surface - have very severe heart weakness (decompensated heart failure)
with HOLOXAN. Where ENDOXAN or Ixoten are being (= 125 mg/kg BW) for which you are not receiving adequate treatment.
used for tumour therapy, UROMITEXAN should always be UROMITEXAN 1 g/m2 body surface Caution is required in patients undergoing dialysis who also have
given with bolus doses (over 10 mg/kg) of the cytotoxic agent bolus dose (= 25 mg/kg BW) high blood pressure (malignant hypertension) and decreased
and in all patients at special risk. The principle risk factors are: blood volume (hypovolaemia); widening of the blood vessels
UROMITEXAN Up to 5g/m2 Up to 2.5g/m2
previous pelvic radiotherapy, cystitis with previous HOLOXAN, (vasodilatation) can cause a substantial fall in blood pressure.
400 mg infusion body surface body surface
ENDOXAN or Ixoten therapy or a history of disorders of the What should you be aware of when pregnant or breast-
urinary tract. (= 125 mg/kg BW) (=62.5 mg/kg BW)
feeding?
Addition to
CONTRAINDICATIONS: ADALAT 10 should not be used at all during pregnancy, as
Ifosfamide infusion
Known hypersensitivity to mesna or other thiol containing studies with the active ingredient nifedipine have shown evidence
compounds. Store drugs out of childrens reach ! of foetal damage. There is not sufcient evidence in humans. If
STABILITY NOTE: UROMITEXAN should not be used you discover that you are pregnant while taking ADALAT 10,
WARNINGS: you must consult your doctor to arrange alternative treatment.
beyond the expiry date indicated on the package.
The occurence of hypersensitivity reactions (hyperergic reactions) Nifedipine passes into breast milk. If you need to take ADALAT
following UROMITEXAN therapy has been reported more ATTENTION:
10 while you are breast-feeding, you should wean your baby
frequently in patients with autoimmune disorders than in tumour The protective effect of Mesna is restricted to the urinary passages. because nothing is known about the possible effects of nifedipine
patients. Skin and mucosal reactions have been observed (rash, All other prophylactic on the infant.
urticaria, exanthema, enanthema), a rise in liver transaminases and measures recommended for oxazaphosphorine treatment are not
non-specic common symptoms like fever, exhaustion, nausea PRECAUTIONS AND WARNINGS
affected and should continue to be used.
and vomiting. Isolated circulatory reactions with hypotension and What precautions should be taken?
Treatment with UROMITEXAN can give rise to a false-positive
tachycardia have been observed as well. Protection of the urinary Nifedipine may break down more slowly in your body if you have
test for ketone bodies.
tract with UROMITEXAN should therefore only be undertaken a liver function disorder. Your doctor will therefore monitor your
in such patients following careful risk-benet analysis and under PRESENTATION: 15 ampoules of 4 ml
progress carefully and reduce the dose if necessary.
medical supervision. UROMITEXAN is available on prescription only.
Patients with a serious disorder of blood circulation in the brain
As UROMITEXAN is used as a Uroprotector in the context (cerebrovascular disease) should receive a lower dose.
of cytostatic treatment with oxazaphosphorines, its use during
pregnancy and lactation is governed by the criteria for this type BAYER HEALTHCARE & What precautions should be taken when driving, operating
machinery or working without a secure foothold?
of cytostatic therapy. Animal studies have shown no evidence of BAYER SCHERING Treatment with this drug requires regular medical check-ups.
embryotoxic or teratogenic effects of UROMITEXAN .
P.O.BOX.708, RIYADH:11421 Reactions to this drug may vary from one person to another, and
The protective action of UROMITEXAN applies only to the
SAUDI ARABIA the effect on your reaction speed may be such that your ability to
urinary tract. All other recommended precautions are unaffected drive, to operate machinery and to work without a secure foothold
by its use and recommendations relating to them remain in force. TEL: 01-4020308, FAX: 01-4032906
may be impaired. This applies particularly at the start of treatment,
SIDE-EFFECTS: when the dose is increased, when medication is changed and in
Isolated cases of partially organ-related hypersensitivity reactions
ADALAT 10 Capsule conjunction with alcohol.
(hyperergic reactions), e.g. skin and mucosal reactions of varying INTERACTIONS WITH OTHER DRUGS
extent and severity (itching, redness, vesiculation), local tissue (Nifedipine) What other drugs affect the way ADALAT 10 works or are
swelling (urticarial oedema), rare cases of drop in blood pressure themselves affected by ADALAT 10?
and increased pulse rate above 100/min (tachycardia) due to severe COMPOSITION
acute hypersensitivity reactions (anaphylactoid reactions), and The blood pressure-lowering effect of nifedipine (the active
also a transient rise in certain liver function tests (transaminases)
Pharmaceutically active ingredient ingredient in ADALAT 10) can be intensied by other drugs
have been reported. There have been rare cases of venous irritation 1 ADALAT 10 capsule contains 10 mg nifedipine. used to reduce blood pressure and by tricyclic antidepressants
at the injection site. In a tolerability study using high intravenous Other ingredients (medication used for the treatment of depression). Concomitant
and oral doses of mesna, single doses of 60 mg/kg body weight treatment with nitrates (used to treat coronary heart disease)
Gelatin, Yellow No. 6 (E 110), puried water, glycerol, macrogol increases the effect of ADALAT 10 on blood pressure and heart
and above were associated with nausea, vomiting, diarrhoea, 400, peppermint oil, saccharin sodium dihydrate, titanium (IV)
headache, pain in the limbs, drop in blood pressure, tachycardia, rate.
oxide (E 171).
skin reactions, exhaustion and weakness. During treatment, the Careful monitoring of the patient is indicated in the event of
MODE OF ACTION AND THERAPEUTIC CATEGORY concomitant treatment with nifedipine and beta blockers (a drug
above side-effects cannot always be clearly differentiated from
those caused by oxazaphosphorines (Holoxan, Endoxan, Calcium antagonist. used for treatment of high blood pressure and coronary heart
Ixoten), or other concomitant medication. ADALAT 10 is a drug used in the treatment of certain types of disease), as this can lead to an extreme reduction in blood pressure;
INTERACTIONS WITH OTHER DRUGS: Mesna is incom- coronary heart disease and high blood pressure. signs of heart failure have also been observed on occasion.
patible in vitro with cisplatin, carboplatin, and nitrogenmustard. Decomposition of nifedipine involves a specic enzyme system
INDICATIONS
(cytochrome P450 3A4). As a result, any concomitant use of drugs
DOSAGE INSTRUCTIONS AND MODE OF USE: Unless - Chronic stable angina pectoris (exercise-induced angina) that inuence this enzyme system can lead to interaction between
otherwise prescribed, UROMITEXAN is normally administered - Vasospastic angina (Prinzmetals or variant angina) the drug in question and nifedipine.
intravenously to adults at a dose of 20 % of the oxazaphosphorine
- Essential hypertension (high blood pressure with no discoverable Diltiazem (a drug used to treat high blood pressure and coronary
dose at time zero (the time of administration of the oxazaphospho-
organic cause) heart disease) reduces the decomposition of nifedipine. If you are
rine), and then at 4 and 8 hours.
- Raynauds disease taking this drug, your doctor will monitor your progress carefully
Example of UROMITEXAN administration with
- Hypertensive emergency. and reduce the dose of nifedipine if necessary.
oxazaphosphorine injection:
Note In isolated cases, nifedipine causes a decrease in the blood
Hour (Time) 0(8.00h) 4(12.00h) 8(16.00h) concentration of quinidine (active substance used to treat
Evidence for a dose-dependent increase in cardiovascular
complications (e.g. heart attack) and mortality rates has been cardiac arrhythmia) or a signicant rise in the quinidine blood
Oxazaphosphorine dose 40 mg/kg BW - -
observed in patients with essential hypertension (hypertension concentration can occur after discontinuing therapy with
with no discoverable organic cause) or chronic angina pectoris nifedipine; the quinidine blood concentration should therefore be
UROMITEXAN 8 mg/kg BW 8 mg/kg BW 8 mg/kg BW
treated with fast-release forms of nifedipine (ADALAT 10 is in monitored in the event of concomitant use.
Clinical experience with children has shown that it is benecial this category). For this reason ADALAT 10 should be used to Nifedipine can increase the blood concentrations of digoxin
in individual cases to give UROMITEXAN at shorter intervals treat these conditions only if other drugs are unsuitable. (active substance used primarily for treatment of cardiac output
(e.g. every three hours, total UROMITEXAN dose = 60 % of deciency) and theophylline (used to treat respiratory diseases);
CONTRAINDICATIONS monitoring is therefore recommended.
oxazaphosphorine dose). With very high-dose oxazaphosphorine
cytostatic therapy (e.g. before bone marrow transplantation), the When must ADALAT 10 not be used? Concomitant use of quinupristin/dalfopristin (antibiotics) and
total UROMITEXAN dose can be increased to between 120 and ADALAT 10 must not be used if you nifedipine can intensify the effect of nifedipine. The patients
122
Book_01.indd 122 6/4/2008 2:20:09 PM

BAYER HEALTHCARE & BAYER SCHERING
SPDI
blood pressure should therefore be monitored and the nifedipine minutes. If the interval is shorter and/or the dose higher, there may may experience an increase in the frequency, duration and severity
dose reduced if necessary. be a dangerous fall in blood pressure. of attacks. Myocardial infarctions have been described in isolated
Cimetidine (a drug used to treat gastric and intestinal ulcers) How and when should you take ADALAT 10? cases.
increases the concentration of nifedipine in blood and can therefore ADALAT 10 capsules should generally be swallowed whole Rarely
intensify the effect of nifedipine. with plenty of liquid after meals, preferably at the same time in the Treatment with nifedipine rarely a bloated sensation, belching and
Rifampicin (a drug used to treat tuberculosis) accelerates morning, at midday and in the evening each day. loss of appetite.
the decomposition of nifedipine. Rifampicin should not be Hypertensive emergency In rare cases, long-term treatment can result in gum changes
administered at the same time as nifedipine, as it will not be The capsule must be bitten through and swallowed immediately (gingival hyperplasia) which are completely reversible after
possible to obtain effective blood concentrations of nifedipine. with its contents. discontinuation of therapy.
Nifedipine decreases the excretion of vincristine (a drug used For how long should you take ADALAT 10? Hives (urticaria), inammation of the skin after exposure to the
in the treatment of cancer), which means that the side effects of sun and UV radiation (photodermatitis) and jaundice have been
The attending doctor must decide on the length of the treatment.
vincristine may increase. For this reason it may be advisable to observed rarely.
reduce the dose of vincristine. INCORRECT USE AND OVERDOSAGE In rare cases, especially in older male patients receiving long-term
Increased blood concentrations of cephalosporin have been What should you do if you take too much ADALAT 10 (either therapy, enlargement of the mammary glands (gynaecomastia) has
observed following simultaneous administration of cephalosporins intentionally or by accident)? been observed; however, so far this has been reversible in all cases
(e.g cexime, an antibiotic) and nifedipine. If you think that you might have taken an overdose, you must after discontinuing medication.
Concomitant use of phenytoin (a drug used to treat cardiac inform your doctor/an emergency doctor immediately so that he In rare cases, changes in the blood count such as a reduction
arrhythmia and epilepsy) and nifedipine weakens the efcacy of can decide on what measures to take. in red or white blood cells or platelets (anaemia, leucopenia,
nifedipine. If both drugs are being used concomitantly, the patients In the event of overdosage, there is a risk of a pronounced drop thrombocytopenia), bleeding in the skin and mucous membranes
reaction to nifedipine should be monitored and an increase to the in blood pressure, deceleration or acceleration of the heart rate, with a reduction in blood platelets (thrombocytopenic purpura)
nifedipine dosage considered if necessary. It may be necessary clouding of consciousness ranging up to coma, elevated blood and small haemorrhages in the skin and mucous membranes
to adjust the nifedipine dosage after treatment with phenytoin has glucose levels (hyperglycaemia), insufcient blood supply to (purpura) have been described in connection with consumption of
been discontinued. the major organs and shock caused by cardiac failure leading to nifedipine.
The risk that the effect of nifedipine will be intensied cannot accumulation of uid in the lungs (pulmonary oedema). In equally rare cases, acute general allergic reactions can occur
be ruled out when nifedipine is used at the same time as drugs What should you do if you have taken too few ADALAT 10 such as fever, swelling of the larynx (oedema of the glottis), and
containing the following active ingredients: capsules or have forgotten to take a dose? spasms in the bronchial muscles which can cause shortness of
- Erythromycin (antibiotic), Do not take more ADALAT 10 next time; simply continue the breath to a potentially fatal degree; these reactions subside after
- Fluoxetine, nefazodone (antidepressants), treatment as prescribed. withdrawal of the drug.
- Amprenavir, indinavir, nelnavir, ritonavir or saquinavir What should you do if you want to interrupt the treatment or There have been rare reports of impaired vision.
(active substances used to treat certain viral infections) or stop using ADALAT 10 before the end of the course? An increase in the serum blood glucose level (hyperglycaemia)
- Ketoconazole, itraconazole or uconazole (active substances You should always consult your doctor before deciding to interrupt has been observed in rare cases. This is an especially important
used to treat fungal infections). the course of treatment or stop taking ADALAT 10 altogether. consideration in patients with diabetes mellitus.
Concomitant use of tacrolimus (a drug used to prevent transplant If you wish to discontinue use of ADALAT 10, especially high- Very rare
rejection after, for example, liver or kidney transplants) and dose use, you should always proceed in stages. In very rare cases, a marked reduction in certain blood cells
nifedipine can lead to elevated levels of tacrolimus in blood; (agranulocytosis) and scaly inammation of the skin (exfoliative
it may be necessary to reduce the tacrolimus dose in isolated SIDE EFFECTS
dermatitis) have been reported.
cases. Regular monitoring of the blood level of tacrolimus is What side effects can occur when using ADALAT 10?
In isolated cases involving in vitro fertilisation, treatment with
recommended. The following adverse effects have been reported after calcium antagonists such as nifedipine has been associated with
Experience with the calcium antagonist nimodipine indicates that administration of nifedipine (the active ingredient of ADALAT transient changes to sperm and impaired sperm function.
the possibility cannot be ruled out that concomitant administration 10). The frequency is indicated as follows:
Furthermore, the yellow no. 6 (E 110) content can cause allergic
of carbamazepine or phenobarbital (drugs used to treat epilepsy) Very frequently: more than 1 in 10 treated patients reactions in predisposed persons.
weakens the effect of nifedipine.
Frequently: fewer than 1 in 10, If you experience side effects that are not mentioned in this
Experience with nimodipine indicates that concomitant use of but more than 1 in 100 treated patients information leaet, please inform your doctor or pharmacist.
valproic acid (a drug used to treat epilepsy) is likely to intensify Occasionally: fewer than 1 in 100,
the effect of nifedipine. What action should be taken if any of these side effects occur?
but more than 1 in 1,000 treated patients
Please note that this information may also apply to medicines Most of the side effects described above are only transient and do
Rarely: fewer than 1 in 1,000,
used recently. not require any particular treatment. However, you should still tell
but more than 1 in 10,000 treated patients
your doctor so that he can decide what steps to take.
What foods and drinks should you avoid? Very rarely: fewer than 1 in 10,000 treated patients,
Do not take ADALAT 10 with grapefruit juice as it inhibits the including isolated cases INFORMATION ON THE SHELF-LIFE OF THE PROD-
decomposition of nifedipine in the body and thus increases the UCT
effect of ADALAT 10. Very frequently The expiry date of this drug product is printed on the cardboard
At the start of treatment especially, headaches and peripheral box and on the blister pack. Do not use the product after this date.
DOSAGE AND ADMINISTRATION oedema (accumulation of uid, e.g. in the lower leg) may very
Unless otherwise prescribed by your doctor, you should use frequently occur due to widening of the blood vessels; these side HOW SHOULD ADALAT 10 BE STORED?
ADALAT 10 as described below. Please follow the directions effects are usually transient. Keep in light-protected conditions.
carefully as otherwise ADALAT 10 cannot work properly. Frequently
How much ADALAT 10 should you take, and how often? Furthermore, at the start of treatment especially, facial ush, skin ADALAT LA 30 mg Tablet
As far as possible, the treatment should be adapted according to reddening with a feeling of warmth (erythema), and conditions {Identical to ADALAT Crono 30 mg}*
the severity of your condition and your response. involving painful swelling and reddening of the arms and legs
The clinical picture may require the dose to be gradually increased (erythromelalgia) can occur.
to the recommended level. There have likewise been frequent reports of palpitations, (Nifedipine)
If you have impaired liver function, your doctor will monitor your dizziness, drowsiness, a feeling of weakness and nausea.
progress carefully and may reduce the dose. Occasionally COMPOSITION
If you have a serious cerebrovascular disease you should receive On occasion, an increased pulse rate (tachycardia), a temporary Pharmaceutically active ingredient
a lower dose. loss of consciousness due to an excessive fall in blood pressure 1 ADALAT LA 30 MG sustained-release tablet contains 30 mg
Adults (syncope) and a drop in blood pressure to below the norm nifedipine.
(hypotonic circulatory reaction) can occur.
Chronic stable angina pectoris (exercise-induced angina) 1-2 Other ingredients
ADALAT 10 capsules 3 times daily (equivalent to 30-60 mg Treatment with nifedipine occasionally causes gastrointestinal
disorders such as upper abdominal complaints (dyspepsia), Cellulose acetate, ferric oxide (E 172), hydroxypropylcellulose,
nifedipine daily) hypromellose, macrogol 3350, macrogol 200,000, macrogol 5
diarrhoea, abdominal pain, constipation, atulence, vomiting and
Vasospastic angina (Prinzmetals or variant angina) a dry mouth. million, magnesium stearate, sodium chloride, propylene glycol,
1-2 ADALAT 10 capsules 3 times daily (equivalent to 30-60 mg titanium dioxide (E 171).
In addition, malaise, respiratory disorders (dyspnea), nervousness,
nifedipine daily) fatigue, sleep disorders or sleepiness, reduced sensitivity to touch SUBSTANCE AND THERAPEUTIC CATEGORY OR
Essential hypertension (high blood pressure with no (hypoaesthesia), tingling in the arms and legs (paraesthesia), MODE OF ACTION
discoverable organic cause) tremor of the ngers, a state of agitation (only on administration of ADALAT LA 30 mg is a drug for the treatment of hypertension.
1-2 ADALAT 10 capsules 3 times daily (equivalent to 30-60 mg Adalat capsules), muscle and joint pain and muscular spasms can (calcium antagonist, antihypertensive)
nifedipine daily) occur on occasion.
Skin hypersensitivity reactions such as itching (pruritus), skin INDICATIONS
Raynauds disease
rash (exanthema), swelling of the skin and mucous membranes For treatment of high blood pressure with no discoverable organic
1-2 ADALAT 10 capsules 3 times daily (equivalent to 30-60 mg
(angioedema, facial oedema), perspiration and liver function cause (essential hypertension).
nifedipine daily)
disorders (intrahepatic cholestasis, increased transaminase levels)
The maximum daily dose is 60 mg nifedipine/day. CONTRAINDICATIONS
have been observed on occasion.
Hypertensive emergency When must ADALAT LA 30 mg not be used?
In patients with kidney failure, use of nifedipine may occasionally
1 ADALAT 10 capsule as required (equivalent to 10 mg cause a transient deterioration in kidney function. An increased ADALAT LA 30 mg must not be used if you
nifedipine) need to urinate and increased daily urine volumes may likewise - are known to be hypersensitive to the active ingredient
Since a very rapid onset of action is required in a hypertensive occasionally occur. nifedipine or the other ingredients of the product;
emergency, the capsule must be bitten through and swallowed A minor, transient change in visual perception has been reported - are in cardiovascular shock;
immediately with its contents. on occasion. - have severe narrowing of the blood vessel leading from the
If there is no effect or the effect is inadequate, another 10 mg Particularly at the start of treatment, angina pectoris attacks may heart to the main artery (high-grade aortic stenosis);
nifedipine may be taken after not less than approximately 30 occasionally occur and patients who already have angina pectoris - have unstable angina pectoris;
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SPDI
- have suffered an acute myocardial infarction (heart attack) in to nifedipine (the active ingredient in ADALAT LA 30 mg) For how long should you take ADALAT LA 30 mg?
the last 4 weeks; should be monitored and an increased dosage of ADALAT LA Your doctor will decide how long you should take the drug. Therapy
- have severe narrowing of the gastrointestinal tract; 30 mg considered if necessary. It may be necessary to adjust of high blood pressure usually involves long-term treatment.
- are taking rifampicin (a tuberculosis drug, see Interactions the dosage of ADALAT LA 30 mg again after treatment with
phenytoin has been discontinued. INCORRECT USE AND OVERDOSAGE
with other drugs) at the same time;
- are pregnant or breast-feeding. - erythromycin (antibiotic), uoxetine, nefazodone What should you do if you take too much ADALAT LA 30 mg
(antidepressants, drugs for the treatment of depression), (either intentionally or by accident)?
When should you consult a doctor before taking ADALAT
LA 30 mg? protease inhibitors such as amprenavir, indinavir, nelnavir, Depending on the degree of overdosage, there is a risk of a
ritonavir or saquinavir (drugs for the treatment of certain pronounced drop in blood pressure, clouding of consciousness and
Described below are cases in which you should only take
viral infections), antimycotic agents such as ketoconazole, even coma, cardiac arrhythmia with deceleration or acceleration
ADALAT LA 30 mg under certain circumstances and with
itraconazole or uconazole (drugs for the treatment of of the heart rate, elevated blood glucose levels (hyperglycaemia),
particular caution. Please consult your doctor in these cases.
fungal infections) and valproic acid (drug for the treatment of insufcient blood supply to the major organs and shock caused
You should also consult your doctor if these details applied to
epilepsy): intensication of the action of ADALAT LA 30 mg by cardiac failure leading to accumulation of uid in the lungs
you in the past.
cannot be ruled out. (pulmonary oedema).
Caution is required if you
- carbamazepine and phenobarbitone (drugs for the treatment If you think that you might have taken an overdose, you must
- have extremely low blood pressure (systolic blood pressure of epilepsy): concomitant use of ADALAT LA 30 mg may inform your doctor immediately so that he can decide on what
lower than 90 mmHg) weaken the effect of ADALAT LA 30 mg. measures to take.
- have very severe heart weakness (decompensated heart failure) What effect does ADALAT LA 30 mg have on the action of What should you do if you have taken too few ADALAT LA
- are undergoing dialysis and also have high blood pressure other drugs? 30 mg sustained release tablets or have forgotten to take a
(malignant hypertension) and decreased blood volume - quinidine (drug used to treat cardiac arrhythmia): in isolated dose?
(hypovolaemia): widening of the blood vessels (vasodilatation) cases, ADALAT LA 30 mg causes a decrease in the blood Do not take more ADALAT LA 30 mg sustained release tablets
can cause a substantial fall in blood pressure. concentration of quinidine or a signicant rise in the quinidine next time; simply continue the treatment as prescribed.
What precautions should you take during pregnancy and if blood concentration can occur after discontinuing therapy with What should you do if you want to interrupt the treatment or
you are breast-feeding? ADALAT LA 30 mg. stop using ADALAT LA 30 mg before the end of the course?
ADALAT LA 30 mg should not be used at all during pregnancy, - digoxin (drug used primarily for treatment of cardiac output You should always consult your doctor before deciding to interrupt
as experimental studies with the active ingredient nifedipine have deciency) and theophylline (drug used to treat respiratory the course of treatment or stop taking ADALAT LA 30 mg
shown evidence of foetal damage. There is not sufcient evidence diseases): concomitant use of ADALAT LA 30 mg may altogether.
in humans. If you discover that you are pregnant while taking increase blood concentrations of these drugs and monitoring is
ADALAT LA 30 mg, you must consult your doctor to arrange therefore recommended. SIDE EFFECTS
alternative treatment. - vincristine (a drug used in the treatment of cancer): nifedipine What side effects can occur when using ADALAT LA 30 mg?
If you need to take ADALAT LA 30 mg while you are breast- (the active ingredient in ADALAT LA 30 mg) decreases the The following undesirable effects have been reported on
feeding, you should wean your baby because nifedipine (the active excretion of vincristine, which means that the side effects of administration of nifedipine (the active ingredient in ADALAT
ingredient in ADALAT LA 30 mg) passes into breast milk and vincristine may increase. For this reason it may be advisable to LA 30 mg). Frequencies of occurrence are as follows:
nothing is known about possible effects on the infant. reduce the dose of vincristine. Very often more than 1 in 10 of those treated
What precautions should be taken for children? - cephalosporins (drugs for the treatment of bacterial Frequently less than 1 in 10 but more than 1 in 100 of those
ADALAT LA 30 mg is not intended for use in children as infections): increased blood concentrations of cephalosporins treated
insufcient experience is available. have been observed following simultaneous administration
Occasionally less than 1 in 100 but more than 1 in 1,000 of
of cephalosporins (e.g. cexime) and nifedipine (the active
PRECAUTIONS AND WARNINGS those treated
ingredient in ADALAT LA 30 mg).
Rarely: less than 1 in 1,000 but more than 1 in 10,000 of
What precautions should be taken? - tacrolimus (a drug used to prevent transplant rejection after, those treated
Nifedipine (the active ingredient in ADALAT LA 30 mg) may for example, liver or kidney transplants): concomitant use of Very rarely: less than 1 in 10,000 of those treated, including
break down more slowly in your body if you have a liver function ADALAT LA 30 mg can lead to elevated levels of tacrolimus isolated cases
disorder. Your treatment should therefore always be started at in blood; it may be necessary to reduce the tacrolimus dose
the lowest dose and the course of treatment should be monitored in isolated cases. Regular monitoring of the blood level of Very often
carefully (see also Dosage and administration). tacrolimus is recommended. At the start of treatment especially, headaches and peripheral
If you have diarrhoea persisting over several days (e.g. with oedema (accumulation of uid, e.g. in the lower leg) may occur
Decomposition of nifedipine (the active ingredient in ADALAT
Crohns disease, inammatory intestinal disorders), absorption of due to widening of the blood vessels; these side effects are usually
LA 30 mg) involves a specic enzyme system (cytochrome P450
the active ingredient may be incomplete due to the retention time transient.
3A4). As a result, any concomitant use of drugs that inuence
of the drug in the gastrointestinal tract being too short. this enzyme system can lead to interaction between the drug in Frequently
What precautions should be taken when driving, operating question and ADALAT LA 30 mg. Particularly at the start of treatment and usually transient:
machinery or working without a secure foothold? Please note that this information may also apply to medicines reddening of the face and skin with a feeling of warmth (ush,
Treatment with this drug requires regular medical check-ups. used recently. erythema, erythromelalgia).
Reactions to this drug may vary from one person to another, and What foods and drinks should you avoid? Palpitations, dizziness, drowsiness, a feeling of weakness, nausea,
the effect on your reaction speed may be such that your ability to constipation.
- grapefruit juice: do not take ADALAT LA 30 mg with
drive, to operate machinery and to work without a secure foothold Occasionally
grapefruit juice as it inhibits the decomposition of nifedipine
may be impaired. This applies particularly at the start of treatment,
in the body and thus increases the effect of ADALAT LA An increased pulse rate (tachycardia), brief fainting as a result of
when the dose is increased, when medication is changed and in
30 mg. an excessive reduction in blood pressure (syncope), a decrease in
conjunction with alcohol.
blood pressure to below the norm, gastrointestinal disorders such
DOSAGE AND ADMINISTRATION as diarrhoea, abdominal pain, atulence, vomiting; dry mouth,
INTERACTIONS WITH OTHER DRUGS
Unless otherwise prescribed by your doctor, you should use malaise, breathing disorders (dyspnoea), irritability, fatigue, sleep
What other drugs affect the way ADALAT LA 30 mg
ADALAT LA 30 mg as described below. Please follow the disorders, sleepiness, a reduced sensitivity to touch (hypaesthesia),
works?
directions carefully as otherwise ADALAT LA 30 mg cannot tingling in the arms and legs (paraesthesia), trembling of the ngers
The following interactions with ADALAT LA 30 mg have been work properly. (tremor), muscle and joint pain, muscle cramps, hypersensitivity
described on concomitant use of:
How much ADALAT LA 30 mg should you take, and how reactions involving the skin such as itching, rash, swelling of skin
- other drugs used to reduce blood pressure and tricyclic often? and mucous membranes (angioneurotic oedema, facial oedema),
antidepressants (medication used for the treatment of sweating; impairment of liver function (intrahepatic cholestasis,
depression): increased reduction in blood pressure. Concomitant The recommended dose for adults is 1 ADALAT LA 30 mg
sustained-release tablet once daily (equivalent to 30 mg nifedipine elevation of transaminases), visual disturbances.
treatment with beta-blockers may in isolated cases give rise to
once daily). In patients with impaired kidney function, a transient deterioration
signs of heart failure. Diltiazem (a drug used to treat high blood
If necessary, the dosage can be increased up to a maximum of in kidney function may occasionally occur. An increased need to
pressure and coronary heart disease) reduces the decomposition
2 ADALAT LA 30 mg sustained-release tablets once daily urinate and increased daily urine volumes may likewise occur
of nifedipine and the effect of ADALAT LA 30 mg may
(equivalent to 60 mg nifedipine once daily; 60 mg sustained- occasionally.
therefore be intensied. If you are taking these drugs, your
doctor will monitor your progress carefully and reduce the dose release tablets are available in this case). Angina pectoris attacks or, in patients with existing angina
if necessary. Dosage for patients with impaired liver function: pectoris, an increase in the frequency, duration and severity of
the attacks may occur occasionally, particularly at the start of
- nitrates (agents for the treatment of coronary heart disease): The starting dose is always 1 ADALAT LA 30 mg sustained- treatment. The occurrence of heart attacks (myocardial infarction)
intensication of the effect on blood pressure and heart rate. release tablet once daily (equivalent to 30 mg nifedipine once has been described in isolated instances.
- cimetidine (a drug used to treat gastric and intestinal ulcers): daily). This is generally also the maintenance dose. The patients
increase the effect of ADALAT LA 30 mg, as the concentration progress should be monitored carefully. Rare
of nifedipine in the blood is increased. Bloating, belching, loss of appetite, hives, inammation of the
Note
- rifampicin (a drug used to treat tuberculosis): accelerated skin following exposure to sunlight or UV light (photodermatitis),
The ADALAT LA 30 mg tablet has an outer membrane that jaundice, poor vision.
decomposition of nifedipine (the active ingredient in
is excreted in the faeces once the active ingredient has been
ADALAT LA 30 mg) in the body. Rifampicin should not be Blood count changes such as a reduction in the number of red
released.
administered at the same time as ADALAT LA 30 mg, as it or white blood cells or blood platelets (anaemia, leukopenia,
will not be possible to obtain effective blood concentrations of How and when should you take ADALAT LA 30 mg? thrombocytopenia), bleeding in the skin and mucous membranes
nifedipine (see also Contraindications). ADALAT LA 30 mg sustained-release tablets should be with a reduction in blood platelets (thrombocytopenic purpura)
- quinupristin/dalfopristin (antibiotics): increase the effect of swallowed whole with plenty of liquid (e.g. a glass of water), and small haemorrhages in the skin and mucous membranes
ADALAT LA 30 mg. Your blood pressure should therefore preferably always at the same time of day. It is advisable not to (purpura).
be monitored and the nifedipine dose reduced if necessary. take the tablets with grapefruit juice (see Interactions with other In rare cases, especially in older male patients receiving long-term
- phenytoin (a drug used to treat cardiac arrhythmia and drugs). therapy, enlargement of the mammary glands (gynaecomastia) has
epilepsy): weakening of the efcacy of ADALAT LA 30 The sustained release tablets can be taken independently of been observed; however, so far this has been reversible in all cases
mg. If both drugs are being used concomitantly, your reaction meals. after discontinuing medication.
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SPDI
In rare cases, long-term treatment can result in gum changes - are undergoing dialysis and also have high blood pressure How does ADALAT LA 60 mg affect the way other drugs
(e.g. gingival hyperplasia) which are completely reversible after (malignant hypertension) and decreased blood volume work?
discontinuation of ADALAT LA 30 mg. (hypovolaemia): widening of the blood vessels (vasodilatation) - quinidine (drug used to treat cardiac arrhythmia): in isolated
In equally rare cases, acute general allergic reactions (anaphylactic can cause a substantial fall in blood pressure. cases, ADALAT LA 60 mg causes a decrease in the blood
reactions) can occur such as fever, swelling of the larynx (laryngeal What precautions should you take during pregnancy and if concentration of quinidine or a signicant rise in the quinidine
oedema) and spasms in the bronchial muscles which can cause you are breast-feeding? blood concentration can occur after discontinuing therapy with
shortness of breath to a potentially fatal degree; these reactions ADALAT LA 60 mg should not be used at all during pregnancy, ADALAT LA 60 mg; the quinidine blood concentration
subside after withdrawal of the drug. should therefore be monitored in the event of concomitant use.
as studies with the active ingredient nifedipine have shown
An increase in blood glucose levels has been observed in rare evidence of foetal damage. There is not sufcient evidence in - digoxin (drug used primarily for treatment of cardiac output
cases. This is an especially important consideration in patients humans. If you discover that you are pregnant while taking deciency) and theophylline (drug used to treat respiratory
with diabetes mellitus. ADALAT LA 60 mg, you must consult your doctor to arrange diseases): concomitant use of ADALAT LA 60 mg may
increase blood concentrations of these drugs and monitoring is
Very rare alternative treatment.
therefore recommended.
In very rare instances, disturbances of intestinal transit with If you need to take ADALAT LA 60 mg while you are breast-
- vincristine (a drug used in the treatment of cancer): nifedipine
symptoms of intestinal obstruction (e.g. atulence, colicky pain) feeding, you should wean your baby because nifedipine (the active (the active ingredient in ADALAT LA 60 mg) decreases the
and the occurrence of inammation of the gullet (oesophagus), ingredient in ADALAT LA 60 mg) passes into breast milk and excretion of vincristine, which means that the side effects of
stony concretions in the stomach (bezoars) and intestinal ulcers nothing is known about possible effects on the infant. vincristine may increase. For this reason it may be advisable to
have been reported during treatment with ADALAT LA 30 mg. What precautions should be taken for children? reduce the dose of vincristine.
A marked reduction in certain blood cells (agranulocytosis) and
ADALAT LA 60 mg is not intended for use in children as - cephalosporins (drugs for the treatment of bacterial
scaly inammation of the skin (exfoliative dermatitis) have also
insufcient experience is available. infections): increased blood concentrations of cephalosporins
been reported.
have been observed following simultaneous administration
In isolated cases involving in vitro fertilisation (fertilisation PRECAUTIONS AND WARNINGS of cephalosporins (e.g. cexime) and nifedipine (the active
outside the body), treatment with calcium antagonists such as What precautions should be taken? ingredient in ADALAT LA 60 mg).
nifedipine (the active ingredient in ADALAT LA 30 mg) has Nifedipine (the active ingredient in ADALAT LA 60 mg) - tacrolimus (a drug used to prevent transplant rejection after,
been associated with transient changes to sperm and impaired may break down more slowly in your body if you have a liver for example, liver or kidney transplants): concomitant use of
sperm function. ADALAT LA 60 mg can lead to elevated levels of tacrolimus
function disorder. Treatment should therefore always be started at
If you experience side effects that are not mentioned in this the lowest dose and the course of treatment should be monitored in blood; it may be necessary to reduce the tacrolimus dose
information leaet, please inform your doctor or pharmacist. carefully (see also Dosage and administration). in isolated cases. Regular monitoring of the blood level of
What action should be taken if any of these side effects occur? If you have diarrhoea persisting over several days (e.g. with tacrolimus is recommended.
Most of the side effects described above occur at the start of Crohns disease, inammatory intestinal disorders), absorption of Decomposition of nifedipine (the active ingredient in ADALAT
treatment, are usually transient and do not require any particular the active ingredient may be incomplete due to the retention time LA 60 mg) involves a specic enzyme system (cytochrome P450
treatment. However, you should still tell your doctor so that he can of the drug in the gastrointestinal tract being too short. 3A4). As a result, any concomitant use of drugs that inuence
decide what steps to take. this enzyme system can lead to interaction between the drug in
What precautions should be taken when driving, operating
question and ADALAT LA 60 mg.
INFORMATION ON THE SHELF-LIFE OF THE machinery or working without a secure foothold?
Please note that this information may also apply to medicines
PRODUCT Treatment with this drug requires regular medical check-ups.
used recently.
The expiry date of this drug is printed on the cardboard box and on Reactions to this drug may vary from one person to another, and
the effect on your reaction speed may be such that your ability to What foods and drinks should you avoid?
the blister pack. Do not use the product after this date.
drive, to operate machinery and to work without a secure foothold - grapefruit juice: do not take ADALAT LA 60 mg with
may be impaired. This applies particularly at the start of treatment, grapefruit juice as it inhibits the decomposition of nifedipine in
ADALAT LA 60 mg Tablet the body and thus increases the effect of ADALAT LA 60 mg.
when the dose is increased, when medication is changed and in
{Identical to ADALAT Crono 60 mg}* conjunction with alcohol. DOSAGE AND ADMINISTRATION
INTERACTIONS WITH OTHER DRUGS Unless otherwise prescribed by your doctor, you should use
(Nifedipine) What other drugs affect the way ADALAT LA 60 mg ADALAT LA 60 mg as described below. Please follow the
works? directions carefully as otherwise ADALAT LA 60 mg cannot
COMPOSITION work properly.
The following interactions with ADALAT LA 60 mg have been
Pharmaceutically active ingredient How much ADALAT LA 60 mg should you take, and how
described on concomitant use of:
often?
1 ADALAT LA 60 mg sustained release tablet contains 60 mg - other drugs used to reduce blood pressure and tricyclic
nifedipine. antidepressants (medication used for the treatment of The recommended dose for adults is 1 ADALAT LA 60 mg
sustained release tablet once daily (equivalent to 60 mg nifedipine
Other ingredients depression): intensied reduction in blood pressure.
once daily).
Cellulose acetate, ferric oxide (E 172), hydroxypropylcellulose, Concomitant treatment with beta-blockers may in isolated cases
give rise to signs of heart failure. Diltiazem (a drug used to Depending on the patients clinical state, it is advisable to increase
hypromellose, macrogol 3350, macrogol 200,000, macrogol 5
treat high blood pressure and coronary heart disease) reduces the dose gradually until the recommended dose is attained.
million, magnesium stearate, sodium chloride, propylene glycol,
the decomposition of nifedipine and may therefore increase the Sustained release tablets containing 30 mg nifedipine are available
titanium dioxide (E 171).
effect of ADALAT LA 60 mg. If you are taking these drugs, for this purpose.
SUBSTANCE AND THERAPEUTIC CATEGORY OR your doctor will monitor your progress carefully and reduce the Dosage for patients with impaired liver function:
MODE OF ACTION dose if necessary. The starting dose is always 1 sustained release tablet containing 30
ADALAT LA 60 mg is a drug for the treatment of hypertension. - nitrates (agents for the treatment of coronary heart disease): mg nifedipine once daily. (Sustained release tablets containing 30
(calcium antagonist, antihypertensive) increase the effect on blood pressure and heart rate. mg nifedipine are available for this purpose). This is generally also
- cimetidine (a drug used to treat gastric and intestinal ulcers): the maintenance dose. The patients progress should be monitored
INDICATIONS
increased effect of ADALAT LA 60 mg, as the concentration carefully.
For treatment of high blood pressure with no discoverable organic
of nifedipine in the blood is increased. Note
cause (essential hypertension).
- rifampicin (a drug used to treat tuberculosis): accelerated The ADALAT LA 60 mg contains a tablet coating that is excreted
CONTRAINDICATIONS decomposition of nifedipine (the active ingredient in in the faeces after the active ingredient has been released.
When must ADALAT LA 60 mg not be used? ADALAT LA 60 mg) in the body. Rifampicin should not be How and when should you take ADALAT LA 60 mg?
ADALAT LA 60 mg must not be used if you administered at the same time as ADALAT LA 60 mg, as it ADALAT LA 60 mg sustained release tablets should be
- are known to be hypersensitive to the active ingredient will not be possible to obtain effective blood concentrations of swallowed whole with plenty of liquid (e.g. a glass of water),
nifedipine or the other ingredients of the product; nifedipine (see also Contraindications). preferably always at the same time of day. It is advisable not to
- are in cardiovascular shock; - quinupristin/dalfopristin (antibiotics): increased effect of take the tablets with grapefruit juice (see Interactions with other
- have severe narrowing of the blood vessel leading from the ADALAT LA 60 mg. Your blood pressure should therefore drugs).
heart to the main artery (high-grade aortic stenosis); be monitored and the nifedipine dose reduced if necessary. The sustained release tablets can be taken independently of
- have unstable angina pectoris; - phenytoin (a drug used to treat cardiac arrhythmia and meals.
- have suffered an acute myocardial infarction (heart attack) in epilepsy): weakening of the efcacy of ADALAT LA 60 For how long should you take ADALAT LA 60 mg?
the last 4 weeks; mg. If both drugs are being used concomitantly, your reaction
The attending doctor must decide on the length of the treatment.
to nifedipine (the active ingredient in ADALAT LA 60 mg)
- have severe narrowing of the gastrointestinal tract; The treatment of high blood pressure is usually a long-term
should be monitored and an increased dosage of ADALAT LA
- are taking rifampicin (a tuberculosis drug, see Interactions process.
60 mg considered if necessary. It may be necessary to adjust
with other drugs) at the same time;
the dosage of ADALAT LA 60 mg again after treatment with INCORRECT USE AND OVER DOSAGE
- are pregnant or breast-feeding.
phenytoin has been discontinued. What should you do if you take too much ADALAT LA 60 mg
When should you consult a doctor before taking ADALAT - erythromycin (antibiotic), uoxetine, nefazodone (either intentionally or by accident)?
LA 60 mg? (antidepressants, drugs for the treatment of depression), Depending on the degree of overdosage, there is a risk of a
Described below are cases in which you should only take protease inhibitors such as amprenavir, indinavir, nelnavir, pronounced drop in blood pressure, clouding of consciousness and
ADALAT LA 60 mg under certain circumstances and with ritonavir or saquinavir (drugs for the treatment of certain viral even coma, cardiac arrhythmia with deceleration or acceleration
particular caution. Please consult your doctor in these cases. infections), antimycotics such as ketoconazole, itraconazole or of the heart rate, elevated blood glucose levels (hyperglycaemia),
You should also consult your doctor if these details applied to uconazole (drugs for the treatment of fungal infections) and insufcient blood supply to the major organs and shock caused
you in the past. valproic acid (drug for the treatment of epilepsy): intensication by cardiac failure leading to accumulation of uid in the lungs
Caution is required if you of the action of ADALAT LA 60 mg cannot be ruled out. (pulmonary oedema).
- have extremely low blood pressure (systolic blood pressure - carbamazepine and phenobarbitone (drugs for the treatment If you think that you might have taken an overdose, you must
lower than 90 mmHg) of epilepsy): concomitant use of ADALAT LA 60 mg may inform your doctor immediately so that he can decide on what
- have very severe heart weakness (decompensated heart failure) weaken the effect of ADALAT LA 60 mg. measures to take.
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SPDI
What should you do if you have taken too few ADALAT concretions in the stomach (bezoars) and intestinal ulcers have PRECAUTIONS AND WARNINGS
LA 60 mg sustained release tablets or have forgotten to take been reported during treatment with ADALAT LA 60 mg. A What precautions should be taken?
a dose? marked reduction in certain blood cells (agranulocytosis) and
Nifedipine may break down more slowly in your body if you have
Do not take more ADALAT LA 60 mg sustained release tablets scaly inammation of the skin (exfoliative dermatitis) have also
a liver function disorder. Your doctor will therefore monitor your
next time; simply continue the treatment as prescribed. been reported.
progress carefully and reduce the dose if necessary.
What should you do if you want to interrupt the treatment or In isolated cases involving in vitro fertilisation (fertilisation
Patients with a serious disorder of blood circulation in the brain
stop using ADALAT LA 60 mg before the end of the course? outside the body), treatment with calcium antagonists such as
(cerebrovascular disease) should receive a lower dose.
You should always consult your doctor before deciding to interrupt nifedipine (the active ingredient in ADALAT LA 60 mg) has
been associated with transient changes to sperm and impaired What precautions should be taken when driving, operating
the course of treatment or stop taking ADALAT LA 60 mg
sperm function. machinery or working without a secure foothold?
altogether.
If you experience side effects that are not mentioned in this Treatment with this drug requires regular medical check-ups.
SIDE EFFECTS Reactions to this drug may vary from one person to another, and
information leaet, please inform your doctor or pharmacist.
What side effects can occur when using ADALAT LA the effect on your reaction speed may be such that your ability to
What action should be taken if any of these side effects occur?
60 mg? drive, to operate machinery and to work without a secure foothold
Most of the side effects described above occur at the start of may be impaired. This applies particularly at the start of treatment,
The following undesirable effects have been reported on
treatment, are usually transient and do not require any particular when the dose is increased, when medication is changed and in
administration of nifedipine (the active ingredient in ADALAT
treatment. However, you should still tell your doctor so that he can conjunction with alcohol.
LA 60 mg). Frequencies of occurrence are as follows:
decide what steps to take.
Very frequent more than 1 in 10 of those treated INTERACTIONS WITH OTHER DRUGS
Frequently less than 1 in 10 but more than 1 in 100 of those INFORMATION ON THE SHELF-LIFE OF THE
What other drugs affect the way Adalat retard works or are
treated PRODUCT
themselves affected by Adalat retard?
Occasionally less than 1 in 100 but more than 1 in 1,000 of The expiry date of this drug is printed on the cardboard box and on
The blood pressure-lowering effect of nifedipine (the active
those treated the blister pack. Do not use the product after this date.
ingredient in ADALAT RETARD) can be intensied by
Rare: less than 1 in 1,000 but more than 1 in 10,000 of other drugs used to reduce blood pressure and by tricyclic
those treated ADALAT RETARD Tablet antidepressants (medication used for the treatment of depression).
Very rare: less than 1 in 10,000 of those treated, including Concomitant treatment with nitrates (used to treat coronary heart
isolated cases (Nifedipine) disease) increases the effect of ADALAT RETARD on blood
Very frequent pressure and heart rate.
At the start of treatment especially, headaches and peripheral COMPOSITION Careful monitoring of the patient is indicated in the event of
oedema (accumulation of uid, e.g. in the lower leg) may occur Pharmaceutically active ingredient concomitant treatment with nifedipine and beta blockers (a drug
due to widening of the blood vessels; these side effects are usually used for treatment of high blood pressure and coronary heart
1 ADALAT RETARD sustained-release tablet contains 20 mg
transient. disease), as this can lead to an extreme reduction in blood pressure;
nifedipine.
Frequently signs of heart failure have also been observed on occasion.
Other ingredients
Particularly at the start of treatment and usually transient: Decomposition of nifedipine involves a specic enzyme system
Ferric oxide, red (E 172), hydroxypropyl methylcellulose, lactose (cytochrome P450 3A4). As a result, any concomitant use of drugs
reddening of the face and skin with a feeling of warmth (ush,
1 H2O, macrogol 4000, magnesium stearate, maize starch, that inuence this enzyme system can lead to interaction between
erythema, erythromelalgia).
microcrystalline cellulose, polysorbate 80, titanium(IV) oxide (E the drug in question and nifedipine.
Palpitations, dizziness, drowsiness, a feeling of weakness, nausea, 171).
constipation. Diltiazem (a drug used to treat high blood pressure and coronary
Occasionally MODE OF ACTION AND THERAPEUTIC CATEGORY heart disease) reduces the decomposition of nifedipine. If you are
Calcium antagonist. taking this drug, your doctor will monitor your progress carefully
An increased pulse rate (tachycardia), brief fainting as a result of
and reduce the dose of nifedipine if necessary.
an excessive reduction in blood pressure (syncope), a decrease in ADALAT RETARD is a drug used in the treatment of certain
blood pressure to below the norm, gastrointestinal disorders such types of coronary heart disease and high blood pressure. In isolated cases, nifedipine causes a decrease in the blood
as diarrhoea, abdominal pain, atulence, vomiting; dry mouth, concentration of quinidine (active substance used to treat
INDICATIONS cardiac arrhythmia) or a signicant rise in the quinidine blood
malaise, breathing disorders (dyspnoea), irritability, fatigue, sleep
disorders, sleepiness, a reduced sensitivity to touch (hypaesthesia), - Chronic stable angina pectoris (exercise-induced angina) concentration can occur after discontinuing therapy with
tingling in the arms and legs (paraesthesia), trembling of the ngers - Essential hypertension (high blood pressure with no discoverable nifedipine; the quinidine blood concentration should therefore be
(tremor), muscle and joint pain, muscle cramps, hypersensitivity organic cause). monitored in the event of concomitant use.
reactions involving the skin such as itching, rash, swelling of skin CONTRAINDICATIONS Nifedipine can increase the blood concentrations of digoxin
and mucous membranes (angioneurotic oedema, facial oedema), (active substance used primarily for treatment of cardiac output
sweating; impairment of liver function (intrahepatic cholestasis, When must Adalat retard not be used?
deciency) and theophylline (used to treat respiratory diseases):
elevation of transaminases), visual disturbances. ADALAT RETARD must not be used if you monitoring is therefore recommended.
In patients with impaired kidney function, a transient deterioration - are in cardiovascular shock; Concomitant use of quinupristin/dalfopristin (antibiotics) and
in kidney function may occasionally occur. An increased need to - have severe narrowing of the blood vessel leading from the nifedipine can intensify the effect of nifedipine. The patients
urinate and increased daily urine volumes may likewise occur heart to the main artery (high-grade aortic stenosis); blood pressure should therefore be monitored and the nifedipine
occasionally. - have unstable angina pectoris; dose reduced if necessary.
Angina pectoris attacks or, in patients with existing angina - have suffered an acute myocardial infarction (heart attack) in Cimetidine (a drug used to treat gastric and intestinal ulcers)
pectoris, an increase in the frequency, duration and severity of the last 4 weeks. increases the concentration of nifedipine in blood and can therefore
the attacks may occur occasionally, particularly at the start of - are taking rifampicin (a tuberculosis drug) at the same time; intensify the effect of nifedipine.
treatment. The occurrence of heart attacks (myocardial infarction) - are hypersensitive to nifedipine or any of the other ingredients; Rifampicin (a drug used to treat tuberculosis) accelerates
has been described in isolated cases.
- are pregnant or breast-feeding. the decomposition of nifedipine. Rifampicin should not be
Rare administered at the same time as nifedipine, as it will not be
When should you consult a doctor before taking Adalat
Bloating, belching, loss of appetite, hives, inammation of the retard? possible to obtain effective blood concentrations of nifedipine.
skin following exposure to sunlight or UV light (photodermatitis),
Described below are cases in which you should only take Nifedipine decreases the excretion of vincristine (a drug used
jaundice, poor vision.
ADALAT RETARD under certain circumstances and with in the treatment of cancer), which means that the side effects of
Blood count changes such as a reduction in the number of red particular caution. Please consult your doctor in these cases. vincristine may increase. For this reason it may be advisable to
or white blood cells or blood platelets (anaemia, leukopenia, You should also consult your doctor if these details applied to reduce the dose of vincristine.
thrombocytopenia), bleeding in the skin and mucous membranes you in the past. Increased blood concentrations of cephalosporin have been
with a reduction in blood platelets (thrombocytopenic purpura)
Particularly careful medical supervision is required in patients observed following simultaneous administration of cephalosporins
and small haemorrhages in the skin and mucous membranes
(purpura). who (e.g cexime, an antibiotic) and nifedipine.
In rare cases, especially in older male patients receiving long-term - have extremely low blood pressure (systolic blood pressure Concomitant use of phenytoin (a drug used to treat cardiac
therapy, enlargement of the mammary glands (gynaecomastia) has lower than 90 mmHg) arrhythmia and epilepsy) and nifedipine weakens the efcacy of
been observed; however, so far this has been reversible in all cases - have very severe heart weakness (decompensated heart failure) nifedipine. If both drugs are being used concomitantly, the patients
after discontinuing medication. for which you are not receiving adequate treatment. reaction to nifedipine should be monitored and an increase to the
nifedipine dosage considered if necessary. It may be necessary
In rare cases, long-term treatment can result in gum changes Caution is required in patients undergoing dialysis who also have
high blood pressure (malignant hypertension) and decreased to adjust the nifedipine dosage after treatment with phenytoin has
(e.g. gingival hyperplasia) which are completely reversible after
been discontinued.
discontinuation of ADALAT LA 60 mg. blood volume (hypovolaemia); widening of the blood vessels
In equally rare cases, acute general allergic reactions (anaphylactic (vasodilatation) can cause a substantial fall in blood pressure. The risk that the effect of nifedipine will be intensied cannot
reactions) can occur such as fever, swelling of the larynx (laryngeal What should you be aware of when pregnant or breast- be ruled out when nifedipine is used at the same time as drugs
oedema) and spasms in the bronchial muscles which can cause feeding? containing the following active ingredients:
shortness of breath to a potentially fatal degree; these reactions Adalat retard should not be used at all during pregnancy, as studies - Erythromycin (antibiotic),
subside after withdrawal of the drug. with the active ingredient nifedipine have shown evidence of - Fluoxetine, nefazodone (antidepressants),
An increase in blood glucose levels has been observed in rare foetal damage. There is not sufcient evidence in humans. If you - Amprenavir, indinavir, nelnavir, ritonavir or saquinavir
cases. This is an especially important consideration in patients discover that you are pregnant while taking ADALAT RETARD (active substances used to treat certain viral infections) or
with diabetes mellitus. , you must consult your doctor to arrange alternative treatment. - Ketoconazole, itraconazole or uconazole (active substances
Very rare Nifedipine passes into breast milk. If you need to take ADALAT used to treat fungal infections).
In very rare cases, disturbances of intestinal transit with symptoms RETARD while you are breast-feeding, you should wean your Concomitant use of tacrolimus (a drug used to prevent transplant
of intestinal obstruction (e.g. atulence, colicky pain) and the baby because nothing is known about the possible effects of rejection after, for example, liver or kidney transplants) and
occurrence of inammation of the gullet (oesophagus), stony nifedipine on the infant. nifedipine can lead to elevated levels of tacrolimus in blood;
126
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SPDI
it may be necessary to reduce the tacrolimus dose in isolated Occasionally: fewer than 1 in 100, What action should be taken if any of these side effects occur?
cases. Regular monitoring of the blood level of tacrolimus is but more than 1 in 1,000 treated patients Most of the side effects described above are only transient and do
recommended. Rarely: fewer than 1 in 1,000, not require any particular treatment. However, you should still tell
Experience with the calcium antagonist nimodipine indicates that but more than 1 in 10,000 treated patients your doctor so that he can decide what steps to take.
the possibility cannot be ruled out that concomitant administration Very rarely: fewer than 1 in 10,000 treated patients, INFORMATION ON THE SHELF-LIFE OF THE
of carbamazepine or phenobarbital (drugs used to treat epilepsy) including isolated cases PRODUCT
weakens the effect of nifedipine. Very frequently The expiry date of this drug product is printed on the cardboard
Experience with nimodipine indicates that concomitant use of At the start of treatment especially, headaches and peripheral box and on the blister pack. Do not use the product after this date.
valproic acid (a drug used to treat epilepsy) is likely to intensify oedema (accumulation of uid, e.g. in the lower leg) may very
the effect of nifedipine. frequently occur due to widening of the blood vessels; these side HOW SHOULD ADALAT RETARD BE STORED?
Please note that this information may also apply to medicines effects are usually transient. Keep in light-protected conditions.
used recently. Frequently
What foods and drinks should you avoid? Furthermore, at the start of treatment especially, facial ush, skin AVALOX Tablet
Do not take ADALAT RETARD with grapefruit juice as it reddening with a feeling of warmth (erythema), and conditions
inhibits the decomposition of nifedipine in the body and thus involving painful swelling and reddening of the arms and legs (Moxioxacin hydrochloride)
increases the effect of ADALAT RETARD . (erythromelalgia) can occur.

There have likewise been frequent reports of palpitations, AVALOX I.V.
dizziness, drowsiness, a feeling of weakness and nausea.
Unless otherwise prescribed by your doctor, you should use
Occasionally
ADALAT RETARD as described below. Please follow the
directions carefully as otherwise ADALAT RETARD cannot On occasion, an increased pulse rate (tachycardia), a temporary (Moxioxacin hydrochloride)
work properly. loss of consciousness due to an excessive fall in blood pressure
(syncope) and a drop in blood pressure to below the norm To reduce the development of drug-resistant bacteria and maintain
How much Adalat retard should you take, and how often? the effectiveness of AVALOX and other antibacterial drugs,
(hypotonic circulatory reaction) can occur.
As far as possible, the treatment should be adapted according to Treatment with nifedipine occasionally causes gastrointestinal AVALOX should be used only to treat or prevent infections that
the severity of your condition and your response. disorders such as upper abdominal complaints (dyspepsia), are proven or strongly suspected to be caused by bacteria.
The clinical picture may require the dose to be gradually increased diarrhoea, abdominal pain, constipation, atulence, vomiting and DESCRIPTION
to the recommended level. a dry mouth. AVALOX (moxioxacin hydrochloride) is a synthetic broad
If you have impaired liver function, your doctor will monitor your In addition, malaise, respiratory disorders (dyspnea), nervousness, spectrum antibacterial agent and is available as AVALOX
progress carefully and may reduce the dose. fatigue, sleep disorders or sleepiness, reduced sensitivity to touch Tablets for oral administration and as AVALOX I.V. for
If you have a serious cerebrovascular disease you should receive (hypoaesthesia), tingling in the arms and legs (paraesthesia), intravenous administration. Moxioxacin, a uoroquinolone,
a lower dose. tremor of the ngers, muscle and joint pain and muscular spasms is available as the monohydrochloride salt of 1-cyclopropyl-7-
can occur on occasion. [(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-uoro-8-methoxy-1,4-
Adults
Skin hypersensitivity reactions such as itching (pruritus), skin dihydro-4-oxo-3 quinoline carboxylic acid. It is a slightly yellow
Chronic stable angina pectoris (exercise-induced angina)
rash (exanthema), swelling of the skin and mucous membranes to yellow crystalline substance with a molecular weight of 437.9.
1 sustained-release ADALAT RETARD tablet twice daily (angioedema, facial oedema), perspiration and liver function Its empirical formula is C21H24FN3O4 *HCl and its chemical
(equivalent to 40 mg nifedipine daily) disorders (intrahepatic cholestasis, increased transaminase levels) structure is as follows:
The recommended dose is 20 mg twice daily. This can be increased have been observed on occasion.
to 40 mg nifedipine twice daily. In patients with kidney failure, use of nifedipine may occasionally
Essential hypertension (high blood pressure with no cause a transient deterioration in kidney function. An increased
discoverable organic cause) need to urinate and increased daily urine volumes may likewise
1 sustained-release ADALAT RETARD tablet twice daily occasionally occur.
(equivalent to 40 mg nifedipine daily) A minor, transient change in visual perception has been reported
The recommended dose is 20 mg twice daily. This can be increased on occasion.
to 40 mg nifedipine twice daily. Particularly at the start of treatment, angina pectoris attacks may
How and when should you take Adalat retard? occasionally occur and patients who already have angina pectoris
may experience an increase in the frequency, duration and severity AVALOX Tablets are available as lm-coated tablets containing
ADALAT RETARD sustained-release tablets should generally
of attacks. Myocardial infarctions have been described in isolated moxioxacin hydrochloride (equivalent to 400 mg moxioxacin).
be swallowed whole with plenty of liquid after meals, preferably at
cases. The inactive ingredients are microcrystalline cellulose, lactose
the same time in the morning and evening each day.
Rarely monohydrate, croscarmellose sodium, magnesium stearate,
The sustained-release tablets must not be split as otherwise the hypromellose, titanium dioxide, and ferric oxide.
Treatment with nifedipine rarely a bloated sensation, belching and
coating cannot provide its light-protective effect.
loss of appetite. AVALOX I.V. is available in ready-to-use 250 mL glass bottles
For how long should you take Adalat retard? as a sterile, preservative free, 0.8% sodium chloride aqueous
In rare cases, long-term treatment can result in gum changes
The attending doctor must decide on the length of the treatment. (gingival hyperplasia) which are completely reversible after solution of moxioxacin hydrochloride (containing 400 mg
discontinuation of therapy. moxioxacin) with pH ranging from 4.1 to 4.6. The appearance of
INCORRECT USE AND OVER DOSAGE
the intravenous solution is yellow. The color does not affect, nor
What should you do if you take too much Adalat retard (either Hives (urticaria), inammation of the skin after exposure to the
is it indicative of, product stability. The inactive ingredients are
intentionally or by accident)? sun and UV radiation (photodermatitis) and jaundice have been
sodium chloride, USP, Water for Injection, USP, and may include
observed rarely.
If you think that you might have taken an overdose, you must hydrochloric acid and/or sodium hydroxide for pH adjustment.
inform your doctor/an emergency doctor immediately so that he In rare cases, especially in older male patients receiving long-term
therapy, enlargement of the mammary glands (gynaecomastia) has CLINICAL PHARMACOLOGY
can decide on what measures to take.
been observed; however, so far this has been reversible in all cases Absorption
In the event of over dosage, there is a risk of a pronounced drop
after discontinuing medication. Moxioxacin, given as an oral tablet, is well absorbed from the
in blood pressure, deceleration or acceleration of the heart rate,
In rare cases, changes in the blood count such as a reduction gastrointestinal tract. The absolute bioavailability of moxioxacin
clouding of consciousness ranging up to coma, elevated blood
in red or white blood cells or platelets (anaemia, leucopenia, is approximately 90 percent. Co-administration with a high fat
glucose levels (hyperglycaemia), insufcient blood supply to
thrombocytopenia), bleeding in the skin and mucous membranes meal (i.e., 500 calories from fat) does not affect the absorption
the major organs and shock caused by cardiac failure leading to
with a reduction in blood platelets (thrombocytopenic purpura) of moxioxacin.
accumulation of uid in the lungs (pulmonary oedema).
and small haemorrhages in the skin and mucous membranes Consumption of 1 cup of yogurt with moxioxacin does not
What should you do if you have taken too few Adalat retard (purpura) have been described in connection with consumption of
sustained-release tablets or have forgotten to take a dose? signicantly affect the extent or rate of systemic absorption
nifedipine. (AUC).
Do not take more ADALAT RETARD sustained-release tablets In equally rare cases, acute general allergic reactions can occur The mean ( SD) Cmax and AUC values following single
next time; simply continue the treatment as prescribed. such as fever, swelling of the larynx (oedema of the glottis), and and multiple doses of 400 mg moxioxacin given orally are
What should you do if you want to interrupt the treatment or spasms in the bronchial muscles which can cause shortness of summarized below.
stop using Adalat retard before the end of the course? breath to a potentially fatal degree; these reactions subside after
withdrawal of the drug. Cmax AUC Half-life
You should always consult your doctor before deciding to interrupt
(mg/L) (mgh/L) (hr)
the course of treatment or stop taking ADALAT RETARD There have been rare reports of impaired vision.
Single Dose Oral
altogether. An increase in the serum blood glucose level (hyperglycaemia) Healthy (n = 372) 3.1 1.0 36.1 9.1 11.5 - 15.6*
If you wish to discontinue use of ADALAT RETARD, especially has been observed in rare cases. This is an especially important Multiple Dose Oral
high-dose use, you should always proceed in stages. consideration in patients with diabetes mellitus. Healthy young male/female 4.5 0.5 48.0 2.7 12.7 1.9
Very rare (n = 15)
SIDE EFFECTS Healthy elderly male (n = 8) 3.8 0.3 51.8 6.7
In very rare cases, a marked reduction in certain blood cells
What side effects can occur when using Adalat retard? Healthy elderly female (n = 8) 4.6 0.6 54.6 6.7
(agranulocytosis) and scaly inammation of the skin (exfoliative
The following adverse effects have been reported after Healthy young male (n = 8) 3.6 0.5 48.2 9.0
dermatitis) have been reported. Healthy young female (n = 9) 4.2 0.5 49.3 9.5
administration of nifedipine (the active ingredient of ADALAT
In isolated cases involving in vitro fertilisation, treatment with
RETARD). The frequency is indicated as follows: * Range of means from different studies
calcium antagonists such as nifedipine has been associated with
Very frequently: more than 1 in 10 treated patients transient changes to sperm and impaired sperm function. The mean ( SD) Cmax and AUC values following single and
Frequently: fewer than 1 in 10, If you experience side effects that are not mentioned in this multiple doses of 400 mg moxioxacin given by 1 hour I.V.
but more than 1 in 100 treated patients information leaet, please inform your doctor or pharmacist. infusion are summarized below.
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Book_01.indd 127 6/4/2008 2:20:13 PM

SPDI
Cmax AUC Half-life sinus concentrations which were measured 3 hours post-dose after 45% and 33% in HD and CAPD patients, respectively, compared
(mg/L) (mgh/L) (hr)
5 days of dosing. to healthy, historical controls. The exposure (AUC) to the sulfate
N=5 conjugate (M1) increased by 1.4- to 1.5-fold in these patients.
Single Dose I.V. The mean AUC of the glucuronide conjugate (M2) increased by
Healthy young male/female 3.9 0.9 39.3 8.6 8.2 - 15.4* N = 7
a factor of 7.5, whereas the mean Cmax values of the glucuronide
(n = 56) #N = 12
conjugate (M2) increased by a factor of 2.5 to 3, compared to
Patients (n = 118) * Reects only non-protein bound concentrations of drug. healthy subjects. The sulfate and the glucuronide conjugates of
Male (n = 64) 4.4 3.7 Metabolism moxioxacin are not microbiologically active, and the clinical
Female (n = 54) 4.5 2.0 implication of increased exposure to these metabolites in patients
Approximately 52% of an oral or intravenous dose of moxioxacin
< 65 years (n = 58) 4.6 4.2 with renal disease including those undergoing HD and CAPD has
is metabolized via glucuronide and sulfate conjugation. The
65 years (n = 60) 4.3 1.3
cytochrome P450 system is not involved in moxioxacin not been studied.
Multiple Dose I.V. metabolism, and is not affected by moxioxacin. The sulfate Oral administration of 400 mg QD moxioxacin for 7 days to
Healthy young male (n = 8) 4.2 0.8 38.0 4.7 14.8 2.2 conjugate (M1) accounts for approximately 38% of the dose, and patients on HD or CAPD produced mean systemic exposure
Healthy elderly 6.1 1.3 48.2 0.9 10.1 1.6 is eliminated primarily in the feces. Approximately 14% of an (AUCss) to moxioxacin similar to that generally seen in healthy
(n =12; 8 male, 4 female) oral or intravenous dose is converted to a glucuronide conjugate volunteers. Steady-state Cmax values were about 22% lower in HD
Patients** (n = 107) (M2), which is excreted exclusively in the urine. Peak plasma patients but were comparable between CAPD patients and healthy
Male (n = 58) 4.2 2.6 concentrations of M2 are approximately 40% those of the parent volunteers. Both HD and CAPD removed only small amounts of
Female (n = 49) 4.6 1.5 drug, while plasma concentrations of M1 are generally less than moxioxacin from the body (approximately 9% by HD, and 3%
< 65 years (n = 52) 4.1 1.4 10% those of moxioxacin. by CAPD). HD and CAPD also removed about 4% and 2% of the
65 years (n = 55) 4.7 2.7
In vitro studies with cytochrome (CYP) P450 enzymes indicate glucuronide metabolite (M2), respectively.
* Range of means from different studies that moxioxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, Hepatic Insufciency
CYP2C19, or CYP1A2, suggesting that moxioxacin is unlikely In 400 mg single oral dose studies in 6 patients with mild (Child
** Expected Cmax (concentration obtained around the time of the
to alter the pharmacokinetics of drugs metabolized by these Pugh Class A), and 10 patients with moderate (Child Pugh Class
end of the infusion)
enzymes. B), hepatic insufciency, moxioxacin mean systemic exposure
Plasma concentrations increase proportionately with dose up to
Excretion (AUC) was 78% and 102%, respectively, of 18 healthy controls
the highest dose tested (1200 mg single oral dose). The mean (
Approximately 45% of an oral or intravenous dose of moxioxacin and mean peak concentration (Cmax) was 79% and 84% of
SD) elimination half-life from plasma is 12 1.3 hours; steady-
is excreted as unchanged drug (~20% in urine and ~25% in feces). controls.
state is achieved after at least three days with a 400 mg once daily
A total of 96% 4% of an oral dose is excreted as either unchanged The mean AUC of the sulfate conjugate of moxioxacin (M1)
regimen.
drug or known metabolites. The mean ( SD) apparent total body increased by 3.9-fold (ranging up to 5.9-fold) and 5.7-fold
Mean Steady-State Plasma Concentrations of Moxioxacin clearance and renal clearance are 12 2.0 L/hr and 2.6 0.5 L/hr, (ranging up to 8.0-fold) in the mild and moderate groups,
Obtained With Once Daily Dosing of 400 mg Either Orally respectively. respectively. The mean Cmax of M1 increased by approximately
(n=10) or by I.V. Infusion (n=12) 3-fold in both groups (ranging up to 4.7- and 3.9-fold). The mean
Special Populations
AUC of the glucuronide conjugate of moxioxacin (M2) increased
Geriatric by 1.5-fold (ranging up to 2.5-fold) in both groups. The mean
Following oral administration of 400 mg moxioxacin for 10 Cmax of M2 increased by 1.6- and 1.3-fold (ranging up to 2.7-
days in 16 elderly (8 male; 8 female) and 17 young (8 male; 9 and 2.1-fold), respectively. The clinical signicance of increased
female) healthy volunteers, there were no age-related changes in exposure to the sulfate and glucuronide conjugates has not been
moxioxacin pharmacokinetics. In 16 healthy male volunteers studied. No dosage adjustment is recommended for mild or
(8 young; 8 elderly) given a single 200 mg dose of oral moderate hepatic insufciency (Child Pugh Classes A and B). The
moxioxacin, the extent of systemic exposure (AUC and Cmax) pharmacokinetics of moxioxacin in severe hepatic insufciency
was not statistically different between young and elderly males (Child Pugh Class C) have not been studied. (See DOSAGE AND
and elimination half-life was unchanged. No dosage adjustment ADMINISTRATION.)
is necessary based on age. In large phase III studies, the Photosensitivity Potential
concentrations around the time of the end of the infusion in elderly
patients following intravenous infusion of 400 mg were similar to A study of the skin response to ultraviolet (UVA and UVB) and
those observed in young patients. visible radiation conducted in 32 healthy volunteers (8 per group)
demonstrated that moxioxacin does not show phototoxicity in
Pediatric comparison to placebo. The minimum erythematous dose (MED)
The pharmacokinetics of moxioxacin in pediatric subjects have was measured before and after treatment with moxioxacin
not been studied. (200 mg or 400 mg once daily), lomeoxacin (400 mg once
Gender daily), or placebo. In this study, the MED measured for both
Distribution Following oral administration of 400 mg moxioxacin daily for doses of moxioxacin were not signicantly different from
10 days to 23 healthy males (19-75 years) and 24 healthy females placebo, while lomeoxacin signicantly lowered the MED. (See
Moxioxacin is approximately 30-50% bound to serum proteins, PRECAUTIONS, Information for Patients.)
independent of drug concentration. The volume of distribution (19-70 years), the mean AUC and Cmax were 8% and 16%
higher, respectively, in females compared to males. There are no DRUG-DRUG INTERACTIONS
of moxioxacin ranges from 1.7 to 2.7 L/kg. Moxioxacin is
signicant differences in moxioxacin pharmacokinetics between
widely distributed throughout the body, with tissue concentrations The potential for pharmacokinetic drug interactions between
male and female subjects when differences in body weight are
often exceeding plasma concentrations. Moxioxacin has been moxioxacin and itraconazole, theophylline, warfarin, digoxin,
taken into consideration.
detected in the saliva, nasal and bronchial secretions, mucosa of atenolol, probenecid, morphine, oral contraceptives, ranitidine,
the sinuses, skin blister uid, subcutaneous tissue, skeletal muscle, A 400 mg single dose study was conducted in 18 young males glyburide, calcium, iron, and antacids has been evaluated. There
and females. The comparison of moxioxacin pharmacokinetics was no clinically signicant effect of moxioxacin on itraconazole,
and abdominal tissues and uids following oral or intravenous
in this study (9 young females and 9 young males) showed no theophylline, warfarin, digoxin, atenolol, oral contraceptives, or
administration of 400 mg. Moxioxacin concentrations measured
differences in AUC or Cmax due to gender. Dosage adjustments glyburide kinetics. Itraconazole, theophylline, warfarin, digoxin,
post-dose in various tissues and uids following a 400 mg oral
based on gender are not necessary. probenecid, morphine, ranitidine, and calcium did not signicantly
or I.V. dose are summarized in the following table. The rates of
Race affect the pharmacokinetics of moxioxacin. These results and the
elimination of moxioxacin from tissues generally parallel the
Steady-state moxioxacin pharmacokinetics in male Japanese data from in vitro studies suggest that moxioxacin is unlikely to
elimination from plasma.
subjects were similar to those determined in Caucasians, with signicantly alter the metabolic clearance of drugs metabolized by
Moxioxacin Concentrations (mean SD) in Tissues and the CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2 enzymes.
a mean Cmax of 4.1 g/mL, an AUC24 of 47 gh/mL, and an
Corresponding Plasma Concentrations After a Single 400 mg
elimination half-life of 14 hours, following 400 mg p.o. daily. As with all other quinolones, iron and antacids signicantly
Oral or Intravenous Dose
Renal Insufciency reduced bioavailability of moxioxacin.
Plasma Tissue or Fluid Tissue Itraconazole: In a study involving 11 healthy volunteers, there
The pharmacokinetic parameters of moxioxacin are not
Concen- Concentration Plasma was no signicant effect of itraconazole (200 mg once daily
tration (g/mL Ratio: signicantly altered in mild, moderate, severe, or end-stage renal
disease. No dosage adjustment is necessary in patients with renal for 9 days), a potent inhibitor of cytochrome P4503A4, on the
Tissue or Fluid N (g/mL) or g/g)
impairment, including those patients requiring hemodialysis (HD) pharmacokinetics of moxioxacin (a single 400 mg dose given on
Respiratory
or continuous ambulatory peritoneal dialysis (CAPD). the 7th day of itraconazole dosing). In addition, moxioxacin was
Alveolar Macrophages 5 3.3 0.7 61.8 27.3 21.2 10.0
In a single oral dose study of 24 patients with varying degrees of shown not to affect the pharmacokinetics of itraconazole.
Bronchial Mucosa 8 3.3 0.7 5.5 1.3 1.7 0.3
Epithelial Lining Fluid 5 3.3 0.7 24.4 14.7 8.7 6.1 renal function from normal to severely impaired, the mean peak Theophylline: No signicant effect of moxioxacin (200 mg every
Sinus concentrations (Cmax) of moxioxacin were reduced by 21% and twelve hours for 3 days) on the pharmacokinetics of theophylline
Maxillary Sinus Mucosa 4 3.7 1.1 7.6 1.7 2.0 0.3 28% in the patients with moderate (CLCR 30 and 60 mL/min) (400 mg every twelve hours for 3 days) was detected in a study
and severe (CLCR < 30 mL/min) renal impairment, respectively. involving 12 healthy volunteers. In addition, theophylline was
Anterior Ethmoid Mucosa 3 3.7 1.1 8.8 4.3 2.2 0.6
The mean systemic exposure (AUC) in these patients was not shown to affect the pharmacokinetics of moxioxacin. The
Nasal Polyps 4 3.7 1.1 9.8 4.5 2.6 0.6
increased by 13%. In the moderate and severe renally impaired effect of co-administration of a 400 mg dose of moxioxacin
Skin, Musculoskeletal
patients, the mean AUC for the sulfate conjugate (M1) increased with theophylline has not been studied, but it is not expected to be
Blister Fluid 5 3.0 0.5 2.6 0.9 0.9 0.2
by 1.7-fold (ranging up to 2.8-fold) and mean AUC and Cmax for clinically signicant based on in vitro metabolic data showing that
Subcutaneous Tissue 6 2.3 0.4# 0.9 0.3* 0.4 0.6
the glucuronide conjugate (M2) increased by 2.8-fold (ranging up moxioxacin does not inhibit the CYP1A2 isoenzyme.
Skeletal Muscle 6 2.3 0.4# 0.9 0.2* 0.4 0.1
to 4.8-fold) and 1.4-fold (ranging up to 2.5-fold), respectively. Warfarin: No signicant effect of moxioxacin (400 mg once
Intra-Abdominal
The pharmacokinetics of single dose and multiple dose daily for eight days) on the pharmacokinetics of R- and S-warfarin
Abdominal tissue 8 2.9 0.5 7.6 2.0 2.7 0.8
moxioxacin were studied in patients with CLCR < 20 mL/min (25 mg single dose of warfarin sodium on the fth day) was
Abdominal exudate 10 2.3 0.5 3.5 1.2 1.6 0.7
on either hemodialysis or continuous ambulatory peritoneal detected in a study involving 24 healthy volunteers. No signicant
Abscess uid 6 2.7 0.7 2.3 1.5 0.80.4
dialysis (8 HD, 8 CAPD). Following a single 400 mg oral dose, change in prothrombin time was observed. (See PRECAUTIONS,
all moxioxacin concentrations were measured 3 hours after the AUC of moxioxacin in these HD and CAPD patients did Drug Interactions.)
a single 400 mg dose, except the abdominal tissue and exudate not vary signicantly from the AUC generally found in healthy Digoxin: No signicant effect of moxioxacin (400 mg once
concentrations which were measured at 2 hours post-dose and the volunteers. Cmax values of moxioxacin were reduced by about daily for two days) on digoxin (0.6 mg as a single dose) AUC
128
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SPDI
was detected in a study involving 12 healthy volunteers. The mean II (DNA gyrase) and topoisomerase IV required for bacterial For testing Enterobacteriaceae and methicillin-susceptible
digoxin Cmax increased by about 50% during the distribution DNA replication, transcription, repair, and recombination. It Staphylococcus aureus:
phase of digoxin. This transient increase in digoxin Cmax is not appears that the C8-methoxy moiety contributes to enhanced MIC (g/mL) Interpretation
viewed to be clinically signicant. Moxioxacin pharmacokinetics activity and lower selection of resistant mutants of Gram-positive
2.0 Susceptible (S)
were similar in the presence or absence of digoxin. No dosage bacteria compared to the C8-H moiety. The presence of the bulky
4.0 Intermediate (I)
adjustment for moxioxacin or digoxin is required when these bicycloamine substituent at the C-7 position prevents active efux,
8.0 Resistant (R)
drugs are administered concomitantly. associated with the NorA or pmrA genes seen in certain Gram-
positive bacteria. For testing Haemophilus inuenzae and Haemophilus
Atenolol: In a crossover study involving 24 healthy volunteers (12
parainuenzae.
male; 12 female), the mean atenolol AUC following a single oral The mechanism of action for quinolones, including moxioxacin,
dose of 50 mg atenolol with placebo was similar to that observed is different from that of macrolides, beta-lactams, aminoglycosides, MIC (g/mL) Interpretation
when atenolol was given concomitantly with a single 400 mg oral or tetracyclines; therefore, microorganisms resistant to these classes 1.0 Susceptible (S)
dose of moxioxacin. The mean Cmax of single dose atenolol of drugs may be susceptible to moxioxacin and other quinolones. a This interpretive standard is applicable only to broth
decreased by about 10% following co-administration with a single There is no known cross-resistance between moxioxacin and microdilution susceptibility tests with Haemophilus inuenzae
dose of moxioxacin. other classes of antimicrobials. and Haemophilus parainuenzae using Haemophilus Test
Morphine: No signicant effect of morphine sulfate (a single In vitro resistance to moxioxacin develops slowly via multiple- Medium1.
10 mg intramuscular dose) on the mean AUC and Cmax of step mutations. Resistance to moxioxacin occurs in vitro at a The current absence of data on resistant strains precludes
moxioxacin (400 mg single dose) was observed in a study of 20 general frequency of between 1.8 x 109 to < 1 x 1011 for Gram- dening any results other than Susceptible. Strains yielding
healthy male and female volunteers. positive bacteria. MIC results suggestive of a nonsusceptible category should
Oral Contraceptives: A placebo-controlled study in 29 healthy Cross-resistance has been observed between moxioxacin and be submitted to a reference laboratory for further testing.
female subjects showed that moxioxacin 400 mg daily for 7 other uoroquinolones against Gram-negative bacteria. Gram- For testing Streptococcus species including Streptococcus
days did not interfere with the hormonal suppression of oral positive bacteria resistant to other uoroquinolones may, however, pneumoniae and Enterococcus faecalis:
contraception with 0.15 mg levonorgestrel/0.03 mg ethinylestradiol still be susceptible to moxioxacin.
(as measured by serum progesterone, FSH, estradiol, and LH), MIC (g/mL) Interpretation
Moxioxacin has been shown to be active against most strains
or with the pharmacokinetics of the administered contraceptive 1.0 Susceptible (S)
of the following microorganisms, both in vitro and in clinical
agents. 2.0 Intermediate (I)
infections as described in the INDICATIONS AND USAGE
Probenecid: Probenecid (500 mg twice daily for two days) did not 4.0 Resistant (R)
section.
alter the renal clearance and total amount of moxioxacin (400 mg b These interpretive standards are applicable only to broth
Aerobic Gram-positive microorganisms
single dose) excreted renally in a study of 12 healthy volunteers. microdilution susceptibility tests using cation-adjusted Mueller-
Enterococcus faecalis (many strains are only moderately
Ranitidine: No signicant effect of ranitidine (150 mg twice Hinton broth with 2 - 5% lysed horse blood.
susceptible)
daily for three days as pretreatment) on the pharmacokinetics Staphylococcus aureus (methicillin-susceptible strains only) A report of Susceptible indicates that the pathogen is likely
of moxioxacin (400 mg single dose) was detected in a study to be inhibited if the antimicrobial compound in the blood
Streptococcus anginosus
involving 10 healthy volunteers. reaches the concentrations usually achievable. A report of
Streptococcus constellatus
Antidiabetic agents: In diabetics, glyburide (2.5 mg once daily Intermediate indicates that the result should be considered
Streptococcus pneumoniae (including multi-drug resistant equivocal, and, if the microorganism is not fully susceptible
for two weeks pretreatment and for ve days concurrently) mean
strains [MDRSP]*) to alternative, clinically feasible drugs, the test should be
AUC and Cmax were 12% and 21% lower, respectively, when
Streptococcus pyogenes repeated. This category implies possible clinical applicability
taken with moxioxacin (400 mg once daily for ve days) in
comparison to placebo. Nonetheless, blood glucose levels were * MDRSP, Multi-drug resistant Streptococcus pneumoniae in body sites where the drug is physiologically concentrated
decreased slightly in patients taking glyburide and moxioxacin includes isolates previously known as PRSP (Penicillin- or in situations where a high dosage of drug can be used.
in comparison to those taking glyburide alone, suggesting no resistant S. pneumoniae), and are strains resistant to two or This category also provides a buffer zone which prevents
interference by moxioxacin on the activity of glyburide. These more of the following antibiotics: penicillin (MIC 2 g/mL), small uncontrolled technical factors from causing major
interaction results are not viewed as clinically signicant. 2nd generation cephalosporins (e.g., cefuroxime), macrolides, discrepancies in interpretation. A report of Resistant indicates
Calcium: Twelve healthy volunteers were administered tetracyclines, and trimethoprim/sulfamethoxazole. that the pathogen is not likely to be inhibited if the antimicrobial
concomitant moxioxacin (single 400 mg dose) and calcium Aerobic Gram-negative microorganisms compound in the blood reaches the concentrations usually
(single dose of 500 mg Ca++ dietary supplement) followed by an Enterobacter cloacae achievable; other therapy should be selected.
additional two doses of calcium 12 and 24 hours after moxioxacin Escherichia coli Standardized susceptibility test procedures require the use of
administration. Calcium had no signicant effect on the mean Haemophilus inuenzae laboratory control microorganisms to control the technical
AUC of moxioxacin. The mean Cmax was slightly reduced Haemophilus parainuenzae aspects of the laboratory procedures. Standard moxioxacin
and the time to maximum plasma concentration was prolonged Klebsiella pneumoniae powder should provide the following MIC values:
when moxioxacin was given with calcium compared to when Microorganism MIC (g/mL)
Moraxella catarrhalis
moxioxacin was given alone (2.5 hours versus 0.9 hours). These
Proteus mirabilis Enterococcus faecalis ATCC 29212 0.06-0.5
differences are not considered to be clinically signicant.
Anaerobic microorganisms Escherichia coli ATCC 25922 0.008 - 0.06
Antacids: When moxioxacin (single 400 mg tablet dose) was Haemophilus inuenzae ATCC 49247c 0.008 - 0.03
administered two hours before, concomitantly, or 4 hours after Bacteroides fragilis
Staphylococcus aureus ATCC 29213 0.015 - 0.06
an aluminum/magnesium-containing antacid (900 mg aluminum Bacteroides thetaiotaomicron
Streptococcus pneumoniae ATCC 49619d 0.06- 0.25
hydroxide and 600 mg magnesium hydroxide as a single oral dose) Clostridium perfringens c This quality control range is applicable to only H. inuenzae
to 12 healthy volunteers there was a 26%, 60% and 23% reduction Peptostreptococcus species
ATCC 49247 tested by a broth microdilution procedure using
in the mean AUC of moxioxacin, respectively. Moxioxacin Other microorganisms
should be taken at least 4 hours before or 8 hours after antacids Haemophilus Test Medium (HTM)1.
Chlamydia pneumoniae d This quality control range is applicable to only S. pneumoniae
containing magnesium or aluminum, as well as sucralfate, metal
Mycoplasma pneumoniae ATCC 49619 tested by a broth microdilution procedure using
cations such as iron, and multivitamin preparations with zinc, or
VIDEX (didanosine) chewable/ buffered tablets or the pediatric The following in vitro data are available, but their clinical cation-adjusted Mueller-Hinton broth with 2 - 5% lysed horse
powder for oral solution. (See PRECAUTIONS, Drug Interactions signicance is unknown. blood.
and DOSAGE AND ADMINISTRATION.) Moxioxacin exhibits in vitro minimum inhibitory concentrations Diffusion Techniques: Quantitative methods that require
Iron: When moxioxacin tablets were administered concomitantly (MICs) of 2 g/mL or less against most ( 90%) strains of the measurement of zone diameters also provide reproducible
with iron (ferrous sulfate 100 mg once daily for two days), the following microorganisms; however, the safety and effectiveness estimates of the susceptibility of bacteria to antimicrobial
mean AUC and Cmax of moxioxacin was reduced by 39% and of moxioxacin in treating clinical infections due to these compounds. One such standardized procedure2 requires the
59%, respectively. Moxioxacin should only be taken more than 4 microorganisms have not been established in adequate and well- use of standardized inoculum concentrations. This procedure
hours before or 8 hours after iron products. (See PRECAUTIONS, controlled clinical trials. uses paper disks impregnated with 5-g moxioxacin to test the
Drug Interactions and DOSAGE AND ADMINISTRATION.) Aerobic Gram-positive microorganisms susceptibility of microorganisms to moxioxacin.
Electrocardiogram: Prolongation of the QT interval in the ECG Staphylococcus epidermidis (methicillin-susceptible strains Reports from the laboratory providing results of the standard
has been observed in some patients receiving moxioxacin. only) single-disk susceptibility test with a 5-g moxioxacin disk
Following oral dosing with 400 mg of moxioxacin the mean Streptococcus agalactiae should be interpreted according to the following criteria:
( SD) change in QTc from the pre-dose value at the time of Streptococcus viridans group The following zone diameter interpretive criteria should be
maximum drug concentration was 6 msec ( 26) (n = 787). Aerobic Gram-negative microorganisms used for testing Enterobacteriaceae and methicillin-susceptible
Following a course of daily intravenous dosing (400 mg; 1 hour Staphylococcus aureus:
Citrobacter freundii
infusion each day) the mean change in QTc from the Day 1 pre-
Klebsiella oxytoca Zone Diameter (mm) Interpretation
dose value was 9 msec ( 24) on Day 1 (n = 69) and 3 msec ( 29)
on Day 3 (n = 290). (See WARNINGS.) Legionella pneumophila 19 Susceptible (S)
Anaerobic microorganisms 16 18 Intermediate (I)
There is limited information available on the potential for a
Fusobacterium species 15 Resistant (R)
pharmacodynamic interaction in humans between moxioxacin and
other drugs that prolong the QTc interval of the electrocardiogram. Prevotella species For testing Haemophilus inuenzae and Haemophilus
Sotalol, a Class III antiarrhythmic, has been shown to further parainuenzaee:
SUSCEPTIBILITY TESTS
increase the QTc interval when combined with high doses of Zone Diameter (mm) Interpretation
intravenous (I.V.) moxioxacin in dogs. Therefore, moxioxacin Dilution Techniques: Quantitative methods are used to determine
18 Susceptible (S)
should be avoided with Class IA and Class III antiarrhythmics. antimicrobial minimum inhibitory concentrations (MICs). These
e This zone diameter standard is applicable only to tests with
(See ANIMAL PHARMACOLOGY, WARNINGS, and MICs provide estimates of the susceptibility of bacteria to
antimicrobial compounds. The MICs should be determined using Haemophilus inuenzae and Haemophilus parainuenzae
PRECAUTIONS.) using Haemophilus Test Medium (HTM)2.
a standardized procedure. Standardized procedures are based on a
MICROBIOLOGY dilution method1 (broth or agar) or equivalent with standardized The current absence of data on resistant strains precludes dening
Moxioxacin has in vitro activity against a wide range of Gram- inoculum concentrations and standardized concentrations of any results other than Susceptible. Strains yielding zone
positive and Gram-negative microorganisms. The bactericidal moxioxacin powder. The MIC values should be interpreted diameter results suggestive of a nonsusceptible category should
action of moxioxacin results from inhibition of the topoisomerase according to the following criteria: be submitted to a reference laboratory for further testing.
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For testing Streptococcus species including Streptococcus Appropriate culture and susceptibility tests should be performed Severe and sometimes fatal events, some due to hypersensitivity,
pneumoniae f and Enterococcus faecalis: before treatment in order to isolate and identify organisms causing and some of uncertain etiology, have been reported in patients
Zone Diameter (mm) Interpretation infection and to determine their susceptibility to moxioxacin. receiving therapy with all antibiotics. These events may be severe
18 Susceptible (S) Therapy with AVALOX may be initiated before results of and generally occur following the administration of multiple doses.
15 17 Intermediate (I) these tests are known; once results become available, appropriate Clinical manifestations may include one or more of the following:
14 Resistant (R) therapy should be continued. rash, fever, eosinophilia, jaundice, and hepatic necrosis.
f These interpretive standards are applicable only to disk To reduce the development of drug-resistant bacteria and maintain Pseudomembranous colitis has been reported with nearly all
diffusion tests using Mueller-Hinton agar supplemented with the effectiveness of AVALOX and other antibacterial drugs, antibacterial agents and may range in severity from mild to
5% sheep blood incubated in 5% CO2. AVALOX should be used only to treat or prevent infections life-threatening. Therefore, it is important to consider this
that are proven or strongly suspected to be caused by susceptible diagnosis in patients who present with diarrhea subsequent to
Interpretation should be as stated above for results using dilution
bacteria. When culture and susceptibility information are available, the administration of antibacterial agents.
techniques. Interpretation involves correlation of the diameter
they should be considered in selecting or modifying antibacterial Treatment with antibacterial agents alters the normal ora of the
obtained in the disk test with the MIC for moxioxacin.
therapy. In the absence of such data, local epidemiology and colon and may permit overgrowth of clostridia. Studies indicate
As with standardized dilution techniques, diffusion methods susceptibility patterns may contribute to the empiric selection of that a toxin produced by Clostridium difcile is one primary
require the use of laboratory control microorganisms that are used therapy. cause of antibiotic-associated colitis. After the diagnosis of
to control the technical aspects of the laboratory procedures. For
pseudomembranous colitis has been established, therapeutic
the diffusion technique, the 5-g moxioxacin disk should provide CONTRAINDICATIONS
measures should be initiated. Mild cases of pseudomembranous
the following zone diameters in these laboratory test quality Moxioxacin is contraindicated in persons with a history of colitis usually respond to drug discontinuation alone. In moderate
control strains: hypersensitivity to moxioxacin or any member of the quinolone to severe cases, consideration should be given to management with
Microorganism Zone class of antimicrobial agents. uids and electrolytes, protein supplementation, and treatment
Diameter (mm) with an antibacterial drug clinically effective against C. difcile
WARNINGS
Escherichia coli ATCC 25922 28 - 35 colitis.
THE SAFETYAND EFFECTIVENESS OF MOXIFLOXACIN
Haemophilus inuenzae ATCC 49247g 31 - 39 Peripheral neuropathy: Rare cases of sensory or sensorimotor
IN PEDIATRIC PATIENTS, ADOLESCENTS (LESS
Staphylococcus aureus ATCC 25923 28 - 35 axonal polyneuropathy affecting small and/or large axons resulting
h THAN 18 YEARS OF AGE), PREGNANT WOMEN, AND
Streptococcus pneumoniae ATCC 49619 25 - 31 in paresthesias, hypoesthesias, dysesthesias and weakness have
g These quality control limits are applicable to only H. inuenzae LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.
(SEE PRECAUTIONS-PEDIATRIC USE, PREGNANCY been reported in patients receiving quinolones.
ATCC 49247 testing using Haemophilus Test Medium AND NURSING MOTHERS SUBSECTIONS.) Tendon Effects: Ruptures of the shoulder, hand, Achilles
(HTM)2. tendon or other tendons that required surgical repair or resulted
h These quality control limits are applicable only to tests Moxioxacin has been shown to prolong the QT interval of
the electrocardiogram in some patients. The drug should in prolonged disability have been reported in patients receiving
conducted with S. pneumoniae ATCC 49619 tested by a disk be avoided in patients with known prolongation of the QT quinolones, including moxioxacin. Post-marketing surveillance
diffusion procedure using Mueller-Hinton agar supplemented interval, patients with uncorrected hypokalemia and patients reports indicate that this risk may be increased in patients
with 5% sheep blood and incubated in 5% CO2. receiving concomitant corticosteroids, especially the elderly.
receiving Class IA (e.g., quinidine, procainamide) or Class
Anaerobic Techniques: For anaerobic bacteria, the susceptibility III (e.g., amiodarone, sotalol) antiarrhythmic agents, due to Moxioxacin should be discontinued if the patient experiences
to moxioxacin as MICs can be determined by standardized the lack of clinical experience with the drug in these patient pain, inammation, or rupture of a tendon. Patients should rest and
procedures3 such as reference agar dilution methodsi. The MICs populations. refrain from exercise until the diagnosis of tendonitis or tendon
obtained should be interpreted according to the following criteria: rupture has been excluded. Tendon rupture can occur during or
Pharmacokinetic studies between moxioxacin and other drugs after therapy with quinolones, including moxioxacin.
MIC (ug/mL) Interpretation that prolong the QT interval such as cisapride, erythromycin,
2.0 Susceptible (S) antipsychotics, and tricyclic antidepressants have not been PRECAUTIONS
4.0 Intermediate (I) performed. An additive effect of moxioxacin and these drugs General: Quinolones may cause central nervous system (CNS)
8.0 Resistant (R) cannot be excluded, therefore caution should be exercised events, including: nervousness, agitation, insomnia, anxiety,
i This interpretive standard is applicable to reference agar dilution when moxioxacin is given concurrently with these drugs. In nightmares or paranoia. (See WARNINGS and Information for
susceptibility tests using Brucella agar supplemented with hemin, premarketing clinical trials, the rate of cardiovascular adverse Patients.)
vitamin K1 and 5% laked sheep blood. events was similar in 798 moxioxacin and 702 comparator Prescribing AVALOX in the absence of a proven or strongly
Acceptable ranges of MICs (ug/mL) for control strains for treated patients who received concomitant therapy with drugs suspected bacterial infection or a prophylactic indication is
reference agar dilution testing j: known to prolong the QTc interval. unlikely to provide benet to the patient and increases the risk of
Microorganism MIC (ug/mL) Moxioxacin should be used with caution in patients with ongoing the development of drug-resistant bacteria.
proarrhythmic conditions, such as clinically signicant bradycardia, Information for Patients:
Bacteroides fragilis ATCC 25285 0.12-0.5
acute myocardial ischemia. The magnitude of QT prolongation may
Bacteroides thetaiotaomicron ATCC 29741 1.0-4.0 To assure safe and effective use of moxioxacin, the following
increase with increasing concentrations of the drug or increasing
Eubacterium lentum ATCC 43055 0.12-0.5 information and instructions should be communicated to the
rates of infusion of the intravenous formulation. Therefore the
j These quality control ranges are applicable to reference agar patient when appropriate:
recommended dose or infusion rate should not be exceeded.
dilution tests using Brucella agar supplemented with hemin, QT prolongation may lead to an increased risk for ventricular Patients should be advised:
vitamin K1 and 5% laked sheep blood. arrhythmias including torsade de pointes. No cardiovascular that antibacterial drugs including AVALOX should only
INDICATIONS AND USAGE morbidity or mortality attributable to QTc prolongation occurred be used to treat bacterial infections. They do not treat viral
with moxioxacin treatment in over 9,200 patients in controlled infections (e.g., the common cold). When AVALOX is
AVALOX Tablets and I.V. are indicated for the treatment of
clinical studies, including 223 patients who were hypokalemic at prescribed to treat a bacterial infection, patients should be told
adults ( 18 years of age) with infections caused by susceptible
the start of treatment, and there was no increase in mortality in over that although it is common to feel better early in the course of
strains of the designated microorganisms in the conditions listed
18,000 moxioxacin tablet treated patients in a post-marketing therapy, the medication should be taken exactly as directed.
below. (See DOSAGE AND ADMINISTRATION for specic
observational study in which ECGs were not performed. (See Skipping doses or not completing the full course of therapy may
recommendations. In addition, for I.V. use see PRECAUTIONS,
CLINICAL PHARMACOLOGY, Electrocardiogram. For I.V. use (1) decrease the effectiveness of the immediate treatment and
Geriatric Use.)
see DOSAGE AND ADMINISTRATION and PRECAUTIONS, (2) increase the likelihood that bacteria will develop resistance
Acute Bacterial Sinusitis caused by Streptococcus pneumoniae, and will not be treatable by AVALOX or other antibacterial
Geriatric Use.)
Haemophilus inuenzae, or Moraxella catarrhalis. drugs in the future.
The oral administration of moxioxacin caused lameness in
Acute Bacterial Exacerbation of Chronic Bronchitis caused that moxioxacin may produce changes in the electrocardiogram
immature dogs. Histopathological examination of the weight-
by Streptococcus pneumoniae, Haemophilus inuenzae, (QTc interval prolongation).
bearing joints of these dogs revealed permanent lesions of the
Haemophilus parainuenzae, Klebsiella pneumoniae, that moxioxacin should be avoided in patients receiving Class
cartilage. Related quinolone-class drugs also produce erosions of
methicillin-susceptible Staphylococcus aureus, or Moraxella IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone,
cartilage of weight-bearing joints and other signs of arthropathy
catarrhalis. sotalol) antiarrhythmic agents.
in immature animals of various species. (See ANIMAL
Community Acquired Pneumonia caused by Streptococcus PHARMACOLOGY.) that moxioxacin may add to the QTc prolonging effects of
pneumoniae (including multi-drug resistant strains*), other drugs such as cisapride, erythromycin, antipsychotics,
Convulsions have been reported in patients receiving quinolones.
Haemophilus inuenzae, Moraxella catarrhalis, methicillin- and tricyclic antidepressants.
Quinolones may also cause central nervous system (CNS)
susceptible Staphylococcus aureus, Klebsiella pneumoniae, to inform their physician of any personal or family history
events including: dizziness, confusion, tremors, hallucinations,
Mycoplasma pneumoniae, or Chlamydia pneumoniae. of QTc prolongation or proarrhythmic conditions such as
depression, and, rarely, suicidal thoughts or acts. These
* MDRSP, Multi-drug resistant Streptococcus pneumoniae reactions may occur following the rst dose. If these reactions recent hypokalemia, signicant bradycardia, acute myocardial
includes isolates previously known as PRSP (Penicillin- occur in patients receiving moxioxacin, the drug should be ischemia.
resistant S. pneumoniae), and are strains resistant to two or discontinued and appropriate measures instituted. As with all to inform their physician of any other medications when taken
more of the following antibiotics: penicillin (MIC 2 g/mL), quinolones, moxioxacin should be used with caution in patients concurrently with moxioxacin, including over-the-counter
2nd generation cephalosporins (e.g., cefuroxime), macrolides, with known or suspected CNS disorders (e.g. severe cerebral medications.
tetracyclines, and trimethoprim/sulfamethoxazole. arteriosclerosis, epilepsy) or in the presence of other risk factors to contact their physician if they experience palpitations or
Uncomplicated Skin and Skin Structure Infections caused by that may predispose to seizures or lower the seizure threshold. fainting spells while taking moxioxacin.
methicillin-susceptible Staphylococcus aureus or Streptococcus (See PRECAUTIONS: General, Information for Patients, and that moxioxacin tablets may be taken with or without meals,
pyogenes. ADVERSE REACTIONS.) and to drink uids liberally.
Complicated Intra-Abdominal Infections including polymi- Serious anaphylactic reactions, some following the rst dose, that moxioxacin tablets should be taken at least 4 hours before
crobial infections such as abscess caused by Escherichia coli, have been reported in patients receiving quinolone therapy, or 8 hours after multivitamins (containing iron or zinc), antacids
Bacteroides fragilis, Streptococcus anginosus, Streptococcus including moxioxacin. Some reactions were accompanied (containing magnesium or aluminum), sucralfate, or VIDEX
constellatus, Enterococcus faecalis, Proteus mirabilis, Clos- by cardiovascular collapse, loss of consciousness, tingling, (didanosine) chewable/buffered tablets or the pediatric powder
tridium perfringens, Bacteroides thetaiotaomicron, or Pepto- pharyngeal or facial edema, dyspnea, urticaria, and itching. Serious for oral solution. (See CLINICAL PHARMACOLOGY, Drug
streptococcus species. anaphylactic reactions require immediate emergency treatment Interactions and PRECAUTIONS, Drug Interactions.)
Complicated Skin and Skin Structure Infections caused by with epinephrine. Moxioxacin should be discontinued at the rst that moxioxacin may be associated with hypersensitivity
methicillin-susceptible Staphylococcus aureus, Escherichia coli, appearance of a skin rash or any other sign of hypersensitivity. reactions, including anaphylactic reactions, even following a
Klebsiella pneumoniae, or Enterobacter cloacae (See Clinical Oxygen, intravenous steroids, and airway management, including single dose, and to discontinue the drug at the rst sign of a skin
Studies). intubation, may be administered as indicated. rash or other signs of an allergic reaction.
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SPDI
to discontinue treatment; rest and refrain from exercise; and human dose based on body surface area (mg/m2)) to pregnant MUSCULOSKELETAL: arthralgia, myalgia
inform their physician if they experience pain, inammation, or rats resulted in maternal toxicity and a marginal effect on fetal NERVOUS SYSTEM: insomnia, nervousness, vertigo,
rupture of a tendon. and placental weights and the appearance of the placenta. There somnolence, anxiety, tremor
that moxioxacin may cause dizziness and lightheadedness; was no evidence of teratogenicity at intravenous doses as high SKIN/APPENDAGES: rash (maculopapular, purpuric, pustular),
therefore, patients should know how they react to this drug as 80 mg/kg/day. Intravenous administration of 20 mg/kg/day pruritus, sweating, urticaria
before they operate an automobile or machinery or engage in (approximately equal to the maximum recommended human
SPECIAL SENSES: taste perversion
activities requiring mental alertness or coordination. oral dose based upon systemic exposure) to pregnant rabbits
that phototoxicity has been reported in patients receiving certain during organogenesis resulted in decreased fetal body weights UROGENITAL: vaginal moniliasis, vaginitis
quinolones, and infrequently moxioxacin. In keeping with and delayed fetal skeletal ossication. When rib and vertebral Additional clinically relevant rare events, judged by investigators
good medical practice, avoid excessive sunlight or articial malformations were combined, there was an increased fetal and to be at least possibly drug-related, that occurred in less than 0.1%
ultraviolet light (e.g. tanning beds). If sunburn-like reaction or litter incidence of these effects. Signs of maternal toxicity in of moxioxacin treated patients were:
skin eruptions occur, contact your physician. (See CLINICAL rabbits at this dose included mortality, abortions, marked reduction abnormal dreams, abnormal vision, agitation, amblyopia, amnesia,
PHARMACOLOGY, Photosensitivity Potential.) of food consumption, decreased water intake, body weight loss anemia, aphasia, arthritis, asthma, atrial brillation, back pain,
that convulsions have been reported in patients receiving and hypoactivity. There was no evidence of teratogenicity when chest pain, confusion, convulsions, depersonalization, depression,
quinolones, and they should notify their physician before taking pregnant cynomolgus monkeys were given oral doses as high as dysphagia, dyspnea, ECG abnormal, emotional lability, face
this drug if there is a history of this condition. 100 mg/kg/day (2.5 times the maximum recommended human edema, gastritis, gastrointestinal disorder, hallucinations,
dose based upon systemic exposure). An increased incidence of hyperglycemia, hyperlipidemia, hypertension, hypertonia,
DRUG INTERACTIONS: smaller fetuses was observed at 100 mg/kg/day. In an oral pre- and hyperuricemia, hypesthesia, hypotension, incoordination, jaundice
Antacids, Sucralfate, Metal Cations, Multivitamins: Quinolones postnatal development study conducted in rats, effects observed at (predominantly cholestatic), kidney function abnormal, lab test
form chelates with alkaline earth and transition metal cations. Oral 500 mg/kg/day included slight increases in duration of pregnancy abnormal (not specied), leg pain, paraesthesia, parosmia, pelvic
administration of quinolones with antacids containing aluminum and prenatal loss, reduced pup birth weight and decreased neonatal pain, peripheral edema, pseudomembranous colitis, prothrombin
or magnesium, with sucralfate, with metal cations such as iron, or survival. Treatment-related maternal mortality occurred during increase (prothrombin time decreased/International Normalized
with multivitamins containing iron or zinc, or with formulations gestation at 500 mg/kg/day in this study. Ratio (INR) decreased), sleep disorders, speech disorders,
containing divalent and trivalent cations such as VIDEX supraventricular tachycardia, syncope, taste loss, tendon disorder,
Since there are no adequate or well-controlled studies in pregnant
(didanosine) chewable/buffered tablets or the pediatric powder thinking abnormal, thrombocytopenia, thromboplastin decrease,
women, moxioxacin should be used during pregnancy only if the
for oral solution, may substantially interfere with the absorption tinnitus, tongue discoloration, ventricular tachycardia
potential benet justies the potential risk to the fetus.
of quinolones, resulting in systemic concentrations considerably
Nursing Mothers: Post-Marketing Adverse Event Reports:
lower than desired. Therefore, moxioxacin should be taken at
least 4 hours before or 8 hours after these agents. (See CLINICAL Moxioxacin is excreted in the breast milk of rats. Moxioxacin Additional adverse events have been reported from worldwide
PHARMACOLOGY, Drug Interactions and DOSAGE AND may also be excreted in human milk. Because of the potential for post-marketing experience with moxioxacin. Because these
ADMINISTRATION.) serious adverse reactions in infants who are nursing from mothers events are reported voluntarily from a population of uncertain
taking moxioxacin, a decision should be made whether to size, it is not always possible to reliably estimate their frequency
No clinically signicant drug-drug interactions between or establish a causal relationship to drug exposure. These
itraconazole, theophylline, warfarin, digoxin, atenolol, oral discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother. events, some of them life-threatening, include anaphylactic
contraceptives or glyburide have been observed with moxioxacin. reaction, anaphylactic shock, angioedema (including laryngeal
Itraconazole, theophylline, digoxin, probenecid, morphine, Pediatric Use: edema), hepatitis (predominantly cholestatic), phototoxicity,
ranitidine, and calcium have been shown not to signicantly Safety and effectiveness in pediatric patients and adolescents less psychotic reaction, Stevens-Johnson syndrome, tendon rupture,
alter the pharmacokinetics of moxioxacin. (See CLINICAL than 18 years of age have not been established. Moxioxacin and ventricular tachyarrhythmias (including in very rare cases
PHARMACOLOGY.) causes arthropathy in juvenile animals. (See WARNINGS.) cardiac arrest and torsade de pointes, and usually in patients with
Warfarin: No signicant effect of moxioxacin on R- and S- Geriatric Use: concurrent severe underlying proarrhythmic conditions).
warfarin was detected in a clinical study involving 24 healthy
In controlled multiple-dose clinical trials, 23% of patients LABORATORY CHANGES
volunteers. No signicant changes in prothrombin time were
receiving oral moxioxacin were greater than or equal to 65 years
noted in the presence of moxioxacin. Quinolones, including Changes in laboratory parameters, without regard to drug
of age and 9% were greater than or equal to 75 years of age. The relationship, which are not listed above and which occurred
moxioxacin, have been reported to enhance the anticoagulant
clinical trial data demonstrate that there is no difference in the in 2% of patients and at an incidence greater than in controls
effects of warfarin or its derivatives in the patient population. In
safety and efcacy of oral moxioxacin in patients aged 65 or included: increases in MCH, neutrophils, WBCs, PT ratio, ionized
addition, infectious disease and its accompanying inammatory
older compared to younger adults. calcium, chloride, albumin, globulin, bilirubin; decreases in
process, age, and general status of the patient are risk factors
for increased anticoagulant activity. Therefore the prothrombin In intravenous trials in community acquired pneumonia, 45% of hemoglobin, RBCs, neutrophils, eosinophils, basophils, PT ratio,
time, International Normalized Ratio (INR), or other suitable moxioxacin patients were greater than or equal to 65 years of age, glucose, pO2, bilirubin and amylase. It cannot be determined if any
anticoagulation tests should be closely monitored if a quinolone is and 24% were greater than or equal to 75 years of age. In the pool of of the above laboratory abnormalities were caused by the drug or
administered concomitantly with warfarin or its derivatives. 491 elderly (> 65 years) patients, the following ECG abnormalities the underlying condition being treated.
Drugs metabolized by Cytochrome P450 enzymes: In vitro were reported in moxioxacin vs. comparator patients: ST-T
wave changes (2 events vs. 0 events), QT prolongation (2 vs. 0), OVERDOSAGE
studies with cytochrome P450 isoenzymes (CYP) indicate that
ventricular tachycardia (1 vs. 0), atrial utter (1 vs. 0), tachycardia Single oral overdoses up to 2.8 g were not associated with any
moxioxacin does not inhibit CYP3A4, CYP2D6, CYP2C9,
(2 vs. 1), atrial brillation (1 vs. 0), supraventricular tachycardia (1 serious adverse events. In the event of acute overdose, the stomach
CYP2C19, or CYP1A2, suggesting that moxioxacin is unlikely to
vs. 0), ventricular extrasystoles (2 vs. 0), and arrhythmia (0 vs. 1). should be emptied and adequate hydration maintained. ECG
alter the pharmacokinetics of drugs metabolized by these enzymes
None of the abnormalities was associated with a fatal outcome and monitoring is recommended due to the possibility of QT interval
(e.g. midazolam, cyclosporine, warfarin, theophylline).
a majority of these patients completed a full course of therapy. prolongation. The patient should be carefully observed and given
Nonsteroidal anti-inammatory drugs (NSAIDs): Although not supportive treatment. The administration of activated charcoal
observed with moxioxacin in preclinical and clinical trials, the ADVERSE REACTIONS as soon as possible after oral overdose may prevent excessive
concomitant administration of a nonsteroidal anti-inammatory Clinical efcacy trials enrolled over 9,200 moxioxacin orally increase of systemic moxioxacin exposure. About 3% and 9%
drug with a quinolone may increase the risks of CNS stimulation and intravenously treated patients, of whom over 8,600 patients of the dose of moxioxacin, as well as about 2% and 4.5% of its
and convulsions. (See WARNINGS.) received the 400 mg dose. Most adverse events reported in glucuronide metabolite are removed by continuous ambulatory
Carcinogenesis, Mutagenesis, Impairment of Fertility: moxioxacin trials were described as mild to moderate in severity peritoneal dialysis and hemodialysis, respectively.
Long term studies in animals to determine the carcinogenic and required no treatment. Moxioxacin was discontinued due Single oral moxioxacin doses of 2000, 500, and 1500 mg/kg
potential of moxioxacin have not been performed. to adverse reactions thought to be drug-related in 2.9% of orally were lethal to rats, mice, and cynomolgus monkeys, respectively.
Moxioxacin was not mutagenic in 4 bacterial strains (TA 98, TA treated patients and 6.3 % of sequentially (intravenous followed The minimum lethal intravenous dose in mice and rats was 100
100, TA 1535, TA 1537) used in the Ames Salmonella reversion by oral) treated patients. The latter studies were conducted in mg/kg. Toxic signs after administration of a single high dose of
assay. As with other quinolones, the positive response observed community acquired pneumonia and complicated skin and skin moxioxacin to these animals included CNS and gastrointestinal
with moxioxacin in strain TA 102 using the same assay may structure infections and complicated intra-abdominal infections effects such as decreased activity, somnolence, tremor, convulsions,
be due to the inhibition of DNA gyrase. Moxioxacin was not with, in general, a sicker patient population compared to the tablet vomiting and diarrhea.
mutagenic in the CHO/HGPRT mammalian cell gene mutation studies.
assay. An equivocal result was obtained in the same assay when Adverse reactions, judged by investigators to be at least possibly
v79 cells were used. Moxioxacin was clastogenic in the v79 The dose of AVALOX is 400 mg (orally or as an intravenous
drug-related, occurring in greater than or equal to 2% of
chromosome aberration assay, but it did not induce unscheduled infusion) once every 24 hours. The duration of therapy depends on
moxioxacin treated patients were: nausea (6%), diarrhea (5%),
DNA synthesis in cultured rat hepatocytes. There was no evidence the type of infection as described below.
dizziness (2%).
of genotoxicity in vivo in a micronucleus test or a dominant lethal Additional clinically relevant uncommon events, judged by Infection * Daily Dose Duration
test in mice. investigators to be at least possibly drug-related, that occurred in Acute Bacterial Sinusitis 400 mg 10 days
Moxioxacin had no effect on fertility in male and female rats greater than or equal to 0.1% and less than 2% of moxioxacin Acute Bacterial Exacerbation 400 mg 5 days
at oral doses as high as 500 mg/kg/day, approximately 12 times treated patients were: of Chronic Bronchitis
the maximum recommended human dose based on body surface BODY AS A WHOLE: abdominal pain, headache, asthenia, Community Acquired Pneumonia 400 mg 7-14 days
area (mg/m2), or at intravenous doses as high as 45 mg/kg/day, injection site reaction (including phlebitis), malaise, moniliasis, Uncomplicated Skin and 400 mg 7 days
approximately equal to the maximum recommended human dose pain, allergic reaction Skin Structure Infections
based on body surface area (mg/m2). At 500 mg/kg orally there Complicated Skin and 400 mg 7 - 21 days
were slight effects on sperm morphology (head-tail separation) in CARDIOVASCULAR: tachycardia, palpitation, vasodilation, QT
interval prolonged Skin Structure Infections
male rats and on the estrous cycle in female rats. Complicated Intra-Abdominal 400 mg 5 - 14 days
Pregnancy: Teratogenic Effects. Pregnancy Category C: DIGESTIVE: vomiting, abnormal liver function test, dyspepsia,
dry mouth, atulence, oral moniliasis, constipation, GGTP Infections
Moxioxacin was not teratogenic when administered to pregnant
increased, anorexia, stomatitis, glossitis * due to the designated pathogens (See INDICATIONS AND
rats during organogenesis at oral doses as high as 500 mg/kg/day
HEMIC AND LYMPHATIC: leukopenia, eosinophilia, USAGE.). For I.V. use see Precautions, Geriatric Use.
or 0.24 times the maximum recommended human dose based
on systemic exposure (AUC), but decreased fetal body weights prothrombin decrease (prothrombin time prolonged/International For Complicated Intra-Abdominal Infections, therapy should be
and slightly delayed fetal skeletal development (indicative of Normalized Ratio (INR) increased), thrombocythemia initiated with the intravenous formulation.
fetotoxicity) were observed. Intravenous administration of 80 METABOLIC AND NUTRITIONAL: lactic dehydrogenase When switching from intravenous to oral dosage administration, no
mg/kg/day (approximately 2 times the maximum recommended increased, amylase increased dosage adjustment is necessary. Patients whose therapy is started
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Book_01.indd 131 6/4/2008 2:20:16 PM

SPDI
with AVALOX I.V. may be switched to AVALOX Tablets toxicity was not observed in 6 month repeat dose studies in rats Clinical Success Rates By Pathogen (Pooled CAP Studies)
when clinically indicated at the discretion of the physician. and monkeys (daily oral doses up to 500 mg/kg and 135 mg/kg, PATHOGEN AVALOX
Oral doses of moxioxacin should be administered at least 4 respectively). In beagle dogs, electroretinographic (ERG) changes Streptococcus pneumoniae 80/85 (94%)
hours before or 8 hours after antacids containing magnesium or were observed in a 2 week study at oral doses of 60 and 90 mg/kg/ Staphylococcus aureus 17/20 (85%)
aluminum, as well as sucralfate, metal cations such as iron, and day. Histopathological changes were observed in the retina from
Klebsiella pneumoniae 11/12 (92%)
multivitamin preparations with zinc, or VIDEX (didanosine) one of four dogs at 90 mg/kg/day, a dose associated with mortality
Haemophilus inuenzae 56/61 (92%)
chewable/buffered tablets or the pediatric powder for oral solution. in this study.
Chlamydia pneumoniae 119/128 (93%)
(See CLINICAL PHARMACOLOGY, Drug Interactions and Some quinolones have been reported to have proconvulsant
Mycoplasma pneumoniae 73/76 (96%)
PRECAUTIONS, Drug Interactions.) activity that is exacerbated with concomitant use of non-steroidal
Moraxella catarrhalis 11/12 (92%)
Impaired Renal Function anti-inammatory drugs (NSAIDs). Moxioxacin at an oral dose
No dosage adjustment is required in renally impaired patients, of 300 mg/kg did not show an increase in acute toxicity or potential Community Acquired Pneumonia caused by Multi-Drug
including those on either hemodialysis or continuous ambulatory for CNS toxicity (e.g., seizures) in mice when used in combination Resistant Streptococcus pneumoniae (MDRSP)*
peritoneal dialysis. with NSAIDs such as diclofenac, ibuprofen, or fenbufen.
AVALOX was effective in the treatment of community acquired
Impaired Hepatic Function In dog studies, at plasma concentrations about ve times the pneumonia (CAP) caused by multi-drug resistant Streptococcus
human therapeutic level, a QT-prolonging effect of moxioxacin pneumoniae MDRSP* isolates. Of 37 microbiologically
No dosage adjustment is required in patients with mild or
was found. Electrophysiological in vitro studies suggested an evaluable patients with MDRSP isolates, 35 patients (95.0%)
moderate hepatic insufciency (Child Pugh Classes A and B). The
inhibition of the rapid activating component of the delayed rectier achieved clinical and bacteriological success post-therapy. The
pharmacokinetics of moxioxacin in patients with severe hepatic
potassium current (IKr) as an underlying mechanism. In dogs, the clinical and bacteriological success rates based on the number of
insufciency (Child Pugh Class C) have not been studied. (See
combined infusion of sotalol, a Class III antiarrhythmic agent, patients treated are shown in the table below.
CLINICAL PHARMACOLOGY, Hepatic Insufciency.)
with moxioxacin induced a higher degree of QTc prolongation
AVALOX I.V. should be administered by INTRAVENOUS * MDRSP, Multi-drug resistant Streptococcus pneumoniae
than that induced by the same dose (30 mg/kg) of moxioxacin
infusion only. It is not intended for intra-arterial, intramuscular, includes isolates previously known as PRSP (Penicillin-
alone.
intrathecal, intraperitoneal, or subcutaneous administration. resistant S. pneumoniae), and are strains resistant to two or
In a local tolerability study performed in dogs, no signs of local more of the following antibiotics: penicillin (MIC 2 g/mL),
AVALOX I.V. should be administered by intravenous infusion intolerability were seen when moxioxacin was administered
over a period of 60 minutes by direct infusion or through a Y- 2nd generation cephalosporins (e.g., cefuroxime), macrolides,
intravenously. After intra-arterial injection, inammatory changes tetracyclines, and trimethoprim/sulfamethoxazole.
type intravenous infusion set which may already be in place. involving the peri-arterial soft tissue were observed suggesting that
CAUTION: RAPID OR BOLUS INTRAVENOUS INFUSION Clinical and Bacteriological Success Rates for Moxioxacin-
intra-arterial administration of moxioxacin should be avoided.
MUST BE AVOIDED. Treated MDRSP CAP Patients (Population: Valid for
Since only limited data are available on the compatibility of CLINICAL STUDIES Efcacy):
moxioxacin intravenous injection with other intravenous Acute Bacterial Exacerbation of Chronic Bronchitis Screening Susceptibility Clinical Success Bacteriological
substances, additives or other medications should not be added AVALOX Tablets (400 mg once daily for ve days) were Success
to AVALOX I.V. or infused simultaneously through the same evaluated for the treatment of acute bacterial exacerbation n/Na % n/Nb %
intravenous line. If the same intravenous line or a Y-type line is of chronic bronchitis in a large, randomized, double-blind, Penicillin-resistant 21/21 100%* 21/21 100%*
used for sequential infusion of other drugs, or if the piggyback controlled clinical trial conducted in the US. This study compared 2nd generation cephalosporin- 25/26 96%* 25/26 96%*
method of administration is used, the line should be ushed before AVALOX with clarithromycin (500 mg twice daily for 10 days) resistant
and after infusion of AVALOX I.V. with an infusion solution and enrolled 629 patients. The primary endpoint for this trial was Macrolide-resistant ** 22/23 96% 22/23 96%
compatible with AVALOX I.V. as well as with other drug(s) clinical success at 7-17 days post-therapy. The clinical success for Trimethoprim/sulfamethoxazole- 28/30 93% 28/30 93%
administered via this common line. AVALOX was 89% (222/250) compared to 89% (224/251) for resistant
AVALOX I.V. is compatible with the following intravenous clarithromycin. Tetracycline-resistant 17/18 94% 17/18 94%
solutions at ratios from 1:10 to 10:1: The following outcomes are the clinical success rates at the follow- a n = number of patients successfully treated; N = number of
0.9% Sodium Chloride Sterile Water for Injection, USP up visit for the clinically evaluable patient groups by pathogen: patients with MDRSP (from a total of 37 patients)
Injection, USP b n = number of patients successfully treated (presumed
PATHOGEN AVALOX Clarithromycin
1M Sodium Chloride Injection 10% Dextrose for Injection, USP
Streptococcus pneumoniae 16/16 (100%) 20/23 (87%) eradication or eradication); N = number of patients with
5% Dextrose Injection, USP Lactated Ringers for Injection
Haemophilus inuenzae 33/37 (89%) 36/41 (88%) MDRSP (from a total of 37 patients)
Preparation for administration of AVALOX I.V. injection glass Haemophilus parainuenzae 16/16 (100%) 14/14 (100%) * One patient had a respiratory isolate that was resistant
bottle : Moraxella catarrhalis 29/34 (85%) 24/24 (100%) to penicillin and cefuroxime but a blood isolate that was
1. Close ow control clamp of administration set. Staphylococcus aureus 15/16 (94%) 6/8 (75%) intermediate to penicillin and cefuroxime. The patient is
2. Remove cover from port of the glass bottle . Klebsiella pneumoniae 18/20 (90%) 10/11 (91%) included in the database based on the respiratory isolate.
3. Insert piercing pin from an appropriate transfer set (e.g. one ** Azithromycin, clarithromycin, and erythromycin were the
The microbiological eradication rates (eradication plus presumed
that does not require excessive force, such as ISO compatible macrolide antimicrobials tested.
eradication) in AVALOX treated patients were Streptococcus
administration set) into port with a gentle twisting motion until Not all isolates were resistant to all antimicrobial classes tested.
pneumoniae 100%, Haemophilus inuenzae 89%,
pin is rmly seated. Success and eradication rates are summarized in the table below:
Haemophilus parainuenzae 100%, Moraxella catarrhalis
NOTE: Refer to complete directions that have been provided with 85%, Staphylococcus aureus 94%, and Klebsiella pneumoniae S. pneumoniae Clinical Success Bacteriological
the administration set. 85%. with MDRSP Eradication Rate
HOW SUPPLIED Community Acquired Pneumonia Resistant to 2 antimicrobials 12/13 (92.3 %) 12/13 (92.3 %)
Tablets A large, randomized, double-blind, controlled clinical trial was Resistant to 3 antimicrobials 10/11 (90.9 %)* 10/11 (90.9 %)*
conducted in the US to compare the efcacy of AVALOX Resistant to 4 antimicrobials 6/6 (100%) 6/6 (100%)
AVALOX (moxioxacin hydrochloride) lm-coated containing
Tablets (400 mg once daily) to that of high-dose clarithromycin Resistant to 5 antimicrobials 7/7 (100%)* 7/7 (100%)*
400 mg moxioxacin.
(500 mg twice daily) in the treatment of patients with clinically Bacteremia with MDRSP 9/9 (100%) 9/9 (100%)
Store at 25C (77F); excursions permitted to 15-30C (59-86F)
and radiologically documented community acquired pneumonia. * One patient had a respiratory isolate resistant to 5 antimicrobials
[see USP Controlled Room Temperature]. Avoid high humidity.
This study enrolled 474 patients (382 of whom were valid for the and a blood isolate resistant to 3 antimicrobials. The patient was
Intravenous Solution primary efcacy analysis conducted at the 14 - 35 day follow- included in the category resistant to 5 antimicrobials.
AVALOX I.V. (moxioxacin hydrochloride in sodium chloride up visit). Clinical success for clinically evaluable patients was
injection) is available in glass bottle containing 400 mg of Acute Bacterial Sinusitis
95% (184/194) for AVALOX and 95% (178/188) for high dose
moxioxacin in 0.8% saline. NO FURTHER DILUTION OF clarithromycin. In a large, controlled double-blind study conducted in the US,
THIS PREPARATION IS NECESSA AVALOX Tablets (400 mg once daily for ten days) were
A large, randomized, double-blind, controlled trial was conducted
Parenteral drug products should be inspected visually for in the US and Canada to compare the efcacy of sequential IV/PO compared with cefuroxime axetil (250 mg twice daily for ten
particulate matter prior to administration. Samples containing AVALOX 400 mg QD for 7-14 days to an IV/PO uoroquinolone days) for the treatment of acute bacterial sinusitis. The trial
visible particulates should not be used. control (trovaoxacin or levooxacin) in the treatment of patients included 457 patients valid for the primary efcacy determination.
Since glass bottle is for single-use only, any unused portion with clinically and radiologically documented community acquired Clinical success (cure plus improvement) at the 7 to 21 day post-
should be discarded. pneumonia. This study enrolled 516 patients, 362 of whom were therapy test of cure visit was 90% for AVALOX and 89% for
valid for the primary efcacy analysis conducted at the 7-30 day cefuroxime.
Store at 25C (77F); excursions permitted to 15-30C (59-86F)
[see USP Controlled Room Temperature]. post-therapy visit. The clinical success rate was 86% (157/182) for An additional non-comparative study was conducted to gather
AVALOX therapy and 89% (161/180) for the uoroquinolone bacteriological data and to evaluate microbiological eradication
DO NOT REFRIGERATE PRODUCT PRECIPITATES
comparators. in adult patients treated with AVALOX 400 mg once daily for
UPON REFRIGERATION.
An open-label ex-US study that enrolled 628 patients compared seven days. All patients (n = 336) underwent antral puncture in this
ANIMAL PHARMACOLOGY AVALOX to sequential IV/PO amoxicillin/clavulanate (1.2 study. Clinical success rates and eradication/ presumed eradication
Quinolones have been shown to cause arthropathy in immature g IV q8h/625 mg PO q8h) with or without high-dose IV/PO rates at the 21 to 37 day follow-up visit were 97% (29 out of 30)
animals. In studies in juvenile dogs oral doses of moxioxacin 30 clarithromycin (500 mg BID). The intravenous formulations of the for Streptococcus pneumoniae, 83% (15 out of 18) for Moraxella
mg/kg/day (approximately 1.5 times the maximum recommended comparators are not FDA approved. The clinical success rate at catarrhalis, and 80% (24 out of 30) for Haemophilus inuenzae.
human dose based upon systemic exposure) for 28 days resulted Day 5-7 (the primary efcacy timepoint) for AVALOX therapy Uncomplicated Skin and Skin Structure Infections
in arthropathy. There was no evidence of arthropathy in mature was 93% (241/258) and demonstrated superiority to amoxicillin/ A randomized, double-blind, controlled clinical trial conducted in
monkeys and rats at oral doses up to 135 and 500 mg/kg/day, clavulanate clarithromycin (85%, 239/280) [95% C.I. 2.9%, the US compared the efcacy of AVALOX 400 mg once daily
respectively. 13.2%]. The clinical success rate at the 21-28 days post-therapy for seven days with cephalexin HCl 500 mg three times daily for
Unlike some other members of the quinolone class, crystalluria visit for AVALOX was 84% (216/258), which also demonstrated seven days. The percentage of patients treated for uncomplicated
was not observed in 6 month repeat dose studies in rats and superiority to the comparators (74%, 208/280) [95% C.I. 2.6%, abscesses was 30%, furuncles 8%, cellulitis 16%, impetigo 20%,
monkeys with moxioxacin. 16.3%]. and other skin infections 26%. Adjunctive procedures (incision
No ocular toxicity was observed in a 13 week oral repeat dose The clinical success rates by pathogen across four CAP studies and drainage or debridement) were performed on 17% of the
study in dogs with a moxioxacin dose of 60 mg/kg/day. Ocular are presented below: AVALOX treated patients and 14% of the comparator treated
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SPDI
patients. Clinical success rates in evaluable patients were 89% Children and adolescents
(108/122) for AVALOX and 91% (110/121) for cephalexin HCl. CIPROBAY 100 Infusion Solution In common with other gyrase inhibitors, ciprooxacin, the active
Complicated Skin and Skin Structure Infections ingredient in CIPROBAY 100, is known to cause damage to
Two randomized, active controlled trials of cSSSI were performed. the weight-bearing joints of juvenile animals. Evaluation of
A double-blind trial was conducted primarily in North America to
(Ciprooxacin Lactate) the safety data of patients aged less than 18 who were mainly
compare the efcacy of sequential IV/PO AVALOX 400 mg QD suffering from cystic brosis (mucoviscidosis) did not reveal
Active ingredient: Ciprooxacin evidence of joint/cartilage damage.
for 7-14 days to an IV/PO beta-lactam/beta-lactamase inhibitor
control in the treatment of patients with cSSSI. This study enrolled Infusion solution Current ndings support the use of CIPROBAY 100 for
617 patients, 335 of which were valid for the primary efcacy - 1 bottle of 50 ml infusion solution contains 127.2 mg treatment of acute infection episodes of cystic brosis caused
analysis. A second open-label International study compared ciprooxacin lactate, equivalent to 100 mg ciprooxacin. by P. aeruginosa in children and adolescents aged between 5
AVALOX 400 mg QD for 7-21 days to sequential IV/PO beta- and 17. Presentations containing higher dosages are available
- The other ingredients are lactic acid, sodium chloride,
lactam/beta-lactamase inhibitor control in the treatment of patients for this indication. At present, only inadequate experience is
hydrochloric acid, water for injections.
with cSSSI. This study enrolled 804 patients, 632 of which available in regard to its use in children and adolescents with
1 bottle of 50 ml infusion solution contains 450 mg sodium other infections and in children aged less than 5. Ciprooxacin
were valid for the primary efcacy analysis. Surgical incision chloride (7.75 mmol). should therefore not be used for other infections and not for
and drainage or debridement was performed on 55% of the
1. WHAT IS Ciprobay 100 AND WHAT IS IT USED FOR? children aged less than 5 in general.
moxioxacin treated and 53% of the comparator treated patients
in these studies and formed an integral part of therapy for this Ciprooxacin, the active ingredient of CIPROBAY 100, Pregnancy
indication. Success rates varied with the type of diagnosis ranging belongs to the quinolone group of substances. The main site CIPROBAY 100 must not be used at any stage during
from 61% in patients with infected ulcers to 90% in patients with of action of quinolones is a bacterial enzyme (gyrase) which pregnancy because no experience has been gained regarding
complicated erysipelas. These rates were similar to those seen plays a vital role in bacterial metabolism and reproduction. its safety in pregnant women. Animal experiments have
with comparator drugs. The overall success rates in the evaluable Blocking this enzyme with ciprooxacin (a gyrase inhibitor) not produced any evidence of malformation of the foetus
patients and the clinical success by pathogen are shown below: has a bactericidal effect on the disease pathogens (i.e. it kills the (teratogenic effects), but it is not entirely improbable that
germs). damage to cartilage may be caused in organisms which have
Overall Clinical Success Rates in Patients with Complicated
Indications not reached maturity.
Skin and Skin Structure Infections
For the treatment of uncomplicated infections caused by Breast-feeding
Study Moxioxacin Comparator 95% Condence
n/ N (%) n/N (%) Interval organisms susceptible to ciprooxacin: It is also recommended on principle that CIPROBAY 100
North America 125/162 (77.2%) 141/173 (81.5%) -14.4%, 2.0% Infections of the efferent urinary tract should not be used while breast-feeding.
International 254/315 (80.6%) 268/317 (84.5%) -9.4%, 2.2% Gonorrhoea Driving and operating machinery:
CIPROBAY 100 is not effective against Treponema pallidum Do not drive or operate power tools or machinery while taking
Clinical Success Rates by Pathogen in Patients with
(the causative organism in syphilis). this medicine; even when used correctly, this medicine may
Complicated Skin and Skin Structure Infections
impair reaction speed so much that the ability to drive, operate
Pathogen Moxioxacin Comparator 2. WHAT SHOULD YOU BE AWARE OF BEFORE USING
machinery or work without a secure foothold may be reduced,
n/ N (%) n/N (%) CIPROBAY 100?
or the patient may not be capable of doing these things at all.
Staphylococcus aureus CIPROBAY 100 must not be used: This applies particularly at the start of treatment, when the dose
(methicillin-susceptible strains) * 106/129 (82.2%) 120/137 (87.6%) - If you are hypersensitive (allergic) to ciprooxacin or other is increased, when medication is changed and in conjunction
Escherichia coli 31/38 (81.6 %) 28/33 (84.8 %) drugs from the same substance group (quinolone type, gyrase with alcohol.
Klebsiella pneumoniae 11/12 (91.7 % ) 7/10 (70.0%) inhibitors). Interactions with other drugs:
Enterobacter cloacae 9/11 (81.8%) 4/7 (57.1%) - If you are pregnant or breast-feeding.
CIPROBAY 100 must be administered separately unless
* methicillin susceptibility was only determined in the North - by children and adolescents in the growth phase. compatibility with other infusion solutions/drug products
American Study Particular caution is required when using CIPROBAY has been conrmed. Visible signs of incompatibility include
100: precipitation, cloudiness and discoloration of the solution.
Complicated Intra-Abdominal Infections
- If you suffer from seizures (epilepsy) or any other form of Incompatibility appears with all infusion solutions/drug
Two randomized, active controlled trials of cIAI were performed.
prior damage to the central nervous system (e.g. an increased products that are physically or chemically unstable at the pH
A double-blind trial was conducted primarily in North America tendency to seizures, a history of seizures, reduced blood ow
to compare the efcacy of sequential IV/PO AVALOX 400 mg of CIPROBAY 100 (e.g. penicillins, heparin solutions),
in the brain, altered brain structure or a stroke in the past). particularly when combined with solutions adjusted to an
QD for 5-14 days to IV/ piperacillin/tazobactam followed by PO Patients in this category are at risk of side effects in the central
amoxicillin/clavulanic acid in the treatment of patients with cIAI, alkaline pH (pH of CIPROBAY 100 infusion solution: 3.9
nervous system. - 4.5).
including peritonitis, abscesses, appendicitis with perforation, In isolated cases, psychotic reactions (psychological
and bowel perforation. This study enrolled 681 patients, 379 of Ciprobay/xanthines
impairment with altered perception ranging up to the point of
which were considered clinically evaluable. A second open-label self-endangerment) occurred, in some cases after rst use. In Taking CIPROBAY 100 and theophylline (an asthma
international study compared AVALOX 400 mg QD for 5-14 these cases, stop using CIPROBAY 100 immediately and treatment) at the same time can lead to an unwanted increase in
days to IV ceftriaxone plus IV metronidazole followed by PO inform the attending doctor. the concentration of theophylline in the blood and, accordingly,
amoxicillin/clavulanic acid in the treatment of patients with cIAI. - If severe and persistent diarrhoea develops during or after to an increase in the rate of side effects caused by theophylline
This study enrolled 595 patients, 511 of which were considered therapy. A doctor should be consulted in such cases as this which, in isolated cases, may be life-threatening or fatal. If
clinically evaluable. The clinically evaluable population consisted may be a sign of a serious, possibly life-threatening intestinal it is imperative to use both medicines at the same time, the
of subjects with a surgically conrmed complicated infection, at disease (pseudomembranous colitis) which requires immediate theophylline concentration in the blood should be monitored
least 5 days of treatment and a 25-50 day follow-up assessment for treatment. Use of CIPROBAY 100 must be discontinued and the dosage should be reduced as required. There have been
patients at the Test of Cure visit. The overall clinical success rates in this case and suitable therapy should be implemented (e.g. reports of raised concentrations of the xanthine derivatives
in the clinically evaluable patients are shown below: vancomycin oral, 4 x 250 mg daily). Do not take drugs that caffeine and pentoxifylline (a medicine that promotes blood
inhibit gastric motility (peristalsis). circulation) in the blood when these substances are administered
Clinical Success Rates in Patients with Complicated Intra-
at the same time as CIPROBAY 100.
Abdominal Infections: In isolated cases, inammation of tendons (tendinitis) and
rupturing of tendons (e.g. the Achilles tendon) have been Ciprobay/non-steroidal anti-inammatory drugs
Study Moxioxacin Comparator 95% Condence
n/ N (%) n/N (%) Interval observed following treatment with uoroquinolones (the Animal studies have shown that using a combination of very
North America 146/183 (79.8 %) 153/196 (78.1 %) -7.4%,9.3% substance group to which CIPROBAY 100 belongs). These high doses of quinolones (gyrase inhibitors) and certain drugs
(overall) occurrences were mainly observed in elderly patients who had which inhibit inammation (non-steroidal anti-inammatory
Abscess 40/57 (70.2 %) 49/63 (77.8 %) * NA a been previously treated with corticosteroids. If inammation of agents) can trigger seizures. This does not apply to medicines
Non-abscess 106/126 (84.1 %) 104/133 (78.2 %) NA a tendon is suspected, treatment with CIPROBAY 100 must containing acetylsalicylic acid.
International 199/246 (80.9 %) 218/265 (82.3 %) -8.9 %,4.2% be discontinued immediately, physical strain must be avoided Ciprobay/cyclosporin
(overall) and appropriate therapy may have to be given. Temporary impairment of kidney function associated with an
Abscess 73/93 (78.5 %) 86/99 (86.9 %) NA Although photosensitivity only occurs very rarely following increase in the concentration of creatinine in the blood has been
Non-abscess 126/153 (82.4 %) 132/166 (79.5 %) NA treatment with ciprooxacin, patients undergoing treatment observed in isolated cases when CIPROBAY 100 is taken at
with CIPROBAY 100 should not be exposed unnecessarily to the same time as cyclosporin (a drug that suppresses the bodys
* excludes 2 patients who required additional surgery within the
sunlight and should avoid exposure to UV light (high-altitude defence mechanisms). Your creatinine concentration should
rst 48 hours.
sun, solariums). Treatment must be discontinued if light- be monitored closely (twice a week) if you are taking both
a NA - not applicable
sensitivity reactions (e.g. skin reactions similar to sunburn) are medicines at the same time.
REFERENCES: observed. Ciprobay/warfarin
In isolated cases, severe immediate allergic reactions occurred Simultaneous use of CIPROBAY 100 and warfarin (a drug
1. Clinical and Laboratory Standards Institute, Methods for
involving swelling (oedema) of the face, blood vessels and that inhibits the coagulation of blood) may increase the action
Dilution Antimicrobial Susceptibility Tests for Bacteria That
larynx and difculty in breathing (dyspnoea) ranging up to life- of warfarin.
Grow Aerobically-Sixth Edition. Approved Standard CLSI
threatening shock (anaphylactic/ anaphylactoid reactions), in
Document M7-A6, Vol. 23, No. 2, CLSI, Wayne, PA, January, Ciprobay/glibenclamide
some cases after rst use of the product. In these cases, stop
2003. In isolated cases, concomitant use of CIPROBAY 100 and
using CIPROBAY 100 immediately and inform the attending
2. Clinical and Laboratory Standards Institute, Performance doctor. glibenclamide (a treatment for diabetes) may increase the action
Standards for Antimicrobial Disk Susceptibility Tests-Eighth of glibenclamide to such an extent that hypoglycaemia may
If consumption of sodium chloride could represent a risk factor
Edition. Approved Standard CLSI Document M2-A8, Vol. 23, occur.
for you for medical reasons, for example because you suffer
No. 1, CLSI, Wayne, PA, January, 2003. from congestive heart failure, impaired kidney function or other Ciprobay/probenecid
3. Clinical and Laboratory Standards Institute, Methods for kidney disorders (nephrotic syndrome), the additional burden of Probenecid (a treatment for gout) affects the excretion of
Antimicrobial Susceptibility Testing of Anaerobic Bacteria; the sodium in this product must be taken into account. 1 bottle ciprooxacin in urine (renal secretion). Simultaneous use of
Approved Standard CLSI Document M11-A6, Vol. 24, No. 2, of 50 ml infusion solution contains 450 mg sodium chloride CIPROBAY 100 and probenecid increases the concentration
CLSI, Wayne, PA, 2004. (7.75 mmol). of ciprooxacin in the blood (serum).
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SPDI
Ciprobay/metoclopramide: Please consult your doctor or pharmacist if you have the Occasionally: Itching (pruritus), raised, spotty skin rash
Metoclopramide (a gastrointestinal medicine) accelerates the impression that the effects of CIPROBAY 100 are too (maculopapular exanthem), nettle rash
absorption of CIPROBAY 100 into the blood and causes the strong or too weak. (urticaria).
maximum concentration in the blood (plasma) to be reached If you have taken a greater quantity of CIPROBAY 100 Rarely: Light sensitivity with reddening of the skin
more rapidly than usual. No effect on the bioavailability of than you were supposed to: (photosensitivity),
Ciprobay 100 in the human body has been observed. A few cases of transient (reversible) kidney damage have been Very rarely: Punctate skin haemorrhages (petechiae), blister
Ciprobay/mexiletine reported following extremely large overdoses. In such cases, formation with accompanying haemorrhages
therefore, kidney function should be checked by a doctor. (haemorrhagic bullae) and small nodules
Simultaneous use of these two medicines may lead to a raised
(papules) with crust formation showing vascular
concentration of mexiletine in the body. 4. WHAT SIDE EFFECTS ARE POSSIBLE? involvement (vasculitis), erythema nodosum,
Ciprobay/phenytoin Like all medicines, CIPROBAY 100 can have side effects. rash on the skin and mucous membranes close
Elevated or lowered serum concentrations of phenytoin have The frequency is indicated as follows: to the skin (xed drug-induced exanthem),
been reported following the simultaneous use of these two frequently: 1% to < 10 % erythema exsudativum multiforme (minor)
medicines. Occasionally: 0.1 % to <1% ranging up to severe forms (Stevens-Johnson
Ciprobay/diazepam Rarely: 0.01 % to < 0.1 % syndrome), blister-like loss of the skin and oral/
nasal mucosa (Lyells syndrome).
There have been reports that concomitant use of CIPROBAY Very rarely: < 0.01 %
100 and diazepam delays the decomposition of diazepam in Sensory organs:
General
the body (reduced clearance, extended half-life). Accordingly, Occasionally: Impaired sense of taste and smell.
Occasionally: A sensation of weakness. Long-term or repeated
careful monitoring of diazepam treatment is recommended. use of Ciprobay can reduce the susceptibility of Rarely: Tinnitus, transient loss of hearing, particularly
Ciprobay/methotrexate disease-causing organisms to ciprooxacin; this with high tones, visual disturbances (e.g. double
means that the patient may become infected again vision, coloured vision), loss of the sense of smell
Simultaneous use of these two substances can lead to delayed
by the same organism or yeast-like organisms which is usually reversible after discontinuation
excretion of methotrexate and thus to increased plasma levels
of therapy.
of methotrexate. These patients should be carefully monitored, before the initial infection has been eradicated.
as this condition can lead to an increased risk of toxic reactions Very rarely: Loss of the sense of smell, which is usually
Rarely: Allergic reactions, drug fever, hypersensitivity
induced by methotrexate. reversible after discontinuation of therapy.
reactions (anaphylactic/anaphylactoid reactions,
e.g. facial, vascular and laryngeal oedema; Urogenital tract
Ciprobay/omeprazole
dyspnoea ranging up to life-threatening shock), Rarely: Inammation of the kidney (interstitial nephritis),
Concomitant administration of ciprooxacin with omeprazole
in some instances after the rst administration; transient impairment in kidney function ranging
can lead to a slight reduction in the peak plasma levels (Cmax )
pain (e.g. pain in the limbs, back, chest). up to transient kidney failure.
and bioavailability (AUC) of ciprooxacin.
Very rarely: Reactions similar to those associated with serum Laboratory ndings
Please inform your doctor or pharmacist if you are taking
other medicines or have taken other medicines recently, sickness (with, for example, fever, swelling of Occasionally: Particularly in patients with pre-existing liver
even if they are non-prescription medicines. the lymph nodes, reddening of the skin, urticaria, damage, temporary effect on liver function with
swelling [oedema]), worsening of the symptoms an increase in liver enzymes (transaminase,
3. HOW SHOULD CIPROBAY 100 BE USED? of myasthenia gravis (load-related fatigue of the alkaline phosphatase) ranging up to jaundice;
Unless otherwise prescribed, the following doses are muscular system, particularly the muscles of the transient increase in the levels of urea, creatinine
recommended (Table 1): face, pharynx and respiratory tract). and bilirubin (a bile pigment) in the blood.
Adults: Central nervous system Rarely: Raised levels of blood glucose (hyperglycaemia)
and blood or crystals in the urine (haematuria
Indications Single/daily dose for adults Occasionally: Headache, dizziness, fatigue, insomnia, agitation,
and crystalluria).
Single dose Total daily dose confusion.
Very rarely: Increased levels of certain enzymes (amylase,
Number of Quantity Number of Quantity Rarely: Hallucinations, sweating, peripheral paraesthesia,
bottles of of active bottles of of active lipase).
anxiety, nightmares, depression, tremor,
Ciprobay ingredient Ciprobay ingredient convulsions, decreased sensitivity to touch, Reactions at the injection site
100 (mg cipro- 100 (mg cipro- Occasionally: Venous inammation (phlebitis), local reactions
oxacin) oxacin
Very rarely: Unsteady gait, increased intracranial pressure,
psychotic reactions (psychological impairment at the injection site.
Infections of the Inform your doctor or pharmacist if you notice any side
urinary tract with altered perception ranging up to the point
of self-endangerment), in some cases after rst effects that are not listed in this patient information leaet.
- uncomplicated 1 bottle 100 2 bottles 200
- cystitis in women 1 bottle 100 1 bottle 100 use, impaired coordination, increased sensitivity 5. HOW SHOULD CIPROBAY 100 BE STORED?
(premenopausal) (single dose) to touch, increased muscular tone, muscular
Keep medicines out of the reach of children.
Gonorrhoea 1 bottle 100 1 bottle 100 twitching.
(single dose) The expiry date of this product is printed on the cardboard box
Gastrointestinal tract and the bottle. Do not use the product after this date.
Table 1: Recommended single/daily dose for adults frequently: Nausea, diarrhoea. Storage instructions
Note Occasionally: Vomiting, impaired digestion, abdominal pain, CIPROBAY 100 is sensitive to light and should therefore not
In addition to CIPROBAY 100, other infusion solutions atulence, loss of appetite. be taken out of the cardboard pack until immediately before
containing higher doses of the active ingredient are available Rarely: Jaundice, pseudomembranous colitis. use. In daylight conditions, complete efcacy of the undiluted
for intravenous therapy, and other delivery forms are available Very rarely: Liver damage (hepatitis, liver cell necrosis solution is guaranteed for a period of 3 days.
for oral therapy. ranging up to life-threatening liver failure), Precipitation can occur if the infusion solutions are stored at
Intravenous administration can be followed by further treatment pancreatitis. low temperatures but will, however, disperse when the infusion
on an oral basis. Cardiovascular is returned to room temperature. Storage in the refrigerator is
therefore not recommended.
Elderly patients: Rarely: Palpitations, migraine, unconsciousness, hot
ushes, swelling in legs (peripheral oedema), If CIPROBAY 100 is mixed with compatible infusion
Elderly patients should receive as low a dose as is compatible
low blood pressure. solutions, it must be used immediately after mixing for
with the severity of the infection and their kidney function
microbiological and light sensitivity reasons.
(creatinine clearance). Blood
Patients with impaired renal and hepatic function: Occasionally: Increased levels of a certain type of white blood
No reduction of the dosage of CIPROBAY 100 is required for cell (eosinophilia), reduced levels of white blood
CIPROBAY 200 Infusion Solution
adults with impaired renal and/or hepatic function. cells (leucocytopenia).
No information is available on the inuence of impaired Rarely: Reduced levels of red or certain white blood cells (Ciprooxacin lactate)
renal and hepatic function on the dosage for children and (anaemia, granulocytopenia) or blood platelets
adolescents. (thrombocytopenia), increased levels of white Active ingredient: Ciproox
How and when should you apply CIPROBAY 100? blood cells (leukocytosis) or blood platelets Infusion solution
(thrombocytosis), changed blood coagulation - 1 bottle of 100 ml infusion solution contains 254.4 mg
The infusion time is 30 minutes for 1 bottle containing 50 ml
factors (prothrombin values). ciprooxacin lactate, equivalent to 200 mg ciprooxacin.
infusion solution, equivalent to 100 mg ciprooxacin.
Very rarely: Increased degradation of red blood corpuscles - The other ingredients are lactic acid, sodium chloride,
CIPROBAY 100 can be administered either directly or after
(haemolytic anaemia), a reduction in all blood hydrochloric acid, water for injections.
being mixed with the compatible infusion solutions specied
cells (pancytopenia, possibly life-threatening), a 1 bottle of 100 ml infusion solution contains 900 mg sodium
below.
severe decrease in a certain type of white blood chloride (15.5 mmol).
CIPROBAY 100 is compatible with the following infusion cell with the possible symptoms of shivering,
solutions: fever, blisters in the oral and throat mucosa 1. WHAT IS CIPROBAY 200 AND WHAT IS IT USED
Physiological saline solution, Ringer solution and Ringer (agranulocytosis), reduced bone marrow function FOR?
Lactate solution, 5% and 10% glucose solutions. (possibly life-threatening). Ciprooxacin, the active ingredient of CIPROBAY 200,
For how long should you use CIPROBAY 100? Locomotor system belongs to the quinolone group of substances. The main site
The duration of treatment depends on the severity of the of action of quinolones is a bacterial enzyme (gyrase) which
Occasionally: Joint pain.
infection and the clinical and bacteriological course. plays a vital role in bacterial metabolism and reproduction.
Rarely: Muscle pain, swelling in the joints. Blocking this enzyme with ciprooxacin (a gyrase inhibitor)
As a rule the average duration of treatment is: Very rarely: Inammation of the tendons (tendinitis), has a bactericidal effect on the disease pathogens (i.e. it kills the
- up to 7 days for infections of the urinary tract, inammation of the tendon sheath (tendovaginitis) germs).
3 days may be sufcient for uncomplicated urinary tract and torn tendons (e.g. the Achilles tendon), Indications
infections in women, muscular weakness (myasthenia). Adults:
- Gonorrhoea: Single dose, Skin For the treatment of infections caused by organisms susceptible
- Cystitis in women: Single dose. frequently: Skin rash. to ciprooxacin:
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SPDI
Infections some cases after rst use of the product. In these cases, stop glibenclamide (a treatment for diabetes) may increase the action
of the respiratory tract. Many of the organisms known as using CIPROBAY 200 immediately and inform the attending of glibenclamide to such an extent that hypoglycaemia may
problem germs (e.g. Klebsiella, Enterobacter, Proteus, doctor. occur.
Pseudomonas, Legionella, Staphylococcus, Escherichia coli) If consumption of sodium chloride could represent a risk factor Ciprobay/probenecid
react very sensitively to Ciprobay. Most cases of pneumonia for you for medical reasons, for example because you suffer Probenecid (a treatment for gout) affects the excretion of
which do not require hospital treatment are caused by from congestive heart failure, impaired kidney function or other ciprooxacin in urine (renal secretion). Simultaneous use of
Streptococcus pneumoniae. In such cases CIPROBAY 200 is kidney disorders (nephrotic syndrome), the additional burden of CIPROBAY 200 and probenecid increases the concentration
not the drug of rst choice. the sodium in this product must be taken into account. 1 bottle of ciprooxacin in the blood (serum).
of the middle ear (otitis media) and the paranasal sinuses of 100 ml infusion solution contains 900 mg sodium chloride Ciprobay/metoclopramide:
(sinusitis), particularly when they are caused by problem germs (15.5 mmol).
Metoclopramide (a gastrointestinal medicine) accelerates the
such as Pseudomonas or Staphylococcus. A different antibiotic Children and adolescents absorption of CIPROBAY 200 into the blood and causes the
should be used for acute tonsillitis. In common with other gyrase inhibitors, ciprooxacin, the active maximum concentration in the blood (plasma) to be reached
- Of the eyes ingredient in CIPROBAY 200, is known to cause damage to more rapidly than usual. No effect on the bioavailability of
- Of the kidneys and/or efferent urinary tract the weight-bearing joints of juvenile animals. Evaluation of CIPROBAY 200 in the human body has been observed.
the safety data of patients aged less than 18 who were mainly Ciprobay/mexiletine
- Of the reproductive organs, including inammation of the
suffering from cystic brosis (mucoviscidosis) did not reveal Simultaneous use of these two medicines may lead to a raised
ovaries and fallopian tubes (adnexitis), gonorrhoea and
evidence of joint/cartilage damage. concentration of mexiletine in the body.
infections of the prostate gland (prostatitis)
Current ndings support the use of CIPROBAY for treatment
CIPROBAY 200 is not effective against Treponema pallidum Ciprobay/phenytoin
of acute infection episodes of cystic brosis caused by P.
(the causative organism in syphilis). Elevated or lowered serum concentrations of phenytoin have
aeruginosa in children and adolescents aged between 5 and
- Of the abdominal cavity, e.g. the gastrointestinal tract, the been reported following the simultaneous use of these two
17; at present, only inadequate experience is available in regard
biliary tract and peritoneum (peritonitis) medicines.
to its use in children and adolescents with other infections and
- Of the skin and soft tissues children aged less than 5. Ciprooxacin should therefore not be Ciprobay/diazepam
- Of the bones and joints. used for other infections and not for children aged less than 5 in There have been reports that concomitant use of CIPROBAY
- Blood poisoning (sepsis) general. 200 and diazepam delays the decomposition of diazepam in
Pregnancy the body (reduced clearance, extended half-life). Accordingly,
- Infections or the risk of infection (prophylaxis) in patients careful monitoring of diazepam treatment is recommended.
with a compromised immune system, e.g. who are being CIPROBAY 200 must not be used at any stage during
pregnancy because no experience has been gained regarding Ciprobay/methotrexate
treated with drugs that suppress the bodys natural immune
defences (immunosuppressants) or whose blood contains a its safety in pregnant women. Animal experiments have Simultaneous use of these two substances can lead to delayed
reduced number of certain white blood cells (neutropenia). not produced any evidence of malformation of the foetus excretion of methotrexate and thus to increased plasma levels
(teratogenic effects), but it is not entirely improbable that of methotrexate. These patients should be carefully monitored,
For children and adolescents aged between 5 and 17:
damage to cartilage may be caused in organisms which have as this condition can lead to an increased risk of toxic reactions
For acute infection episodes of cystic brosis (mucoviscidosis, induced by methotrexate.
not reached maturity.
an inherited metabolic disorder with increased production and
Breast-feeding Ciprobay/omeprazole
increased viscosity of glandular secretions in the bronchi and
digestive tract) caused by P. aeruginosa, provided that more It is also recommended on principle that CIPROBAY 200 Concomitant administration of ciprooxacin with omeprazole
effective parenteral treatment options do not appear practicable. should not be used while breast-feeding. can lead to a slight reduction in the peak plasma levels (Cmax )
CIPROBAY 200 is not recommended for other indications. and bioavailability (AUC) of ciprooxacin.
Driving and operating machinery:
Please inform your doctor or pharmacist if you are taking
Anthrax: Do not drive or operate power tools or machinery while taking
other medicines or have taken other medicines recently,
For immediate therapy and for treatment of anthrax following this medicine; even when used correctly, this medicine may even if they are non-prescription medicines.
inhalation of anthrax bacilli (Bacillus anthracis). The efcacy of impair reaction speed so much that the ability to drive, operate
Ciprobay in anthrax has been conrmed in studies. machinery or work without a secure foothold may be reduced, 3. HOW SHOULD CIPROBAY 200 BE USED?
or the patient may not be capable of doing these things at all. Unless otherwise prescribed, the following doses are
2. WHAT SHOULD YOU BE AWARE OF BEFORE USING This applies particularly at the start of treatment, when the dose recommended (Table 1):
CIPROBAY 200? is increased, when medication is changed and in conjunction Adults
CIPROBAY 200 must not be used: with alcohol.
Indications Single/daily dose for adults
- if you are hypersensitive (allergic) to ciprooxacin or other Interactions with other drugs: Single dose Total daily dose
drugs from the same substance group (quinolone type, gyrase CIPROBAY 200 must be administered separately unless Number of Quantity Number of Quantity
inhibitors). compatibility with other infusion solutions/drug products bottles of of active bottles of of active
- if you are pregnant or breast-feeding. has been conrmed. Visible signs of incompatibility include Ciprobay ingredient Ciprobay ingredient
Particular caution is required when using CIPROBAY precipitation, cloudiness and discoloration of the solution. 200 (mg cipro- 200 (mg cipro-
200: oxacin) oxacin
Incompatibility appears with all infusion solutions/drug
products that are physically or chemically unstable at the pH Respiratory tract 1-2** 200-400 2-4 bottles 400-800
- if you suffer from seizures (epilepsy) or any other form of
infections * bottles
prior damage to the central nervous system (e.g. an increased of CIPROBAY 200 (e.g. penicillins, heparin solutions),
(depending on
tendency to seizures, a history of seizures, reduced blood particularly when combined with solutions adjusted to an the severity and
ow in the brain, altered brain structure or a stroke in the alkaline pH (pH of CIPROBAY 200 infusion solution: 3.9 pathogen)
past). Patients in this category are at risk of side effects in the - 4.5). Complicated 1 bottle 200 2 bottles 400
central nervous system. Ciprobay/xanthines infections of
In isolated cases, psychotic reactions (psychological Taking CIPROBAY 200 and theophylline (an asthma the urinary tract
impairment with altered perception ranging up to the point of treatment) at the same time can lead to an unwanted increase in Diarrhoea 1 bottle 200 2 bottles 400
self-endangerment) occurred, in some cases after rst use. In the concentration of theophylline in the blood and, accordingly, Other infections * 1-2** 200-400 2-4 bottles 400-800
these cases, stop using CIPROBAY 200 immediately and to an increase in the rate of side effects caused by theophylline (cf. indications) bottles
inform the attending doctor. which, in isolated cases, may be life-threatening or fatal. If Table 1: Recommended single/daily dose for adults
- if severe and persistent diarrhoea develops during or after it is imperative to use both medicines at the same time, the
* The recommended dose for patients with particularly severe,
therapy. A doctor should be consulted in such cases as this theophylline concentration in the blood should be monitored life-threatening infections, especially those involving
may be a sign of a serious, possibly life-threatening intestinal and the dosage should be reduced as required. There have been Pseudomonas, Staphylococcus or Streptococcus, e.g. pneumonia
disease (pseudomembranous colitis) which requires reports of raised concentrations of the xanthine derivatives caused by Streptococcus, recurrent infection episodes in
immediate treatment. Use of CIPROBAY 200 must be caffeine and pentoxifylline (a medicine that promotes blood mucoviscidosis patients (an inherited metabolic disorder with
discontinued in this case and suitable therapy should be circulation) in the blood when these substances are administered increased production and increased viscosity of glandular
implemented (e.g. vancomycin oral, 4 x 250 mg daily). Do at the same time as CIPROBAY 200. secretions in the bronchi and digestive tract), infections of
not take drugs that inhibit gastric motility (peristalsis). Ciprobay/non-steroidal anti-inammatory drugs bones and joints, blood poisoning (sepsis) and infections of the
In isolated cases, inammation of tendons (tendinitis) and Animal studies have shown that using a combination of very peritoneum (peritonitis) is 3 x 2 bottles each containing 200 mg
rupturing of tendons (e.g. the Achilles tendon) have been high doses of quinolones (gyrase inhibitors) and certain drugs ciprooxacin daily.
observed following treatment with uoroquinolones (the which inhibit inammation (non-steroidal anti-inammatory ** This product is also available with an active ingredient content
substance group to which CIPROBAY 200 belongs). These agents) can trigger seizures. This does not apply to medicines of 400 mg ciprooxacin for this dosage.
occurrences were mainly observed in elderly patients who had containing acetylsalicylic acid. Anthrax:
been previously treated with corticosteroids. If inammation of Ciprobay/cyclosporin Adults: 2 bottles of CIPROBAY 200 each containing 100 ml
a tendon is suspected, treatment with CIPROBAY 200 must
Temporary impairment of kidney function associated with an infusion solution twice daily (400 mg ciprooxacin)
be discontinued immediately, physical strain must be avoided
and appropriate therapy may have to be given. increase in the concentration of creatinine in the blood has been Children: 10 mg/kg body weight twice daily.
observed in isolated cases when CIPROBAY 200 is taken at The maximum single dose for children must not exceed
Although photosensitivity only occurs very rarely following the same time as cyclosporin (a drug that suppresses the bodys
treatment with ciprooxacin, patients undergoing treatment 400 mg.
defence mechanisms). Your creatinine concentration should
with CIPROBAY 200 should not be exposed unnecessarily to Treatment should commence immediately after the suspected or
be monitored closely (twice a week) if you are taking both conrmed inhalation of anthrax pathogens.
sunlight and should avoid exposure to UV light (high-altitude medicines at the same time.
sun, solariums). Treatment must be discontinued if light- Note
sensitivity reactions (e.g. skin reactions similar to sunburn) are Ciprobay/warfarin
In addition to CIPROBAY 200, other infusion solutions
observed. Simultaneous use of CIPROBAY 200 and warfarin (a drug containing lower and higher doses of the active ingredient are
In isolated cases, severe immediate allergic reactions occurred that inhibits the coagulation of blood) may increase the action available for intravenous therapy, and other delivery forms are
involving swelling (oedema) of the face, blood vessels and of warfarin. available for oral therapy.
larynx and difculty in breathing (dyspnoea) ranging up to life- Ciprobay/glibenclamide Intravenous administration can be followed by further treatment
threatening shock (anaphylactic/ anaphylactoid reactions), in In isolated cases, concomitant use of CIPROBAY 200 and on an oral basis.
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Elderly patients If you have taken a greater quantity of CIPROBAY 200 Rarely: Light sensitivity with reddening of the skin
Elderly patients should receive as low a dose as is compatible than you were supposed to: (photosensitivity),
with the severity of the infection and their kidney function A few cases of transient (reversible) kidney damage have been Very rarely: Punctate skin haemorrhages (petechiae), blister
(creatinine clearance). reported following extremely large overdoses. In such cases, formation with accompanying haemorrhages
Children and adolescents therefore, kidney function should be checked by a doctor. (haemorrhagic bullae) and small nodules
(papules) with crust formation showing vascular
The recommended dose for acute infection episodes caused by 4. WHAT SIDE EFFECTS ARE POSSIBLE?
involvement (vasculitis), erythema nodosum,
P. aeruginosa in mucoviscidosis patients (an inherited metabolic Like all medicines, CIPROBAY 200 can have side effects. rash on the skin and mucous membranes close
disorder with increased production and increased viscosity of The frequency is indicated as follows: to the skin (xed drug-induced exanthem),
glandular secretions in the bronchi and digestive tract) is 3 x frequently: 1% to < 10 % erythema exsudativum multiforme (minor)
daily 10 mg/kg i.v. (maximum 1,200 mg/day). Occasionally: 0.1 % to <1% ranging up to severe forms (Stevens-Johnson
Patients with impaired renal and hepatic function: Rarely: 0.01 % to < 0.1 % syndrome), blister-like loss of the skin and oral/
Adults Very rarely: < 0.01 % nasal mucosa (Lyells syndrome).
1. The following doses are recommended for moderate to severe General Sensory organs:
impairment of renal function: Occasionally: A sensation of weakness. Long-term or Occasionally: Impaired sense of taste and smell.
- For patients with a creatinine clearance between 31 ml/min repeated use of CIPROBAY can reduce the Rarely: Tinnitus, transient loss of hearing, particularly
and 60 ml/min (serum creatinine between 1.4 mg/100 ml susceptibility of disease-causing organisms to with high tones, visual disturbances (e.g. double
and 1.9 mg/100 ml), the maximum dose for intravenous ciprooxacin; this means that the patient may vision, coloured vision), loss of the sense of taste
administration is 800 mg ciprooxacin per day. become infected again by the same organism or which is usually reversible after discontinuation
- For patients with a creatinine clearance 30 ml/min (serum yeast-like organisms before the initial infection of therapy.
creatinine 2 mg/100 ml), the maximum dose for intravenous has been eradicated. Very rarely: Loss of the sense of smell, which is usually
administration is 400 mg ciprooxacin per day. Rarely: Allergic reactions, drug fever, hypersensitivity reversible after discontinuation of therapy.
2. Patients with impaired renal function who are undergoing reactions (anaphylactic/anaphylactoid reactions, Urogenital tract
haemodialysis should receive the same dose after each dialysis e.g. facial, vascular and laryngeal oedema;
Rarely: Inammation of the kidney (interstitial nephritis),
session as patients with moderate to severe impairment of renal dyspnoea ranging up to life-threatening shock),
transient impairment in kidney function ranging
function (see point 1). in some instances after the rst administration;
up to transient kidney failure.
pain (e.g. pain in the limbs, back, chest).
3. In patients with impaired renal function who use continuous Laboratory ndings
Very rarely: Reactions similar to those associated with serum
ambulatory peritoneal dialysis (CAPD), CIPROBAY infusion Occasionally: Particularly in patients with pre-existing liver
sickness (with, for example, fever, swelling of
solution can be added to the (intraperitoneal) dialysate 4 x daily damage, temporary effect on liver function with
the lymph nodes, reddening of the skin, urticaria,
at 6-hour intervals at a dosage of 50 mg ciprooxacin per litre an increase in liver enzymes (transaminase,
swelling [oedema]), worsening of the symptoms
dialysate for peritonitis. alkaline phosphatase) ranging up to jaundice;
of myasthenia gravis (load-related fatigue of the
There is only limited clinical experience involving a muscular system, particularly the muscles of the transient increase in the levels of urea, creatinine
small number of patients in this indication. High doses of face, pharynx and respiratory tract). and bilirubin (a bile pigment) in the blood.
CIPROBAY should be used in order to attain sufciently high Rarely: Raised levels of blood glucose (hyperglycaemia)
Central nervous system
concentrations of ciprooxacin in the peritoneum. As a result, and blood or crystals in the urine (haematuria
patients must be closely monitored for side effects. If clinically Occasionally: Headache, dizziness, fatigue, insomnia, agitation,
and crystalluria).
relevant side effect or symptoms of an overdosage occur, the confusion.
Very rarely: Increased levels of certain enzymes (amylase,
dosage must be lowered or use of CIPROBAY discontinued. Rarely: Hallucinations, sweating, peripheral paraesthesia,
lipase).
anxiety, nightmares, depression, tremor,
4. It is not necessary to adjust the dosage for patients with impaired Reactions at the injection site
convulsions, decreased sensitivity to touch,
hepatic function.
Very rarely: Unsteady gait, increased intracranial pressure, Occasionally: Venous inammation (phlebitis), local reactions
5. In patients with impaired renal and hepatic function, the dosage at the injection site.
psychotic reactions (psychological impairment
should be adjusted as for impaired renal function; it may be
with altered perception ranging up to the point Inform your doctor or pharmacist if you notice any side
necessary to monitor the concentration of ciprooxacin in the
of self-endangerment), in some cases after rst effects that are not listed in this patient information
blood.
use, impaired coordination, increased sensitivity leaet.
Children and adolescents to touch, increased muscular tone, muscular
5. HOW SHOULD CIPROBAY 200 BE STORED?
No information is available on the inuence of impaired twitching.
renal and hepatic function on the dosage for children and Keep medicines out of the reach of children.
Gastrointestinal tract
adolescents. The expiry date of this product is printed on the cardboard box
frequently: Nausea, diarrhoea.
How and when should you apply CIPROBAY 200? and the bottle. Do not use the product after this date.
Occasionally: Vomiting, impaired digestion, abdominal pain,
The infusion time is 30 minutes for 1 bottle or 60 minutes for 2 Storage instructions
atulence, loss of appetite.
bottles containing 100 ml infusion solution each, equivalent to CIPROBAY 200 is sensitive to light and should therefore not
Rarely: Jaundice, pseudomembranous colitis.
200 mg ciprooxacin. be taken out of the cardboard pack until immediately before
Very rarely: Liver damage (hepatitis, liver cell necrosis use. In daylight conditions, complete efcacy of the undiluted
CIPROBAY 200 can be administered either directly or after ranging up to life-threatening liver failure), solution is guaranteed for a period of 3 days.
being mixed with the compatible infusion solutions specied pancreatitis.
below. Precipitation can occur if the infusion solutions are stored at
Cardiovascular low temperatures but will, however, disperse when the infusion
CIPROBAY 200 is compatible with the following infusion
Rarely: Palpitations, migraine, unconsciousness, hot is returned to room temperature. Storage in the refrigerator is
solutions: Physiological saline solution, Ringer solution and
ushes, swelling in legs (peripheral oedema), therefore not recommended.
Ringer Lactate solution, 5% and 10% glucose solutions.
low blood pressure. If CIPROBAY 200 is mixed with compatible infusion
For how long should you use CIPROBAY 200?
Blood solutions, it must be used immediately after mixing for
The duration of treatment depends on the severity of the microbiological and light sensitivity reasons.
Occasionally: Increased levels of a certain type of white blood
infection and the clinical and bacteriological course. In general, cell (eosinophilia), reduced levels of white blood
therapy should always be continued systematically for at least
3 days after the fever has subsided and the clinical signs have
cells (leucocytopenia). CIPROBAY 250 Tablet
Rarely: Reduced levels of red or certain white blood cells
disappeared.
(anaemia, granulocytopenia) or blood platelets
As a rule the average duration of treatment is: (thrombocytopenia), increased levels of white (Ciprooxacin hydrochloride monohydrate)
Adults blood cells (leukocytosis) or blood platelets
- Up to 7 days for infections of the kidneys, urinary tract and (thrombocytosis), changed blood coagulation Active ingredient: Ciprooxacin
abdominal cavity, factors (prothrombin values).
Film-coated tablets
- In patients with a compromised immune system, therapy Very rarely: Increased degradation of red blood corpuscles
- 1 lm-coated tablet contains 291 mg ciprooxacin hydrochloride
should be continued for as long as the total white blood cell (haemolytic anaemia), a reduction in all blood
monohydrate, equivalent to 250 mg ciprooxacin.
count is depressed (neutropenic phase), cells (pancytopenia, possibly life-threatening), a
severe decrease in a certain type of white blood - The other ingredients are microcrystalline cellulose,
- A maximum of 2 months for inammation of the bone crospovidone, hydroxypropyl methylcellulose, polyethylene
cell with the possible symptoms of shivering,
marrow (osteomyelitis), glycol 4000, magnesium stearate, maize starch, colloidal silicon
fever, blisters in the oral and throat mucosa
7-14 days for all other infections. (agranulocytosis), reduced bone marrow function dioxide, titanium dioxide (E 171).
In streptococcal infections therapy should be continued for at (possibly life-threatening). 1. WHAT IS CIPROBAY 250 AND WHAT IS IT USED
least 10 days because of the risk of late complications. Locomotor system FOR?
Chlamydia infections should likewise be treated for at least 10 Occasionally: Joint pain. Ciprooxacin, the active ingredient of CIPROBAY 250,
days.
Rarely: Muscle pain, swelling in the joints. belongs to the quinolone group of substances. The main site
For children and adolescents aged between 5 and 17 of action of quinolones is a bacterial enzyme (gyrase) which
Very rarely: Inammation of the tendons (tendinitis),
10 14 days for acute infection episodes of cystic brosis inammation of the tendon sheath (tendovaginitis) plays a vital role in bacterial metabolism and reproduction.
caused by P. aeruginosa. and torn tendons (e.g. the Achilles tendon), Blocking this enzyme with ciprooxacin (a gyrase inhibitor)
Anthrax: muscular weakness (myasthenia). has a bactericidal effect on the disease pathogens (i.e. it kills the
Skin germs).
- 60 days of treatment for immediate therapy and for treatment
of infections following inhalation of anthrax pathogens. frequently: Skin rash. Indications
Please consult your doctor or pharmacist if you have the Occasionally: Itching (pruritus), raised, spotty skin rash Adults:
impression that the effects of CIPROBAY 200 are too (maculopapular exanthema), nettle rash For the treatment of uncomplicated and complicated infections
strong or too weak. (urticaria). caused by organisms susceptible to ciprooxacin:
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SPDI
Infections In isolated cases, severe immediate allergic reactions occurred Ciprobay/probenecid
of the respiratory tract. Many of the organisms known as involving swelling (oedema) of the face, blood vessels and Probenecid (a treatment for gout) affects the excretion of
problem germs (e.g. Klebsiella, Enterobacter, Proteus, larynx and difculty in breathing (dyspnoea) ranging up to life- ciprooxacin in urine (renal secretion). Simultaneous use of
Pseudomonas, Legionella, Staphylococcus, Escherichia threatening shock (anaphylactic/ anaphylactoid reactions), in CIPROBAY 250 and probenecid increases the concentration
coli) react very sensitively to CIPROBAY. Most cases of some cases after rst use of the product. In these cases, stop of ciprooxacin in the blood (serum).
pneumonia which do not require hospital treatment are caused using CIPROBAY 250 immediately and inform the attending
doctor. Ciprobay/metoclopramide
by Streptococcus pneumoniae. In such cases CIPROBAY 250
Children and adolescents Metoclopramide (a gastrointestinal medicine) accelerates
is not the drug of rst choice.
the absorption of ciprooxacin into the blood and causes the
of the middle ear (otitis media) and the paranasal sinuses In common with other gyrase inhibitors, ciprooxacin, the active
maximum concentration in the blood (plasma) to be reached
(sinusitis), particularly when they are caused by problem germs ingredient in CIPROBAY 250, is known to cause damage to
more rapidly than usual. No effect on the bioavailability of
such as Pseudomonas or Staphylococcus. A different antibiotic the weight-bearing joints of juvenile animals. Evaluation of
CIPROBAY 250 in the human body has been observed.
should be used for acute tonsillitis. the safety data of patients aged less than 18 who were mainly
suffering from cystic brosis (mucoviscidosis) did not reveal Ciprobay/mexiletine
- of the eyes
evidence of joint/cartilage damage. Simultaneous use of these two medicines may lead to a raised
- of the kidneys and/or efferent urinary tract
Current ndings support the use of CIPROBAY 250 for concentration of mexiletine in the body.
- of the reproductive organs, including inammation of the
treatment of acute infection episodes of cystic brosis caused Ciprobay/phenytoin
ovaries and fallopian tubes (adnexitis), gonorrhoea and by P. aeruginosa in children and adolescents aged between 5 and
infections of the prostate gland (prostatitis) Elevated or lowered serum concentrations of phenytoin have
17; at present, only inadequate experience is available in regard been reported following the simultaneous use of these two
CIPROBAY 250 is not effective against Treponema to its use in children and adolescents with other infections and
pallidum (the causative organism in syphilis). medicines.
children aged less than 5. Ciprooxacin should therefore not be
- of the abdominal cavity, e.g. the gastrointestinal tract, the used for other infections and not for children aged less than 5 in Ciprobay/diazepam
biliary tract and peritoneum (peritonitis) general. There have been reports that concomitant use of CIPROBAY
- of the skin and soft tissues Pregnancy 250 and diazepam delays the decomposition of diazepam in
the body (reduced clearance, extended half-life). Accordingly,
- of the bones and joints. CIPROBAY 250 must not be used at any stage during
careful monitoring of diazepam treatment is recommended.
- Blood poisoning (sepsis) pregnancy because no experience has been gained regarding
its safety in pregnant women. Animal experiments have Ciprobay/methotrexate
- Infections or the risk of infection (prophylaxis) in patients
not produced any evidence of malformation of the foetus Simultaneous use of these two substances can lead to delayed
with a compromised immune system, e.g. who are being
(teratogenic effects), but it is not entirely improbable that excretion of methotrexate and thus to increased plasma levels
damage to cartilage may be caused in organisms which have of methotrexate. These patients should be carefully monitored,
defences (immunosuppressants) or whose blood contains a
not reached maturity. as this condition can lead to an increased risk of toxic reactions
reduced number of certain white blood cells (neutropenia).
Breast-feeding induced by methotrexate.
- Targeted elimination of gut bacteria (selective gut
decontamination) during treatment with drugs that suppress It is also recommended on principle that CIPROBAY 250 Ciprobay/omeprazole
the bodys immune system (immunosuppressants). should not be used while breast-feeding. Simultaneous use of ciprooxacin and omeprazole can lead to
For children and adolescents aged between 5 and 17: Driving and operating machinery: a slight decrease in the peak plasma concentrations (Cmax) and
Do not drive or operate power tools or machinery while taking bioavailability (AUC) of ciprooxacin.
For acute infection episodes of cystic brosis (mucoviscidosis,
an inherited metabolic disorder with increased production and this medicine; even when used correctly, this medicine may Please inform your doctor or pharmacist if you are taking
impair reaction speed so much that the ability to drive, operate other medicines or have taken other medicines recently,
increased viscosity of glandular secretions in the bronchi and
machinery or work without a secure foothold may be reduced, even if they are non-prescription medicines.
digestive tract) caused by P. aeruginosa, provided that oral
therapy seems sufcient or more effective parenteral treatment 3. HOW SHOULD CIPROBAY 250 BE USED?
This applies particularly at the start of treatment, when the dose
options do not appear practicable. CIPROBAY 250 is not
is increased, when medication is changed and in conjunction Always take CIPROBAY 250 in accordance with your
recommended for other indications.
with alcohol. doctors instructions. Please ask your doctor or pharmacist if
Anthrax: you are unsure how to take this medicine. Unless otherwise
Interactions with other drugs:
For immediate therapy and for treatment of anthrax following prescribed by your doctor, the usual dose is:
Ciprobay/products containing iron/antacids and products
inhalation of anthrax bacilli (Bacillus anthracis). The efcacy of
with a high buffering capacity which contain magnesium, Adults:
CIPROBAY in anthrax has been conrmed in studies.
aluminium or calcium Indications Single/daily dose for adults
2. WHAT SHOULD YOU BE AWARE OF BEFORE USING Simultaneous use of CIPROBAY 250 and any of the above- Single dose Total daily dose
CIPROBAY 250? mentioned products reduces the absorption of ciprooxacin; Number of Quantity Number of Quantity
CIPROBAY 250 must not be used: the same applies, for example, to sucralfate, drugs containing Ciprobay of active Ciprobay of active
the antiviral agent didanosine, oral nutrient solutions, drinks 250 lm ingredient 250 lm ingredient
- if you are hypersensitive (allergic) to ciprooxacin,
enriched with minerals and large quantities of dairy products. coated (mg cipro- coated (mg cipro-
other drugs from the same substance group (quinolone
For this reason, CIPROBAY 250 must be taken either 1-2 tablets oxacin) tablets oxacin
type, gyrase inhibitors) or any of the other ingredients of
hours before or at least 4 hours after these products. This Respiratory tract
CIPROBAY 250.
restriction does not apply to antacid medications of the H2- infections *
- if you are pregnant or breast-feeding. (e.g. bronchitis)
receptor blocker type.
Particular caution is required when using -depending on the 1-2 tablets 250-500 2-4 tablets 500-1000
Ciprobay/xanthines severity and pathogen
CIPROBAY 250:
Taking CIPROBAY 250 and theophylline (an asthma Urinary tract infections
- if you suffer from seizures (epilepsy) or any other form of treatment) at the same time can lead to an unwanted increase in - acute, uncomplicated -2 tablets 125-500 1-2 tablets 250-500
prior damage to the central nervous system (e.g. an increased the concentration of theophylline in the blood and, accordingly, - cystitis in women 1 tablet 250 1 tablet 250
tendency to seizures, a history of seizures, reduced blood to an increase in the rate of side effects caused by theophylline (before menopause) (single dose)
ow in the brain, altered brain structure or a stroke in the which, in isolated cases, may be life-threatening or fatal. If - complicated 1-2 tablets 250-500 2-4 tablets 500-1000
past). Patients in this category are at risk of side effects in the it is imperative to use both medicines at the same time, the Gonorrhoea, acute, 1 tablet 250 1 tablet 250
central nervous system. theophylline concentration in the blood should be monitored uncomplicated (single dose)
In isolated cases, psychotic reactions (psychological and the dosage should be reduced as required. There have been Diarrhoea up to 2 up to up to 2-4 up to
impairment with altered perception ranging up to the point of reports of raised concentrations of the xanthine derivatives tablets 500 tablets 500-1000
self-endangerment) occurred, in some cases after rst use. In caffeine and pentoxifylline (a medicine that promotes blood Other infections * 2 tablets 500 4 tablets 1000
these cases, stop using CIPROBAY 250 immediately and circulation) in the blood when these substances are administered (cf. indications)
inform the attending doctor. at the same time as CIPROBAY 250.
Table 1: Recommended single/daily dose for adults
- if severe and persistent diarrhoea develops during or after Ciprobay/non-steroidal anti-inammatory drugs
therapy. A doctor should be consulted in such cases as this * Patients with particularly severe, life-threatening infections
Animal studies have shown that using a combination of very (especially those involving Pseudomonas, Staphylococcus
may be a sign of a serious, possibly life-threatening intestinal high doses of quinolones (gyrase inhibitors) and certain drugs
disease (pseudomembranous colitis) which requires or Streptococcus), e.g. pneumonia caused by Streptococcus,
which inhibit inammation (non-steroidal anti-inammatory
immediate treatment. Use of CIPROBAY 250 must be recurrent infection episodes in mucoviscidosis patients (an
agents) can trigger seizures. This does not apply to medicines
discontinued in this case and suitable therapy should be inherited metabolic disorder with increased production and
containing acetylsalicylic acid.
implemented (e.g. vancomycin oral, 4 x 250 mg daily). Do increased viscosity of glandular secretions in the bronchi and
Ciprobay/cyclosporin digestive tract), infections of bones and joints, blood poisoning
not take drugs that inhibit gastric motility (peristalsis).
Temporary impairment of kidney function associated with an (sepsis) and infections of the peritoneum (peritonitis) are
In isolated cases, inammation of tendons (tendinitis) and
increase in the concentration of creatinine in the blood has been generally given CIPROBAY intravenously. Alternatively,
rupturing of tendons (e.g. the Achilles tendon) have been
observed in isolated cases when CIPROBAY 250 is taken at the patient can be treated by administering 2 x 750 mg
observed following treatment with uoroquinolones (the
the same time as cyclosporin (a drug that suppresses the bodys (equivalent to 2 x 3 lm-coated tablets CIPROBAY 250).
substance group to which CIPROBAY 250 belongs). These
defence mechanisms). Your creatinine concentration should
occurrences were mainly observed in elderly patients who had For patients with infections of the urinary tract or reproductive
be monitored closely (twice a week) if you are taking both
been previously treated with corticosteroids. If inammation of organs caused by Chlamydia, the daily dose can be increased
medicines at the same time.
a tendon is suspected, treatment with CIPROBAY 250 must to 2 x 750 mg ciprooxacin (equivalent to 2 x 3 lm-coated
be discontinued immediately, physical strain must be avoided Ciprobay/warfarin tablets CIPROBAY 250) if necessary.
and appropriate therapy may have to be given. Simultaneous use of CIPROBAY 250 and warfarin (a drug Anthrax:
Although photosensitivity only occurs very rarely following that inhibits the coagulation of blood) may increase the action
of warfarin. Adults: 2 lm-coated tablets CIPROBAY 250 (500 mg
treatment with ciprooxacin, patients undergoing treatment ciprooxacin) twice daily
with CIPROBAY 250 should not be exposed unnecessarily to Ciprobay/glibenclamide
Children: 15 mg/kg body weight twice daily.
sunlight and should avoid exposure to UV light (high-altitude In isolated cases, concomitant use of CIPROBAY 250 and
sun, solariums). Treatment must be discontinued if light- glibenclamide (a treatment for diabetes) may increase the action The maximum single dose for children must not exceed 500 mg.
sensitivity reactions (e.g. skin reactions similar to sunburn) are of glibenclamide to such an extent that hypoglycaemia may Treatment should commence immediately after the suspected or
observed. occur. conrmed inhalation of anthrax pathogens.
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SPDI
Note Chlamydia infections should likewise be treated for at least 10 Rarely: Reduced levels of red or certain white blood cells
In addition to CIPROBAY 250, other presentations containing days. (anaemia, granulocytopenia) or blood platelets
lower and higher doses of the active ingredient are available for For children and adolescents aged between 5 and 17 (thrombocytopenia), increased levels of white
oral therapy, and infusion solutions are available for intravenous blood cells (leukocytosis) or blood platelets
10 14 days for acute infection episodes of cystic brosis
therapy. caused by P. aeruginosa. (thrombocytosis), changed blood coagulation
factors (prothrombin values).
If the patient is not able to swallow lm-coated tablets, it Anthrax:
is recommended that treatment should be started with a Very rarely: Increased degradation of red blood corpuscles
- 60 days of treatment for immediate therapy and for treatment (haemolytic anaemia), a reduction in all blood
ciprooxacin infusion solution for intravenous therapy. of infections following inhalation of anthrax pathogens. cells (pancytopenia, possibly life-threatening), a
Elderly patients Please consult your doctor or pharmacist if you have the severe decrease in a certain type of white blood
Elderly patients should receive as low a dose as is compatible impression that the effects of CIPROBAY 250 are too cell with the possible symptoms of shivering,
with the severity of the infection and their kidney function strong or too weak. fever, blisters in the oral and throat mucosa
(creatinine clearance). If you have taken a greater quantity of CIPROBAY 250 (agranulocytosis), reduced bone marrow function
Children and adolescents than you were supposed to: (possibly life-threatening).
The recommended oral dose for acute infection episodes caused A few cases of transient (reversible) kidney damage have been Locomotor system
by P. aeruginosa in mucoviscidosis patients (an inherited reported following extremely large overdoses. In such cases, Occasionally: Joint pain.
metabolic disorder with increased production and increased therefore, kidney function should be checked by a doctor.
Rarely: Muscle pain, swelling in the joints.
viscosity of glandular secretions in the bronchi and digestive Administration of products containing magnesium or calcium
tract) is 2 x daily 15 (-20) mg/kg (maximum 1500 mg/day). neutralises stomach acid and thus reduces the absorption of Very rarely: Inammation of the tendons (tendinitis),
ciprooxacin into the bloodstream. inammation of the tendon sheath (tendovaginitis)
Patients with impaired renal and hepatic function: and torn tendons (e.g. the Achilles tendon),
Adults If you have forgotten to take CIPROBAY 250:
muscular weakness (myasthenia).
1. The following doses are recommended for moderate to severe Do not take a double dose the next time if you have forgotten
Skin
impairment of renal function: to take a dose. Simply continue treatment with the prescribed
dose. Frequently: Skin rash.
- For patients with a creatinine clearance between 31 ml/min Occasionally: Itching, elevated blotchy skin rash (maculopapular
and 60 ml/min (serum creatinine between 1.4 mg/100 ml and Effects of discontinuing treatment with CIPROBAY 250:
exanthem), nettle rash (urticaria).
1.9 mg/100 ml), the maximum dose for oral administration is If you want to interrupt treatment with CIPROBAY 250 or stop
it early, for example because you are feeling better or because Rarely: Light sensitivity with reddening of the skin
1000 mg ciprooxacin per day.
you are experiencing side effects, please talk to your doctor (photosensitivity),
- For patients with a creatinine clearance 30 ml/min (serum
creatinine 2 mg/100 ml), the maximum dose for oral rst. If you stop taking CIPROBAY 250 without asking your Very rarely: Punctate skin haemorrhages (petechiae), blister
doctor rst, the bacteria which caused your infection will be formation with accompanying haemorrhages
administration is 500 mg ciprooxacin per day.
able to start reproducing again and your condition may worsen (haemorrhagic bullae) and small nodules
2. Patients with impaired renal function who are undergoing considerably. (papules) with crust formation showing vascular
haemodialysis should receive the same dose after each dialysis involvement (vasculitis), erythema nodosum,
session as patients with moderate to severe impairment of renal 4. WHAT SIDE EFFECTS ARE POSSIBLE? rash on the skin and mucous membranes close
function (see point 1). Like all medicines, CIPROBAY 250 can have side effects. to the skin (xed drug eruption), erythema
3. In patients with impaired renal function who use continuous The frequency is indicated as follows: exsudativum multiforme (minor) ranging up
ambulatory peritoneal dialysis (CAPD), 500 mg ciprooxacin Frequently: 1% to < 10 % to severe forms (Stevens-Johnson syndrome),
(equivalent to 2 lm-coated tablets CIPROBAY 250) is Occasionally: 0.1 % to <1% blister-like loss of the skin and oral/nasal mucosa
required 4 x daily at 6-hour intervals for peritonitis. Rarely: 0.01 % to < 0.1 % (Lyells syndrome).
Alternatively, CIPROBAY infusion solutions can be Very rarely: < 0.01 % Sensory organs:
added to the (intraperitoneal) dialysate. The dosage is 50 mg General Occasionally: Impaired sense of taste and smell.
ciprooxacin per litre dialysate 4 x daily at 6-hour intervals. Occasionally: A sensation of weakness. Long-term or repeated Rarely: Tinnitus, transient loss of hearing, particularly
There is only limited clinical experience involving a use of CIPROBAY 250 can reduce the with high tones, visual disturbances (e.g. double
small number of patients in this indication. High doses of susceptibility of disease-causing organisms to vision, coloured vision), loss of the sense of taste
CIPROBAY 250 should be used in order to attain sufciently ciprooxacin; this means that the patient may which is usually reversible after discontinuation
high concentrations of ciprooxacin in the peritoneum. As a become infected again by the same organism or of therapy.
result, patients must be closely monitored for side effects. If yeast-like organisms before the initial infection
Very rarely: Loss of the sense of smell which is usually
clinically relevant side effect or symptoms of an overdosage has been eradicated.
reversible after discontinuation of therapy.
occur, the dosage must be lowered or use of CIPROBAY 250 Rarely: Allergic reactions, drug fever, hypersensitivity
discontinued. Urogenital tract
e.g. facial, vascular and laryngeal oedema; Rarely: Inammation of the kidney (interstitial nephritis),
4. It is not necessary to adjust the dosage for patients with impaired
dyspnoea ranging up to life-threatening shock), transient impairment in kidney function ranging
hepatic function.
in some instances after the rst administration; up to transient kidney failure.
5. In patients with impaired renal and hepatic function, the dosage
pain (e.g. pain in the limbs, back, chest). Laboratory ndings
should be adjusted as for impaired renal function; it may be
necessary to monitor the concentration of ciprooxacin in the Very rarely: Reactions similar to those associated with serum Occasionally: Particularly in patients with pre-existing liver
blood. sickness (with, for example, fever, swelling of damage, temporary effect on liver function with
the lymph nodes, reddening of the skin, urticaria, an increase in liver enzymes (transaminases,
Children and adolescents
swelling [oedema]), worsening of the symptoms alkaline phosphatase) ranging up to jaundice;
No information is available on the inuence of impaired of myasthenia gravis (load-related fatigue of the transient increase in the levels of urea, creatinine
renal and hepatic function on the dosage for children and muscular system, particularly the muscles of the and bilirubin (a bile pigment) in the blood.
adolescents. face, pharynx and respiratory tract). Rarely: Raised levels of blood glucose (hyperglycaemia)
How and when should you take CIPROBAY 250? Central nervous system and blood or crystals in the urine (haematuria
Swallow the lm-coated tablets whole with liquid. You do not Occasionally: Headache, dizziness, fatigue, insomnia, agitation, and crystalluria).
have to take the tablets at meal times. Taking the tablets on an confusion. Very rarely: Increased levels of certain enzymes (amylase,
empty stomach accelerates absorption of the active ingredient. lipase).
Rarely: Hallucinations, sweating, peripheral paraesthesia,
The lm-coated tablets should not be taken together with dairy anxiety, nightmares, depression, tremor, Inform your doctor or pharmacist if you notice any side
products or drinks enriched with minerals (e.g. milk, yoghurt convulsions, decreased sensitivity to touch. effects that are not listed in this patient information
or orange juice enriched with calcium) in this case. Absorption
Very rarely: Unsteady gait, increased intracranial pressure, leaet.
of the active ingredient is not signicantly affected by meals
containing calcium, however. psychotic reactions (psychological impairment 5. HOW SHOULD CIPROBAY 250 BE STORED?
with altered perception ranging up to the point
For how long should you use CIPROBAY 250? of self-endangerment), in some cases after rst Keep medicines out of the reach of children.
Your doctor will decide how long you should take CIPROBAY use, impaired coordination, increased sensitivity The expiry date of this product is printed on the cardboard box.
250. This will depend on the severity of your infection and how to touch, increased muscular tone, muscular Do not use the product after this date.
it responds to treatment, on your general state of health and twitching.
on the susceptibility of the organism causing the infection to Gastrointestinal tract CIPROBAY 500 Tablet
the active ingredient ciprooxacin. Therapy should always be
Frequently: Nausea, diarrhoea.
continued systematically for at least 3 days after the fever has
subsided and the clinical signs have disappeared. Occasionally: Vomiting, impaired digestion, abdominal pain,
atulence, loss of appetite. (Ciprooxacin hydrochloride monohydrate)
As a rule the average duration of treatment is:
Rarely: Jaundice, inammation of the large bowel
Adults Active ingredient: Ciprooxacin
(pseudomembranous colitis).
- 1 day for acute uncomplicated gonorrhoea and cystitis, Very rarely: Liver damage (hepatitis, liver cell necrosis Film-coated tablets
- up to 7 days for infections of the kidneys, urinary tract and ranging up to life-threatening liver failure), - 1 lm-coated tablet contains 582 mg ciprooxacin hydrochloride
abdominal cavity, inammation of the pancreas (pancreatitis). monohydrate, equivalent to 500 mg ciprooxacin.
in patients with a compromised immune system, therapy Cardiovascular - The other ingredients are microcrystalline cellulose,
should be continued for as long as the total white blood cell Rarely: Palpitations, migraine, unconsciousness, hot crospovidone, hydroxypropyl methylcellulose, polyethylene
count is depressed, ushes, swelling in legs (peripheral oedema), glycol 4000, magnesium stearate, maize starch, colloidal silicon
- a maximum of 2 months for inammation of the bone low blood pressure. dioxide, titanium dioxide (E 171).
marrow (osteomyelitis), Blood 1. WHAT IS CIPROBAY 500 AND WHAT IS IT USED
- 7-14 days for all other infections. Occasionally: Increased levels of a certain type of white blood FOR?
In streptococcal infections therapy should be continued for at cell (eosinophilia), reduced levels of white blood Ciprooxacin, the active ingredient of CIPROBAY 500,
least 10 days because of the risk of late complications. cells (leucocytopenia). belongs to the quinolone group of substances. The main site
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SPDI
of action of quinolones is a bacterial enzyme (gyrase) which a tendon is suspected, treatment with CIPROBAY 500 must Ciprobay/warfarin
plays a vital role in bacterial metabolism and reproduction. be discontinued immediately, physical strain must be avoided Simultaneous use of CIPROBAY 500 and warfarin (a drug
Blocking this enzyme with ciprooxacin (a gyrase inhibitor) and appropriate therapy may have to be given. that inhibits the coagulation of blood) may increase the action
has a bactericidal effect on the disease pathogens (i.e. it kills the Although photosensitivity only occurs very rarely following of warfarin.
germs). treatment with ciprooxacin, patients undergoing treatment Ciprobay/glibenclamide
Indications with CIPROBAY 500 should not be exposed unnecessarily to
sunlight and should avoid exposure to UV light (high-altitude In isolated cases, concomitant use of CIPROBAY 500 and
Adults: glibenclamide (a treatment for diabetes) may increase the action
sun, solariums). Treatment must be discontinued if light-
For the treatment of uncomplicated and complicated infections sensitivity reactions (e.g. skin reactions similar to sunburn) are of glibenclamide to such an extent that hypoglycaemia may
caused by organisms susceptible to ciprooxacin: observed. occur.
- Infections In isolated cases, severe immediate allergic reactions occurred Ciprobay/probenecid
- of the respiratory tract. Many of the organisms known as involving swelling (oedema) of the face, blood vessels and Probenecid (a treatment for gout) affects the excretion of
problem germs (e.g. Klebsiella, Enterobacter, Proteus, larynx and difculty in breathing (dyspnoea) ranging up to life- ciprooxacin in urine (renal secretion). Simultaneous use of
Pseudomonas, Legionella, Staphylococcus, Escherichia coli) threatening shock (anaphylactic/ anaphylactoid reactions), in CIPROBAY 500 and probenecid increases the concentration
react very sensitively to Ciprobay. Most cases of pneumonia some cases after rst use of the product. In these cases, stop of ciprooxacin in the blood (serum).
which do not require hospital treatment are caused by using CIPROBAY 500 immediately and inform the attending Ciprobay/metoclopramide
Streptococcus pneumoniae. In such cases CIPROBAY 500 doctor.
is not the drug of rst choice. Metoclopramide (a gastrointestinal medicine) accelerates
- of the middle ear (otitis media) and the paranasal sinuses In common with other gyrase inhibitors, ciprooxacin, the active
(sinusitis), particularly when they are caused by problem maximum concentration in the blood (plasma) to be reached
ingredient in CIPROBAY 500, is known to cause damage to more rapidly than usual. No effect on the bioavailability of
germs such as Pseudomonas or Staphylococcus. A different the weight-bearing joints of juvenile animals. Evaluation of
antibiotic should be used for acute tonsillitis. CIPROBAY 500 in the human body has been observed.
the safety data of patients aged less than 18 who were mainly
- of the eyes Ciprobay/mexiletine
suffering from cystic brosis (mucoviscidosis) did not reveal
- of the kidneys and/or efferent urinary tract evidence of joint/cartilage damage. Simultaneous use of these two medicines may lead to a raised
- of the reproductive organs, including inammation of the Current ndings support the use of CIPROBAY 500 for concentration of mexiletine in the body.
ovaries and fallopian tubes (adnexitis), gonorrhoea and treatment of acute infection episodes of cystic brosis caused by Ciprobay/phenytoin
infections of the prostate gland (prostatitis) P. aeruginosa in children and adolescents aged between 5 and Elevated or lowered serum concentrations of phenytoin have
CIPROBAY 500 is not effective against Treponema pallidum 17; at present, only inadequate experience is available in regard been reported following the simultaneous use of these two
(the causative organism in syphilis). to its use in children and adolescents with other infections and medicines.
- of the abdominal cavity, e.g. the gastrointestinal tract, the children aged less than 5. Ciprooxacin should therefore not be
Ciprobay/diazepam
biliary tract and peritoneum (peritonitis) used for other infections and not for children aged less than 5 in
general. There have been reports that concomitant use of CIPROBAY
- of the skin and soft tissues 500 and diazepam delays the decomposition of diazepam in
Pregnancy
- of the bones and joints. the body (reduced clearance, extended half-life). Accordingly,
- Blood poisoning (sepsis) CIPROBAY 500 must not be used at any stage during careful monitoring of diazepam treatment is recommended.
pregnancy because no experience has been gained regarding
- Infections or the risk of infection (prophylaxis) in patients Ciprobay/methotrexate
its safety in pregnant women. Animal experiments have
with a compromised immune system, e.g. who are being Simultaneous use of these two substances can lead to delayed
not produced any evidence of malformation of the foetus
treated with drugs that suppress the bodys natural immune excretion of methotrexate and thus to increased plasma levels
(teratogenic effects), but it is not entirely improbable that
defences (immunosuppressants) or whose blood contains a of methotrexate. These patients should be carefully monitored,
damage to cartilage may be caused in organisms which have
reduced number of certain white blood cells (neutropenia). not reached maturity. as this condition can lead to an increased risk of toxic reactions
- Targeted elimination of gut bacteria (selective gut induced by methotrexate.
Breast-feeding
decontamination) during treatment with drugs that suppress
It is also recommended on principle that CIPROBAY 500 Ciprobay/omeprazole
the bodys immune system (immunosuppressants).
should not be used while breast-feeding. Simultaneous use of ciprooxacin and omeprazole can lead to
For children and adolescents aged between 5 and 17:
Driving and operating machinery: a slight decrease in the peak plasma concentrations (Cmax) and
- For acute infection episodes of cystic brosis (mucoviscidosis, bioavailability (AUC) of ciprooxacin.
an inherited metabolic disorder with increased production Do not drive or operate power tools or machinery while taking
this medicine; even when used correctly, this medicine may Please inform your doctor or pharmacist if you are taking
and increased viscosity of glandular secretions in the bronchi
and digestive tract) caused by P. aeruginosa, provided that
machinery or work without a secure foothold may be reduced, even if they are non-prescription medicines.
oral therapy seems sufcient or more effective parenteral
treatment options do not appear practicable. CIPROBAY 3. HOW SHOULD CIPROBAY 500 BE USED?
500 is not recommended for other indications. Always take CIPROBAY 500 in accordance with your
is increased, when medication is changed and in conjunction
Anthrax: with alcohol. doctors instructions. Please ask your doctor or pharmacist if
- For immediate therapy and for treatment of anthrax following Interactions with other drugs: you are unsure how to take this medicine. Unless otherwise
inhalation of anthrax bacilli (Bacillus anthracis). The prescribed by your doctor, the usual dose is:
Ciprobay/products containing iron/antacids and products
efcacy of CIPROBAY 500 in anthrax has been conrmed with a high buffering capacity which contain magnesium, Adults
in studies. aluminium or calcium Indications Single/daily dose for adults
2. WHAT SHOULD YOU BE AWARE OF BEFORE USING Simultaneous use of CIPROBAY 500 and any of the above- Single dose Total daily dose
CIPROBAY 500? mentioned products reduces the absorption of ciprooxacin; Number of Quantity Number of Quantity
CIPROBAY 500 must not be used: the same applies, for example, to sucralfate, drugs containing Ciprobay of active Ciprobay of active
- if you are hypersensitive (allergic) to ciprooxacin, other the antiviral agent didanosine, oral nutrient solutions, drinks 500 lm ingredient 500 lm ingredient
drugs from the same substance group (quinolone type, gyrase enriched with minerals and large quantities of dairy products. coated (mg cipro- coated (mg cipro-
For this reason, CIPROBAY 500 must be taken either 1- tablets oxacin) tablets oxacin
inhibitors) or any of the other ingredients of CIPROBAY
500. 2 hours before or at least 4 hours after these products. This Respiratory tract
restriction does not apply to antacid medications of the H2- infections *
- if you are pregnant or breast-feeding. (e.g. bronchitis)
Particular caution is required when using CIPROBAY -depending on the -1 tablet 250-500 1-2 tablets 500-1000
Ciprobay/xanthines
500: severity and pathogen
Taking CIPROBAY 500 and theophylline (an asthma Urinary tract infections
- if you suffer from seizures (epilepsy) or any other form of treatment) at the same time can lead to an unwanted increase in - uncomplicated up to up to up to up to 500
prior damage to the central nervous system (e.g. an increased the concentration of theophylline in the blood and, accordingly, 1 tablet 500 1 tablet
tendency to seizures, a history of seizures, reduced blood to an increase in the rate of side effects caused by theophylline (single dose)
ow in the brain, altered brain structure or a stroke in the which, in isolated cases, may be life-threatening or fatal. If - cystitis in women tablet 250 tablet 250
past). Patients in this category are at risk of side effects in the it is imperative to use both medicines at the same time, the (before menopause) (single dose)
central nervous system. theophylline concentration in the blood should be monitored - complicated -1 tablet 250-500 1-2 tablets 500-1000
In isolated cases, psychotic reactions (psychological and the dosage should be reduced as required. There have been Gonorrhoea, acute, tablet 250 tablet 250
impairment with altered perception ranging up to the point of reports of raised concentrations of the xanthine derivatives uncomplicated (single dose)
self-endangerment) occurred, in some cases after rst use. In caffeine and pentoxifylline (a medicine that promotes blood Diarrhoea up to up to up to up to
these cases, stop using CIPROBAY 500 immediately and circulation) in the blood when these substances are administered 1 tablet 500 1-2 tablets 500-1000
inform the attending doctor. at the same time as CIPROBAY 500. Other infections *
(cf. indications) 1 tablet 500 2 tablets 1000
- if severe and persistent diarrhoea develops during or after Ciprobay/non-steroidal anti-inammatory drugs
therapy. A doctor should be consulted in such cases as this Animal studies have shown that using a combination of very Table 1: Recommended single/daily dose for adults
may be a sign of a serious, possibly life-threatening intestinal high doses of quinolones (gyrase inhibitors) and certain drugs * Patients with particularly severe, life-threatening infections
disease (pseudomembranous colitis) which requires which inhibit inammation (non-steroidal anti-inammatory (especially those involving Pseudomonas, Staphylococcus
immediate treatment. Use of CIPROBAY 500 must be agents) can trigger seizures. This does not apply to medicines or Streptococcus), e.g. pneumonia caused by Streptococcus,
discontinued in this case and suitable therapy should be containing acetylsalicylic acid. recurrent infection episodes in mucoviscidosis patients (an
implemented (e.g. vancomycin oral, 4 x 250 mg daily). Do Ciprobay/cyclosporin inherited metabolic disorder with increased production and
not take drugs that inhibit gastric motility (peristalsis). Temporary impairment of kidney function associated with an increased viscosity of glandular secretions in the bronchi and
In isolated cases, inammation of tendons (tendinitis) and increase in the concentration of creatinine in the blood has been digestive tract), infections of bones and joints, blood poisoning
rupturing of tendons (e.g. the Achilles tendon) have been observed in isolated cases when CIPROBAY 500 is taken at (sepsis) and infections of the peritoneum (peritonitis) are
observed following treatment with uoroquinolones (the the same time as cyclosporin (a drug that suppresses the bodys generally given CIPROBAY intravenously. Alternatively,
substance group to which CIPROBAY 500 belongs). These defence mechanisms). Your creatinine concentration should the patient can be treated by administering 2 x 750 mg
occurrences were mainly observed in elderly patients who had be monitored closely (twice a week) if you are taking both (equivalent to 2 x 1 lm-coated tablets CIPROBAY
been previously treated with corticosteroids. If inammation of medicines at the same time. 500).
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SPDI
For patients with infections of the urinary tract or reproductive As a rule the average duration of treatment is: Occasionally: Vomiting, impaired digestion, abdominal pain,
organs caused by Chlamydia, the daily dose can be increased Adults atulence, loss of appetite.
to 2 x 750 mg ciprooxacin (equivalent to 2 x 1 lm-coated Rarely: Jaundice, inammation of the large bowel
- up to 7 days for infections of the kidneys, urinary tract and
tablets CIPROBAY 500) if necessary. (pseudomembranous colitis).
abdominal cavity,
Anthrax: - in patients with a compromised immune system, therapy Very rarely: Liver damage (hepatitis, liver cell necrosis ranging
Adults: 1 lm-coated tablet CIPROBAY 500 (500 mg should be continued for as long as the total white blood cell up to life-threatening liver failure), inammation
ciprooxacin) twice daily count is depressed, of the pancreas (pancreatitis).
Children: 15 mg/kg body weight twice daily. - a maximum of 2 months for inammation of the bone Cardiovascular
The maximum single dose for children must not marrow (osteomyelitis), Rarely: Palpitations, migraine, unconsciousness, hot
exceed 500 mg. - 7-14 days for all other infections. ushes, swelling in legs (peripheral oedema), low
Treatment should commence immediately after the suspected or In streptococcal infections therapy should be continued for at blood pressure.
conrmed inhalation of anthrax pathogens. least 10 days because of the risk of late complications. Blood
Note Chlamydia infections should likewise be treated for at least 10 Occasionally: Increased levels of a certain type of white blood
days.
In addition to CIPROBAY 500, other presentations containing cell (eosinophilia), reduced levels of white blood
lower and higher doses of the active ingredient are available for For children and adolescents aged between 5 and 17 cells (leucocytopenia).
oral therapy, and infusion solutions are available for intravenous 10 - 14 days for acute infection episodes of cystic brosis Rarely: Reduced levels of red or certain white blood cells
therapy. caused by P. aeruginosa. (anaemia, granulocytopenia) or blood platelets
If the patient is not able to swallow lm-coated tablets, it Anthrax: (thrombocytopenia), increased levels of white
is recommended that treatment should be started with a - 60 days of treatment for immediate therapy and for treatment blood cells (leukocytosis) or blood platelets
ciprooxacin infusion solution for intravenous therapy. of infections following inhalation of anthrax pathogens. (thrombocytosis), changed blood coagulation
Elderly patients Please consult your doctor or pharmacist if you have the factors (prothrombin values).
Elderly patients should receive as low a dose as is compatible impression that the effects of CIPROBAY 500 are too Very rarely: Increased degradation of red blood corpuscles
with the severity of the infection and their kidney function strong or too weak. (haemolytic anaemia), a reduction in all blood
(creatinine clearance). If you have taken a greater quantity of CIPROBAY 500 cells (pancytopenia, possibly life-threatening), a
Children and adolescents than you were supposed to: severe decrease in a certain type of white blood
The recommended oral dose for acute infection episodes caused cell with the possible symptoms of shivering,
A few cases of transient (reversible) kidney damage have been
by P. aeruginosa in mucoviscidosis patients (an inherited reported following extremely large overdoses. In such cases, fever, blisters in the oral and throat mucosa
metabolic disorder with increased production and increased therefore, kidney function should be checked by a doctor. (agranulocytosis), reduced bone marrow function
viscosity of glandular secretions in the bronchi and digestive Administration of products containing magnesium or calcium (possibly life-threatening).
tract) is 2 x daily 15 (-20) mg/kg (maximum 1500 mg/day). neutralises stomach acid and thus reduces the absorption of Locomotor system
Patients with impaired renal and hepatic function: ciprooxacin into the bloodstream. Occasionally: Joint pain.
Adults If you have forgotten to take CIPROBAY 500: Rarely: Muscle pain, swelling in the joints.
1. The following doses are recommended for moderate to Do not take a double dose the next time if you have forgotten Very rarely: Inammation of the tendons (tendinitis),
severe impairment of renal function: to take a dose. Simply continue treatment with the prescribed inammation of the tendon sheath (tendovaginitis)
- For patients with a creatinine clearance between 31 ml/ dose. and torn tendons (e.g. the Achilles tendon),
min and 60 ml/min (serum creatinine between 1.4 mg/ Effects of discontinuing treatment with CIPROBAY 500: muscular weakness (myasthenia).
100 ml and 1.9 mg/100 ml), the maximum dose for oral If you want to interrupt treatment with CIPROBAY 500 or stop Skin
administration is 1000 mg ciprooxacin per day. it early, for example because you are feeling better or because Frequently: Skin rash.
- For patients with a creatinine clearance 30 ml/min you are experiencing side effects, please talk to your doctor
Occasionally: Itching, elevated blotchy skin rash (maculopapular
(serum creatinine 2 mg/100 ml), the maximum dose for rst. If you stop taking CIPROBAY 500 without asking your
exanthem), nettle rash (urticaria).
oral administration is 500 mg ciprooxacin per day. doctor rst, the bacteria which caused your infection will be
able to start reproducing again and your condition may worsen Rarely: Light sensitivity with reddening of the skin
2. Patients with impaired renal function who are undergoing
considerably. (photosensitivity),
haemodialysis should receive the same dose after each
dialysis session as patients with moderate to severe Very rarely: Punctate skin haemorrhages (petechiae), blister
4. WHAT SIDE EFFECTS ARE POSSIBLE?
impairment of renal function (see point 1). formation with accompanying haemorrhages
Like all medicines, CIPROBAY 500 can have side effects. (haemorrhagic bullae) and small nodules
3. In patients with impaired renal function who use continuous The frequency is indicated as follows:
ambulatory peritoneal dialysis (CAPD), 500 mg ciprooxacin (papules) with crust formation showing vascular
Frequently: 1% to < 10 % involvement (vasculitis), erythema nodosum, rash
(equivalent to 1 lm-coated tablet CIPROBAY 500) is
Occasionally: 0.1 % to <1% on the skin and mucous membranes close to the
required 4 x daily at 6-hour intervals for peritonitis.
Rarely: 0.01 % to < 0.1 % skin (xed drug eruption), erythema exsudativum
Alternatively, CIPROBAY infusion solutions can be Very rarely: < 0.01 % multiforme (minor) ranging up to severe forms
added to the (intraperitoneal) dialysate. The dosage is 50 mg
ciprooxacin per litre dialysate 4 x daily at 6-hour intervals. General (Stevens-Johnson syndrome), blister-like loss
Occasionally: A sensation of weakness. Long-term or repeated of the skin and oral/nasal mucosa (Lyells
There is only limited clinical experience involving a
use of CIPROBAY 500 can reduce the syndrome).
small number of patients in this indication. High doses of
CIPROBAY 500 should be used in order to attain sufciently susceptibility of disease-causing organisms to Sensory organs:
high concentrations of ciprooxacin in the peritoneum. As a ciprooxacin; this means that the patient may Occasionally: Impaired sense of taste and smell.
result, patients must be closely monitored for side effects. If become infected again by the same organism or
Rarely: Tinnitus, transient loss of hearing, particularly
clinically relevant side effect or symptoms of an overdosage yeast-like organisms before the initial infection
with high tones, visual disturbances (e.g. double
occur, the dosage must be lowered or use of CIPROBAY 500 has been eradicated.
vision, coloured vision), loss of the sense of taste
discontinued. Rarely: Allergic reactions, drug fever, hypersensitivity which is usually reversible after discontinuation
4. It is not necessary to adjust the dosage for patients with reactions (anaphylactic/anaphylactoid reactions, of therapy.
impaired hepatic function. e.g. facial, vascular and laryngeal oedema;
dyspnoea ranging up to life-threatening shock), in Very rarely: Loss of the sense of smell which is usually
5. In patients with impaired renal and hepatic function, the reversible after discontinuation of therapy.
some instances after the rst administration; pain
dosage should be adjusted as for impaired renal function; Urogenital tract
(e.g. pain in the limbs, back, chest).
it may be necessary to monitor the concentration of
ciprooxacin in the blood. Very rarely: Reactions similar to those associated with serum Rarely: Inammation of the kidney (interstitial nephritis),
sickness (with, for example, fever, swelling of transient impairment in kidney function ranging
the lymph nodes, reddening of the skin, urticaria, up to transient kidney failure.
No information is available on the inuence of impaired swelling [oedema]), worsening of the symptoms Laboratory ndings
renal and hepatic function on the dosage for children and of myasthenia gravis (load-related fatigue of the
adolescents. Occasionally: Particularly in patients with pre-existing liver
muscular system, particularly the muscles of the
damage, temporary effect on liver function with
How and when should you take CIPROBAY 500? face, pharynx and respiratory tract).
an increase in liver enzymes (transaminases,
Swallow the lm-coated tablets whole with liquid. You do not Central nervous system alkaline phosphatase) ranging up to jaundice;
have to take the tablets at meal times. Taking the tablets on an Occasionally: Headache, dizziness, fatigue, insomnia, agitation, transient increase in the levels of urea, creatinine
empty stomach accelerates absorption of the active ingredient. confusion. and bilirubin (a bile pigment) in the blood.
The lm-coated tablets should not be taken together with dairy
Rarely: Hallucinations, sweating, peripheral paraesthesia, Rarely: Raised levels of blood glucose (hyperglycaemia)
products or drinks enriched with minerals (e.g. milk, yoghurt
anxiety, nightmares, depression, tremor, and blood or crystals in the urine (haematuria and
or orange juice enriched with calcium) in this case. Absorption
convulsions, decreased sensitivity to touch. crystalluria).
of the active ingredient is not signicantly affected by meals
containing calcium, however. Very rarely: Unsteady gait, increased intracranial pressure, Very rarely: Increased levels of certain enzymes (amylase,
For how long should you use CIPROBAY 500? psychotic reactions (psychological impairment lipase).
Your doctor will decide how long you should take CIPROBAY Inform your doctor or pharmacist if you notice any side
of self-endangerment), in some cases after rst
500. This will depend on the severity of your infection and how effects that are not listed in this patient information leaet.
use, impaired coordination, increased sensitivity
it responds to treatment, on your general state of health and to touch, increased muscular tone, muscular 5. HOW SHOULD CIPROBAY 500 BE STORED?
on the susceptibility of the organism causing the infection to
twitching. Keep medicines out of the reach of children.
continued systematically for at least 3 days after the fever has Gastrointestinal tract The expiry date of this product is printed on the cardboard box.
subsided and the clinical signs have disappeared. Frequently: Nausea, diarrhoea. Do not use the product after this date.
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SPDI
substance group to which CIPROBAY 750 belongs). These observed in isolated cases when CIPROBAY 750 is taken at
CIPROBAY 750 Tablet occurrences were mainly observed in elderly patients who had the same time as cyclosporin (a drug that suppresses the bodys
been previously treated with corticosteroids. If inammation of defence mechanisms). Your creatinine concentration should
a tendon is suspected, treatment with CIPROBAY 750 must be monitored closely (twice a week) if you are taking both
(Ciprooxacin hydrochloride monohydrate) be discontinued immediately, physical strain must be avoided medicines at the same time.
and appropriate therapy may have to be given. Ciprobay/warfarin
Active ingredient: Ciprooxacin
Although photosensitivity only occurs very rarely following Simultaneous use of CIPROBAY 750 and warfarin (a drug
Film-coated tablets treatment with ciprooxacin, patients undergoing treatment that inhibits the coagulation of blood) may increase the action
- 1 lm-coated tablet contains 873 mg ciprooxacin hydrochloride with CIPROBAY 750 should not be exposed unnecessarily to of warfarin.
monohydrate, equivalent to 750 mg ciprooxacin. sunlight and should avoid exposure to UV light (high-altitude Ciprobay/glibenclamide
- The other ingredients are microcrystalline cellulose, sun, solariums). Treatment must be discontinued if light-
In isolated cases, concomitant use of CIPROBAY 750 and
crospovidone, hydroxypropyl methylcellulose, polyethylen sensitivity reactions (e.g. skin reactions similar to sunburn) are
glibenclamide (a treatment for diabetes) may increase the action
glycol 4000, magnesium stearate, maize starch, colloidal silicon observed.
of glibenclamide to such an extent that hypoglycaemia may
dioxide, titanium dioxide (E 171). In isolated cases, severe immediate allergic reactions occurred occur.
1. WHAT IS CIPROBAY 750 AND WHAT IS IT USED involving swelling (oedema) of the face, blood vessels and
Ciprobay/probenecid
FOR? larynx and difculty in breathing (dyspnoea) ranging up to life-
threatening shock (anaphylactic/ anaphylactoid reactions), in Probenecid (a treatment for gout) affects the excretion of
Ciprooxacin, the active ingredient of CIPROBAY 750, some cases after rst use of the product. In these cases, stop ciprooxacin in urine (renal secretion). Simultaneous use of
belongs to the quinolone group of substances. The main site using CIPROBAY 750 immediately and inform the attending CIPROBAY 750 and probenecid increases the concentration
of action of quinolones is a bacterial enzyme (gyrase) which of ciprooxacin in the blood (serum).
doctor.
plays a vital role in bacterial metabolism and reproduction. Ciprobay/metoclopramide
Blocking this enzyme with ciprooxacin (a gyrase inhibitor) Children and adolescents
Metoclopramide (a gastrointestinal medicine) accelerates
has a bactericidal effect on the disease pathogens (i.e. it kills the In common with other gyrase inhibitors, ciprooxacin, the active
germs). ingredient in CIPROBAY 750, is known to cause damage to
maximum concentration in the blood (plasma) to be reached
Indications the weight-bearing joints of juvenile animals. Evaluation of
more rapidly than usual. No effect on the bioavailability of
the safety data of patients aged less than 18 who were mainly
Adults: CIPROBAY 750 in the human body has been observed.
suffering from cystic brosis (mucoviscidosis) did not reveal
For the treatment of complicated infections caused by organisms evidence of joint/cartilage damage. Ciprobay/mexiletine
susceptible to ciprooxacin: Current ndings support the use of CIPROBAY 750 for Simultaneous use of these two medicines may lead to a raised
- Infections treatment of acute infection episodes of cystic brosis caused by concentration of mexiletine in the body.
- of the respiratory tract. Many of the organisms known as P. aeruginosa in children and adolescents aged between 5 and Ciprobay/phenytoin
problem germs (e.g. Klebsiella, Enterobacter, Proteus, 17; at present, only inadequate experience is available in regard Elevated or lowered serum concentrations of phenytoin have
Pseudomonas, Legionella, Staphylococcus, Escherichia coli) to its use in children and adolescents with other infections and been reported following the simultaneous use of these two
react very sensitively to Ciprobay. Most cases of pneumonia children aged less than 5. Ciprooxacin should therefore not be medicines.
which do not require hospital treatment are caused by used for other infections and not for children aged less than 5 in Ciprobay/diazepam
Streptococcus pneumoniae. In such cases CIPROBAY 750 general.
There have been reports that concomitant use of CIPROBAY
is not the drug of rst choice. Pregnancy 750 and diazepam delays the decomposition of diazepam in
- of the middle ear (otitis media) and the paranasal sinuses
CIPROBAY 750 must not be used at any stage during the body (reduced clearance, extended half-life). Accordingly,
(sinusitis), particularly when they are caused by problem careful monitoring of diazepam treatment is recommended.
pregnancy because no experience has been gained regarding
germs such as Pseudomonas or Staphylococcus. A different
its safety in pregnant women. Animal experiments have Ciprobay/methotrexate
antibiotic should be used for acute tonsillitis.
not produced any evidence of malformation of the foetus Simultaneous use of these two substances can lead to delayed
- of the eyes (teratogenic effects), but it is not entirely improbable that excretion of methotrexate and thus to increased plasma levels
- of the skin and soft tissues damage to cartilage may be caused in organisms which have of methotrexate. These patients should be carefully monitored,
- of the bones and joints. not reached maturity. as this condition can lead to an increased risk of toxic reactions
- Peritonitis Breast-feeding induced by methotrexate.
- Blood poisoning (sepsis) It is also recommended on principle that CIPROBAY 750 Ciprobay/omeprazole
- Infections or the risk of infection (prophylaxis) in patients should not be used while breast-feeding. Simultaneous use of ciprooxacin and omeprazole can lead to
with a compromised immune system, e.g. who are being
Driving and operating machinery: a slight decrease in the peak plasma concentrations (Cmax) and
Do not drive or operate power tools or machinery while taking bioavailability (AUC) of ciprooxacin.
defences (immunosuppressants) or whose blood contains a
reduced number of certain white blood cells (neutropenia). this medicine; even when used correctly, this medicine may Please inform your doctor or pharmacist if you are taking
For children and adolescents aged between 5 and 17: even if they are non-prescription medicines.
machinery or work without a secure foothold may be reduced,
- For acute infection episodes of cystic brosis (mucoviscidosis, or the patient may not be capable of doing these things at all.
an inherited metabolic disorder with increased production 3. HOW SHOULD CIPROBAY 750 BE USED?
and increased viscosity of glandular secretions in the bronchi is increased, when medication is changed and in conjunction Always take CIPROBAY 750 in accordance with your
and digestive tract) caused by P. aeruginosa, provided that with alcohol. doctors instructions. Please ask your doctor or pharmacist if
oral therapy seems sufcient or more effective parenteral you are unsure how to take this medicine.
Interactions with other drugs:
treatment options do not appear practicable. CIPROBAY You should follow your doctors instructions exactly concerning
750 is not recommended for other indications. Ciprobay/products containing iron/antacids and products how much to take and how often to take it, and you should not
with a high buffering capacity which contain magnesium, stop taking the medicine or change the amount you are taking
2. WHAT SHOULD YOU BE AWARE OF BEFORE USING aluminium or calcium without rst consulting your doctor.
CIPROBAY 750? Simultaneous use of CIPROBAY 750 and any of the above- Your doctor will decide how much CIPROBAY 750 you
CIPROBAY 750 must not be used: mentioned products reduces the absorption of ciprooxacin; need to take depending on your personal requirements because
- if you are hypersensitive (allergic) to ciprooxacin, other the same applies, for example, to sucralfate, drugs containing CIPROBAY works differently in different people, and not
drugs from the same substance group (quinolone type, gyrase the antiviral agent didanosine, oral nutrient solutions, drinks everyone tolerates it the same way.
inhibitors) or any of the other ingredients of CIPROBAY enriched with minerals and large quantities of dairy products.
Unless otherwise prescribed by your doctor, the usual single
750. For this reason, CIPROBAY 750 must be taken either 1-2
dose is 1 CIPROBAY 750 lm-coated tablet, equivalent to
- if you are pregnant or breast-feeding. hours before or at least 4 hours after these products. This
750 mg ciprooxacin. The total daily dose is 2 CIPROBAY
restriction does not apply to antacid medications of the H2-
Particular caution is required when using CIPROBAY 750 lm-coated tablets, equivalent to 1,500 mg ciprooxacin.
750: Note
Ciprobay/xanthines
- if you suffer from seizures (epilepsy) or any other form of In addition to CIPROBAY 750, other presentations containing
prior damage to the central nervous system (e.g. an increased Taking CIPROBAY 750 and theophylline (an asthma lower doses of the active ingredient are available for oral
tendency to seizures, a history of seizures, reduced blood ow treatment) at the same time can lead to an unwanted increase in therapy, and infusion solutions are available for intravenous
in the brain, altered brain structure or a stroke in the past). the concentration of theophylline in the blood and, accordingly, therapy.
Patients in this category are at risk of side effects in the central to an increase in the rate of side effects caused by theophylline
which, in isolated cases, may be life-threatening or fatal. If If the patient is not able to swallow lm-coated tablets, it
nervous system. is recommended that treatment should be started with a
it is imperative to use both medicines at the same time, the
In isolated cases, psychotic reactions (psychological impairment ciprooxacin infusion solution for intravenous therapy.
theophylline concentration in the blood should be monitored
with altered perception ranging up to the point of self- Elderly patients
and the dosage should be reduced as required. There have been
endangerment) occurred, in some cases after rst use. In these
reports of raised concentrations of the xanthine derivatives Elderly patients should receive as low a dose as is compatible
cases, stop using CIPROBAY 750 immediately and inform
caffeine and pentoxifylline (a medicine that promotes blood with the severity of the infection and their kidney function
the attending doctor.
circulation) in the blood when these substances are administered (creatinine clearance).
- if severe and persistent diarrhoea develops during or after at the same time as CIPROBAY 750. Children and adolescents
therapy. A doctor should be consulted in such cases as this
Ciprobay/non-steroidal anti-inammatory drugs The recommended oral dose for acute infection episodes caused
may be a sign of a serious, possibly life-threatening intestinal
disease (pseudomembranous colitis) which requires immediate Animal studies have shown that using a combination of very by P. aeruginosa in mucoviscidosis patients (an inherited
treatment. Use of CIPROBAY 750 must be discontinued high doses of quinolones (gyrase inhibitors) and certain drugs metabolic disorder with increased production and increased
which inhibit inammation (non-steroidal anti-inammatory viscosity of glandular secretions in the bronchi and digestive
in this case and suitable therapy should be implemented (e.g.
agents) can trigger seizures. This does not apply to medicines tract) is 2 x daily 15 (-20) mg/kg (maximum 1500 mg/day).
vancomycin oral, 4 x 250 mg daily). Do not take drugs that
inhibit gastric motility (peristalsis). containing acetylsalicylic acid. Patients with impaired renal and hepatic function:
- In isolated cases, inammation of tendons (tendinitis) and Ciprobay/cyclosporin Adults
rupturing of tendons (e.g. the Achilles tendon) have been Temporary impairment of kidney function associated with an 1. The following doses are recommended for moderate to
observed following treatment with uoroquinolones (the increase in the concentration of creatinine in the blood has been severe impairment of renal function:
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SPDI
- For patients with a creatinine clearance between 31 ml/ 4. WHAT SIDE EFFECTS ARE POSSIBLE? (haemorrhagic bullae) and small nodules
min and 60 ml/min (serum creatinine between 1.4 mg/ Like all medicines, CIPROBAY 750 can have side effects. (papules) with crust formation showing vascular
100 ml and 1.9 mg/100 ml), the maximum dose for oral The frequency is indicated as follows: involvement (vasculitis), erythema nodosum,
administration is 1000 mg ciprooxacin per day. rash on the skin and mucous membranes close
Frequently: 1% to < 10 %
- For patients with a creatinine clearance 30 ml/min to the skin (xed drug eruption), erythema
Occasionally: 0.1 % to <1%
(serum creatinine 2 mg/100 ml), the maximum dose for exsudativum multiforme (minor) ranging up
Rarely: 0.01 % to < 0.1 %
oral administration is 500 mg ciprooxacin per day. to severe forms (Stevens-Johnson syndrome),
Very rarely: < 0.01 %
2. Patients with impaired renal function who are undergoing blister-like loss of the skin and oral/nasal mucosa
General (Lyells syndrome).
haemodialysis should receive the same dose after each
dialysis session as patients with moderate to severe Occasionally: A sensation of weakness. Long-term or repeated Sensory organs:
impairment of renal function (see point 1). use of CIPROBAY 750 can reduce the
Occasionally: Impaired sense of taste and smell.
susceptibility of disease-causing organisms to
3. In patients with impaired renal function who use continuous Rarely: Tinnitus, transient loss of hearing, particularly
ciprooxacin; this means that the patient may
ambulatory peritoneal dialysis (CAPD), 500 mg ciprooxacin with high tones, visual disturbances (e.g. double
become infected again by the same organism or
is required 4 x daily at 6-hour intervals for peritonitis. vision, coloured vision), loss of the sense of taste
yeast-like organisms before the initial infection
Alternatively, CIPROBAY infusion solutions can be has been eradicated. which is usually reversible after discontinuation
added to the (intraperitoneal) dialysate. The dosage is 50 mg of therapy.
Rarely: Allergic reactions, drug fever, hypersensitivity
ciprooxacin per litre dialysate 4 x daily at 6-hour intervals. Very rarely: Loss of the sense of smell which is usually
There is only limited clinical experience involving a e.g. facial, vascular and laryngeal oedema; reversible after discontinuation of therapy.
small number of patients in this indication. High doses dyspnoea ranging up to life-threatening shock), Urogenital tract
of CIPROBAY 750 should be used in order to attain in some instances after the rst administration; Rarely: Inammation of the kidney (interstitial nephritis),
sufciently high concentrations of ciprooxacin in the pain (e.g. pain in the limbs, back, chest). transient impairment in kidney function ranging
peritoneum. As a result, patients must be closely monitored
Very rarely: Reactions similar to those associated with serum up to transient kidney failure.
for side effects. If clinically relevant side effect or symptoms
of an overdosage occur, the dosage must be lowered or use of sickness (with, for example, fever, swelling of Laboratory ndings
CIPROBAY 750 discontinued. the lymph nodes, reddening of the skin, urticaria, Occasionally: Particularly in patients with pre-existing liver
swelling [oedema]), worsening of the symptoms damage, temporary effect on liver function with
4. It is not necessary to adjust the dosage for patients with
of myasthenia gravis (load-related fatigue of the an increase in liver enzymes (transaminases,
impaired hepatic function.
muscular system, particularly the muscles of the alkaline phosphatase) ranging up to jaundice;
5. In patients with impaired renal and hepatic function, the face, pharynx and respiratory tract).
dosage should be adjusted as for impaired renal function; transient increase in the levels of urea, creatinine
it may be necessary to monitor the concentration of Central nervous system and bilirubin (a bile pigment) in the blood.
ciprooxacin in the blood. Occasionally: Headache, dizziness, fatigue, insomnia, agitation, Rarely: Raised levels of blood glucose (hyperglycaemia)
Children and adolescents confusion. and blood or crystals in the urine (haematuria
Rarely: Hallucinations, sweating, peripheral paraesthesia, and crystalluria).
No information is available on the inuence of impaired
renal and hepatic function on the dosage for children and anxiety, nightmares, depression, tremor, Very rarely: Increased levels of certain enzymes (amylase,
adolescents. convulsions, decreased sensitivity to touch. lipase).
How and when should you take CIPROBAY 750? Very rarely: Unsteady gait, increased intracranial pressure, Inform your doctor or pharmacist if you notice any side
psychotic reactions (psychological impairment effects that are not listed in this patient information leaet.
Swallow the lm-coated tablets whole with liquid. You do not
have to take the tablets at meal times. Taking the tablets on an 5. HOW SHOULD CIPROBAY 750 BE STORED?
of self-endangerment), in some cases after rst
empty stomach accelerates absorption of the active ingredient. Keep medicines out of the reach of children.
The lm-coated tablets should not be taken together with dairy use, impaired coordination, increased sensitivity
products or drinks enriched with minerals (e.g. milk, yoghurt to touch, increased muscular tone, muscular The expiry date of this product is printed on the cardboard box.
or orange juice enriched with calcium) in this case. Absorption twitching. Do not use the product after this date.
of the active ingredient is not signicantly affected by meals Gastrointestinal tract
containing calcium, however. Frequently: Nausea, diarrhoea. GLUCOBAY 50/100 Tablets
For how long should you use CIPROBAY 750? Occasionally: Vomiting, impaired digestion, abdominal pain,
Your doctor will decide how long you should take CIPROBAY atulence, loss of appetite.
750. This will depend on the severity of your infection and how
(Acarbose)
Rarely: Jaundice, inammation of the large bowel
it responds to treatment, on your general state of health and (pseudomembranous colitis). Active ingredient: Acarbose
on the susceptibility of the organism causing the infection to
Very rarely: Liver damage (hepatitis, liver cell necrosis - The pharmaceutically active ingredient is acarbose.
ranging up to life-threatening liver failure),
continued systematically for at least 3 days after the fever has 1 tablet GLUCOBAY 50 contains 50 mg acarbose.
inammation of the pancreas (pancreatitis).
subsided and the clinical signs have disappeared. 1 tablet GLUCOBAY 100 contains 100 mg acarbose.
Cardiovascular
As a rule the average duration of treatment is: - The other ingredients are microcrystalline cellulose, magnesium
Rarely: Palpitations, migraine, unconsciousness, hot stearate, maize starch, colloidal silicon dioxide.
Adults
ushes, swelling in legs (peripheral oedema),
- in patients with a compromised immune system, therapy low blood pressure. 1. WHAT IS GLUCOBAY 50 /100 AND WHAT IS IT USED
should be continued for as long as the total white blood cell FOR?
count is depressed, Blood
Occasionally: Increased levels of a certain type of white blood GLUCOBAY belongs to a class of medicines (alpha-
- a maximum of 2 months for inammation of the bone glucosidase inhibitors) taken orally for the treatment of diabetes
marrow (osteomyelitis), cell (eosinophilia), reduced levels of white blood
cells (leucocytopenia). mellitus.
- 7-14 days for all other infections. The active ingredient in GLUCOBAY is produced
Rarely: Reduced levels of red or certain white blood cells
In streptococcal infections therapy should be continued for at biologically. Its main site of action is the small intestine.
(anaemia, granulocytopenia) or blood platelets
least 10 days because of the risk of late complications. Almost none of the active ingredient is absorbed by the body.
(thrombocytopenia), increased levels of white
Chlamydia infections should likewise be treated for at least 10 GLUCOBAY delays the digestion of carbohydrates. This
blood cells (leukocytosis) or blood platelets
days. slows down the release of glucose from carbohydrates and its
(thrombocytosis), changed blood coagulation
For children and adolescents aged between 5 and 17 absorption into the bloodstream. In this way, GLUCOBAY
factors (prothrombin values).
reduces the increase in blood glucose after meals. Due to
10 - 14 days for acute infection episodes of cystic brosis Very rarely: Increased degradation of red blood corpuscles the smoothing effect on glucose uptake from the intestine,
caused by P. aeruginosa. (haemolytic anaemia), a reduction in all blood uctuations in blood glucose over the day are reduced and
Please consult your doctor or pharmacist if you have the cells (pancytopenia, possibly life-threatening), a blood glucose concentrations are lowered.
impression that the effects of CIPROBAY 750 are too severe decrease in a certain type of white blood
Indications
strong or too weak. cell with the possible symptoms of shivering,
fever, blisters in the oral and throat mucosa GLUCOBAY is used as a supplement to dietary therapy in
If you have taken a greater quantity of CIPROBAY 750 than
(agranulocytosis), reduced bone marrow function patients with diabetes mellitus.
you were supposed to:
A few cases of transient (reversible) kidney damage have been (possibly life-threatening). 2. WHAT SHOULD YOU BE AWARE OF BEFORE USING
reported following extremely large overdoses. In such cases, Locomotor system GLUCOBAY 50/100?
therefore, kidney function should be checked by a doctor. Occasionally: Joint pain. GLUCOBAY 50/100 must not be used if you:
Administration of products containing magnesium or calcium Rarely: Muscle pain, swelling in the joints. - are hypersensitive (allergic) to acarbose and/or any of the
neutralises stomach acid and thus reduces the absorption of other ingredients of GLUCOBAY 50/100.
ciprooxacin into the bloodstream. Very rarely: Inammation of the tendons (tendinitis),
inammation of the tendon sheath (tendovaginitis) - suffer from chronic intestinal disorders associated with
If you have forgotten to take CIPROBAY 750: and torn tendons (e.g. the Achilles tendon), distinct disturbances of digestion and of the uptake of
Do not take a double dose the next time if you have forgotten muscular weakness (myasthenia). nutrients into the blood (impaired absorption)
to take a dose. Simply continue treatment with the prescribed - suffer from conditions which can worsen as a result of gas
Skin
dose. build-up in the intestine (e.g. elevation of the diaphragm
Frequently: Skin rash. due to intestinal distension (Roemhelds syndrome), serious
Effects of discontinuing treatment with CIPROBAY 750:
Occasionally: Itching, elevated blotchy Skin rash inguinal and diaphragmatic hernias, intestinal obstructions
If you want to interrupt treatment with CIPROBAY 750 or stop
(maculopapular exanthem), nettle rash and intestinal ulcers)
it early, for example because you are feeling better or because
(urticaria). - have severe impairment of renal function (creatinine
you are experiencing side effects, please talk to your doctor
rst. If you stop taking CIPROBAY 750 without asking your Rarely: Light sensitivity with reddening of the skin clearance below 25 ml/min)
doctor rst, the bacteria which caused your infection will be (photosensitivity), Particular caution is required when using GLUCOBAY
able to start reproducing again and your condition may worsen Very rarely: Punctate skin haemorrhages (petechiae), blister 50/100:
considerably. formation with accompanying haemorrhages - during the rst 6-12 months of treatment.
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Very rarely, an increase in the liver enzymes in the blood may 3 x 2 GLUCOBAY 50 tablets or 3x1 GLUCOBAY 100
occur during treatment with GLUCOBAY; this will not make tablets daily (equivalent to 300 mg acarbose per day). LEVITRA 5 mg Film-coated tablets
you feel unwell. Therefore, your doctor will check your liver In rare cases the dose may be increased further up to:
enzymes at regular intervals during the rst 6-12 months of
3 x 2 GLUCOBAY 100 tablets daily (equivalent to 600 mg [Vardenal (as hydrochloride trihydrate)]
treatment. In the cases reported, the increase in liver enzymes
acarbose per day)
subsided after treatment with GLUCOBAY was discontinued
(see also Side effects). if necessary. - The active substance is vardenal (as hydrochloride trihydrate).
If distressing complaints develop in spite of strict adherence to Each tablet contains 5 mg of vardenal.
- if acute symptoms of hypoglycaemia develop (such as rapid
pulse, perspiration, trembling). In this case, you must take your diet (see Side effects), the dose should not be increased The other ingredients of the tablets are: In the tablet core:
glucose and not household sugar (cane sugar) to relieve the further, and if necessary should be slightly reduced. crospovidone, magnesium stearate, microcrystalline cellulose,
problem (see also Interactions with other drugs). How and when should you take GLUCOBAY 50/100? colloidal anhydrous silica. In the lm coat: macrogol 400,
hypromellose, titanium dioxide (E171), ferric oxide yellow
Even if you are taking GLUCOBAY it is still vital for you to Maximum effects can only be achieved when GLUCOBAY
(E172), ferric oxide red (E172).
keep strictly to your prescribed diet. is taken at the beginning of a meal.
Treatment with GLUCOBAY must be recorded on your Swallow the tablets whole with a little liquid immediately 1. WHAT LEVITRA IS AND WHAT IT DOES
diabetes card. before meals or with the rst mouthful of food. LEVITRA 5 mg lm-coated tablets are orange with the
Children and adolescents Note: BAYER cross on one side and the strength (5) on the other.
Since the information available on its effects and tolerability in If your doctor has prescribed other antidiabetic drugs in addition LEVITRA is a treatment for erectile dysfunction (ED) in men
children and adolescents is insufcient, GLUCOBAY 50/100 to GLUCOBAY, you must take these drugs as well. You - the medical name for difculties in getting or keeping an
must not be taken by patients under 18 years of age. should never discontinue any medication or change the dosage erection.
Pregnancy without consulting your doctor. About erection difculties
GLUCOBAY 50/100 must not be used at any stage during For how long should you take GLUCOBAY 50/100? At least one in ten men has trouble getting or keeping an erection
pregnancy because no experience has been gained regarding its Your doctor will decide how long you should take at some time. There may be physical causes or psychological
safety in pregnant women. GLUCOBAY. The length of treatment depends on the causes, or most likely, a mixture of both . Whatever the cause,
severity and course of your illness. the effect is the same: muscle and blood vessel changes mean
Breast-feeding
that not enough blood stays in the penis to make it hard and
It is also recommended on principle that GLUCOBAY 50/100 Please consult your doctor or pharmacist if you have the keep it hard.
should not be used while breast-feeding. impression that the effects of GLUCOBAY are too strong
or too weak. How LEVITRA works
Ability to drive and use machines
Erections are usually controlled by a balance of two body
Treatment with GLUCOBAY alone does not give rise If you have taken a greater quantity of GLUCOBAY 50/
chemicals. The rst brings on erections; the second takes
to abnormally low concentrations of glucose in the blood 100 than you were supposed to:
erections away. If the two chemicals are out of balance, you can
(hypoglycaemia) and therefore has no effect on ability to drive Severe atulence and diarrhoea may develop when an overdose lose an erection before it starts. LEVITRA works by reducing
or to use machines. If GLUCOBAY is taken in combination of GLUCOBAY is taken together with drinks and/or food the action of the second chemical (called PDE-5). LEVITRA
with other antidiabetic medication (metformin, sulphonylureas, containing carbohydrates. Overdosage without food is unlikely allows an erection to last long enough for you to satisfactorily
insulin), your ability to drive and to use machines may to cause extreme gastrointestinal complaints. complete sexual activity. It is taken about 25 to 60 minutes
be impaired by the low blood glucose concentrations If you have taken too much GLUCOBAY it is important for before sexual activity and it will only work when you are
(hypoglycaemia) that may occur. you to avoid drinks and food containing carbohydrates for the sexually stimulated.
Interactions with other drugs: next 4-6 hours.
2. BEFORE YOU TAKE LEVITRA
Please note that this information may also apply to medicines If you have forgotten to take GLUCOBAY 50/100:
Do not use LEVITRA
used recently. Do not take a double dose the next time if you have forgotten
- If you have an allergy (if youre hypersensitive) to vardenal
Acute episodes of hypoglycaemia are not likely to occur if to take a dose. Simply continue treatment with the prescribed
or any of the other ingredients of LEVITRA. See the
you are being treated solely with GLUCOBAY and diet. If dose.
ingredients in the box, over the page. Signs of an allergic
GLUCOBAY is prescribed in addition to other blood-glucose Effects of discontinuing treatment with GLUCOBAY 50/ reaction include a rash, itching, swollen face or lips and
reducing treatment with sulphonylureas or metformin tablets or 100: shortness of breath.
with insulin, the doses of these tablets or of insulin must be
If you want to interrupt treatment with GLUCOBAY or - If you take nitrates, such as glycerol trinitrate for angina, or
suitably reduced if your blood glucose falls so much that you
stop it early, for example because you are experiencing side nitric oxide donors, such as amyl nitrite. Taking these drugs
become hypoglycaemic. In isolated cases, shock can occur as
effects, please talk to your doctor rst. If you stop taking with LEVITRA could seriously affect your blood pressure.
a result of hypoglycaemia. If acute hypoglycaemia develops,
GLUCOBAY without consulting your doctor, this may lead - If you are taking ritonavir or indinavir, medicines for HIV.
remember that household sugar (cane sugar) is digested and
absorbed more slowly during treatment with GLUCOBAY . to a distinct increase in your blood glucose concentration. - If you are over 75 years of age and are taking ketaconazole or
This means that hypoglycaemia can be corrected rapidly only 4. WHAT SIDE EFFECTS ARE POSSIBLE? itraconazole, anti-fungal medicines
with glucose and not with household sugar. - If you have a severe heart or liver problem
Like all medicines, GLUCOBAY can have side effects.
In isolated cases, acarbose may affect the bioavailability of - If you are having kidney dialysis
These side effects may be intensied if you do not follow the
digoxin (an active substance used mainly to treat heart failure); prescribed diabetic diet in particular. If you experience severe - If you have recently had a stroke or heart attack
the dosage of digoxin may have to be adjusted. pain despite following the prescribed diet precisely, please - If you have low blood pressure, or used to
The following medicines must not be taken at the same time as consult your doctor. In such cases, your doctor may consider - If your family has a history of degenerative eye diseases
GLUCOBAY because they may weaken its effect: temporarily or permanently reducing the dose. (such as retinitis pigmentosa)
- cholestyramine (a drug which lowers elevated blood The gastrointestinal complaints may be severe and pronounced. If any of these applies to you, talk to your doctor, without
cholesterol), In such cases please consult your doctor, who will decide taking LEVITRA.
- charcoal products and other intestinal adsorbents, whether treatment with GLUCOBAY should be continued. Talk to your doctor rst
- substances that promote digestion (digestive enzyme Evaluation of side effects is based on the following frequencies If you have heart trouble.. It may be risky for you to have
products). of occurrence: sex
Please inform your doctor or pharmacist if you are taking Very frequently: > 10 % If you suffer from cardiac arrythmia or any congenital
other medicines or have taken other medicines recently, Frequently: >1% to 10 % cardiac disease affecting your electrocardiogram
even if they are non-prescription medicines. Occasionally: > 0.1 % to 1% If you have a physical condition affecting the shape of
When taking GLUCOBAY 50/100 together with food and Rarely: > 0.01 % to 0.1 % the penis. This includes conditions called angulation,
drinks: Very rarely: 0.01 % Peyronies disease and cavernosal brosis.
Household sugar (cane sugar) and foods containing it can easily Very frequently: Flatulence, abdominal noise, If you have an illness that can cause erections which wont go
lead to severe abdominal discomfort and also diarrhoea during away (priapism). These include sickle cell disease, multiple
Frequently: Diarrhoea, abdominal pain,
treatment with GLUCOBAY (see Side effects). myeloma and leukaemia
Occasionally: Nausea,
If you have stomach ulcers (also called gastric or peptic
3. HOW SHOULD GLUCOBAY 50 /100 BE TAKEN? Rarely: Elevated liver enzymes,
ulcers)
Always take GLUCOBAY in accordance with your doctors Very rarely: Hypersensitivity reactions (e.g. reddening, skin If you have a bleeding disorder (such as haemophilia)
instructions. Please ask your doctor or pharmacist if you are rash and nettle rash), oedema (accumulation If you are using any other treatments for erection
unsure how to take this medicine. of uid, particularly in the legs), constipation, difculties.
incomplete obstruction of the intestines
Your doctor will decide how much GLUCOBAY you need If you have ever experienced a partial, sudden, temporary or
(subileus), complete obstruction of the intestines
to take depending on your personal requirements because permanent decrease or loss of vision in one eye.
(ileus), inammation of the liver (hepatitis) and/
GLUCOBAY works differently in different people, and not If any of these applies to you, make sure youve talked to the
everyone tolerates it the same way. or jaundice. There have been isolated reports of
doctor before taking LEVITRA.
sudden liver failure in Japan; it has however not
Unless otherwise prescribed by your doctor, treatment may been conrmed that these cases are associated Food and drink with LEVITRA
begin with: with administration of acarbose. You can take LEVITRA with or without food but
3 x 1 GLUCOBAY 50 tablet or 3x GLUCOBAY 100 preferably not after a heavy or high-fat meal as this may
Inform your doctor or pharmacist if you notice any side
tablet daily (equivalent to 150 mg acarbose per day). delay the effect.
effects that are not listed in this patient information leaet.
In some patients, a gradual increase in the dosage has helped to Dont drink grapefruit juice when you use LEVITRA. It can
reduce gastrointestinal side effects, starting with: 5. HOW SHOULD GLUCOBAY 50/100 BE STORED? interfere with the usual effect of the medicine.
1 to 2 x 1 GLUCOBAY 50 tablet or 1 to 2x GLUCOBAY Keep medicines out of the reach of children. Alcoholic drink can make erection difculties worse.
100 tablet daily (equivalent to 50 to 100 mg acarbose per day). Do not remove the tablets from the foil until immediately before Driving and using machines
Your doctor will increase the dose gradually depending on your use. LEVITRA might make some people feel dizzy or affect their
blood glucose level, and also as treatment progresses if it is not The expiry date of this product is printed on the cardboard box vision. If you feel dizzy, or if your vision is affected after taking
effective enough, up to: and the blister pack. Do not use the product after this date. LEVITRA dont drive or operate any tools or machines.
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LEVITRA is for men of 18 years and over If any of these affects you badly, or doesnt go away as you You can take LEVITRA with or without food but
It is not intended for use by women, children or men under 18. carry on taking LEVITRA, tell your doctor. preferably not after a heavy or high-fat meal as this may
If you notice any side effects not mentioned in this leaet, delay the effect.
Other medicines and LEVITRA
please tell your doctor or pharmacist. Dont drink grapefruit juice when you use LEVITRA. It can
Tell your doctor or pharmacist about any medicine you are
interfere with the usual effect of the medicine.
taking, or recently took even products you bought without a 5. STORING LEVITRA
Alcoholic drink can make erection difculties worse.
prescription, like herbals and vitamins. LEVITRA will usually Keep out of the reach and sight of children.
be ne with most medicines. But some may cause problems, Driving and using machines
Do not use after the expiry date stated on the packaging.
especially these: LEVITRA might make some people feel dizzy or affect their
Nitrates, medicines for angina, or nitric oxide donors, such as Do not store above 25 C. vision. If you feel dizzy, or if your vision is affected after taking
amyl nitrite. Taking these medicines with LEVITRA could LEVITRA dont drive or operate any tools or machines.
seriously affect your blood pressure. Talk to a doctor without LEVITRA 10 mg Film-coated tablets LEVITRA is for men of 18 years and over
taking LEVITRA It is not intended for use by women, children or men under 18.
Medication for the treatment of arrythmias, such as
Other medicines and LEVITRA
quinidine, procainamide, amiodarone or sotalol [Vardenal (as hydrochloride trihydrate)] Tell your doctor or pharmacist about any medicine you are
Ritonavir or indinavir, medicines for HIV. Talk to a doctor
taking, or recently took even products you bought without a
without taking LEVITRA - The active substance is vardenal (as hydrochloride trihydrate).
prescription, like herbals and vitamins. LEVITRA will usually
Ketoconazole or itraconazole, anti-fungal medicines Each tablet contains 10 mg of vardenal.
be ne with most medicines. But some may cause problems,
Erythromycin, an antibiotic. The other ingredients of the tablets are: In the tablet core: especially these:
Alpha-blockers, a type of medicine used to treat high blood crospovidone, magnesium stearate, microcrystalline cellulose,
Nitrates, medicines for angina, or nitric oxide donors, such as
pressure and benign prostatic hyperplasia. colloidal anhydrous silica. In the lm coat: macrogol 400,
amyl nitrite. Taking these medicines with LEVITRA could
If you have recently taken any of these medicines, please tell hypromellose, titanium dioxide (E171), ferric oxide yellow
seriously affect your blood pressure. Talk to a doctor without
your doctor or pharmacist (E172), ferric oxide red (E172).
taking LEVITRA
3. HOW TO TAKE LEVITRA 1. WHAT LEVITRA IS AND WHAT IT DOES Medication for the treatment of arrythmias, such as
LEVITRA 10 mg lm-coated tablets are orange with the quinidine, procainamide, amiodarone or sotalol
How much to take and how to take it
BAYER cross on one side and the strength (10) on the other. Ritonavir or indinavir, medicines for HIV. Talk to a doctor
Your doctor will have suggested a suitable dose for you. without taking LEVITRA
Always take LEVITRA exactly as your doctor has instructed LEVITRA is a treatment for erectile dysfunction (ED) in men
the medical name for difculties in getting or keeping an Ketoconazole or itraconazole, anti-fungal medicines
you, and check with the doctor or pharmacist if you are
erection. Erythromycin, an antibiotic.
unsure.
About erection difculties Alpha-blockers, a type of medicine used to treat high blood
Tell the doctor if you think LEVITRA is too strong or too
pressure and benign prostatic hyperplasia.
weak. He or she may suggest a different dose, depending on At least one in ten men has trouble getting or keeping an erection
how well it works for you. at some time. There may be physical causes or psychological If you have recently taken any of these medicines, please tell
causes, or most likely, a mixture of both . Whatever the cause, your doctor or pharmacist
Take a LEVITRA tablet about 25 to 60 minutes before sexual
activity. With sexual stimulation you may achieve an erection the effect is the same: muscle and blood vessel changes mean 3. HOW TO TAKE LEVITRA
anywhere from 25 minutes up to four to ve hours after taking that not enough blood stays in the penis to make it hard and
LEVITRA. keep it hard.
Your doctor will have suggested a suitable dose for you.
Swallow one tablet with a glass of water How LEVITRA works
Always take LEVITRA exactly as your doctor has instructed
You can take LEVITRA with or without food but Erections are usually controlled by a balance of two body
you, and check with the doctor or pharmacist if you are
preferably not after a heavy or high-fat meal. chemicals. The rst brings on erections; the second takes
unsure.
Dont use LEVITRA more than once a day. erections away. If the two chemicals are out of balance, you can
lose an erection before it starts. LEVITRA works by reducing Tell the doctor if you think LEVITRA is too strong or too
If you take more LEVITRA than you should weak. He or she may suggest a different dose, depending on
the action of the second chemical (called PDE-5). LEVITRA
Men who take too much LEVITRA may experience more side how well it works for you.
allows an erection to last long enough for you to satisfactorily
effects or may get severe back pain. If you take more LEVITRA Take a LEVITRA tablet about 25 to 60 minutes before sexual
complete sexual activity. It is taken about 25 to 60 minutes
than you should, tell your doctor. activity. With sexual stimulation you may achieve an erection
before sexual activity and it will only work when you are
4. POSSIBLE SIDE EFFECTS sexually stimulated. anywhere from 25 minutes up to four to ve hours after taking
LEVITRA.
Taking LEVITRA can cause side effects, although not 2. BEFORE YOU TAKE LEVITRA
everybody gets them. Most of the effects are mild or moderate. Swallow one tablet with a glass of water
Do not use LEVITRA You can take LEVITRA with or without food but
Very common side effects - If you have an allergy (if youre hypersensitive) to vardenal preferably not after a heavy or high-fat meal.
(These may affect 1 in 10 people or more) or any of the other ingredients of LEVITRA. See the
Dont use LEVITRA more than once a day.
Headaches ingredients in the box, over the page. Signs of an allergic
reaction include a rash, itching, swollen face or lips and If you take more LEVITRA than you should
Flushing.
shortness of breath. Men who take too much LEVITRA may experience more side
Common side effects
- If you take nitrates, such as glycerol trinitrate for angina, or effects or may get severe back pain. If you take more LEVITRA
(These may affect between 1 in 10 and 1 in 100 people) than you should, tell your doctor.
nitric oxide donors, such as amyl nitrite. Taking these drugs
Indigestion with LEVITRA could seriously affect your blood pressure. 4. POSSIBLE SIDE EFFECTS
Feeling sick (nausea) - If you are taking ritonavir or indinavir, medicines for HIV.
Dizziness Taking LEVITRA can cause side effects, although not
- If you are over 75 years of age and are taking ketaconazole or everybody gets them. Most of the effects are mild or moderate.
Blocked or runny nose. itraconazole, anti-fungal medicines
Very common side effects
Uncommon side effects - If you have a severe heart or liver problem
(These may affect 1 in 10 people or more)
(These may affect between 1 in 100 and 1 in 1000 people) - If you are having kidney dialysis
- If you have recently had a stroke or heart attack Headaches
Sensitivity of the skin to sunlight
- If you have low blood pressure, or used to Flushing.
High or low blood pressure
Back or muscle pain - If your family has a history of degenerative eye diseases Common side effects
Effects on vision (such as retinitis pigmentosa) (These may affect between 1 in 10 and 1 in 100 people)
Bloodshot or watery eyes If any of these applies to you, talk to your doctor, without Indigestion
Rash taking LEVITRA. Feeling sick (nausea)
Sleepiness Talk to your doctor rst Dizziness
Effect in results of blood tests to check liver function If you have heart trouble.. It may be risky for you to have Blocked or runny nose.
Increase in blood of a muscle enzyme (creatine sex Uncommon side effects
phosphokinase) If you suffer from cardiac arrythmia or any congenital (These may affect between 1 in 100 and 1 in 1000 people)
Breathlessness cardiac disease affecting your electrocardiogram
Sensitivity of the skin to sunlight
Fast heart beat or pounding heart If you have a physical condition affecting the shape of
High or low blood pressure
Nose bleeds the penis. This includes conditions called angulation,
Back or muscle pain
Facial swelling Peyronies disease and cavernosal brosis
Effects on vision
If you have an illness that can cause erections which wont go
Rare side effects Bloodshot or watery eyes
away (priapism). These include sickle cell disease, multiple
(These may affect less than 1 in 1000 people) myeloma and leukaemia Rash
Fainting If you have stomach ulcers (also called gastric or peptic Sleepiness
Muscle stiffness ulcers) Effect in results of blood tests to check liver function
Increase pressure in the eye (glaucoma) If you have a bleeding disorder (such as haemophilia) Increase in blood of a muscle enzyme (creatine
Prolonged or painful erections If you are using any other treatments for erection phosphokinase)
Allergic reaction difculties. Breathlessness
Effects on the heart (such as angina) If you have ever experienced a partial, sudden, temporary or Fast heart beat or pounding heart
Anxiety permanent decrease or loss of vision in one eye. Nose bleeds
Swelling of the larynx If any of these applies to you, make sure youve talked to the Facial swelling
Partial, sudden, temporary or permanent decrease or loss of doctor before taking LEVITRA. Rare side effects
vision in one or both eyes has been reported. Food and drink with LEVITRA (These may affect less than 1 in 1000 people)
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Fainting If you have stomach ulcers (also called gastric or peptic Effect in results of blood tests to check liver function
Muscle stiffness ulcers) Increase in blood of a muscle enzyme (creatine
Increase pressure in the eye (glaucoma) If you have a bleeding disorder (such as haemophilia) phosphokinase)
Prolonged or painful erections If you are using any other treatments for erection Breathlessness
Allergic reaction difculties. Fast heart beat or pounding heart
Effects on the heart (such as angina) If you have ever experienced a partial, sudden, temporary or Nose bleeds
Anxiety permanent decrease or loss of vision in one eye. Facial swelling
Swelling of the larynx If any of these applies to you, make sure youve talked to the Rare side effects
doctor before taking LEVITRA. (These may affect less than 1 in 1000 people)
Partial, sudden, temporary or permanent decrease or loss of
vision in one or both eyes has been reported. Food and drink with LEVITRA Fainting
If any of these affects you badly, or doesnt go away as you You can take LEVITRA with or without food but Muscle stiffness
carry on taking LEVITRA, tell your doctor. preferably not after a heavy or high-fat meal as this may Increase pressure in the eye (glaucoma)
delay the effect. Prolonged or painful erections
If you notice any side effects not mentioned in this leaet,
please tell your doctor or pharmacist. Dont drink grapefruit juice when you use LEVITRA. It can Allergic reaction
interfere with the usual effect of the medicine.
Effects on the heart (such as angina)
5. STORING LEVITRA Alcoholic drink can make erection difculties worse. Anxiety
Keep out of the reach and sight of children. Driving and using machines Swelling of the larynx
Do not use after the expiry date stated on the packaging. LEVITRA might make some people feel dizzy or affect their Partial, sudden, temporary or permanent decrease or loss of
Do not store above 25 C. vision. If you feel dizzy, or if your vision is affected after taking vision in one or both eyes has been reported.
LEVITRA dont drive or operate any tools or machines.
If any of these affects you badly, or doesnt go away as you
LEVITRA 20 mg Film-coated tablets LEVITRA is for men of 18 years and over carry on taking LEVITRA, tell your doctor.
It is not intended for use by women, children or men under 18. If you notice any side effects not mentioned in this leaet,
Other medicines and LEVITRA please tell your doctor or pharmacist.
[Vardenal (as hydrochloride trihydrate)] Tell your doctor or pharmacist about any medicine you are 5. STORING LEVITRA
taking, or recently took even products you bought without a
- The active substance is vardenal (as hydrochloride trihydrate). Keep out of the reach and sight of children.
prescription, like herbals and vitamins. LEVITRA will usually
Each tablet contains 20 mg of vardenal. be ne with most medicines. But some may cause problems, Do not use after the expiry date stated on the packaging.
The other ingredients of the tablets are: In the tablet core: especially these: Do not store above 25 C.
crospovidone, magnesium stearate, microcrystalline cellulose, Nitrates, medicines for angina, or nitric oxide donors, such
colloidal anhydrous silica. In the lm coat: macrogol 400, as amyl nitrite. Taking these medicines with LEVITRA MYCOSPOR CREAM
hypromellose, titanium dioxide (E171), ferric oxide yellow could seriously affect your blood pressure. Talk to a doctor
(E172), ferric oxide red (E172). without taking LEVITRA
1. WHAT LEVITRA IS AND WHAT IT DOES Medication for the treatment of arrythmias, such as (Bifonazole)
LEVITRA 20 mg lm-coated tablets are orange with the quinidine, procainamide, amiodarone or sotalol
The pharmaceutically active ingredient is bifonazole.
BAYER cross on one side and the strength (20) on the other. Ritonavir or indinavir, medicines for HIV. Talk to a doctor
without taking LEVITRA 1 g MYCOSPOR CREAM contains 0.01 g bifonazole
LEVITRA is a treatment for erectile dysfunction (ED) in men
Ketoconazole or itraconazole, anti-fungal medicines The other ingredients are:
the medical name for difculties in getting or keeping an
erection. Erythromycin, an antibiotic. Benzyl alcohol, cetyl palmitate, cetostearyl alcohol, puried water,
Alpha-blockers, a type of medicine used to treat high blood 2-octyldodecanol, polysorbate 60, sorbitan stearate.
About erection difculties
pressure and benign prostatic hyperplasia. 1. WHAT IS MYCOSPOR CREAM AND WHAT IS IT USED
At least one in ten men has trouble getting or keeping an erection
at some time. There may be physical causes or psychological If you have recently taken any of these medicines, please tell FOR?
causes, or most likely, a mixture of both . Whatever the cause, your doctor or pharmacist MYCOSPOR CREAM is a drug for the treatment of fungal
the effect is the same: muscle and blood vessel changes mean 3. HOW TO TAKE LEVITRA infections (mycoses) of the skin caused by dermatophytes,
that not enough blood stays in the penis to make it hard and yeasts, moulds and other organisms such as Malassezia furfur,
keep it hard. and infections caused by Corynebacterium minutissimum.
Your doctor will have suggested a suitable dose for you. Fungal infections can occur at practically every part of the body;
How LEVITRA works
Always take LEVITRA exactly as your doctor has instructed the areas particularly at risk are those where skin touches skin,
Erections are usually controlled by a balance of two body you, and check with the doctor or pharmacist if you are i.e. between the toes, in the groin or the armpits. Fungi grow in
chemicals. The rst brings on erections; the second takes unsure. the skin. Bifonazole, the active ingredient in MYCOSPOR
erections away. If the two chemicals are out of balance, you can
Tell the doctor if you think LEVITRA is too strong or too CREAM, attacks the fungal infection in the skin.
lose an erection before it starts. LEVITRA works by reducing
weak. He or she may suggest a different dose, depending on MYCOSPOR CREAM is used to treat, for example, fungal
the action of the second chemical (called PDE-5). LEVITRA
how well it works for you. infections of the feet and hands (tinea pedis, tinea manuum),
allows an erection to last long enough for you to satisfactorily
complete sexual activity. It is taken about 25 to 60 minutes Take a LEVITRA tablet about 25 to 60 minutes before sexual fungal infections of the skin and folds of the skin (tinea corporis,
before sexual activity and it will only work when you are activity. With sexual stimulation you may achieve an erection tinea inguinalis), pityriasis versicolor (fungal infection caused
anywhere from 25 minutes up to four to ve hours after taking by Malassezia furfur); erythrasma (skin disorder caused by
sexually stimulated.
LEVITRA. Corynebacterium minutissimum).
2. BEFORE YOU TAKE LEVITRA Swallow one tablet with a glass of water 2. WHAT SHOULD YOU BE AWARE OF BEFORE USING
Do not use LEVITRA You can take LEVITRA with or without food but MYCOSPOR CREAM?
- If you have an allergy (if youre hypersensitive) to preferably not after a heavy or high-fat meal. Mycospor Cream must not be used
vardenal or any of the other ingredients of LEVITRA. Dont use LEVITRA more than once a day. - if you are hypersensitive (allergic) to the active ingredient
See the ingredients in the box, over the page. Signs of an
If you take more LEVITRA than you should bifonazole or any of the other ingredients (e.g. cetostearyl
allergic reaction include a rash, itching, swollen face or lips alcohol).
and shortness of breath. Men who take too much LEVITRA may experience more side
effects or may get severe back pain. If you take more LEVITRA If you are known to be hypersensitive to cetostearyl alcohol,
- If you take nitrates, such as glycerol trinitrate for angina, or
than you should, tell your doctor. an ingredient of MYCOSPOR CREAM, it is recommended
nitric oxide donors, such as amyl nitrite. Taking these drugs
that a presentation that does not contain this ingredient (e.g.
with LEVITRA could seriously affect your blood pressure. 4. POSSIBLE SIDE EFFECTS Mycospor Solution) be used instead of the cream.
- If you are taking ritonavir or indinavir, medicines for HIV. Taking LEVITRA can cause side effects, although not Particular caution is required when using MYCOSPOR
- If you are over 75 years of age and are taking ketaconazole or everybody gets them. Most of the effects are mild or moderate. CREAM:
itraconazole, anti-fungal medicines Very common side effects Do not allow MYCOSPOR CREAM to come into contact
- If you have a severe heart or liver problem (These may affect 1 in 10 people or more) with the eyes.
- If you are having kidney dialysis Headaches Children
- If you have recently had a stroke or heart attack Flushing. Mycospor Cream should not be used for infants without
- If you have low blood pressure, or used to
Common side effects medical supervision.
- If your family has a history of degenerative eye diseases (These may affect between 1 in 10 and 1 in 100 people) Ensure that MYCOSPOR CREAM does not get into the
(such as retinitis pigmentosa)
Indigestion infants mouth.
If any of these applies to you, talk to your doctor, without
Feeling sick (nausea) Pregnancy
taking LEVITRA.
Dizziness MYCOSPOR CREAM should only be used during
Talk to your doctor rst
Blocked or runny nose. pregnancy after careful consideration of the risk/benet ratio,
If you have heart trouble.. It may be risky for you to have as there is no experience of its use in pregnant women.
Uncommon side effects
sex Breast-feeding
(These may affect between 1 in 100 and 1 in 1000 people)
If you suffer from cardiac arrythmia or any congenital
Sensitivity of the skin to sunlight If you are breast-feeding, you must not apply bifonazole to the
cardiac disease affecting your electrocardiogram
High or low blood pressure breast area.
If you have a physical condition affecting the shape of
Back or muscle pain Driving and operating machinery
the penis. This includes conditions called angulation,
Peyronies disease and cavernosal brosis Effects on vision No special precautions are necessary.
If you have an illness that can cause erections which wont go Bloodshot or watery eyes Interactions with other drugs
away (priapism). These include sickle cell disease, multiple Rash No interactions with other drug products have been reported to
myeloma and leukaemia Sleepiness date.
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3. HOW SHOULD MYCOSPOR CREAM BE USED? Fungal infections can occur at practically every part of the body; The following incidence rating is used to evaluate the frequency
Always use MYCOSPOR CREAM exactly as instructed the areas particularly at risk are those where skin touches skin, of side effects:
by this patient information leaet. Please ask your doctor or i.e. between the toes, in the groin or the armpits. Fungi grow in Very frequently: Frequently:
pharmacist if you are unsure how to take this medicine. the skin. Bifonazole, the active ingredient in MYCOSPOR more than 1 in 10 treated patients fewer than 1 in 10 but more than
Type of administration SOLUTION, attacks the fungal infection in the skin. 1 in 100 treated patients
Rub a thin layer of MYCOSPOR CREAM onto the affected MYCOSPOR SOLUTION is used to treat, for example, Occasionally: Rarely:
fungal infections of the feet and hands (tinea pedis, tinea fewer than 1 in 100 but more fewer than 1 in 1,000 but more
areas of skin.
manuum), fungal infections of the skin and folds of the skin than 1 in 1,000 treated patients than 1 in 10,000 treated patients
Unless otherwise prescribed by your doctor, the usual dose is: Very rare:
(tinea corporis, tinea inguinalis), pityriasis versicolor (fungal
Apply a thin layer of MYCOSPOR CREAM to the affected infection caused by Malassezia furfur). fewer than 1 in 10,000 treated patients, including isolated cases
areas of skin once daily, preferably in the evening before going
to bed, and rub in well. A small quantity of cream (approx. 1 2. WHAT SHOULD YOU BE AWARE OF BEFORE USING Skin
cm long strip) is usually sufcient for an area of skin about the MYCOSPOR SOLUTION? Occasionally: Transient skin reactions (e.g. blistering,
size of the palm of the hand. MYCOSPOR SOLUTION must not be used reddening, burning, itching or scaling)
Duration of use if you are hypersensitive (allergic) to the active ingredient Hypersensitivity reactions
For a permanent cure, you should continue treatment with bifonazole or any of the other ingredients. Rarely: Hypersensitivity reactions (allergic reactions)
MYCOSPOR CREAM after the symptoms such as burning Particular caution is required when using MYCOSPOR against the active ingredient bifonazole or one of
or itching have subsided. Depending on the type of disorder, SOLUTION: the adjuvants
you should continue the treatment as follows:
Do not allow MYCOSPOR SOLUTION to come into Countermeasures
The duration of treatment is usually: contact with the eyes. If you experience any of the above-mentioned side effects,
Fungal infections of the feet and between 3 weeks Children please contact your doctor or pharmacist.
the toes (tinea pedis, tinea pedis
MYCOSPOR SOLUTION should not be used for infants Inform your doctor or pharmacist if you notice any side
interdigitalis)
without medical supervision. effects that are not listed in this patient information leaet.
Fungal infections of the body, hands and 2-3 weeks
skin folds (tinea corporis, tinea manuum, Ensure that MYCOSPOR SOLUTION does not get into the
5. HOW SHOULD MYCOSPOR SOLUTION BE
tinea inguinalis) infants mouth.
STORED?
Pityriasis versicolor, erythrasma 2 weeks Pregnancy
Keep medicines out of the reach of children.
Supercial candidiasis (fungal infections 2-4 weeks MYCOSPOR SOLUTION should only be used during
The expiry date of this product is printed on the cardboard box
caused by yeasts) of the skin pregnancy after careful consideration of the risk/benet ratio,
and the bottle label. Do not use the product after this date.
as there is no experience of its use in pregnant women.
If your condition worsens or has not improved within 4 days,
you must consult a doctor. Breast-feeding
If you are breast-feeding, you must not apply bifonazole to the
NIMOTOP Infusion solution
Please consult your doctor or pharmacist if you have the
impression that the effects of MYCOSPOR CREAM are too breast area.
strong or too weak. Driving and operating machinery (Nimodipine)
What else can you do? No special precautions are necessary.
Wash the infected areas of skin each time before applying the Interactions with other drugs COMPOSITION
cream to remove any loose akes of skin and residue from the No interactions with other drug products have been reported to Pharmaceutically active ingredients
previous treatment. Dry yourself thoroughly after washing, date. 1 bottle of 50 ml infusion solution contains 10 mg nimodipine in
particularly in less accessible areas such as between the toes. 50 ml alcoholic solvent.
Change any towels and items of clothing that come into contact 3. HOW SHOULD MYCOSPOR SOLUTION BE USED?
Other ingredients
with the infected areas daily. This measure will prevent the Always use MYCOSPOR SOLUTION exactly as instructed
by this patient information leaet. Please ask your doctor or Ethanol 96%, macrogol 400, sodium citrate 2 H2O, anhydrous
fungal infection from spreading to other parts of your body or
to other people. pharmacist if you are unsure how to take this medicine. citric acid, water for injections.
Type of administration Mode of action
4. WHAT SIDE EFFECTS ARE POSSIBLE?
Rub a thin layer of MYCOSPOR SOLUTION onto the NIMOTOP is a drug product that counteracts the effects of
Like all medicines, MYCOSPOR CREAM can have side vasospasm after cerebral haemorrhage (cerebral therapeutic agent;
effects. affected areas of skin.
calcium antagonist).
The following incidence rating is used to evaluate the frequency Unless otherwise prescribed by your doctor, the usual dose
is: Indications
of side effects:
Apply a thin layer of MYCOSPOR SOLUTION to the For the prevention and treatment of ischaemic neurological decits
Very frequently: Frequently:
affected areas of skin once daily, preferably in the evening due to cerebral vasospasm after subarachnoid haemorrhage of
more than 1 in 10 treated patients fewer than 1 in 10 but more than
before going to bed, and rub in well. A few drops of solution aneurysmal origin.
1 in 100 treated patients
Occasionally: Rarely: (approx. 3 drops) are usually sufcient for an area of skin about Explanation: Following cerebral haemorrhage, the blood vessels
fewer than 1 in 100 but more fewer than 1 in 1,000 but more the size of the palm of the hand. may go into spasm. This may result in inadequate circulation in the
than 1 in 1,000 treated patients than 1 in 10,000 treated patients Note: After unscrewing the lid, hold the bottle straight upside affected areas of the brain and thus damage the nervous system.
Very rare: down and tap on the bottom of the bottle with your nger if NIMOTOP is used to prevent and, if necessary, to treat such
fewer than 1 in 10,000 treated patients, including isolated cases necessary. damage.
Skin Duration of use CONTRAINDICATIONS
Occasionally: Transient skin reactions (e.g. blistering, For a permanent cure, you should continue treatment with When should you not take NIMOTOP?
reddening, burning, itching or scaling) MYCOSPOR SOLUTION after the symptoms such as
NIMOTOP should not be taken when there is a known
Hypersensitivity reactions burning or itching have subsided. Depending on the type of
hypersensitivity to the active ingredient, nimodipine.
disorder, you should continue the treatment as follows:
Rarely: Hypersensitivity reactions (allergic reactions) In what circumstances should you take NIMOTOP only after
against the active ingredient bifonazole or one of The duration of treatment is usually:
consulting your doctor?
the adjuvants (e.g. cetostearyl alcohol) Fungal infections of the feet and between 3 weeks
The following directions describe cases where NIMOTOP
Countermeasures the toes (tinea pedis, tinea pedis
should only be used for you in certain circumstances and
interdigitalis)
If you experience any of the above-mentioned side effects, with great care. Please consult your doctor in these cases. You
please contact your doctor or pharmacist. Fungal infections of the body, hands and 2-3 weeks should also consult your doctor if these details applied to you
Inform your doctor or pharmacist if you notice any side skin folds (tinea corporis, tinea manuum, in the past.
effects that are not listed in this patient information leaet. tinea inguinalis)
NIMOTOP should be taken only with great care in the following
Pityriasis versicolor 2 weeks
5. HOW SHOULD MYCOSPOR CREAM BE STORED? circumstances:
Supercial candidiasis (fungal infections 2-4 weeks
Keep medicines out of the reach of children. - raised water content of the brain tissue (generalised cerebral
caused by yeasts) of the skin
The expiry date of this product is printed on the cardboard box oedema)
If your condition worsens or has not improved within 4 days, - markedly raised cerebral pressure
and the tube. Do not use the product after this date. you must consult a doctor.
- pronounced hypotension (systolic blood pressure below 90
Please consult your doctor or pharmacist if you have the mmHg).
MYCOSPOR SOLUTION impression that the effects of MYCOSPOR SOLUTION are
Particular careful medical supervision is required if it is necessary
too strong or too weak.
to combine NIMOTOP infusion solution with other calcium
(Bifonazole) What else can you do? antagonists or methyldopa (see also Interactions).
Wash the infected areas of skin each time before applying the What should you be aware of when pregnant or breast-
The pharmaceutically active ingredient is bifonazole. solution to remove any loose akes of skin and residue from feeding?
1 ml MYCOSPOR SOLUTION contains 0.01 g bifonazole. the previous treatment. Dry yourself thoroughly after washing,
particularly in less accessible areas such as between the toes. No investigations have been carried out into the potential damaging
The other ingredients are: effects of infusion of NIMOTOP during pregnancy and breast-
Change any towels and items of clothing that come into contact
Ethanol, isopropyl myristate. feeding. As a precaution, and in accordance with the general
with the infected areas daily. This measure will prevent the
1. WHAT IS MYCOSPOR SOLUTION AND WHAT IS IT guidelines for the use of drugs, NIMOTOP infusion solution
fungal infection from spreading to other parts of your body or
USED FOR? should be taken during pregnancy only after careful consideration
to other people.
MYCOSPOR SOLUTION is a drug product for the of the risks and expected benets.
treatment of fungal infections (mycoses) of the skin caused 4. WHAT SIDE EFFECTS ARE POSSIBLE? Since nimodipine (the active ingredient in NIMOTOP) may
by dermatophytes, yeasts, moulds and other fungi such as Like all medicines, MYCOSPOR SOLUTION can have side pass into breast milk, you should discontinue breast-feeding while
Malassezia furfur. effects. you take this drug.
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SPDI
What precautions should be taken for children and How and when should NIMOTOP be taken? If you notice side-effects other than those listed in this leaet,
adolescents? Continuous intravenous infusion please tell your doctor or pharmacist.
Insufcient experience is available concerning the use of Patients in whom volume loading is unwanted or contraindicated NOTES AND INFORMATION ABOUT THE SHELF-LIFE
NIMOTOP in children and adolescents; therapy with this can be administered NIMOTOP via a central catheter without OF THIS DRUG
medicine is currently not indicated for this age group. administration of an additional co-infusion solution. NIMOTOP NIMOTOP infusion solution can be stored safely but is sensitive
PRECAUTIONS FOR USE AND WARNINGS infusion solution is administered as a continuous intravenous
to light to a certain extent. Direct exposure to sunlight should
infusion in the bypass via a central catheter using an infusion
What precautions should be taken? therefore be avoided. NIMOTOP infusion solution can be used
pump. The lines are connected to each other using a three-way
In severe renal or hepatic dysfunction, particularly cirrhosis of the in diffuse daylight or articial light for up to 48 hours without
stopcock.
liver, the effects and side-effects, e.g. hypotension, may be more protection against light.
NIMOTOP infusion solution must not be mixed with other drug
pronounced; in these cases, the doctor should reduce the dose Keep away from light.
products or added to infusion bags or bottles.
depending on the severity of the symptoms and, in extreme cases, Diluted NIMOTOP infusion solution used for intracisternal
should consider discontinuing the treatment. Suitable substances for co-infusion include: glucose 5%,
instillation must be administered directly after preparation.
physiological saline solution, lactated Ringers solution,
Use of NIMOTOP infusion solution in patients with impaired lactated Ringers solution with magnesium, dextran 40 solution, INFORMATION ON THE SHELF-LIFE OF THE
kidney function or in combination with potentially nephrotoxic poly(O-2-hydroxyethyl) starch 6%, human albumin 5% or PRODUCT
medicines can exacerbate renal function. Careful monitoring blood. Experimental ndings suggest that mannitol can also be
of kidney function is required in this case. If the patients The expiry date of this drug is printed on the box and on the label
administered as a co-infusion for a period of up to 24 hours. on the bottle. Do not use the drug after this date.
kidney function further deteriorates, your doctor should
The ratio of NIMOTOP infusion solution to the co-infusion
consider discontinuing treatment with NIMOTOP (see also Always ensure that NIMOTOP is kept out of the reach of
solution should be about 1 : 4.
Interactions). children.
It is recommended that administration of NIMOTOP infusion
Instructions for use
solution be continued during anaesthesia, surgery or angiography
Nimodipine is absorbed by polyvinylchloride (PVC); NIMOTOP (X-ray of the blood vessels). NIMOTOP Film-coated tablets
infusion solution may therefore only be used in infusion pumps
Intracisternal instillation
with infusion lines made of polyethylene (PE).
Freshly prepared, diluted NIMOTOP solution at body (Nimodipine)
WARNING temperature can be instilled intracisternally during surgery (see
This medicine contains 23.7 % by volume alcohol (200 ml alcohol also Information on the shelf-life of this drug). COMPOSITION
to 1 ml solution). For how long should NIMOTOP be used? Pharmaceutically active ingredients
INTERACTIONS Prophylactic use 1 NIMOTOP lm-coated tablet contains 30 mg nimodipine.
Which other drugs affect the action of NIMOTOP or are Intravenous treatment should not be started later than 4 days Other ingredients
themselves affected by NIMOTOP? after haemorrhaging and should be continued over the entire Microcrystalline cellulose, maize starch, povidone 25 (poly(1-
Please note that these details may also apply to drugs which period during which there is the greatest danger of vasospasm vinyl-2-pyrrolidone)), ring cleavage cross-linked, magnesium
you have taken recently. occurring, i.e. until the 10th to 14th day after subarachnoidal stearate, hydroxypropyl methylcellulose, macrogol 4000,
haemorrhaging. titanium(IV) oxide (E 171), ferric oxide, yellow (E 172).
In patients who are taking antihypertensive drugs, NIMOTOP
may increase the hypotensive effect of these drugs. On completion of the treatment by infusion, it is recommended Mode of action
that the patient continue to take 6 x 60 mg nimodipine at intervals
Combination with other calcium antagonists (certain drugs used to NIMOTOP is a drug product that counteracts the effects of
of 4 hours for about another 7 days.
treat high blood pressure and/or angina pectoris such as nifedipine, vasospasm after cerebral haemorrhage (cerebral therapeutic agent;
Therapeutic use calcium antagonist).
diltiazem, verapamil) or methlydopa should be avoided if possible.
If it is essential to administer a combination of these drugs, Treatment of existing ischaemic neurological decits caused
by vasospasm following subarachnoidal haemorrhage due to INDICATIONS
particularly careful medical supervision is required.
inadequate circulation should start as early as possible and Administration of lm-coated tablets following prior administration
Concomitant intravenous administration of beta blockers with
continue for at least 5 but not more than 14 days. of NIMOTOP infusion solution: For the prevention and treatment
NIMOTOP should be avoided as this can potentiate the
It is recommended that this regimen be followed by administration of ischaemic neurological decits due to cerebral vasospasm after
hypotensive effect; the negative inotropic effects (weakening
of 6 x 60 mg nimodipine daily at intervals of 4 hours for about subarachnoid haemorrhage of aneurysmal origin.
myocardial contraction) can be increased and lead to reduced
cardiac output (decompensated heart failure). another 7 days. Explanation: Following cerebral haemorrhage, the blood vessels
If, during therapeutic or prophylactic administration of may go into spasm. This may result in inadequate circulation in the
Simultaneous use of cimetidine (a drug used to treat gastric and
NIMOTOP infusion solution, the source of the haemorrhage affected areas of the brain and thus damage the nervous system.
intestinal ulcers) or valproic acid (an antispasmodic drug) may
is treated surgically, intravenous treatment with NIMOTOP NIMOTOP is used to prevent and, if necessary, to treat such
increase the concentration of nimodipine in the blood and thus
infusion solution should be continued for at least 5 days after the damage.
potentiate its effects.
operation. CONTRAINDICATIONS
Concomitant treatment with potentially nephrotoxic medicines
(e.g. aminoglycosides or cephalosporins [antibiotics], furosemide The doctor will decide on the duration of administration. When should you not take NIMOTOP?
[diuretic]) can exacerbate renal function. MISUSE AND OVERDOSE NIMOTOP should not be taken when there is a known
There is insufcient experience of the simultaneous use of What should you do if too much NIMOTOP is taken hypersensitivity to the active ingredient, nimodipine.
nimodipine and neuroleptic (tension-relieving) or antidepressant (intentionally or inadvertently)? In what circumstances should you take NIMOTOP only after
drugs. consulting your doctor?
An overdose can result in more pronounced side effects such as
The solution contains alcoholic solvent; consideration must facial ushing, headaches, marked hypotension and raised or The following directions describe cases where NIMOTOP
therefore be given to the risk of interactions with medicines that lowered heart rate. should only be used for you in certain circumstances and
are not compatible with alcohol. Medical action for overdose with great care. Please consult your doctor in these cases. You
In experiments, simultaneous intravenous administration of In the event of acute overdosage, treatment with NIMOTOP should also consult your doctor if these details applied to you
zidovudine and nimodipine resulted in raised plasma concentrations should be discontinued immediately. in the past.
of zidovudine. NIMOTOP should be taken only with great care in the following
There is as yet no specic antidote; the action to be taken should
What food, drink and other substances should you avoid? be guided by the clinical symptoms (intravenous dopamine or circumstances:
We recommend that you avoid drinking grapefruit juice at the noradrenaline for a drop in blood pressure). - raised water content of the brain tissue (generalised cerebral
same time as using NIMOTOP, since this may lead to increased oedema)
concentrations of nimodipine in the blood. SIDE EFFECTS
- markedly raised cerebral pressure
Dosage, administration and duration of treatment What side effects can occur when NIMOTOP is taken and
- pronounced hypotension (systolic blood pressure below 90
what action is recommended?
The following directions apply unless your doctor has mmHg).
instructed you to use NIMOTOP differently. The following may occur: headaches, increases in certain laboratory
Previous long-term use of antiepileptic drugs of the enzyme-
values (transaminases, alkaline phosphatase, -GT), deterioration
How often and in what quantity should NIMOTOP be inducing type (phenobarbitone, phenytoin, carbamazepine)
of renal function with a rise in serum urea and/or creatinine, facial
given? reduces the concentration of nimodipine (active ingredient in
ushing, sensations of warmth or heat, perspiration, a fall in heart
The following recommended doses apply: NIMOTOP) in the blood and thus reduces its efcacy. For this
rate (bradycardia); also, less frequently, an increase in heart rate
reason, you are recommended not to take NIMOTOP lm-
At the start of treatment, 1 mg nimodipine should be administered (tachycardia), ectopic beats (extrasystoles) and an undesirable
coated tablets with these drugs. (See Interactions).
per hour for 2 hours (approximately 15 g/kg body weight/hour), drop in blood pressure, especially when the initial value was too
equivalent to 5 ml NIMOTOP infusion solution per hour. If high. What should you be aware of when pregnant or breast-
this dose is well tolerated, and in particular if there is no severe Other effects which have been described are gastrointestinal feeding?
drop in blood pressure, the dose can be increased after the second complaints, dizziness, venous inammation (on administration of As a precautionary measure and in accordance with the general
hour to 2 mg nimodipine per hour (approximately 30 g/kg body undiluted NIMOTOP infusion solution in peripheral veins), in guidelines for the use of drugs, NIMOTOP lm-coated tablets
weight/hour), equivalent to 10 ml NIMOTOP infusion solution a few cases, impaired gut motility as a result of enteroparalysis should be taken during pregnancy only after careful consideration
per hour. (ileus) or a reduced blood platelet count (thrombocytopenia). of the risks and expected benets. Inadequate information is
Patients with a body weight markedly lower than 70 kg or unstable If the undesirable effects are severe, your doctor should consider available regarding the use of NIMOTOP lm-coated tablets
blood pressure should start with a dose of 0.5 mg nimodipine per reducing the dose or, if necessary, discontinuing use of the drug. during pregnancy in humans.
hour, equivalent to 2.5 ml NIMOTOP infusion solution per Note Since nimodipine may pass into breast milk, you should
hour. discontinue breast-feeding while you take this drug.
In some patients taking nimodipine for age-related brain
Dosage during surgery: syndromes, there have been indications of excessive stimulation What precautions should you take for children and
(Intracisternal instillation:) of the brain, manifested in the form of insomnia, increased adolescents?
20 ml of a dilute solution of NIMOTOP infusion solution at a restlessness, excitation, aggressiveness, sweating and, in isolated Insufcient experience is available concerning the use of
ratio of 1 ml NIMOTOP infusion solution to 19 ml Ringers cases, exaggerated and uncontrolled movements (hyperkinesis) NIMOTOP in children and adolescents; therapy with this
solution. and depression. medicine is currently not indicated for this age group.
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PRECAUTIONS AND WARNINGS MEDICAL ACTION FOR OVERDOSE: CLINICAL PHARMACOLOGY
What precautions should be taken? There is as yet no specic antidote; the action to be taken should General
In severe renal or hepatic dysfunction, particularly cirrhosis of the be guided by the clinical symptoms. Interferons are a family of naturally occurring proteins and glyco-
liver, the effects and side-effects, e.g. hypotension, may be more What should you do if you have taken too little NIMOTOP or proteins that are produced by eukaryotic cells in response to viral
pronounced; in these cases, the doctor should reduce the dose have forgotten a dose? infection and other biological inducers. Interferon beta, one mem-
depending on the severity of the symptoms and, in extreme cases, Do not take more lm-coated tablets next time; simply continue ber of this family, is produced by various cell types including -
should consider discontinuing the treatment. the treatment at the prescribed dose. broblasts and macrophages. Natural interferon beta and Interferon
What precautions should be taken when driving, operating What should you do if you wish to stop your treatment or beta-1a are glycosylated, with each containing a single N-linked
machinery or working without a secure foothold? nish it early? complex carbohydrate moiety. Glycosylation of other proteins is
known to affect their stability, activity, aggregation, biodistribu-
Treatment with this drug requires regular medical check-ups. You should always consult your doctor before deciding to interrupt
tion, and half-life in blood. However, the effects of glycosylation
Reactions to this drug may vary from one person to another, and the course of treatment or stop taking NIMOTOP altogether, for
of interferon beta on these properties have not been fully dened.
the effect on your reaction speed may be such that your ability example on account of side effects.
to drive, to operate machinery and to work without a secure Biologic Activities
foothold may be impaired. This applies even more so at the start of SIDE EFFECTS Interferons are cytokines that mediate antiviral, antiproliferative
treatment and in conjunction with alcohol. What side effects can occur when taking NIMOTOP, and and immunomodulatory activities in response to viral infection
what measures should be taken to treat them? and other biological inducers. Three major interferons have been
INTERACTIONS
The following may occur: headaches, facial ushing, nausea, distinguished: alpha, beta, and gamma. Interferons alpha and beta
Which other drugs affect the action of NIMOTOP or are sensations of warmth or heat, a fall in heart rate (bradycardia); form the Type I class of interferons, and interferon gamma is a
themselves affected by NIMOTOP? also, less frequently, an increase in heart rate (tachycardia) and Type II interferon. These interferons have overlapping but clearly
Please note that this information may also apply to medicines an undesirable drop in blood pressure, especially when the initial distinct biological activities.
used recently. value was too high. Interferon beta exerts its biological effects by binding to specic
In patients who are taking antihypertensive drugs, NIMOTOP Other effects which have been described are gastrointestinal receptors on the surface of human cells. This binding initiates a
may increase the hypotensive effect of these drugs. complaints, dizziness, in a few cases, impaired gut motility as a complex cascade of intracellular events that leads to the expres-
Concomitant intravenous administration of beta blockers result of enteroparalysis (ileus) or a reduced blood platelet count sion of numerous interferon-induced gene products and markers.
with NIMOTOP should be avoided as this can potentiate the (thrombocytopaenia). These include 2, 5-oligoadenylate synthetase, 2-microglobulin,
hypotensive effect. If the undesirable effects are severe, your doctor should consider and neopterin. These products have been measured in the serum
reducing the dose or, if necessary, discontinuing use of the drug. and cellular fractions of blood collected from patients treated with
Simultaneous use of cimetidine (a drug used to treat gastric and
Note AVONEX.
intestinal ulcers) or valproic acid (an antispasmodic drug) may
increase the concentration of nimodipine in the blood and thus In some patients taking nimodipine for age-related brain The specic interferon-induced proteins and mechanisms by
potentiate its effects. syndromes, there have been indications of excessive stimulation which AVONEX exerts its effects in multiple sclerosis have not
of the brain, manifested in the form of insomnia, increased been fully dened. Clinical studies conducted in multiple sclerosis
There is insufcient experience of the simultaneous use of
restlessness, excitation, aggressiveness, sweating and, in isolated patients showed that interleukin 10 (IL-10) levels in cerebrospinal
nimodipine and neuroleptic (tension-relieving) or antidepressant
cases, exaggerated and uncontrolled movements (hyperkinesis) uid were increased in patients treated with AVONEX compared
drugs.
and depression. to placebo. Serum IL-10 levels were increased 48 hours after
Previous long-term use of antiepileptic drugs of the enzyme- intramuscular (IM) injection of AVONEX and remained
inducing type (phenobarbitone, phenytoin, carbamazepine) If you experience side effects that are not mentioned in this
elevated for 1 week. However, no relationship has been established
reduces the concentration of nimodipine in the blood and thus information leaet, please inform your doctor or pharmacist.
between absolute levels of IL-10 and clinical outcome in multiple
reduces its efcacy. For this reason, you are recommended not to INFORMATION ON THE SHELF-LIFE OF THE sclerosis.
take NIMOTOP lm-coated tablets with these drugs. PRODUCT Pharmacokinetics
It has been reported in connection with related drugs of the The expiry date of this drug product is printed on the cardboard Pharmacokinetics of AVONEX in multiple sclerosis patients
dihydropyridine group (nifedipine, nisoldipine) that the box and on the blister pack. Do not use the product after this date. have not been evaluated. The pharmacokinetic and pharmacody-
simultaneous use of rifampicin (antibiotic/antitubercular drug)
Keep NIMOTOP out of the reach of children. namic proles of AVONEX in healthy subjects following doses
may reduce the concentration of dihydropines in the blood by
of 30 mcg through 75 mcg have been investigated. Serum levels
reducing their bioavailability.
of AVONEX as measured by antiviral activity are slightly above
In experiments, simultaneous intravenous administration of BIOGEN IDEC INC. detectable limits following a 30 mcg IM dose, and increase with
zidovudine and nimodipine resulted in raised plasma concentrations higher doses.
P.O.BOX: 991, RIYADH: 11421
of zidovudine.
SAUDIARABIA After an IM dose, serum levels of AVONEX typically peak
What foods and drinks should you avoid? between 3 and 15 hours and then decline at a rate consistent with
TEL: 01-463 3248, FAX: 01-463 4362
We recommend that you avoid drinking grapefruit juice at the a 10 hour elimination half-life. Serum levels of AVONEX may
same time as taking NIMOTOP, since this may lead to increased be sustained after IM administration due to prolonged absorption
concentrations of nimodipine in the blood. AVONEX IM Injection from the IM site. Systemic exposure, as determined by AUC and
Cmax values, is greater following IM than subcutaneous (SC)
administration.
The following directions apply unless your doctor has (Interferon beta-1a) Subcutaneous administration of AVONEX should not be
instructed you to use NIMOTOP differently. Please follow
substituted for intramuscular administration. Subcutaneous and
the directions carefully as otherwise NIMOTOP may not DESCRIPTION
intramuscular administration have been observed to have non-
work properly. AVONEX (Interferon beta-1a) is a 166 amino acid glycopro- equivalent pharmacokinetic and pharmacodynamic parameters
How much NIMOTOP should you take, and how often? tein with a predicted molecular weight of approximately 22,500 following administration to healthy volunteers.
Following prior administration of NIMOTOP infusion solution daltons. It is produced by recombinant DNA technology using
Biological response markers (e.g., neopterin and 2-microglobulin)
for a period of 5 to 14 days, the recommended dose is 6 x 60 mg genetically engineered Chinese Hamster Ovary cells into which
the human interferon beta gene has been introduced. The amino are induced by AVONEX following parenteral doses of 15 mcg
nimodipine daily, equivalent to 2 NIMOTOP lm-coated tablets through 75 mcg in healthy subjects and treated patients. Biological
6 times daily at 4-hour intervals. acid sequence of AVONEX is identical to that of natural human
interferon beta. response marker levels increase within 12 hours of dosing and
In severe renal or hepatic dysfunction, particularly cirrhosis of the remain elevated for at least 4 days. Peak biological response
liver, the effects and side-effects, e.g. hypotension, may be more Using the World Health Organization (WHO) natural interferon
marker levels are typically observed 48 hours after dosing.
beta standard, Second International Standard for Interferon, Hu-
pronounced; in these cases, the doctor should reduce the dose The relationship of serum AVONEX levels or levels of these
depending on the severity of the symptoms and, in extreme cases, man Fibroblast (Gb-23-902-531), AVONEX has a specic activ-
induced biological response markers to the mechanisms by which
ity of approximately 200 million international units (IU) of antivi-
should consider discontinuing the treatment. AVONEX exerts its effects in multiple sclerosis is unknown.
ral activity per mg of Interferon beta-1a determined specically by
How and when should you take NIMOTOP? an in vitro cytopathic effect bioassay using lung carcinoma cells Clinical Studies
Take the lm-coated tablets whole with some liquid: they do not (A549) and Encephalomyocarditis virus (ECM). AVONEX 30 The clinical effects of AVONEX in multiple sclerosis were
need to be taken with meals. You must ensure that intervals of not mcg contains approximately 6 million IU of antiviral activity us- studied in two randomized, multicenter, double-blind, placebo-
less than 4 hours are observed between the timepoints for taking ing this method. The activity against other standards is not known. controlled studies in patients with multiple sclerosis.1,2 Safety
the tablets. Comparison of the activity of AVONEX with other Interferon and efcacy of treatment with AVONEX beyond 3 years is not
For how long should you take NIMOTOP? betas is not appropriate, because of differences in the reference known.
standards and assays used to measure activity. In Study 1, 301 patients received either 30 mcg of AVONEX
It is generally recommended that NIMOTOP lm-coated tablets
should be taken for a period of approximately 7 days following 5 to 30 mcg Lyophilized Powder Vial (n=158) or placebo (n=143) by IM injection once weekly. Patients
14 days of prior treatment with NIMOTOP infusion solution. A vial of AVONEX is formulated as a sterile, white to off-white were entered into the trial over a 2 year period, received injec-
The attending doctor must decide on the length of the treatment lyophilized powder for intramuscular injection after reconstitu- tions for up to 2 years, and continued to be followed until study
in each individual case. The length of treatment depends on the tion with supplied diluent (Sterile Water for Injection, USP). Each completion. Two hundred eighty-two patients completed 1 year on
severity and course of your illness. vial of reconstituted AVONEX contains 30 mcg of Interferon study, and 172 patients completed 2 years on study. There were
beta-1a; 15 mg Albumin (Human), USP; 5.8 mg Sodium Chlo- 144 patients treated with AVONEX for more than 1 year, 115
Incorrect use and overdosage ride, USP; 5.7 mg Dibasic Sodium Phosphate, USP; and 1.2 mg patients for more than 18 months and 82 patients for 2 years.
What should you do if too much NIMOTOP is taken Monobasic Sodium Phosphate, USP, in 1.0 mL at a pH of approxi- All patients had a denite diagnosis of multiple sclerosis of at least
(intentionally or inadvertently)? mately 7.3. 1 year duration and had at least 2 exacerbations in the 3 years
An overdose can result in more pronounced side effects such as 30 mcg Prelled Syringe (N.R) prior to study entry (or 1 per year if the duration of disease was
facial ushing, headaches, marked hypotension, raised or lowered A prelled syringe of AVONEX is formulated as a sterile liquid less than 3 years). At entry, study participants were without ex-
heart rate, gastrointestinal problems and nausea. for intramuscular injection. acerbation during the prior 2 months and had Kurtzke Expanded
If you think that you might have taken an overdose, you must Each 0.5 mL (30 mcg dose) of AVONEX in a prelled glass Disability Status Scale (EDSS3) scores ranging from 1.0 to 3.5.
inform your doctor immediately so that he can decide on what syringe contains 30 mcg of Interferon beta-1a, 0.79 mg Sodium Patients with chronic progressive multiple sclerosis were excluded
measures to take. Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 from this study.
In the event of acute overdose, treatment with NIMOTOP mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in The primary outcome assessment was time to progression in dis-
should be discontinued immediately. Water for Injection, USP at a pH of approximately 4.8. ability, measured as an increase in the EDSS score of at least 1.0
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point that was sustained for at least 6 months. An increase in EDSS A summary of the effects of AVONEX on the clinical and MRI AVONEX group was 0.56 of the rate in the placebo group (95%
score reects accumulation of disability. This endpoint was used to endpoints of this study is presented in Table 1. condence interval 0.38 to 0.81). The brain MRI ndings are de-
ensure that progression reected permanent increase in disability scribed in Table 2.
Table 1
rather than a transient effect due to an exacerbation.
Clinical and MRI Endpoints in Study 1
Secondary outcomes included exacerbation frequency and results
of magnetic resonance imaging (MRI) scans including gadolini- Endpoint Placebo AVONEX P-Value
um (Gd)-enhanced lesion number and volume and T2-weighted PRIMARY ENDPOINT:
(Percentage of Patient exacerbation)

(proton density) lesion volume. Additional secondary endpoints Time to sustained
included 2 upper limb (tested in both arms) and 3 lower limb func- progression
tion tests. in disability (N: 143, 158)1 --- See Figure 1 --- 0.022
Twenty-three of the 301 patients (8%) discontinued treatment Percentage of patients
prematurely. Of these, 1 patient treated with placebo (1%) and 6 progressing in disability at 2
patients treated with AVONEX (4%) discontinued treatment due years (Kaplan-Meier estimate)1 34.9% 21.9%
to adverse events. Thirteen of these 23 patients remained on study SECONDARY ENDPOINTS:
and were evaluated for clinical endpoints. DISABILITY
Mean conrmed change in
EDSS from study entry to end
of study (N: 136, 150)1 0.50 0.20 0.0063
EXACERBATIONS
Number of exacerbations in
subset completing 2 years
(N: 87, 85) Table 2
0 26% 38% 0.033 Brain MRI Data According to Treatment Group
1 30% 31% AVONEX Placebo
2 11% 18%
14%
CHANGE IN T2 VOLUME N = 119 N = 109
3 7%
4 18% 7% @18 MONTHS:
Percentage of patients Actual Change (mm3)1*
exacerbation free in subset Median (25th%, 75th%) 28 (-576, 397) 313 (5, 1140)
completing 2 years (N: 87, 85) 26% 38% 0.104 Percentage Change1*
Annual exacerbation rate Median (25th%, 75th%) 1 (-24, 29) 16 (0, 53)
Note: Disability progression represents at least a 1.0 point increase
in EDSS score sustained for at least 6 months. (N: 143, 158)1 0.82 0.67 0.045 NUMBER OF NEW OR N = 132 N = 119
Time to onset of sustained progression in disability was signi- Table 1 (continued) ENLARGING T2 LESIONS N (%) N (%)
cantly longer in patients treated with AVONEX than in patients Clinical and MRI Endpoints in Study 1 @ 18 MONTHS1*:
receiving placebo (p = 0.02). The Kaplan-Meier plots of these data Endpoint Placebo AVONEX P-Value 0 62 (47) 22 (18)
are presented in Figure 1. The Kaplan-Meier estimate of the per-
MRI 1-3 41 (31) 47 (40)
centage of patients progressing by the end of 2 years was 34.9%
for placebo-treated patients and 21.9% for AVONEX-treated pa- Number of Gd-enhanced lesions: 4 29 (22) 50 (42)
tients, indicating a slowing of the disease process. This represents At study entry (N: 132, 141) Mean (SD) 2.13 (3.19) 4.97 (7.71)
a 37% relative reduction in the risk of accumulating disability in Mean (Median) 2.3(1.0) 3.2 (1.0) NUMBER OF GD- N = 165 N = 152
the AVONEX-treated group compared to the placebo-treated Range 0-23 0-56 ENHANCING LESIONS @ N (%) N (%)
group.
Year 1 (N: 123, 134) 6 MONTHS2*:
Mean (Median) 1.6(0) 1.0 (0) 0.023 0 115 (70) 93 (61)
Range 0-22 0-28 1 27 (16) 16 (11)
Year 2 (N: 82, 83) >1 23 (14) 43 (28)
Mean (Median) 1.6 (0) 0.8 (0) 0.053 Mean (SD) 0.87 (2.28) 1.49 (3.14)
Range 0-34 0-13
1 P value <0.001
T2 lesion volume: -
2 P value <0.03
Percentage change from study
* P value from a Mann-Whitney rank-sum test
entry to Year 1 (N: 116, 123)
Median 3.3% -13.1% 0.023 INDICATIONS AND USAGE
Percentage change from study AVONEX (Interferon beta-1a) is indicated for the treatment of
entry to Year 2 (N: 83, 81) patients with relapsing forms of multiple sclerosis to slow the ac-
cumulation of physical disability and decrease the frequency of
Median -6.5% 13.2% 0.363
clinical exacerbations. Patients with multiple sclerosis in whom
Note: (N: , ) denotes the number of evaluable placebo and efcacy has been demonstrated include patients who have expe-
The distribution of conrmed EDSS change from study entry AVONEX patients, respectively. rienced a rst clinical episode and have MRI features consistent
(baseline) to the end of the study is shown in Figure 2. There was 1 Patient data included in this analysis represent variable periods with multiple sclerosis. Safety and efcacy in patients with chron-
a statistically signicant difference between treatment groups in ic progressive multiple sclerosis have not been established.
of time on study.
conrmed change for patients with at least 2 scheduled visits (136 2 Analyzed by Mantel-Cox (logrank) test. CONTRAINDICATIONS
placebo-treated and 150 AVONEX-treated patients; p = 0.006; 3 Analyzed by Mann-Whitney rank-sum test. AVONEX is contraindicated in patients with a history of hyper-
see Table 1). sensitivity to natural or recombinant interferon beta, or any other
4 Analyzed by Cochran-Mantel-Haenszel test.
The rate and frequency of exacerbations were determined as sec- component of the formulation.
5 Analyzed by likelihood ratio test.
ondary outcomes. For all patients included in the study, irrespec- The lyophilized vial formulation of AVONEX is contraindicated
tive of time on study, the annual exacerbation rate was 0.67 per In Study 2, 383 patients who had recently experienced an iso- in patients with a history of hypersensitivity to albumin (human).
year in the AVONEX-treated group and 0.82 per year in the pla- lated demyelinating event involving the optic nerve, spinal cord, WARNINGS
cebo-treated group (p = 0.04). or brainstem/cerebellum, and who had lesions typical of multiple
Depression and Suicide
AVONEX treatment signicantly decreased the frequency sclerosis on brain MRI, received either 30 mcg AVONEX (n =
of exacerbations in the subset of patients who were enrolled in 193) or placebo (n = 190) by IM injection once weekly. All pa- AVONEX should be used with caution in patients with depres-
the study for at least 2 years (87 placebo-treated patients and 85 tients received intravenous steroid treatment for the initiating sion or other mood disorders, conditions that are common with
AVONEX-treated patients; p = 0.03; see Table 1). clinical exacerbation. Patients were enrolled into the study over multiple sclerosis. Depression and suicide have been reported
a two-year period and followed for up to three years or until they to occur with increased frequency in patients receiving inter-
Gd-enhanced and T2-weighted (proton density) MRI scans of the feron compounds, including AVONEX. Patients treated with
brain were obtained in most patients at baseline and at the end of developed a second clinical exacerbation in an anatomically dis-
AVONEX should be advised to report immediately any symp-
1 and 2 years of treatment. Gd-enhancing lesions seen on brain tinct region of the central nervous system. Sixteen percent of sub-
toms of depression and/or suicidal ideation to their prescribing
MRI scans represent areas of breakdown of the blood brain bar- jects on AVONEX and 14% of subjects on placebo withdrew
physicians. If a patient develops depression or other severe psy-
rier thought to be secondary to inammation. Patients treated from the study for a reason other than the development of a second
chiatric symptoms, cessation of AVONEX therapy should be
with AVONEX demonstrated signicantly lower Gd-enhanced exacerbation2.
considered. In Study 2, AVONEX-treated patients were more
lesion number after 1 and 2 years of treatment (p 0.05; see Table The primary outcome measure was time to development of a sec- likely to experience depression than placebo-treated patients. An
1). The volume of Gd-enhanced lesions was also analyzed, and ond exacerbation in an anatomically distinct region of the central equal incidence of depression was seen in the placebo-treated and
showed similar treatment effects (p 0.03). Percentage change in nervous system. Secondary outcomes were brain MRI measures, AVONEX-treated patients in Study 1. Additionally, there have
T2-weighted lesion volume from study entry to Year 1 was signi- including the cumulative increase in the number of new or en- been post-marketing reports of depression, suicidal ideation and/or
cantly lower in AVONEX-treated than placebo-treated patients larging T2 lesions, T2 lesion volume compared to baseline at 18 development of new or worsening of pre-existing other psychiatric
(p = 0.02). A signicant difference in T2-weighted lesion volume months, and the number of Gd-enhancing lesions at 6 months. disorders, including psychosis. Some of these patients improved
change was not seen between study entry and Year 2. Time to development of a second exacerbation was signicantly upon cessation of AVONEX dosing.
The exact relationship between MRI ndings and the clinical sta- delayed in patients treated with AVONEX compared to placebo Anaphylaxis
tus of patients is unknown. The prognostic signicance of MRI (p = 0.002). The Kaplan-Meier estimates of the percentage of pa- Anaphylaxis has been reported as a rare complication of
ndings in these studies has not been evaluated. tients developing an exacerbation within 24 months were 38.6% AVONEX use. Other allergic reactions have included dyspnea,
Of the limb function tests, only 1 demonstrated a statistically signif- in the placebo group and 21.1% in the AVONEX group (Figure orolingual edema, skin rash and urticaria (see ADVERSE REAC-
icant difference between treatment groups (favoring AVONEX). 3). The relative rate of developing a second exacerbation in the TIONS).
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Decreased Peripheral Blood Counts technique and importance of proper syringe and needle disposal GERIATRIC USE
Decreased peripheral blood counts in all cell lines, including rare and be cautioned against reuse of these items. Clinical studies of AVONEX did not include sufcient numbers
pancytopenia and thrombocytopenia, have been reported from LABORATORY TESTS of patients aged 65 and over to determine whether they respond
post-marketing experience (see ADVERSE REACTIONS). Some differently than younger patients.
cases of thrombocytopenia have had nadirs below 10,000/L. In addition to those laboratory tests normally required for monitor-
ing patients with multiple sclerosis, complete blood and differential ADVERSE REACTIONS
Some cases reoccur with rechallenge (see ADVERSE REAC-
TIONS). Patients should be monitored for signs of these disorders white blood cell counts, platelet counts, and blood chemistries, in- Depression, suicidal ideation, and new or worsening other psychi-
(see Precautions: Laboratory Tests). cluding liver function tests, are recommended during AVONEX atric disorders have been observed to be increased in patients using
therapy (see WARNINGS: Decreased Peripheral Blood Counts and interferon compounds including AVONEX (see WARNINGS:
Hepatic Injury PRECAUTIONS: Cardiomyopathy and Congestive Heart Failure, Depression and Suicide). Anaphylaxis and other allergic reactions
Severe hepatic injury, including cases of hepatic failure, has been and Autoimmune Disorders). During the placebo-controlled stud- have been reported in patients using AVONEX (see WARN-
reported rarely in patients taking AVONEX. Asymptomatic el- ies in multiple sclerosis, these tests were performed at least every 6 INGS: Anaphylaxis). Decreased peripheral blood counts have
evation of hepatic transaminases has also been reported, and in months. There were no signicant differences between the placebo been reported in patients using AVONEX (see WARNINGS:
some patients has recurred upon rechallenge with AVONEX. In and AVONEX groups in the incidence of liver enzyme elevation, Decreased Peripheral Blood Counts). Hepatic injury, including he-
some cases, these events have occurred in the presence of other leukopenia, or thrombocytopenia. However, these are known to patic failure, hepatitis, and elevated serum hepatic enzyme levels,
drugs that have been associated with hepatic injury. The potential be dose-related laboratory abnormalities associated with the use has been reported in post-marketing experience (see WARNINGS:
risk of AVONEX used in combination with known hepatotoxic of interferons. Patients with myelosuppression may require more Hepatic Injury). Seizures, cardiovascular adverse events, and auto-
drugs or other products (e.g. alcohol) should be considered prior intensive monitoring of complete blood cell counts, with differ- immune disorders also have been reported in association with the
to AVONEX administration, or when adding new agents to the ential and platelet counts. Thyroid function should be monitored use of AVONEX (see Precautions).
regimen of patients already on AVONEX. Patients should be periodically. If patients have or develop symptoms of thyroid dys-
monitored for signs of hepatic injury (see Precautions: Laboratory The adverse reactions most commonly reported in patients associ-
function (hypo- or hyperthyroidism), thyroid function tests should ated with the use of AVONEX were u-like and other symptoms
Tests). be performed according to standard medical practice. occurring within hours to days following an injection. Symptoms
Albumin (Human) can include myalgia, fever, fatigue, headaches, chills, nausea, and
DRUG INTERACTIONS
The lyophilized vial of AVONEX contains albumin, a derivative vomiting. Some patients have experienced paresthesias, hyperto-
of human blood. Based on effective donor screening and product No formal drug interaction studies have been conducted with
nia and myasthenia.
manufacturing processes, it carries an extremely remote risk for AVONEX. In the placebo-controlled studies in multiple sclero-
sis, corticosteroids or ACTH were administered for treatment of The most frequently reported adverse reactions resulting in clini-
transmission of viral diseases. A theoretical risk for transmission cal intervention (e.g., discontinuation of AVONEX, or the need
of Creutzfeldt-Jakob disease (CJD) also is considered extremely exacerbations in some patients concurrently receiving AVONEX.
In addition, some patients receiving AVONEX were also treated for concomitant medication to treat an adverse reaction symptom)
remote. No cases of transmission of viral diseases or CJD have were u-like symptoms and depression.
been identied for albumin. The prelled syringe of AVONEX with anti-depressant therapy and/or oral contraceptive therapy. No
does not contain albumin. unexpected adverse events were associated with these concomi- Because clinical trials are conducted under widely varying con-
tant therapies. However, the potential for hepatic injury should be ditions, adverse reaction rates observed in the clinical trials of
PRECAUTIONS considered when AVONEX is used in combination with other AVONEX cannot be directly compared to rates in clinical trials
Seizures products associated with hepatic injury, or when new agents are of other drugs and may not reect the rates observed in practice.
Caution should be exercised when administering AVONEX added to the regimen of patients already on AVONEX (see The data described below reect exposure to AVONEX in 351
to patients with pre-existing seizure disorders. In the two pla- WARNINGS: Hepatic Injury). patients, including 319 patients exposed for 6 months, and 288 pa-
cebo-controlled studies in multiple sclerosis, 4 patients receiving tients exposed for greater than one year in placebo-controlled tri-
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT
AVONEX experienced seizures, while no seizures occurred als. The mean age of patients receiving AVONEX was 35 years,
OF FERTILITY
in the placebo group. Three of these 4 patients had no prior his- 74% were women and 89% were Caucasian. Patients received
tory of seizure (see ADVERSE REACTIONS). It is not known Carcinogenesis: No carcinogenicity data for AVONEX are either 30 mcg AVONEX or placebo.
whether these events were related to the effects of multiple scle- available in animals or humans.
Table 3 enumerates adverse events and selected laboratory abnor-
rosis alone, to AVONEX, or to a combination of both. The ef- Mutagenesis: AVONEX was not mutagenic when tested in the malities that occurred at an incidence of at least 2% higher fre-
fect of AVONEX administration on the medical management of Ames bacterial test and in an in vitro cytogenetic assay in human quency in AVONEX-treated subjects than was observed in the
patients with seizure disorder is unknown. lymphocytes in the presence and absence of metabolic activation. placebo group. Reported adverse events have been classied using
Cardiomyopathy and Congestive Heart Failure These assays are designed to detect agents that interact directly standard COSTART terms.
with and cause damage to cellular DNA. AVONEX is a glyco-
Patients with cardiac disease, such as angina, congestive heart Table 3
sylated protein that does not directly bind to DNA.
failure, or arrhythmia, should be closely monitored for worsening Adverse Events and Selected Laboratory Abnormalities in
of their clinical condition during initiation and continued treatment Impairment of Fertility: No studies were conducted to evaluate the Placebo-Controlled Studies
with AVONEX. While AVONEX does not have any known the effects of AVONEX on fertility in normal women or women
Placebo AVONEX
direct-acting cardiac toxicity, during the post-marketing period with multiple sclerosis. It is not known whether AVONEX can
affect human reproductive capacity. Adverse Event (N = 333) (N = 351)
infrequent cases of congestive heart failure, cardiomyopathy, and
cardiomyopathy with congestive heart failure have been reported Menstrual irregularities were observed in monkeys administered Body as a Whole
in patients without known predisposition to these events, and AVONEX at a dose 100 times the recommended weekly hu- Headache 55% 58%
without other known etiologies being established. In rare cases, man dose (based upon a body surface area comparison). Anovu- Flu-like symptoms (otherwise 29% 49%
these events have been temporally related to the administration lation and decreased serum progesterone levels were also noted unspecied)
of AVONEX. In some of these instances recurrence upon transiently in some animals. These effects were reversible after Pain 21% 23%
rechallenge was observed. discontinuation of drug. Asthenia 18% 24%
Autoimmune Disorders Treatment of monkeys with AVONEX at 2 times the recom- Fever 9% 20%
Autoimmune disorders of multiple target organs have been mended weekly human dose (based upon a body surface area Chills 5% 19%
reported post-marketing including idiopathic thrombocytopenia, comparison) had no effects on cycle duration or ovulation.
Abdominal pain 6% 8%
hyper- and hypothyroidism, and rare cases of autoimmune The accuracy of extrapolating animal doses to human doses is Injection site pain 6% 8%
hepatitis have also been reported. Patients should be monitored for not known. In the placebo-controlled studies in multiple sclero-
signs of these disorders (see Precautions: Laboratory Tests) and Infection 4% 7%
sis, 5% of patients receiving placebo and 6% of patients receiving
appropriate treatment implemented when observed. AVONEX experienced menstrual disorder. If menstrual irregu- Injection site inammation 2% 6%
larities occur in humans, it is not known how long they will persist Chest pain 2% 5%
INFORMATION TO PATIENTS
following treatment. Injection site reaction 1% 3%
All patients should be instructed to read the AVONEX Medi- Toothache 1% 3%
cation Guide supplied to them. Patients should be cautioned not PREGNANCY - TERATOGENIC EFFECTS
Nervous System
to change the dosage or the schedule of administration without Pregnancy Category C: The reproductive toxicity of AVONEX
medical consultation. Depression 14% 18%
has not been studied in animals or humans. In pregnant monkeys
given AVONEX at 100 times the recommended weekly human Dizziness 12% 14%
Patients should be informed of the most serious (see WARNINGS)
and the most common adverse events associated with AVONEX dose (based upon a body surface area comparison), no teratogenic Respiratory System
administration, including symptoms associated with u syndrome or other adverse effects on fetal development were observed. Upper respiratory tract infection 12% 14%
(see ADVERSE REACTIONS). Symptoms of u syndrome are Abortifacient activity was evident following 3 to 5 doses at this Sinusitis 12% 14%
most prominent at the initiation of therapy and decrease in fre- level. No abortifacient effects were observed in monkeys treated at Bronchitis 5% 8%
quency with continued treatment. Concurrent use of analgesics 2 times the recommended weekly human dose (based upon a body Digestive System
and/or antipyretics may help ameliorate u-like symptoms on surface area comparison). Although no teratogenic effects were Nausea 19% 23%
treatment days. seen in these studies, it is not known if teratogenic effects would
Musculoskeletal System
Patients should be cautioned to report depression or suicidal ide- be observed in humans. There are no adequate and well-controlled
studies with interferons in pregnant women. If a woman becomes Myalgia 22% 29%
ation (see WARNINGS).
pregnant or plans to become pregnant while taking AVONEX, Arthralgia 6% 9%
Patients should be advised about the abortifacient potential of
she should be informed of the potential hazards to the fetus, and Urogenital
AVONEX (see Precautions: Pregnancy - Teratogenic Effects). If
a woman becomes pregnant while taking AVONEX, she should discontinuation of AVONEX therapy should be considered. Urinary tract infection 15% 17%
be advised to consider enrolling in the AVONEX Pregnancy If a woman becomes pregnant while taking AVONEX, consider Urine constituents abnorma 0% 3%
Registry by calling 1-800-456-2255. enrolling her in the AVONEX Pregnancy Registry by calling 1- Skin and Appendages
The prelled syringe cap contains dry natural rubber. 800-456-2255. Alopecia 2% 4%
When a physician determines that AVONEX can be used out- NURSING MOTHERS Special Senses
side of the physicians ofce, persons who will be administering It is not known whether AVONEX is excreted in human milk. Eye disorder 2% 4%
AVONEX should receive instruction in reconstitution and injec- Because of the potential of serious adverse reactions in nursing Hemic and Lymphatic System
tion, including the review of the injection procedures. If a patient infants, a decision should be made to either discontinue nursing or Injection site ecchymosis 4% 6%
is to self-administer, the physical ability of that patient to self-in- to discontinue AVONEX. Anemia 1% 4%
ject intramuscularly should be assessed. The rst injection should
PEDIATRIC USE Cardiovascular System
be performed under the supervision of a qualied health care pro-
Migraine 3% 5%
fessional. A puncture-resistant container for disposal of needles Safety and effectiveness of AVONEX in pediatric patients below
and syringes should be used. Patients should be instructed in the the age of 18 years have not been evaluated. Vasodilation 0% 2%
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No AVONEX-treated patients attempted suicide in the two DOSAGE AND ADMINISTRATION
placebo-controlled studies. In Study 2, AVONEX-treated The recommended dosage of AVONEX (Interferon beta-1a) is BIOTEST
patients were more likely to experience depression than placebo- 30 mcg injected intramuscularly once a week. P.O. BOX 250649, RIYADH 11391
treated patients (20% in AVONEX group vs. 13% in placebo AVONEX is intended for use under the guidance and supervision SAUDI ARABIA
group). The incidences of depression in the placebo-treated and of a physician. Patients may self-inject only if their physician TEL: 01-4765288
AVONEX-treated patients in Study 1 were similar. In Study 1, determines that it is appropriate and with medical follow-up,
suicidal tendency was seen more frequently in AVONEX-treated
patients (4% in AVONEX group vs. 1% in placebo group) (see
as necessary, after proper training in intramuscular injection BISEKO Solution for intravenous
technique. Sites for injection include the thigh or upper arm (see
WARNINGS). Medication Guide).
Seizures A 25 gauge, 1 needle for intramuscular injection may be (Human Serum)
Seizures have been reported in 4 of 351 AVONEX-treated substituted for the 23 gauge, 1 needle by the prescribing
physician, if deemed appropriate. COMPOSITION
patients in the placebo-controlled studies, compared to none in the
placebo-treated patients (see Precautions: Seizures). Reconstitution of AVONEX Vials Solution contains:
Human serum protein of which: 50 g
Post-Marketing Experience Use appropriate aseptic technique during the preparation of
Albumin approx. 31 g
The following adverse events have been identied and reported AVONEX. To reconstitute lyophilized AVONEX, use a sterile Human immunoglobulin of which: approx. 10 g
during post-approval use of AVONEX: New or worsening syringe and MICRO PIN to inject 1.1 mL of the supplied diluent, Immunoglobulin G approx. 7.1 g
other psychiatric disorders, and anaphylaxis (see WARNINGS). Sterile Water for Injection, USP, into the AVONEX vial. Gently immunoglobulin A approx. 1.55 g
Autoimmune disorders including autoimmune hepatitis, idiopathic swirl the vial of AVONEX to dissolve the drug completely. Immunoglobulin M approx. 0.48 g
DO NOT SHAKE. The reconstituted solution should be clear to Further constituents: Sodium ions (3.56 g). potassium ions (0.16
thrombocytopenia, hyper- and hypothyroidism, and seizures in
slightly yellow without particles. Inspect the reconstituted product g), calcium ions (0.08 g), magnesium ions (0.02 g), chloride ions
patients without prior history (see Precautions).
visually prior to use. Discard the product if it contains particulate (3.65 g), water for injections.
Infrequent reports of congestive heart failure, cardiomyopathy, matter or is discolored. Each vial of reconstituted solution contains
and cardiomyopathy with congestive heart failure with rare cases PHARMACEUTICAL FORM
30 mcg/1.0 mL Interferon beta-1a.
being temporally related to the administration of AVONEX (see Solution for intravenous use
Withdraw 1.0 mL of reconstituted solution from the vial into a
Precautions: Cardiomyopathy and Congestive Heart Failure).
sterile syringe. Replace the cover on the MICRO PIN, attach PRESENTATIONS
Decreased peripheral blood counts in all cell lines, including rare the sterile needle and inject the solution intramuscularly. The Ampoule with 20 ml
pancytopenia and thrombocytopenia (see WARNINGS: Decreased AVONEX and diluent vials are for single-use only; unused Infusion bottle with 50 ml
Peripheral Blood Counts). Some cases of thrombocytopenia have portions should be discarded. Infusion bottle with 250 ml
had nadirs below 10,000/L. Some of these cases reoccur upon
Using AVONEX Prelled Syringes infusion bottle with 500 ml
rechallenge.
The AVONEX prelled syringe should be held upright (rubber PHARMACOTHERAPEUTIC GROUP
Hepatic injury, including hepatic failure and elevated serum
cap faces up). Remove the protective cover by turning and gently Sera
hepatic enzyme levels, some of which have been severe, has been pulling the rubber cap in a clockwise motion. Attach the needle
reported post-marketing (see WARNINGS: Hepatic Injury). and inject the solution intramuscularly. The AVONEX prelled INDICATIONS
\Meno- and metrorrhagia, rash (including vesicular rash), and syringe is for single-use only. Volume therapy
rare cases of injection site abscess or cellulitis that may require Hypoproteinaemia
surgical intervention have also been reported in post-marketing HOW SUPPLIED Hypogammaglobulinaemia
experience. 30 mcg Lyophilized Powder Vial Hypalbuminaemia
Because reports of these reactions are voluntary and the population A vial of AVONEX is supplied as a lyophilized powder in a sin- Prophylaxis against infectious disease in case of antibody
is of an uncertain size, it is not always possible to reliably estimate gle-use vial containing 33 mcg (6.6 million IU) of Interferon beta- deciency syndrome
the frequency of the event or establish a causal relationship to drug 1a; 16.5 mg Albumin (Human), USP; 6.4 mg Sodium Chloride, Haemodilution
exposure. USP; 6.3 mg Dibasic Sodium Phosphate, USP; and 1.3 mg Mono- Note: BISEKO is free of hemolysins and can therefore be
basic Sodium Phosphate, USP, and is preservative-free. Diluent is administered regardiess of blood group.
Adverse Reactions Associated with Subcutaneous Use supplied in a single-use vial (Sterile Water for Injection, USP).
AVONEX has also been evaluated in 290 patients with diseases CONTRAINDICATIONS
AVONEX lyophilized vials are available in the following pack- Hypersensitivity to human protein
other than multiple sclerosis, primarily chronic viral hepatitis B age conguration (NDC 59627-001-03): A package containing
and C, in which the doses studied ranged from 15 mcg to 75 mcg, APPROPRIATE PRECAUTION FOR USE
four Administration Dose Packs (each containing one vial of
given SC, 3 times a week, for up to 6 months. Inammation at AVONEX, one 10 mL diluent vial, two alcohol wipes, one gauze Certain severe adverse drug reactions may related to the rate of
the site of the subcutaneous injection was observed in 52% of infusion. The recommended infusion rate given under Route
pad, one 3 mL syringe, one MICRO PIN* vial access pin, one 23
treated patients in these studies. Subcutaneous injections were of administration must be closely followed and patients must
gauge, 1 inch needle, and one adhesive bandage).
also associated with the following local reactions: injection site be closely monitored and carefully observed for any symptoms
30 mcg Prelled Syringe (N.R) throughout the infusion period.
necrosis, injection site atrophy, injection site edema and injection
site hemorrhage. None of the above was observed in the multiple A prelled syringe of AVONEX is supplied as a sterile liquid Patients should be observed for at least 20 minutes after
albumin-free formulation containing 30 mcg of Interferon beta-1a, administration.
sclerosis patients participating in Study 1. Injection site edema
0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic EFFECT ON ABILITY TO DRIVE AND USE MACHINES
and injection site hemorrhage were observed in multiple sclerosis
Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg There are no indications that BISEKO may impair the ability to
patients participating in Study 2.
Polysorbate 20 in Water for Injection, USP. Each prelled glass drive and use machines.
Immunogenicity syringe contains 0.5 mL for IM injection.
INTERACTIONS WITH OTHER DRUGS
As with all therapeutic proteins, there is a potential for AVONEX prelled syringes are available in the following pack-
immunogenicity. In recent studies assessing immunogenicity in Live attenuated vaccines:
age conguration (NDC 59627-002-05): A package containing
multiple sclerosis patients administered AVONEX for at least 1 four Administration Dose Packs (each containing one single-use The administration of BISEKO may impair for a period of at
least 6 weeks and up to 3 months the efcacy of live attenuated
year, 5% (21 of 390 patients) showed the presence of neutralizing syringe of AVONEX and one 23 gauge, 1 inch needle), and a
virus vaccines such as measles, rubella, mumps and varicella.
antibodies at one or more times. The clinical signicance of recloseable accessory pouch containing 4 alcohol wipes, 4 gauze
neutralizing antibodies to AVONEX is unknown. pads, and 4 adhesive bandages. Interference with serological testing:
These data reect the percentage of patients whose test results After administration of BISEKO the transitory rise of the various
STABILITY AND STORAGE passively transferred antibodies in the patients blood mav result in
were considered positive for antibodies to AVONEX using a
30 mcg Lyophilized Powder Vial positive results in serological testlng These results ate based on the
two-tiered assay (ELISA binding assay followed by an antiviral transferred antibodies( passive immunization) and should possibly
cytopathic effect assay), and are highly dependent on the Vials of AVONEX must be stored in a 2-8C (36-46F) refrigera-
be taken into account by the physician
sensitivity and specicity of the assay. Additionally, the observed tor. Should refrigeration be unavailable, vials of AVONEX can
be stored at 25C (77F) for a period of up to 30 days. Remark:
incidence of neutralizing activity in an assay may be inuenced
BISEKO is miscible with physiological saline solution.
by several factors including sample handling, timing of sample DO NOT EXPOSE TO HIGH TEMPERATURES. DO NOT
However, no other preparations may be added to the BISEKO
collection, concomitant medications, and underlying disease. FREEZE.
solution as any change in the electrolyte concentration or the pH
For these reasons, comparison of the incidence of antibodies to Protect from light. Do not use beyond the expiration date stamped may result in precipitation or denaturisation of the proteins.
AVONEX with the incidence of antibodies to other products may on the vial. Following reconstitution, it is recommended the prod- BISEKO is suitable for resuspending the erythrocyte
be misleading. uct be used as soon as possible within 6 hours stored at 2-8C concentrates.
Anaphylaxis has been reported as a rare complication of (36-46F). DOSAGE INSTRUCTIONS AND DURATION OF
AVONEX use. Other allergic reactions have included dyspnea, DO NOT FREEZE RECONSTITUTED AVONEX. APPLICATION
orolingual edema, skin rash and urticaria (see WARNINGS: Adults: up to 2000 ml per patient per day
30 mcg Prelled Syringe
Anaphylaxis). Children: 15 to 20 ml/kg body weight per day
AVONEX in prelled syringes must be stored in a 2-8C
DRUG ABUSE AND DEPENDENCE (36-46F) refrigerator. Once removed from the refrigerator, ROUTE OF ADMINISTRATION
There is no evidence that abuse or dependence occurs with AVONEX in a prelled syringe should be allowed to warm to BISEKO should be Inspected visually for particulate matter and
AVONEX therapy. However, the risk of dependence has not room temperature (about 30 minutes) and used within 12 hours. discoloration prior to admlnistration
been systematically evaluated. Do not use external heat sources such as hot water to warm Do not use solution which are cloudy or have a deposit
AVONEX in a prelled syringe. BISEKO should be warmed to room or body temperature before
OVERDOSAGE administration
Safety of doses higher than 60 mcg once a week have not been DO NOT EXPOSE TO HIGH TEMPERATURES.
BISEKO is intended for Intravenous use
adequately evaluated. The maximum amount of AVONEX that DO NOT FREEZE. Protect from light.
At the beginning of infusion, the rate of 20 drops per minute
can be safely administered has not been determined. Do not use beyond the expiration date stamped on the syringe. (corresponding to 1 ml per minute) must not be exceeded. After 10
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minutes the rate of administration may gradually be increased to 3 Human plasma protein 50 mg In all patients, intravenous immunoglobulin administration
- 4 ml per minute for the remainder of the infusion of which immunoglobulin G 95 % requires:
HBs antibody content 50 I.U. - adequate hydration prior to the initiation of the infusion of
OVERDOSE
Excipients: intravenous immunoglobulin,
In neonates and Infants receiving BISEKO at a dosage which
is greater than the recommended maximum dosage and which Glycine, water for injections - monitoring of urine output,
corresponds to their estimated circulating volume or exceeds this, The IgG subclass distribution is approx. 59% (IgG1), 36% (IgG2), - monitoring of serum creatinine levels,
it is conceivable that even the very low content of isoagglutinins 3% (IgG3), 2% (IgG4) - avoidance of concomitant use of loop diuretics.
may result in clinical symptoms. Signs of increased haemolysis The IgA content is 2.5 mg/ml In case of renal impairment, intravenous immunoglobulin
should be looked out for. discontinuation should be considered.
PHARMACEUTICAL FORM AND PRESENTATIONS
UNDESIRABLE EFFECTS While these reports of renal dysfunction and acute renal failure have
Solution for intravenous infusion been associated with the use of many of the licensed intravenous
Adverse reactions such as chills, headache, fever, vomiting,
Ampoule with 2 ml (100 I.U.) immunoglobulin products, those containing sucrose as a stabiliser
allergic reactions, nausea. arthralaia and mild back pain mav occur
occasionallv. Vial with 10 ml (500 I.U.) accounted for a disproportionate share of the total number. In
Vial with 40 ml (2000 I.U.) (N.R.) patients at risk, the use of intravenous immunoglobulin products
Rarely the contained immunoglobulins may cause a fall in blood
that do not contain sucrose may be considered. In addition, the
pressure and, In isolated cases, anaphylactic reactions up to PHARMACOTHERAPEUTIC GROUP product should be administered at the minimum concentration and
shock, even when the patient has shown no sensitivity to previous Human hepatitisB immunoglobulin for intravenous administration
administration. infusion rate practicable.
When medicinal products prepared from human blood or plasma are THERAPEUTIC INDICATIONS When medicinal products prepared from human blood or plasma
administered, infectious diseases due to transmission of infective A. Prophylaxis against hepatitis B in adults and children over two are administered, infectious diseases due to transmission of
agents cannot be totally excluded. This applies also to pathogens years of age who have not been vaccinated against hepatitis B infective agents cannot be totally excluded. This also applies to
of hitherto unknown nature. To reduce the risk of transmission (including persons whose vaccination is incomplete or missing) pathogens of unknown nature. The risk of transmission of infective
of infective agents, stringent controls are applied to the selection who are at risk of infection with hepatitis B by accidental contact agents is however reduced by:
of blood donors and donations. In addition, virus removal and/or with hepatitis B virus containing material following - selection of donors by a medical interview and screening of
inactivation procedures are included in the production process (see - percutaneous exposure (e.g., accidental needle stick) individual donations and plasma pools for Hepatitis B surface
Additional information). antigen (HBsAg) and antibodies to human immunodeciency
- direct mucous membrane contact
The patient is invited to communicate any undesirable effect not virus (HIV) and hepatitis C virus (HCV)
when the administration of an intramuscular hepatitis B
mentioned above to his doctor or pharmacist. - testing of plasma pools for Hepatitis C virus genomic material
immunoglobulin is not possible.
In case of adverse reactions either the rate of administration must - inactivation/removal procedures included in the production
The immunoglobulin should be administered in association with process that have been validated using model viruses.
be reduced or the infusion stopped until sym.ptoms disappear.
hepatitis B vaccine. These procedures are considered effective for human
If severity of reactions persist after discontinuation of the infusion,
appropriate treatment is recommended. B. Prophylaxis against re-infection of a transplanted liver in immunodeciency virus, hepatitis C and hepatitis B virus.
patients who carry the surface antigen of the hepatitis B virus The viral removal/inactivation procedures may be of limited value
Immediate measures for severe anaphylactic reactions (shock)
CONTRAINDICATIONS against non-enveloped viruses such as hepatitis A virus and/or
Anaphylactic shocks are rare but always acutely Iife-threatening,
Hypersensitivity to any of the compounds. parvovirus B 19.
generally, the following measures are recommended.
If the rst symptoms occur (sweat, nausea, cyanosts) Hypersensitivity to homologous immunoglobulins, especially in In the interest of patients, it is recommended that whenever
discontinue injection/infusion leave cannula In the vein or create very rare cases of IgA deciency, when the patient has antibodies possible, every time that HEPATECT CP is administered to
venous Inlet against immunoglobulin A (IgA). them, the name and the batch number of the product is registered.
Besides other usual Iife-saving measures Treatment with HEPATECT CP in the prophylaxis against EFFECTS ON THE ABILITY TO DRIVE OR USE
apply Trendelenburgs position hepatitis B is not indicated if the person at risk has been fully MACHINES
keep respiratory system free vaccinated against hepatitis B and his immune response has been No effects on the ability to drive and use machines have been
adequate. observed.
Immediate medical measures
immediately Epinephrin (Adrenalin) i.v. PREGNANCY AND LACTATION INTERACTIONS WITH OTHER MEDICINAL
After diluting t ml of commercial adrenaline solution The safety of this medicinal product for use in human pregnancy PRODUCTS
(1 : 1000) to 10 ml or using a ready-to-use syringe has not been established in controlled clinical trials. It should Live attenuated vaccines:
therefore only be given with caution to pregnant women and Immunoglobulin administration may impair for a period of at least
(1 : 10,000) 1 ml of this dilution (= 0.1 mg adrenaline) is injected breast-feeding mothers.
slowly (cave cardiac rhythm disorder!) with pulse and blood 6 weeks and up to 3 months the efcacy of live attenuated virus
pressure monitoring. Clinical experience with immunoglobulins suggests that no vaccines such as measles, rubella, mumps and varicella. After
harmful effects on the course of pregnancy, or on the foetus and administration of this product, an interval of 3 months should
Adrenaline administration can be repeated.
the neonate are to be expected. elapse before vaccination with live attenuated virus vaccines. In
subsequently Volume substitution i.v.
Immunoglobulins are excreted into the milk and may contribute to the case of measles, this impairment may persist for up to one year.
e.g. plasma expander, human albumin, whole-electrolyte solution. the transfer of protective antibodies to the neonate. Therefore patients receiving measles vaccine should have their
afterwards Glucocorticoids i.v. antibody status checked.
APPROPRIATE PRECAUTIONS FOR USE
e.g. 250 to 1000 mg prednisolon (or equivalent amount of Interference with serological testing:
derivative). Certain severe side effects may be related to the rate of infusion. The
recommended infusion rate given under Route of administration After injection of immunoglobulins the transitory rise of the
Glucocorticoid administration can be repeated. various passively transferred antibodies in the patients blood may
must be closely followed as the incidence of adverse events tends
Other therapy measures include: e.g. artical respiration, to increase with the rate of infusion. Patients must be closely result in misleading positive results in serological testing.
oxygen inhalation, antihistamines. monitored and carefully observed for any symptoms throughout Passive transmission of antibodies to erythrocyte antigens,
STORAGE the infusion period. e.g., A, B, D, may interfere with some serological tests for red
Certain adverse effects may occur more frequently cell allo-antibodies (e.g., Coombs test), reticulocyte count and
BISEKO has to be stored at +2 to +8C, protected from light.
haptoglobin.
Do not freeze. - in case of high rate of infusion
BISEKO should not be used after the expiry date indicated on - in patients with hypo- or agammaglobulinaemia with or without INCOMPATIBILITIES:
the label. IgA deciency; No other preparations may be added to the HEPATECT CP
The solution should be administered immediately after opening - in patients who receive human immunoglobulin for the rst solution as any change in the electrolyte concentration or the pH
the container. time or, in rare cases, when the human immunoglobulin product may result in precipitation or denaturisation of the proteins.
Any unused solution must be discarded because of bacterial is switched or when there has been a long interval since the DOSAGE AND METHOD OF ADMINISTRATION
contamination risk. previous infusion.
Unless otherwise prescribed, the following recommendations
Drugs should be stored out of reach of children True hypersensitivity reactions are rare. They can occur in the very apply:
seldom cases of IgA deciency with anti IgA antibodies.
ADDITIONAL INFORMATION After exposure to material containing hepatitis B surface antigen:
Rarely, human immunoglobulin can induce a fall in blood pressure As soon as possible but not later than within 72 hours, injection
For the manufacture of BISEKO only plasma IS used which with anaphylactic reaction, even in patients who had tolerated
obtained from healthy donors tested and found negative for of 8-10 I.U. (0.16 to 0.20 ml) of HEPATECT CP per kg body
previous treatment with human immunoglobulin. weight after investigation of the at-risk person for HBsAg and
HbsAq, for HCV antibodies,for HIV-1/2 antibodies, and showing
Potential complications can often be avoided by ensuring: anti-HBs. Unless the anti HBs antibody determination at monthly
no pathologically raised ALT-activity. Furthermore, only plasma
pools tested and found negative for HbsAg, for HCV antibodies - that patients are not sensitive to human immunoglobulin by rst intervals (which also acts as a control of the success of vaccination
and for HIV-1/2 antibodies are processed. injecting the product slowly (0.1 ml/kg/hr) following the simultaneous vaccination) indicates that earlier
- that patients are carefully monitored for any symptoms administration is necessary, repetition of the dose at intervals of
In addition, removal and/or inactivation procedures are included
throughout the infusion period. In particular, patients who 2 months.
in the production process (treatment with propiolactone. UV
irradiation and heating to 37 C). have never been treated with human immunoglobulin, patients Continuation of the immunisation schedule up to the onset of
switched from an alternative intravenous immunoglobulin seroconversion in ongoing risk of infection. Passive administration
product or when there has been a long interval since the is no longer necessary once active raising of anti HBs antibodies
HEPATECT CP previous infusion should be monitored during the rst infusion has commenced.
Solution for intravenous infusion and for the rst hour after the rst infusion, in order to detect For prophylaxis against re-infection of a transplanted liver in
potential adverse signs. All other patients should be observed HBsAg-positive patients, 10000 I.U. (200 ml) of HEPATECT
for at least 20 minutes after administration. CP is infused intravenously during surgery in the anhepatic phase
(Human hepatitis B immunoglobulin) Cases of acute renal failure have been reported in patients receiving and 2000 I.U. (40 ml) is infused daily over a period of 7 days
intravenous immunoglobulin therapy. In most cases, risk factors after surgery. During the subsequent long-term treatment, a serum
COMPOSITION
have been identied, such as pre-existing renal insufciency, level of 100 I.U./litre should be maintained with monthly checks
1 ml of solution for infusion contains: diabetes mellitus, hypovolaemia, overweight, concomitant of the anti-HBs serum level. The duration of treatment should be
Active substance(s): nephrotoxic medicinal products or age over 65 years. at least 6 months.
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Mode of administration from its contribution to oncotic pressure of the blood and transport DOSAGE
The product should be inspected visually for particulate matter and function. Albumin stabilise circulating blood volume and is a The dose required depends on the size of the patient, the severity
discoloration prior to administration. Do not use solutions which carrier of hormones, enzymes, medicinal products and toxins. of trauma or illness and on continuing uid or protein losses.
are cloudy of have deposits. Measures of adequacy of circulating volume and not plasma
INDICATIONS
The product should be brought to room or body temperature before albumin levels should be used to determine the dose required.
Restoration and maintenance of circulating blood volume where
use. If human albumin is to be administered, haemodynamic
volume deciency has been demonstrated and use of a colloid is performance should be monitored regularly; this may include:
HEPATECT CP should be infused intravenously at an initial appropriate.
rate of 0.1 ml/kg/hr for 10 minutes. If well tolerated, the rate of - arterial blood pressure and pulse rate
The choice of albumin rather than articial colloid will depend - central venous pressure
infusion may gradually be increased to a maximum of 1 ml/kg/hr.
on the clinical situation of the individual patient, based on ofcial
- pulmonary artery wedge pressure
OVERDOSE recommendations.
- urine output
Overdose may lead to uid overload and hyperviscosity, CONTRAINDICATIONS - electrolyte
particularly in patients at risk, including elderly patients and - haemaotcrit / haemoglobin
Hypersensitivity to albumin preparations or to any of the
patients with renal impairment.
excipients. Human Albumin 5% Biotest isotonic is suitable for dialysis
UNDESIRABLE EFFECTS patients and premature infants.
Adverse effects such as chills, headache, fever, vomiting, allergic MODE OF ADMINISTRATION
The safety of HUMAN ALBUMIN 5% BIOTEST ISOTONIC
reactions, nausea, arthralgia, low blood pressure and mild back Human albumin can be directly administered by the intravenous
for use in human pregnancy has not been established in controlled
pain may occur occasionally. route, or it can also be diluted in an isotonic solution (e.g. 0.9 %
clinical trials. However, clinical experience with albumin suggests
Rarely, human immunoglobulins may cause a sudden fall in blood that no harmful effects on the course of pregnancy, or on the foetus sodium chloride).
pressure and, in isolated cases, anaphylactic shock, even when the and the neonate are to be expected. The infusion rate should be adjusted according to the individual
patient has shown no hypersensitivity to previous administration. circumstances and the indi-cation.
Experimental animal studies are insufcient to assess the safety
Cases of reversible aseptic meningitis, isolated cases of with respect to reproduction, development of the embryo or foetus, In plasma exchange the infusion rate should be adjusted to the rate
reversible haemolytic anaemia/haemolysis and rare cases of of removal.
the course of gestation and peri- and postnatal development.
transient cutaneous reactions, have been observed with human
immunoglobulin. However, human albumin is a normal constituent of human OVERDOSE
blood. Hypervolaemia may occur if the dosage and rate of infusion are
Increase in serum creatinine level and/or acute renal failure have
too high. At the rst clinical signs of cardiovascular overload
been observed. SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
(headache, dyspnoea, jugular vein congestion), or in-creased blood
Thrombotic events have been reported in the elderly, in patients FOR USE
pressure, raised central venous pressure and pulmonary oedema,
with signs of cerebral or cardiac ischemia, and in overweight and If allergic or anaphylactic-type reactions occur, the infusion should the infusion should be stopped immediately and the patients
severely hypovolaemic patients. be stopped immediately and appropriate treatment instituted. In haemodynamic parameters carefully monitored.
See Precautions for information regarding anaphylaxis, aseptic case of shock, the current medical standards for shock-treatment
should be observed. UNDESIRABLE EFFECTS
meningitis syndrome (AMS), renal dysfunction and haemolysis.
Mild reactions such as ush, urticaria, fever and nausea occur
The following adverse reactions were reported spontaneously to be Albumin should be used with caution in conditions where
rarely. Undesirable effects such as shivering, vomiting, erythema,
possible or probably related to HEPATECT CP administration hypervolaemia and its conse-quences or haemodilution could
drop in blood pressure with tachycardia and dyspnoea occurred
with an incidence of less than 0.1% each: represent a special risk for the patient. Examples of such conditions
in single cases. These reactions normally disappear rapidly when
Skin and subcutaneous tissue: Cutaneous reactions, exanthema, are: the infusion rate is slowed down or the infusion is stopped. Very
itching, pruritus, rash, sweating, urticaria. - Decompensated cardiac insufciency rarely, severe reactions as far as shock may occur. In these cases,
In case of adverse reaction, either the rate of infusion must be - Hypertension the infusion should be stopped and an appropriate treatment
reduced or the infusion stopped. The treatment required depends - Oesophageal varices should be initiated.
on the nature and severity of side effect. - Pulmonary oedema For information on infection risk see Special warnings and
- Haemorrhagic diathesis special precautions for use
In the case of renal impairment, discontinuation of administration
- Severe anaemia The patient is recommended to communicate any undesirable
of intravenous immunoglobulin should be considered.
- Renal and post-renal anuria effect not mentioned above to his doctor or pharmacist.
In the case of shock, the current medical standards for shock
If comparatively large volumes are to be replaced, controls of
therapy should be observed. STORAGE AND NOTES FOR THE HANDLING
coagulation and haematocrit are necessary. Care must be taken
The patient is invited to communicate any undesirable effect not to ensure adequate substitution of other blood constitu-ents Do not store above 25C. Do not freeze.
mentioned above to the doctor or pharmacist. (coagulation factors, electrolytes, platelets and erythrocytes). Keep the container in the outer carton in order to protect from
SHELF-LIFE AND SPECIAL PRECAUTIONS FOR Hypervolaemia may occur if the dosage and rate of infusion light.
STORAGE are not adjusted to the patients circulatory situation. At the rst Human albumin can be directly administered by the intravenous
The product should not be used after the expiry date indicated on clinical signs of cardiovascular overload (headache, dysp-noea, route, or it can also be diluted in an isotonic solution (e.g. 0.9 %
jugular vein congestion), or increased blood pressure, raised sodium chloride).
the label.
venous pressure and pulmonary oedema, the infusion is to be Albumin solutions must not be diluted with water for injections as
HEPATECT CP should be stored at +2C to +8C. Do not
stopped immediately. this may cause haemolysis in recipients.
freeze.
When medicinal products prepared from human blood or plasma If large volumes are administered, the product should be warmed
Keep container in the outer carton. The solution should be
are administered, infectious diseases due to transmission of to room or body temperature before use.
administered immediately after opening the container.
infective agents cannot be totally excluded. This applies to The solution should be clear or slightly opalescent.
Any unused product or waste material should be disposed in
pathogens of hitherto unknown nature. The risk of transmission of Do not use solutions which are cloudy or have deposits. This may
accordance with local requirements.
infective agents is however reduced by: indicate that the protein is unstable or that the solution has become
- selection of donors by a medical interview and screening contaminated.
HUMAN ALBUMIN 5 % BIOTEST ISOTONIC of individual donations and plasma pools for HBsAg and Once the container has been opened, the contents should be used
Solution for intravenous infusion antibodies to HIV and HCV. immediately.
- testing of plasma pools for HCV genomic material. Any unused product should be disposed of in accordance with
- inactivation/removal procedures included in the production local requirements.
(Human Albumin)
process that have been validated using model viruses. This
COMPOSITION procedures are considered effective for HIV, HCV, HBV and HUMAN ALBUMIN 20 %
HAV.
1000 ml solution contain: BIOTEST LOW SALT CONTENT
The viral inactivation/removal procedures may be of limited value
- active ingredients:
against non-enveloped viruses such as parvovirus B19.
Solution for intravenous infusion.
Human plasma protein 50 g
Albumin manufactured to European Pharmacopoeia specications
of which albumin at least 96 % by established processes has a reassuring viral safety record. (Human Albumin)
- excipients:
In the interest of patients, it is recommended that, whenever
Caprylate* 0.58 g (4 mmol) possible, every time that a me-dicinal product derived from human COMPOSITION
N-Acetyl-DL-tryptophanate* 0.98 g (4 mmol) blood or plasma is administered to them, the name and the batch 1000 ml solution contain:
Sodium 3.33 g (145 mmol) number of the product is registered. - active ingredients:
Chloride 4.96 g ( 140 mmol) EFFECTS ON ABILITY TO DRIVE AND USE MACHINES Human plasma protein 200 g
Water for injections ad 1000 ml of which albumin at least 96 %
There are no indications that human albumin may impair the
*Stabilizer - excipients:
abilities to drive or to operate machines.
Caprylate* 2.31 g (16 mmol)
PRESENTATION INTERACTIONS WITH OTHER MEDICINAL PRODUCTS N-Acetyl-DL-tryptophanate* 3.94 g (16 mmol)
Solution for intravenous infusion AND OTHER FORMS OF INTERACTIONS Sodium .80 g (122 mmol)
Vial with 50 ml No specic interactions of human albumin with other products are Chloride 3.90 g ( 110 mmol)
Vial with 250 ml known. Water for injections ad 1000 ml
Vial with 500 ml (N.R.) *Stabilizer
DOSAGE INSTRUCTIONS AND MODE OF ADMINISTRA-
PHARMACOTHERAPEUTIC GROUP / TION PRESENTATION
MODE OF ACTION Solution for intravenous infusion.
The concentration of the albumin preparation, dosage and the
Plasma protein fraction, plasma substitute infusion-rate should be adjusted to the patients individual Vial with 50 ml
The most important physiological functions of albumin results requirements. Vial with 100 ml
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PHARMACOTHERAPEUTIC GROUP / EFFECTS ON ABILITY TO DRIVE AND USE MACHINES - excipient(s):
MODE OF ACTION There are no indications that human albumin may impair the glucose monohydrate (corresponding to 25 mg glucose), sodium
Plasma protein fraction, plasma substitute abilities to drive or to operate machines. ions (78 mol), chloride ions (78 mol), water for injections.
The most important physiological functions of albumin result INTERACTIONS WITH OTHER MEDICINAL PRODUCTS The distribution of IgG subclasses is dened around 62 % IgG1,
from its contribution to oncotic pressure of the blood and transport AND OTHER FORMS OF INTERACTIONS 34 % IgG2, 0.5 % IgG3 and 3.5 % IgG4.
function. Albumin stabilises circulating blood volume and is a The IgA content is limited to 2.5 mg/ml.
No specic interactions of human albumin with other products are
carrier of hormones, enzymes, medicinal products and toxins.
known.
PHARMACEUTICAL FORM
INDICATIONS DOSAGE INSTRUCTIONS AND MODE OF ADMINISTRATION
Solution for infusion.
Restoration and maintenance of circulating blood volume where The concentration of the albumin preparation, dosage and the
volume deciency has been demonstrated and use of a colloid is The solution is clear to slightly opalescent and colourless to pale
infusion-rate should be adjusted to the patients individual
appropriate. yellow.
requirements.
The choice of albumin rather than articial colloid will depend PRESENTATIONS
on the clinical situation of the individual patient, based on ofcial DOSAGE
The dose required depends on the size of the patient, the severity Ampoule with 10 ml (N.R) and 20 ml (N.R.)
recommendations.
of trauma or illness and on continuing uid or protein losses. Vial with 50 ml, 100 ml (N.R.) and 200 ml (N.R.)
CONTRAINDICATIONS Measures of adequacy of circulating volume and not plasma PHARMACOTHERAPEUTIC GROUP
Hypersensitivity to albumin preparations or to any of the albumin levels should be used to determine the dose required.
excipients. Human normal immunoglobulin for intravenous administration
If human albumin is to be administered, haemodynamic
PREGNANCY AND LACTATION performance should be monitored regularly; this may include: INDICATIONS
The safety of HUMAN ALBUMIN 20 % BIOTEST LOW SALT - arterial blood pressure and pulse rate Replacement therapy in:
CONTENT for use in human pregnancy has not been established - central venous pressure Primary immunodeciency syndromes:
in controlled clinical trials. However, clinical experience with - pulmonary artery wedge pressure
- congenital agammaglobulinaemia and hypogamma-
albumin suggests - urine output
- electrolyte globulinaemia
HUMAN ALBUMIN 20% BIOTEST LOW SALT CONTENT - common variable immunodeciency
that no harmful effects on the course of pregnancy, or on the foetus - haemaotcrit / haemoglobin
and the neonate are to be expected. - severe combined immunodeciencies
HUMAN ALBUMIN 20% BIOTEST LOW SALT CONTENT
Experimental animal studies are insufcient to assess the safety is suitable for use in dialysis patients and premature infants. Secondary hypogammaglobulinaemia in patients with chronic
with respect to reproduction, development of the embryo or foetus, lymphocytic leukaemia and multiple myeloma with recurrent
MODE OF ADMINISTRATION
the course of gestation and peri- and postnatal development. bacterial infections.
Human albumin can be directly administered by the intravenous
However, human albumin is a normal constituent of human Children with congenital AIDS who have repeated bacterial
route, or it can also be diluted in an isotonic solution (e.g. 0.9 %
blood. sodium chloride). infections.
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS The infusion rate should be adjusted according to the individual Immunomodulation
FOR USE circumstances and the indication. Idiopathic thrombocytopenic purpura (ITP), in adults or children
If allergic or anaphylactic-type reactions occur, the infusion should at high risk of bleeding or prior to surgery to correct the platelet
OVERDOSE
be stopped immediately and appropriate treatment instituted. In count.
Hypervolaemia may occur if the dosage and rate of infusion are
case of shock, the current medical standards for shock-treatment Kawasaki disease.
should be observed. too high. At the rst clinical signs of cardiovascular overload
(headache, dyspnoea, jugular vein congestion), or increased blood Allogeneic bone marrow transplantation
Albumin should be used with caution in conditions where pressure, raised central venous pressure and pulmonary oedema,
hypervolaemia and its consequences or haemodilution could CONTRA-INDICATIONS
the infusion should be stopped immediately and the patients
represent a special risk for the patient. Examples of such conditions haemodynamic parameters carefully monitored. Hypersensitivity to any of the components.
are: Hypersensitivity to homologous immunoglobulins, especially in
UNDESIRABLE EFFECTS AND COUNTERMEASURES
- Decompensated cardiac insufciency very rare cases of IgA deciency when the patient has antibodies
- Hypertension Mild reactions such as ush, urticaria, fever and nausea occur against IgA.
- Oesophageal varices rarely. Undesirable effects such as shivering, vomiting, erythema,
- Pulmonary oedema drop in blood pressure with tachycardia and dyspnoea occurred PREGNANCY AND LACTATION:
- Haemorrhagic diathesis in single cases. These reactions normally disappear rapidly when The safety of this medicinal product for use in human pregnancy
- Severe anaemia the infusion rate is slowed down or the infusion is stopped. Very has not been established in controlled clinical trials and therefore
- Renal and post-renal anuria rarely, severe reactions as far as shock may occur. In these cases, should only be given with caution to pregnant women and
The colloid-osmotic effect of HUMAN ALBUMIN 20 % the infusion should be stopped and an appropriate treatment breast-feeding mothers. Long lasting clinical experience with
is approximately four times that of blood plasma. Therefore, should be initiated.
immunoglobulins does indicate that no harmful effects on the
when concentrated albumin is administered, care must be taken For information on infection risk see Special warnings and course of pregnancy, on the foetus and the neonate are to be
to ensure adequate hydration of the patient. Patients should be special precautions for use. expected.
monitored carefully to guard against circulatory overload and The patient is recommended to communicate any undesirable Immunoglobulins are excreted into the milk and may contribute to
hyperhydration. effect not mentioned above to his doctor or pharmacist. the transfer of protective antibodies to the neonate.
20-25 % human albumin solutions are relatively low in electrolytes STORAGE AND NOTES FOR THE HANDLING
compared to the 4-5 % human albumin solutions. When albumin APPROPRIATE PRECAUTIONS FOR USE
Do not use after expiry date indicated on the label and outer
is given, the electrolyte status of the patient should be monitored Certain severe adverse drug reactions may be related to the rate
and appropriate steps taken to restore or maintain the electrolyte carton.
of infusion. The recommended infusion rate given under Route
balance. Store at 2 C to 8 C. Do not freeze.
of administration must be closely followed as the incidence of
Albumin solutions must not be diluted with water for injections as Keep the container in the outer carton in order to protect from adverse events tends to increase with the rate of infusion and
this may cause haemolysis in recipients. light. patients must be closely monitored and carefully observed for any
If comparatively large volumes are to be replaced, controls of The solution can be directly administered by the intravenous route, symptoms throughout the infusion period.
coagulation and haematocrit are necessary. Care must be taken or it can be diluted in an isotonic solution (e.g. 0.9 % sodium
Certain adverse reactions may occur more frequently
to ensure adequate substitution of other blood constituents chloride).
(coagulation factors, electrolytes, platelets and erythrocytes). - in case of high rate of infusion,
Albumin solutions must not be diluted with water for injections as
Hypervolaemia may occur if the dosage and rate of infusion this may cause haemolysis in recipients. - in patients with hypo- or agammaglobulinaemia with or without
are not adjusted to the patients circulatory situation. At the rst IgA deciency
If large volumes are administered, the product should be warmed
clinical signs of cardiovascular overload (headache, dyspnoea, to room or body temperature before use. - in patients who receive human normal immunoglobulin
jugular vein congestion), or increased blood pressure, raised The solution should be clear or slightly opalescent. for the rst time or, in rare cases, when the human normal
venous pressure and pulmonary oedema, the infusion is to be immunoglobulin product is switched or when there has been a
stopped immediately. Do not use solutions which are cloudy or have deposits. This may
long interval since the previous infusion.
indicate that the protein is unstable or that the solution has become
When medicinal products prepared from human blood or plasma contaminated. True hypersensitivity reactions are rare. They can occur in the very
are administered, infectious diseases due to transmission of seldom cases of IgA deciency with anti-IgA antibodies.
infective agents cannot be totally excluded. This applies to Once the container has been opened, the contents should be used
immediately. Rarely, human normal immunoglobulin can induce a fall in
pathogens of hitherto unknown nature. The risk of transmission of
Any unused product and packaging materials should be disposed blood pressure with anaphylactic reaction, even in patients
infective agents is however reduced by:
of in accordance with local requirements. who had tolerated previous treatment with human normal
- selection of donors by a medical interview and screening
immunoglobulin.
of individual donations and plasma pools for HBsAg and
Potential complications can often be avoided by ensuring:
antibodies to HIV and HCV. INTRAGLOBIN F 50 mg/ml
- testing of plasma pools for HCV genomic material. - that patients are not sensitive to human normal immunoglobulin
- inactivation/removal procedures included in the production
Solution for infusion by rst injecting the product slowly (0.024 ml/kg/min),
process that have been validated using model viruses. These - that patients are carefully monitored for any symptoms
procedures are considered effective for HIV, HCV, HBV and (Human normal immunoglobulin) throughout the infusion period. In particular, patients naive
HAV. to human normal immunoglobulin, patients switched from an
The viral inactivation/removal procedures may be of limited value ACTIVE SUBSTANCE alternative IVIg product or when there has been a long interval
against non-enveloped viruses such as parvovirus B19. since the previous infusion should be monitored during the rst
Human normal immunoglobulin for intravenous administration
Albumin manufactured to European Pharmacopoeia specications infusion and for the rst hour after the rst infusion, in order
by established processes has a reassuring viral safety record. COMPOSITION to detect potential adverse signs. All other patients should be
In the interest of patients, it is recommended that, whenever 1 ml solution contains observed for at least 20 minutes after administration.
possible, every time that a medicinal product derived from human - active substance(s): - that the glucose content (0.5 g/g of IgG) is taken into account
blood or plasma is administered to them, the name and the batch human plasma protein 50 mg in case of latent diabetes (where transient glycosuria could
number of the product is registered. thereof immunoglobulin 95 % appear), diabetes, or in patients on a low sugar diet.
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SPDI
There is clinical evidence of an association between IVIg replacement therapy the dosage may need to be individualised For information on infection risk see Appropriate precautions
administration and thromboembolic events such as myocardial for each patient dependent on the pharmacokinetic response. The for use.
infarction, stroke, pulmonary embolism and deep vein thromboses following dosage regimens are given as a guideline: In case of adverse reaction, either the rate of administration must
which is assumed to be related to a relative increase in blood Replacement therapy in primary immunodeciencies: be reduced or the infusion stopped until symptoms disappear.
viscosity through the high inux of immunoglobulin in at-risk The treatment required depends on the nature and severity of side
2 - 8 ml (0.1 - 0.4 g)/kg body weight (b.w.) at monthly intervals
patients. Caution should be exercised in prescribing and infusing effect.
in order to restore abnormal low IgG levels to the normal range.
IVIg in obese patients and in patients with pre-existing risk factors
Administration may be increased up to 16 ml (0.8 g)/kg b.w. or be In case of renal impairment the discontinuation of the
for thrombotic events (such as advanced age, hypertension,
more frequent if the IgG level achieved in blood is not sufcient or immunoglobulin administration should be considered.
diabetes mellitus and a history of vascular disease or thrombotic
if the decrease is particularly rapid. In case of shock, standard medical treatment for shock should be
episodes, patients with acquired or inherited thrombophilic
disorders, patients with prolonged periods of immobilisation, Replacement therapy in secondary immunodeciencies implemented.
severely hypovolemic patients, patients with diseases which (including children with AIDS): The patient is invited to communicate any undesirable effect not
increase blood viscosity). 2 - 8 ml (0.1 - 0.4 g)/kg body weight (b.w.) at monthly intervals mentioned above to his doctor or pharmacist.
Cases of acute renal failure have been reported in patients in order to restore abnormal low IgG levels to the normal range.
Administration may be increased up to 16 ml (0.8 g)/kg b.w. or be SHELF-LIFE AND SPECIAL PRECAUTIONS FOR
receiving IVIg therapy. In most cases, risk factors have been
more frequent if the IgG level achieved in blood is not sufcient or STORAGE
identied, such as pre-existing renal insufciency, diabetes
mellitus, hypovolaemia, overweight, concomitant nephrotoxic if the decrease is particularly rapid. Keep container in the outer carton. Store at +2 C to +8 C. Do
medicinal products or age over 65. Idiopathic thrombocytopenic purpura: not freeze.
While these reports of renal dysfunction and acute renal failure For the treatment of an acute episode, 16 - 20 ml (0.8 - 1.0 g)/kg INTRAGLOBIN F should not be used after the expiry date
have been associated with the use of many of the licensed IVIg b.w. on day one, repeated on day two or three if necessary, or 8 indicated on the label.
products, those containing sucrose as a stabiliser accounted for ml (0.4 g)/kg b.w. daily for two to ve days. The treatment can be The solution should be administered immediately after opening
a disproportionate share of the total number. In patients at risk, repeated if relapse occurs. the receptacle.
the use of IVIg products that do not contain sucrose may be Kawasaki disease: Any unused solution must be discarded because of bacterial
considered. INTRAGLOBIN F does not contain sucrose. contamination risk.
32 - 40 ml (1.6 - 2.0 g)/kg b.w. should be administered in divided
In patients at risk for acute renal failure or thromboembolic adverse doses over two to ve days or 40 ml (2.0 g)/kg b.w. as a single
reactions, IVIg products should be administered at the minimum
rate of infusion and dose practicable.
dose. Patients should receive a concomitant treatment with PENTAGLOBIN
acetylsalicylic acid.
In all patients, IVIg administration requires: Solution for Intravenous Administration
Allogeneic bone marrow transplantation:
- adequate hydration prior to the initiation of the infusion of
IVIG treatment may be used as part of the conditioning regimen
IVIg,
and after the transplant. The regimen should be individualised. A (Human normal immunoglobulin)
- monitoring of urine output
starting dose of 10 ml (0.5 g)/kg b.w./week is recommended.
- monitoring of serum creatinine levels,
The dosage recommendations are summarised in the following COMPOSITION:
- avoidance of concomitant use of loop diuretics.
table: 1 ml solution contains:
Patients at risk: see section Overdose.
Indications Dose Frequency of Infusions - active ingredient:
When medicines are made from human blood or plasma, certain
Replacement therapy in 0.1-0.4 every 2-4 weeks to obtain Human plasma protein 50 mg
measures are put in place to prevent infections being passed on
primary immunodeciency g/kg IgG through level of of which immunoglobulin is at least 95 %
the patients. These include careful selection of blood and plasma at least 4-6 g/l
donors to make sure those at risk of carrying infections are Immunoglobulin M (IgM) 6 mg
Replacement therapy in 0.1-0.4 every month to obtain Immunoglobulin A (IgA) 6 mg
excluded, and the testing of each donation and pools of plasma secondary immunodeciency g/kg IgG through level of
for signs of virus/infections. Manufacturers of these products Immunoglobulin G (IgG) 38 mg
at least 4-6 g/l
also include steps in the processing of the blood or plasma that Children with AIDS 0.1-0.4 every 2-4 weeks to obtain
- excipients:
can inactivate or remove viruses. Despite these measures, when g/kg IgG through level of Glucose monohydrate (27.5 mg), sodium chloride (78 mol),
medicines prepared from human blood or plasma are administered, at least 4-6 g/l water for injections ad 1 ml
the possibility of passing on infection cannot be totally excluded. Immunomodulation: The distribution of IgG subclasses is approx. 63 % IgG1, 26 %
This also applies to any unknown or emerging viruses or other Idiopathic Thrombocytopenic 0.8-1 on day 1, possibly repeated IgG2, 4 % IgG3, and 7 % IgG4
types of infections. Purpura g/kg once on day 2 or 3
The measures taken are considered effective for enveloped viruses PRESENTATIONS AND CONTENTS OF CONTAINER
such as human immunodeciency virus (HIV), hepatitis B virus or Solution for intravenous infusion.
(HBV) and hepatitis C virus (HCV). The measures taken may be 0.4 g/kg/d for 2-5 days
Ampoule with 10 ml (0.5 g)
of limited value against non-enveloped viruses such as hepatitis A Kawasaki disease 1.6-2 in several doses for 2-5 days Ampoule with 20 ml (1.0 g)
virus and parvovirus B19. g/kg in association with
Vial with 50 ml (2.5 g), infusion set on request
acetylsalicylic acid
Immunoglobulins have not been associated with hepatitis A Vial with 100 ml (5.0 g), infusion set on request
or
or parvovirus B19 infections possibly because the antibodies 2 g/kg in one dose in association PHARMACOTHERAPEUTIC GROUP
against these infections, which are contained in the product, are with acetylsalicylic acid
protective. Human immunoglobulin
Allogeneic bone marrow
It is strongly recommended that every time you receive a dose of transplantation: INDICATIONS
INTRAGLOBIN F the name and batch number of the product - treatment of infections and 0.5 g/kb every week from day 7 Adjuvant therapy of severe bacterial infections additional to
are recorded in order to maintain a record of the batches used. prophylaxis of graft versus upto 3 months after
antibiotic therapy.
host disease transplantation
EFFECTS ON ABILITY TO DRIVE AND TO USE - Persistent lack of antibody 0.5 g/kg every month until antibody Immunoglobulin substitution in immunocompromized patients.
MACHINES: production levels return to normal CONTRAINDICATIONS
There is no indication that immunoglobulin may impair the ability
ROUTE OF ADMINISTRATION Hypersensitivity to any of the components of the product.
to drive and use machines.
INTRAGLOBIN F should be warmed to room or body Hypersensitivity to homologous immunoglobulins, especially in
INTERACTIONS WITH OTHER DRUGS temperature before administration. very rare cases of IgA deciency, when the patient has antibodies
Live attenuated virus vaccines: INTRAGLOBIN F should be infused intravenously at an initial against IgA.
Immunoglobulin administration may impair for a period of at least rate of not more than 1.4 ml/kg/hr for 10 minutes. PREGNANCY AND LACTATION
6 weeks and up to 3 months the efcacy of live attenuated virus If well tolerated the rate of administration may gradually be
vaccines such as measles, rubella, mumps and varicella. After The safety of this medicinal product for use in human pregnancy
increased to a maximum of 1.9 ml/kg/hr for the remainder of the has not been established in controlled clinical trials and therefore
administration of this product, an interval of 3 months should
infusion. should only be given with caution to pregnant women and breast-
elapse before vaccination with live attenuated virus vaccines. In
the case of measles, this impairment may persist for up to 1 year. OVERDOSE feeding mothers. Clinical experience with immunoglobulins
suggests that no harmful effects on the course of pregnancy, or on
Therefore patients receiving measles vaccine should have their Overdose may lead to uid overload and hyperviscosity,
the foetus and the neonate are to be expected.
antibody status checked. particularly in patients at risk, including elderly patients and
patients with renal impairment. Immunoglobulins are excreted into the milk and may contribute to
Interference with serological testing:
the transfer of protective antibodies to the neonate.
After injection of immunoglobulin the transitory rise of the various UNDESIRABLE EFFECTS SPECIAL PRECAUTIONS FOR USE
passively transferred antibodies in the patients blood may result in Adverse reactions such as chills, headache, fever, vomiting,
misleading positive results in serological testing. Certain severe drug reactions may be related to the rate of infusion.
allergic reactions, nausea, arthralgia, low blood pressure and mild The recommended infusion rate given under Posology and method
Passive transmission of antibodies to erythrocyte antigens, e.g. A, back pain may occur occasionally. of administration must be closely followed as the incidence
B D may interfere with some serological tests for red cell allo-
Rarely immunoglobulins may cause a sudden fall in blood pressure of adverse events tends to increase with the rate of infusion.
antibodies (e.g. Coombs test), reticulocyte count and haptoglobin.
and, in isolated cases, anaphylactic shock, even when the patient Patients must be closely monitored and carefully observed for any
Incompatibilities: has shown no hypersensitivity to previous administration. symptoms of adverse reactions throughout the infusion period.
This medicinal product must not be mixed with other medicinal Cases of reversible aseptic meningitis, isolated cases of reversible Certain adverse reactions may occur more frequently
products. The product is miscible with physiological saline haemolytic anaemia/haemolysis and rare cases of transient - in case of high rate of infusion
solution. No other preparations may be added to the Intraglobin cutaneous reactions, have been observed with human normal
F solution as any change in the electrolyte concentration or the pH - in patients with hypo- or agammaglobulinemia with or without
immunoglobulin. IgA deciency
may result in precipitation or denaturisation of the proteins.
Increase in serum creatinine level and/or acute renal failure have - in patients who receive human normal immunoglobulin
DOSAGE INSTRUCTIONS AND DURATION OF been observed. for the rst time or, in rare cases, when the human normal
ADMINISTRATION Very rarely: Thromboembolic reactions such as myocardial immunoglobulin product is switched or when there has been a
The dose and dosage regimen is dependant on the indication. In infarction, stroke, pulmonary embolism, deep vein thromboses. long interval since the previous infusion
155
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BIOTEST
SPDI
True hypersensitivity reactions are rare. They can occur in the very antibodies (e.g. Coombs test), reticulocyte count and haptoglobin.
seldom cases of lack of IgA with anti-IgA antibodies. Note: PENTAGLOBIN is miscible with physiological saline PLASMA PROTEIN FRACTION
Rarely, human normal immunoglobulin can induce a fall in solution. However, no other preparations must be added to the HUMAN, 5% U.S.P.
blood pressure with anaphylactic reaction, even in patients PENTAGLOBIN solution, as a change in the electrolyte Solution for intravenous infusion
who had tolerated previous treatment with human normal concentration or of the pH value may give rise to precipitation or
immunoglobulin. denaturing of the proteins.
Potential complications can often be avoided by ensuring that (Human Albumin)
DOSAGE INSTRUCTIONS AND MODE OF
- patients are not sensitive to human normal immunoglobulin ADMINISTRATION COMPOSITION
- the product is administered slowly (0.4 ml/kg body weight/ The dosage is dependent on the patient.s immune status and on the 1000 ml solution contain:
hour) severity of the disease. The following dosage suggestions may be
- patients are carefully monitored for any symptoms of adverse - active ingredients:
used as reference:
reactions throughout the infusion period. In particular, patients Human plasma protein 50 g
1. Neonates and infants:
naive to human normal immunoglobulin, patients switched of which albumin at least 83 %
5 ml (0.25 g)/kg body weight daily on three consecutive days. Alpha and beta globulins max. 17 %
from an alternative immunoglobulin product or when there
has been a long interval since the previous infusion should be Further infusions may be required depending on the clinical - excipients:
monitored during the rst infusion and for the rst hour after the course. Caprylate* 0.58 g (4 mmol)
rst infusion, in order to detect potential adverse reactions. All 2. Children and adults: N-Acetyl-DL-tryptophanate* 0.98 g (4 mmol)
other patients should be observed for at least 20 minutes after a) Therapy of severe bacterial infections: 5 ml (0.25 g)/kg body Sodium 3.33 g (145 mmol)
administration weight daily on three consecutive days. Further infusions Chloride 4.96 g ( 140 mmol)
- the glucose content is taken into account in patients with known may be required depending on the clinical course. Water for injections ad 1000 ml
disturbance of glucose metabolism b) Immunoglobulin substitution in immunocompromized *Stabilizer
Cases of acute renal failure have been reported in patients patients: 3 - 5 ml (0.15 - 0.25 g)/kg body weight. Repetition PRESENTATION
receiving intravenous immunoglobulin (IVIg) therapy. In most at weekly intervals if necessary. Solution for intravenous infusion
cases, risk factors have been identied, such as pre-existing Vial with 50 ml (N.R.)
renal insufciency, diabetes mellitus, hypovolemia, overweight, MODE OF ADMINISTRATION
Vial with 250 ml
concomitant nephrotoxic medicinal products or age over 65 The product should be warmed to room or body temperature Vial with 500 ml (N.R.)
years. before use.
PENTAGLOBIN should be infused intravenously at the PHARMACOTHERAPEUTIC GROUP / MODE OF
In all patients the IVIg administration requires
ACTION
- adequate hydration prior to the initiation of the infusion of following rates:
Plasma protein fraction, plasma substitute
IVIg in neonates and infants : 1.7 ml/kg/hour by infusion pump
The most important physiological functions of albumin results
- monitoring of urine output in children and adults : 0.4 ml/kg/hour
from its contribution to oncotic pressure of the blood and transport
- monitoring of serum creatinine level alternatively : the rst 100 ml at 0.4 ml/kg/hour function. Albumin stabilise circulating blood volume and is a
- avoidance of concomitant use of loop diuretics then 0.2 ml/kg/hour continuously carrier of hormones, enzymes, medicinal products and toxins.
until 15 ml/kg is reached within 72 hours
In case of renal impairment the discontinuation of the INDICATIONS
immunoglobulin administration should be considered. Examples Body Total dose Infusion Infusion
weight day 1 rate Duration Restoration and maintenance of circulating blood volume where
While these reports of renal dysfunction and acute renal failure volume deciency has been demonstrated and use of a colloid is
Neonate 3 kg 15 ml 5 ml/h 3h
have been associated with the use of many of the licensed IVIg Child 20 kg 100 ml 8 ml/h 12.5 h appropriate.
products, those containing sucrose as a stabiliser accounted Adult 70 kg 350 ml 28 ml/h 12.5h The choice of albumin rather than articial colloid will depend
for a disproportionate share of the total number. In patients at Alternatively: on the clinical situation of the individual patient, based on ofcial
risk, the use of IVIg products that do not contain sucrose may 28 ml/h 3.5 h initially, then recommendations.
be considered. PENTAGLOBIN does not contain sucrose. In 14 ml/h for 68 continuously
addition, the product should be administered at the minimum CONTRAINDICATIONS
OVERDOSE
infusion rate practicable. Hypersensitivity to albumin preparations or to any of the
Overdose may lead to uid overload and hyperviscosity, excipients.
When medicinal products prepared from human blood or plasma particularly in patients at risk, including elderly patients or patients
are administered, infectious diseases due to transmission of with renal impairment. PREGNANCY AND LACTATION
infective agents cannot be totally excluded. This also applies to The safety of PLASMA PROTEIN FRACTION HUMAN,
pathogens of hitherto unknown nature. The risk of transmission of UNDESIRABLE EFFECTS AND COUNTERMEASURES 5% U.S.P. for use in human pregnancy has not been established
infective agents is however reduced by: Adverse reactions such as chills, headache, fever, nausea and in controlled clinical trials. However, clinical experience
- selection of donors by stringent criteria vomiting, allergic reactions, low blood pressure, arthralgia and with albumin suggests that no harmful effects on the course of
moderate low back pain may occur occasionally. pregnancy, or on the foetus and the neonate are to be expected.
- screening of individual plasma donations and plasma pools for
HBsAg and antibodies to HIV and HCV Rarely human normal immunoglobulins may cause a sudden Experimental animal studies are insufcient to assess the safety
- testing of plasma pools for HCV genomic material fall in blood pressure and, in isolated cases, anaphylactic shock, with respect to reproduction, development of the embryo or foetus,
even when the patient has shown no sensitivity to previous the course of gestation and peri- and postnatal development.
- inactivation/removal procedures included in the production
administration. However, human albumin is a normal constituent of human
process that have been validated using model viruses. These
procedures are considered effective for HIV, HCV, and HBV Cases of reversible aseptic meningitis, isolated cases of reversible blood.
haemolytic anaemia/ haemolysis and rare cases of transient
The viral inactivation/removal procedures may be of limited value SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
cutaneous reactions, have been observed with human normal
against non-enveloped viruses such as HAV and/or Parvovirus FOR USE
immunoglobulin.
B19. If allergic or anaphylactic-type reactions occur, the infusion should
Increase in serum creatinine level and/or acute renal failure have
In the interest of patients, it is recommended that, whenever be stopped immediately and appropriate treatment instituted. In
been observed.
possible, every time that a medicinal product derived from human case of shock, the current medical standards for shock-treatment
Thrombotic events have been reported in the elderly, in patients should be observed.
blood or plasma is administered to them, the name and the batch
with signs of cerebral or cardiac ischemia, and in overweight and
number of the product is registered. Albumin should be used with caution in conditions where
severely hypovolaemic patients.
hypervolaemia and its conse-quences or haemodilution could
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES For information on infection risk see Special precautions for represent a special risk for the patient. Examples of such conditions
There are no indications that immunoglobulins may impair the use are:
ability to drive and use machines. In case of adverse reactions either the rate of administration - Decompensated cardiac insufciency
INTERACTIONS WITH OTHER MEDICAMENTS AND must be reduced or the infusion stopped. The treatment required - Hypertension
depends on the nature and severity of the side effect. - Oesophageal varices
OTHER FORMS OF INTERACTIONS
In case of renal impairment the discontinuation of the - Pulmonary oedema
PENTAGLOBIN should not be administered to infants
immunoglobulin administration should be considered. - Haemorrhagic diathesis
concomitantly with calcium gluconate as the suspicion exists that
adverse reactions may occur after simultaneous administration. In case of shock, the current medical standards for shock treatment - Severe anaemia
should be observed. - Renal and post-renal anuria
Live attenuated vaccines
The patient is recommended to communicate any undesirable If comparatively large volumes are to be replaced, controls of
Immunoglobulin administration may impair for a period of at least
effect not mentioned above to his doctor or pharmacist. coagulation and haematocrit are necessary. Care must be taken
6 weeks and up to 3 months the efcacy of live attenuated virus
vaccines such as measles, rubella, mumps and varicella. After STORAGE AND NOTES FOR THE HANDLING to ensure adequate substitution of other blood constitu-ents
(coagulation factors, electrolytes, platelets and erythrocytes).
administration of this product, an interval of 3 months should Do not use after expiry date indicated on the label and outer
elapse before vaccination with live attenuated virus vaccines. In package. Hypervolaemia may occur if the dosage and rate of infusion
the case of measles, this impairment may persist for up to one year. are not adjusted to the patients circulatory situation. At the rst
Store in the original package at +2 C to +8 C, protected from clinical signs of cardiovascular overload (headache, dysp-noea,
Therefore patients receiving measles vaccine should have their light. Do not freeze.
antibody status checked. jugular vein congestion), or increased blood pressure, raised
PENTAGLOBIN should be inspected visually prior to venous pressure and pulmonary oedema, the infusion is to be
Interference with serological testing (laboratory testing) administration. Do not use solutions which are cloudy or stopped immediately.
After injection of an immunoglobulin the transitory rise of the which have deposits. The slightly opalescence is a property of When medicinal products prepared from human blood or plasma
various passively transferred antibodies in the patients blood may PENTAGLOBIN. are administered, infectious diseases due to transmission of
result in misleading positive results in serological testing. Once a container has been opened, the content should be used infective agents cannot be totally excluded. This applies to
Passive transmission of antibodies to erythrocyte antigens, e.g. A, immediately. Any unused solution must be discarded because of pathogens of hitherto unknown nature. The risk of transmission of
B, and D may interfere with some serological tests for red cell allo- bacterial contamination risk. infective agents is however reduced by:
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BOEHRINGER INGELHEIM
SPDI
- selection of donors by a medical interview and screening Do not use solutions which are cloudy or have deposits. This may about 20% and 35% respectively after 4 hours and increase again
of individual donations and plasma pools for HBsAg and indicate that the protein is unstable or that the solution has become to more than 80% at 24 hours. A marked and prolonged decrease of
antibodies to HIV and HCV. contaminated. the circulating brinogen level is only seen in few patients.
- testing of plasma pools for HCV genomic material. Once the container has been opened, the contents should be used PHARMACOKINETICS:
- inactivation/removal procedures included in the production immediately. ACTILYSE is cleared rapidly from the circulating blood and
process that have been validated using model viruses. This Any unused product should be disposed of in accordance with metabolised mainly by the liver (plasma clearance 550 - 680 ml/
procedures are considered effective for HIV, HCV, HBV and local requirements. min.). The relevant plasma half-life T1/2 alpha is 4 - 5 minutes.
HAV. This means that after 20 minutes less than 10% of the initial
The viral inactivation/removal procedures may be of limited value value is present in the plasma. For the residual amount remaining
against non-enveloped viruses such as parvovirus B19. BOEHRINGER INGELHEIM in a deep compartment, a beta-half-life of about 40 minutes was
P.O.BOX: 68423, RIYADH: 11527 measured.
Albumin manufactured to European Pharmacopoeia specications
by established processes has a reassuring viral safety record. SAUDI ARABIA INDICATIONS:
In the interest of patients, it is recommended that, whenever TEL: 01-419 1637, FAX: 01-460 1755 1. Thrombolytic treatment in acute myocardial infarction.
possible, every time that a me-dicinal product derived from human 90 minutes (accelerated) dose regimen (see Dosage and
blood or plasma is administered to them, the name and the batch administration): For patients in whom treatment can be started
number of the product is registered.
ACTILYSE within 6 h of symptom onset;
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES Powder and solvent for solution for injection 3 hour dose regimen (see Dosage and administration): For
There are no indications that human albumin may impair the patients in whom treatment can be started between 6 - 12 h after
abilities to drive or to operate machines. symptom onset.
(Alteplase) ACTILYSE has proven to reduce 30-day-mortality in patients
INTERACTIONS WITH OTHER MEDICINAL PRODUCTS with acute myocardial infarction.
AND OTHER FORMS OF INTERACTIONS COMPOSITION: 2. Thrombolytic treatment in acute massive pulmonary embolism
No specic interactions of human albumin with other products are ACTILYSE 10 mg: (N.R) with haemodynamic instability. The diagnosis should be
known. 1 vial contains: 10 mg alteplase conrmed whenever possible by objective means such as
DOSAGE INSTRUCTIONS AND MODE OF 1 vial of solvent contains: 10 ml sterile water for injections pulmonary angiography or non-invasive procedures such as
ADMINISTRATION ACTILYSE 20 mg: 1 vial contains: 20 mg alteplase (N.R) lung scanning. There are no clinical trials on mortality and late
1 vial of solvent contains: 20 ml sterile water for injections morbidity related to pulmonary embolism.
The concentration of the albumin preparation, dosage and the
ACTILYSE 50 mg: 3. Thrombolytic treatment of acute ischaemic stroke. Treatment
infusion-rate should be ad-justed to the patients individual
1 vial contains: 50 mg alteplase should only be initiated within 3 hours after the onset of stroke
requirements.
1 vial of solvent contains: 50 ml sterile water for injections symptoms and after exclusion of intracranial haemorrhage by
DOSAGE ACTILYSE 100 mg (N.R): appropriate imaging techniques such as cranial computerized
The dose required depends on the size of the patient, the severity 1 vial contains: 100 mg alteplase tomography (CT).
of trauma or illness and on continuing uid or protein losses. 1 vial of solvent contains: 100 ml sterile water for injections
Measures of adequacy of circulating volume and not plasma CONTRAINDICATIONS:
Excipients: l-arginine, phosphoric acid, polysorbate 80 The
albumin levels should be used to determine the dose required. The following contraindications apply in general:
reconstituted solution contains 1 mg alteplase.
As with all thrombolytic agents, ACTILYSE should not be used
If human albumin is to be administered, haemodynamic in cases where there is a high risk of haemorrhage such as:
PHARMACOLOGICAL PROPERTIES:
performance should be monitored regularly; this may include:
The active ingredient of ACTILYSE is alteplase, a recombinant - Signicant bleeding disorder at present or within the past 6
- arterial blood pressure and pulse rate human tissue-type plasminogen activator, a glycoprotein, which months, known haemorrhagic diathesis
- central venous pressure activates plasminogen directly to plasmin. When administered - Patients receiving oral anticoagulants, e.g. warfarin sodium
- pulmonary artery wedge pressure intravenously, alteplase remains relatively inactive in the (INR >1.3)
- urine output circulatory system. Once bound to brin, it is activated, inducing - any history of central nervous system damage
- electrolyte the conversion of plasminogen to plasmin leading to the dissolution (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
- haemaotcrit / haemoglobin of the brin clot. - History or evidence or suspicion of intracranial haemorrhage
Acute Myocardial Infarction: In a study including more than including subarachnoid haemorrhage
PLASMA PROTEIN FRACTION HUMAN, 5% U.S.P. is
40,000 patients with an acute myocardial infarction (GUSTO) the
suitable for dialysis patients and premature infants. - Severe uncontrolled arterial hypertension
administration of 100 mg ACTILYSE over 90 minutes, with
- Major surgery or signicant trauma in the past 10 days
MODE OF ADMINISTRATION concomitant i.v. heparin infusion, led to a lower mortality after 30
(this includes any trauma associated with the current acute
Plasma PROTEIN FRACTION HUMAN, 5% U.S.P. can be days (6.3%) as compared to the administration of streptokinase,
myocardial infarction), recent trauma to head or cranium -
directly administered by the intravenous route, or it can also be 1.5 million U over 60 minutes, with s.c. or i.v. heparin (7.3%).
Prolonged or traumatic cardiopulmonary resuscitation (> 2
diluted in an isotonic solution (e.g. 0.9 % sodium chloride). ACTILYSE treated patients showed higher infarct related vessel
minutes), obstetrical delivery, within the past 10 days, recent
patency rates at 60 and 90 minutes after thrombolysis than the
The infusion rate should be adjusted according to the individual puncture of a non-compressible bloodvessel (e.g. subclavian or
streptokinase-treated patients. No differences in patency rates
circumstances and the indication. jugular vein puncture)
were noted at 180 minutes or longer. 30-day-mortality is reduced
In plasma exchange the infusion rate should be adjusted to the rate - Severe hepatic dysfunction, including hepatic failure, cirrhosis,
as compared to patients not undergoing thrombolytic therapy.
of removal. portal hypertension (oesophageal varices) and active hepatitis
The release of alpha-hydroxybutyrate-dehydrogenase (HBDH) is
reduced. Global ventricular function as well as regional wall motion - Haemorrhagic retinopathy, e.g. in diabetes (vision disturbances
OVERDOSE
is less impaired as compared to patients receiving no thrombolytic may indicatehaemorrhagic retinopathy) or other haemorrhagic
Hypervolaemia may occur if the dosage and rate of infusion are ophthalmic conditions
too high. At the rst clinical signs of cardiovascular overload therapy. A placebo controlled trial with 100 mg ACTILYSE over
3 hours (LATE) showed a reduction of 30-day-mortality compared - Bacterial endocarditis, pericarditis
(headache, dyspnoea, jugular vein congestion), or in-creased blood - Acute pancreatitis
pressure, raised central venous pressure and pulmonary oedema, to placebo for patients treated within 6 - 12 hours after symptom
onset. In cases, in which clear signs of myocardial infarction are - Documented ulcerative gastro-intestinal disease during the last
the infusion should be stopped immediately and the patients
present, treatment initiated up to 24 hours after symptom onset 3 months
haemodynamic parameters carefully monitored.
may still be benecial. - Arterial aneurysms, arterial/venous malformations
UNDESIRABLE EFFECTS Acute Massive Pulmonary Embolism: In patients with acute - Neoplasm with increased bleeding risk
Mild reactions such as ush, urticaria, fever and nausea occur massive pulmonary embolism with haemodynamic instability - Hypersensitivity to the active substance alteplase or to any of
rarely. Undesirable effects such as shivering, vomiting, erythema, thrombolytic treatment with ACTILYSE leads to a fast reduction the excipients
drop in blood pressure with tachycardia and dyspnoea occurred of the thrombus size and a reduction of pulmonary artery pressure. In the indications of acute myocardial infarction and pulmonary
in single cases. These reactions normally disappear rapidly when Mortality data are not available. embolism the following contraindication applies in addition:
the infusion rate is slowed down or the infusion is stopped. Very - History of stroke In the indication acute ischaemic stroke
Ischaemic stroke:
rarely, severe reactions as far as shock may occur. In these cases, the following contraindications apply in addition
In two US studies (NINDS A/B) a signicant higher proportion of
the infusion should be stopped and an appropriate treatment
patients with ischaemic stroke , when compared to placebo, had - symptoms of ischaemic attack began more than 3 hours prior to
should be initiated.
a favourable outcome (no or minimal disability). These ndings infusion start or when time of symptom onset is unknown
For information on infection risk see Special warnings and were not conrmed in two European studies and an additional USA - symptoms of acute ischaemic stroke that were either rapidly
special precautions for use. study. In the latter studies however, the majority of patients were improving or only minor before start of infusion
The patient is recommended to communicate any undesirable not treated within 3 hours of stroke onset. In a meta-analysis of - severe stroke as assessed clinically (e.g. NIHSS>25) and/or by
effect not mentioned above to his doctor or pharmacist. all patients treated within 3 hours after stroke onset the benecial appropriate imaging techniques
effect of alteplase was conrmed. - seizure at the onset of stroke
STORAGE AND NOTES FOR THE HANDLING
The risk difference versus placebo for a good recovery was 14.9% - history of previous stroke or serious head-trauma
Do not use after expiry date indicated on the label and outer (CI 95% 8.1% to 21.7%) despite an increased risk of severe and
carton. within three months
fatal intracranial haemorrhage. The data do not allow drawing a
Do not store above 25C. Do not freeze. - a combination of previous stroke and diabetes mellitus
denite conclusion on the treatment effect on death. Nevertheless
overall, the benet/risk of alteplase, given within 3 hours of stroke - administration of heparin within 48 hours preceding the onset
Keep the container in the outer carton in order to protect from
onset and taking into account the precautions stated, is considered of stroke with an elevated activated partial thromboplastin time
light.
favourable. A meta-analysis of all clinical data show that, the (aPTT) at presentation
Plasma PROTEIN FRACTION HUMAN, 5% U.S.P. can be - platelet count of less than 100,000 / mm3
directly administered by the intravenous route, or it can also be agent is less effective in patients treated after 3 hours of onset (3
to 6 hours) compared with those treated within 3 hours of onset of - systolic blood pressure > 185 or diastolic blood pressure > 110
diluted in an isotonic solution (e.g. 0.9 % sodium chloride).
symptoms, while the risks were higher, which makes the benet/ mm Hg, or aggressive management (IV medication) necessary
Albumin solutions must not be diluted with water for injections as to reduce blood pressure to these limits
risk ratio of alteplase unfavourable outside the 0 - 3h time frame.
this may cause haemolysis in recipients. - blood glucose < 50 or > 400 mg/dl
Due to its relative brin-specicity, alteplase at a dose of 100 mg
If large volumes are administered, the product should be warmed leads to a modest decrease of the circulating brinogen levels to ACTILYSE is not indicated for the therapy of acute stroke in
to room or body tempera-ture before use. about 60% at 4 hours, which is generally reverted to more than 80% children and adolescents under 18 years or adults over 80 years
The solution should be clear or slightly opalescent. after 24 hours. Plasminogen and alpha-2-antiplasmin decrease to of age.
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SPDI
SIDE EFFECTS: bleeding sites (including those following catheter insertion, haemorrhage and death and should not be treated with
The following adverse events, which may be causally related arterial and venous puncture cutdown and needle puncture). The ACTILYSE. Patients with extensive infarctions are at greater
to the administration of ACTILYSE, have been reported. The use of rigid catheters, intramuscular injections and nonessential risk of poor outcome including severe haemorrhage and death.
most frequent adverse reaction associated with ACTILYSE is handling of the patient should be avoided during treatment with In such patients, the benet/risk ratio should be thoroughly
bleeding resulting in a fall in haematocrit and/or haemoglobin ACTILYSE. considered. In stroke patients the likelihood of a favourable
values. The type of bleeds associated with thrombolytic therapy Should serious bleeding occur, in particular cerebral haemorrhage, outcome decreases with increasing age, increasing stroke severity
can be divided into two broad categories: the brinolytic therapy must be discontinued and concomitant and increased levels of blood glucose on admission while the
- Supercial bleeding, normally from punctures or damaged heparin administration should be terminated immediately. likelihood of severe disability and death or relevant intracranial
blood vessels, Administration of protamine should be considered if heparin has bleeding increases, independently of treatment.
- Internal bleedings into the gastro-intestinal or uro-genital been administered within 4 hours before the onset of bleeding. Patients over 80, patients with severe stroke (as assessed clinically
tract, retro-peritoneum or CNS or bleeding of parenchymatous In the few patients who fail to respond to these conservative and/or by appropriate imaging techniques) and patients with blood
organs. measures, judicious use of transfusion products may be indicated. glucose levels < 50 mg/dl or >400 mg/dl at baseline should not be
Death and permanent disability are reported in patients who have Transfusion of cryoprecipitate, fresh frozen plasma, and platelets treated with ACTILYSE. Reperfusion of the ischaemic area may
experienced stroke (including intracranial bleeding) and other should be considered with clinical and laboratory reassessment induce cerebral oedema in the infarcted zone. Due to an increased
serious bleeding episodes. The frequencies given below are based after each administration. haemorrhagic risk, treatment with platelet aggregation inhibitors
on corresponding occurrences in a clinical trial involving 8,299 A target brinogen level of 1 g/l is desirable with cryoprecipitate should not be initiated within the rst 24 hours following
patients treated with ACTILYSE for myocardial infarction. The infusion. Antibrinolytic agents should also be considered. A dose thrombolysis with alteplase.
classication of cholesterol crystal embolisation, which was not exceeding 100 mg of ACTILYSE should not be given in acute DRUG INTERACTIONS:
observed in the clinical trial population, was based on spontaneous myocardial infarction as well as pulmonary embolism and 90 mg No formal interaction studies with ACTILYSE and medicinal
reporting. The number of patients treated in clinical trials in the in acute ischaemic stroke because it has been associated with an products commonly administered in patients with acute myocardial
indications pulmonary embolism and stroke (within the 0 - 3 hours increase in intracranial bleeding. infarction have been performed.
time window) is very small in comparison to the number in the As yet, there is only limited experience with the use of
trial for myocardial infarction described above. Medicinal products that affect coagulation or those that alter platelet
ACTILYSE in children. No sustained antibody formation to the function may increase the risk of bleeding prior to, during or after
Therefore, small numerical differences observed in comparison recombinant human tissue-type plasminogen activator molecule ACTILYSE therapy.Concomitant treatment with ACE inhibitors
with the number in myocardial infarction were presumably has been observed after treatment. There is no systematic may enhance the risk of suffering an anaphylactoid reaction, as in
attributable to the small sample size. Except for intracranial experience with re-administration of ACTILYSE the cases describing such reactions a relatively larger proportion of
haemorrhage as side effect in the indication stroke as well as for If an anaphylactoid reaction occurs, the infusion should be patients were receiving ACE inhibitors concomitantly.
reperfusion arrhythmias in the indication myocardial infarction discontinued and appropriate treatment should be initiated.
there is no medical reason to assume that the qualitative and Monitoring is recommended particularly for patients receiving INCOMPATIBILITIES:
quantitative side effect prole of ACTILYSE in the indications ACE-inhibitors concomitantly (see Side effects). As with all The reconstituted solution may be diluted further with sterile
pulmonary embolism and acute ischaemic stroke is different from thrombolytics, the use of ACTILYSE therapy has to be carefully physiological saline solution (0.9 %) up to a minimal concentration
the prole in the indication myocardial infarction. of 0.2 mg alteplase per ml.It may not, however, be diluted further
evaluated in order to balance the potential risks of bleeding with
Indication myocardial infarction: expected benets under the following conditions: with water for injections or carbohydrate infusion solutions, e.g.
Cardiac disorders: Very common: reperfusion arrhythmias, Recent intramuscular injection or small recent traumas, such dextrose. ACTILYSE must not be mixed with other drugs,
which can be life threatening and may require the use of as biopsies, puncture of major vessels, cardiac massage for neither in the same infusion-vial nor via the same venous line (not
conventional antiarrhythmic therapies. Indications myocardial resuscitation. even with heparin).
infarction and pulmonary embolism: PREGNANCY AND LACTATION:
Conditions with an increased risk of haemorrhage, which are
Nervous system disorders: Uncommon: intracranial haemorrhage not mentioned under contraindications. There is very limited experience with the use of ACTILYSE
Indication acute ischaemic stroke: during pregnancy and lactation. In cases of an acute life-threatening
For the treatment of acute myocardial infarction and acute
Nervous system disorders: Common: intracranial haemorrhage. pulmonary embolism the following special warnings and disease the benet has to be evaluated against the potential risk. It
Symptomatic intracerebral haemorrhages represent the major precautions apply in addition: is not known if alteplase is excreted into breast milk.
adverse event (up to 10 % of patients). However, this had not
Systolic blood pressure > 160 mm Hg. DOSAGE AND ADMINISTRATION:
shown an increased overall morbidity or mortality. Indications
myocardial infarction, pulmonary embolism and acute Advanced age, which may increase the risk of intracerebral ACTILYSE should be given as soon as possible after symptom
ischaemic stroke: haemorrhage. As the therapeutic benet is also increased in onset.
elderly patients, the risk-benet-evaluation should be carried 1. Myocardial infarction:
Gastro-intestinal disorders: Common: bleeding into gastro-
out carefully.
intestinal tract, nausea, vomiting. Nausea and vomiting can a) 90 minutes (accelerated) dose regimen for patients with
also occur as symptoms of myocardial infarction. Uncommon: For the treatment of acute myocardial infarction the following myocardial infarction, in whom treatment can be started
bleeding into retroperitoneum, gingival bleeding General special warnings and precautions apply in addition: within 6 hours after symptom onset:
disorders and administration site conditions: Very common: Arrhythmias: Coronary thrombolysis may result in arrhythmia 15 mg as an intravenous bolus,
supercial bleeding, normally from punctures or damaged blood associated with reperfusion.
50 mg as an infusion over the rst 30 minutes,
vessels Injury and poisoning and procedural complications: Glyco-ProteinIIb/IIIa antagonists: There is no experience with followed by an infusion of 35 mg over 60 minutes,
Uncommon: anaphylactoid reactions, which are usually mild, the use of GPIIb/IIIa antagonists within the rst 24 hours after
but can be life threatening in isolated cases. They may appear as until the maximal dose of 100 mg.
start of treatment.
rash, urticaria, bronchospasm, angio-oedema, hypotension, shock In patients with a body weight below 65 kg the total dose
Thrombo-embolism: The use of thrombolytics can increase
or any other symptom associated with allergic reactions. If they should be weight adjusted With 15 mg as an intravenous
the risk of thrombo-embolic events in patients with left heart
occur, conventional anti-allergic therapy should be initiated. In bolus, and 0.75 mg/kg body weight over 30 minutes
thrombus, e.g., mitral stenosis or atrial brillation.
such cases a relatively larger proportion of patients were receiving (maximum 50 mg), followed by an infusion of 0.5 mg/kg
concomitant Angiotensin Converting Enzymes inhibitors. For the treatment of acute stroke the following special over 60 minutes (maximum 35 mg).
warnings and precautions apply in addition: Treatment must b) 3 h dose regimen for patients, in whom treatment can be
No denite anaphylactic (IgE mediated) reactions to ACTILYSE
be performed only by a physician trained and experienced in started between 6 and 12 hours after symptom onset:
are known. Transient antibody formation to ACTILYSE has been
neurological care. Compared to other indications patients with
observed in rare cases and with low titres, but a clinical relevance 10 mg as an intravenous bolus,
acute ischaemic stroke treated with ACTILYSE have a markedly
of this nding could not be established. Rare: cholesterol crystal 50 mg as an intravenous infusion over the rst hour,
increased risk of intracranial haemorrhage as the bleeding occurs
embolisation, which may lead to corresponding consequences in followed by infusions of 10 mg over 30 minutes,
predominantly into the infarcted area. This applies in particular in
the organs concerned. until the maximal dose of 100 mg over 3 hours.
the following cases:
Investigations: Very common: drop in blood pressure Common: In patients with a body weight below 65 kg the total dose
- All situations listed in section Contraindications and in general
increased temperature should not exceed 1.5 mg/kg. The accepted maximum dose
all situations involving a high risk of haemorrhage
Reproductive system and breast disorders: Common: bleeding - Small asymptomatic aneurysms of the cerebral vessels in acute myocardial infarction is 100 mg alteplase.
into urogenital tract
- Patients pre-treated with acetyl salicylic acid (ASA) may ADJUNCTIVE THERAPY:
Respiratory, thoracic and mediastinal disorders: Common: have a greater risk of intracerebral haemorrhage, particularly Acetylsalicylic acid should be initiated as soon as possible
epistaxis if ACTILYSE treatment is delayed. Not more than 0.9 mg after symptom onset and continued for the rst months after
Surgical and medical procedures: Common: blood transfusion alteplase/kg bodyweight (max. of 90 mg) should be administered myocardial infarction. The recommended dose is 160 - 300 mg/
necessary in view of the increased risk of cerebral haemorrhage. d. Heparin should be administered concomitantly for 24 hours
Vascular disorders: Common: ecchymosis Uncommon: Treatment should not be initiated later than 3 hours after the onset or longer (at least 48 hours with the accelerated dose regimen).
thrombotic embolisation, which may lead to corresponding of symptoms because of unfavourable benet/risk ratio mainly It is recommended to start with an initial intravenous bolus of
consequences in the organs concerned based on the following: 5,000 units prior to thrombolytic therapy and to continue with
Rare: bleeding of parenchymatous organs - Positive treatment effects decrease over time an infusion of 1,000 units/hour.
Special warnings and precautions ACTILYSE should be used - Particularly in patients with prior ASA treatment the mortality The dose of heparin should be adjusted according to repeated
by physicians experienced in the use of thrombolytic treatment and rate increases measurements of aPTT values of 1.5 to 2.5 folds of the initial
with the facilities to monitor that use. As with other thrombolytics, value.
- Increased risk of symptomatic haemorrhage.
it is recommended that when ACTILYSE is administered Blood pressure (BP) monitoring during treatment administration 2. Pulmonary embolism
standard resuscitation equipment and medication be available in and up to 24 hours is necessary; i.v. antihypertensive therapy A total dose of 100 mg should be administered in 2 hours. The
all circumstances. is recommended if systolic BP > 180 mm Hg or diastolic BP > most experience available is with the following dose regimen:
The following special precautions apply in general: 105 mm Hg. The therapeutic benet is reduced in patients who - 10 mg as an intravenous bolus over 1 - 2 minutes,
Bleeding: have had a prior stroke or in whom uncontrolled diabetes exists. - 90 mg as an intravenous infusion over two hours.
The most common complication encountered during ACTILYSE The benet/risk ratio is considered less favourable, although still
The total dose should not exceed 1.5 mg/kg in patients with a
therapy is bleeding. The concomitant use of heparin anticoagulation positive in these patients.
body weight below 65 kg.
may contribute to bleeding. As brin is lysed during ACTILYSE In patients with very mild stroke, the risks outweigh the expected
therapy, bleeding from recent puncture sites may occur. Therefore, benet and they should not be treated with ACTILYSE. ADJUNCTIVE THERAPY:
thrombolytic therapy requires careful attention to all possible Patients with very severe stroke are at higher risk of intracerebral After treatment with ACTILYSE heparin therapy should be
158
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SPDI
initiated (or resumed) when aPTT values are less than twice reversible bronchospasm. It is postulated that betaadrenergic AVAILABILITY:
the upper limit of normal. The infusion should be adjusted agonists produce many of their pharmacological effects by Syrup
according to aPTT values of 1.5 to 2.5 fold of the initial value. activation of adenylcyclase, the enzyme that catalizes the
conversion of adenosine triphosphate to cyclic adenosine STORAGE INSTRUCTIONS
3. Ischaemic stroke
monophosphate. With ALUPENT it was possible to inhibit the Store in a safe place out of the reach of children.
The recommended dose is 0.9 mg/kg (maximum of 90 mg)
antigen-induced histamine release both in vitro in human lung
infused over 60 minutes with 10% of the total dose administered
tissue and in isolated mast cells. Furthermore, an increase in the
as an initial intravenous bolus. Therapy should be initiated as
rate of ciliary movement is known for beta-adrenergic agonists.
ATROVENT 20 mcg Metered Aerosol
early as possible within 3 hours after onset of symptoms.
This enhances mucociliary clearance, a phenomenon that has also
ADJUNCTIVE THERAPY: been described for ALUPENT [Ipratropium Bromide & HFA (Hydrouo-
The safety and efcacy of this regimen with concomitant ralkane) 134a]
INDICATIONS:
administration of heparin and acetylsalicylic acid during the
rst 24 hours after the symptom-onset has not been investigated ALUPENT is indicated as a bronchodilator for bronchial asthma
and reversible bronchospasm which may occur in association with COMPOSITION:
sufciently. Therefore, administration of acetylsalicylic acid
or intravenous heparin should be avoided in the rst 24 hours bronchititis and pulmonary emphysema, including bronchospasm 1 metered dose (puff) contains 0.021 mg (8r)-3-hydroxy-8-
after treatment with ACTILYSE. If heparin is required for due to the use of beta-blocking agents. Digitalis-related bradycardia, isopropyl-1H,5H-tropanium bromide ()-tropate monohydrate
other indications (e.g. prevention of deep vein thrombosis) when pacemaker therapy is not indicated or available. (= Ipratropium bromide) corresponding to 0.020 mg ipratropium
the dose should not exceed 10.000 IU per day, administered bromide anhydrous Propellant: 1,1,1,2-Tetrauoroethane (HFA
CONTRAINDICATIONS: [hydrouoralkane] 134a) Other excipients: citric acid anhydrous,
subcutaneously.
Hypertrophic obstructive cardiomyopathy, tachyarrhythmia. puried water, ethanol absolute, Nitrogen as inert gas.
INSTRUCTIONS FOR USE/HANDLING: Hypersensitivity to the active ingredient or other components of
Under aseptic conditions the contents of an injection vial of the product. PHARMACOLOGICAL PROPERTIES:
ACTILYSE (10 or 20 or 50 mg) dry substance is dissolved with Trials with treatment duration of up to three months involving
DRUG INTERACTIONS: adult asthmatics and COPD patients, and asthmatic children, in
water for injection according to the following table to obtain a nal
concentration of 1 mg alteplase per ml. Beta-adrenergics, anticholinergics and xanthine derivatives (such which the HFA formulation and the CFC formulation have been
as theophylline) may enhance the effect of ALUPENT. The compared have shown the two formulations to be therapeutically
ACTILYSE
concurrent administration of other beta-mimetics, systemically equivalent. ATROVENT is a quaternary ammonium compound
vial 10 mg 20 mg 50 mg 100 mg
absorbed anticholinergics and xanthine derivatives (e.g. with anticholinergic (parasympatholytic) properties. In preclinical
Volume of water for injections to be added to dry substance theophylline) may increase the side effects. A potentially serious studies, it appears to inhibit vagally mediated reexes by
Final concentration: reduction in bronchodilatation may occur during concurrent antagonising the action of acetylcholine, the transmitter agent
1 mg alteplase / ml 10 ml 2 0 ml 50 ml 2 x 50 ml administration of beta-blockers.Beta-adrenergic agonists should released from the vagus nerve. Anticholinergics prevent the increase
be administered with caution to patients being treated with in intracellular concentration of cyclic guanosine monophosphate
Thus, for reconstitution to the nal concentration of 1 mg alteplase/ monoamine oxidase inhibitors or tricyclic antidepressants, since (cyclic GMP) caused by interaction of acetylcholine with the
ml the full volume of solvent provided should be transferred to the the action of beta adrenergic agonists may be enhanced. Inhalation muscarinic receptor on bronchial smooth muscle.
vial containing the ACTILYSE dry substance. For this purpose
of halogenated hydrocarbon anaesthetics such as halothane, The bronchodilation following inhalation of ATROVENT is
a transfer cannula is included with the pack-sizes of 20 mg and
trichloroethylene and enurane may increase the susceptibility to induced by local drug concentrations sufcient for anticholinergic
50mg and 2 transfer cannulas with the pack-size of 100mg. For the
the cardiovascular effects of beta-agonists. efcacy at the bronchial smooth muscle and not by systemic
pack-size of 10mg a syringe should be used.
drug concentrations. In controlled 90 day studies in patients with
The reconstituted solution should then be administered PREGNANCY AND LACTATION:
bronchospasm associated with chronic obstructive pulmonary
intravenously as described above. The reconstituted solution may In some preclinical studies at doses corresponding to 640 times disease (chronic bronchitis and emphysema) signicant
be diluted further with sterile physiological saline solution (0.9 %) the maximum recommended dose, orciprenaline has shown the improvements in pulmonary function (FEV1 and FEF25-75%
up to a minimal concentration of 0.2 mg alteplase per ml. It may potential to cause fetal abnormalities. The signicance to humans increases of 15% or more) occurred within 15 minutes, reached
not, however, be diluted with water for injections or carbohydrate is not known. There is no well documented experience in pregnant a peak in 1-2 hours, and persisted in the majority of patients
infusion solutions, e.g. dextrose. ACTILYSE must not be mixed women. ALUPENT should only be used during pregnancy,
with other drugs, neither in the same infusion-vial nor via the same for up to 6 hours. In controlled 90 day studies in patients with
especially during the rst trimester, if the potential benet bronchospasm associated with asthma, signicant improvements
venous line (not even with heparin). outweighs the potential risk to the fetus. The inhibitory effect of in pulmonary function (FEV1 increases of 15% or more) occurred
OVERDOSE ALUPENT on uterine contraction should be taken into account. in 40% of the patients. Preclinical and clinical evidence suggest no
The relative brin specicity notwithstanding, a clinical signicant It is not known whether ALUPENT is excreted in human milk; deleterious effect of ATROVENT on airway mucous secretion,
reduction in brinogen and other blood coagulation components therefore, ALUPENT should be used during nursing only if the mucociliary clearance or gas exchange.
may occur after overdose. In most cases, it is sufcient to await the potential benet justies the possible risk to the newborn.
physiological regeneration of these factors after the ACTILYSE INDICATIONS:
SIDE EFFECTS:
therapy has been terminated. If, however, severe bleeding results, Atrovent metered aerosol is indicated as a bronchodilator for
Frequent undesirable effects of ALUPENT are ne tremor maintenance treatment of bronchospasm associated with chronic
the infusion of fresh frozen plasma or fresh blood is recommended
of skeletal muscles and nervousness, headache, dizziness, obstructive pulmonary disease, including chronic bronchitis,
and if necessary, synthetic antibrinolytics may be administered.
tachycardia and palpitations. Potentially serious hypokalaemia emphysema and asthma.
SPECIAL PRECAUTIONS FOR STORAGE may result from beta2-agonist therapy. As with use of other
Protect the lyophilised substance from light. Store below 25C inhalation therapy, cough, local irritation and less common, CONTRAINDICATIONS:
Reconstituted solution paradoxical bronchoconstriction have been reported. As with Atrovent should not be taken by patients with known
other beta-mimectis, nausea, vomiting, sweating, weakness and hypersensitivity to atropine or its derivatives or to any other
The prepared solution may be stored in a refrigerator up to 24
myalgia/muscle cramps may occur. component of the product.
hours and up to 8 hours at temperatures not exceeding 25C.
From a microbiological point of view, the product should be used In rare cases decrease in diastolic blood pressure, increase in
SPECIAL WARNINGS AND PRECAUTIONS:
immediately after reconstitution. If not used immediately, in-use systolic blood pressure, arrhythmias, particularly after higher
doses, may occur. In rare cases skin reactions or allergic reactions When using the new formulation of Atrovent for the rst time,
storage times and conditions prior to use are the responsibility
have been reported, especially in hypersensitive patients. There some patients may notice that the taste is slightly different from that
of the user and would normally not be longer than 24 hours at
2 8C. have been isolated cases of anaphylactic or anaphylactoid of the CFC (chlorouorocarbon) containing formulation. Patients
reactions. In individual cases psychological alterations have been should be made aware of this when changing from one formulation
AVAILABILITY reported under inhalational therapy with beta-mimetics. to the other. They should also be told that the formulations have
Pack with 1 vial containing 10 mg of the active ingredient and 1 been shown to be interchangeable for all practical purposes and that
vial with 10 ml water for injections (N.R) DOSAGE AND ADMINISTRATION: the difference in taste has no consequences in terms of the safety or
Pack with 1 vial containing 20 mg of the active ingredient and 1 The dosage should be adapted to individual requirements. Unless the efcacy of the new formulation. Atrovent should be used with
vial with 20 ml water for injections (N.R) otherwise prescribed by the physician, the following doses are caution in patients predisposed to narrowangle glaucoma, or with
Pack with 1 vial containing 50 mg of the active ingredient and 1 recommended: prostatic hyperplasia or bladder-neck obstruction.
vial with 50 ml water for injections (N.R) In bronchial asthma and reversible bronchospasm Patients with cystic brosis may be more prone to gastro-intestinal
Pack with 1 vial containing 100 mg of the active ingredient and 1 Syrup (sugar-free) (5 ml = 1 teasp. = 10 mg): motility disturbances. Immediate hypersensitivity reactions may
vial with 100 ml water for injections (N.R) Adults and children over the age of 9: occur after administration of ATROVENT, as demonstrated
Treatment-set containing 2 packs Actilyse 50mg with 50 ml water 1 - 2 teaspoonful 4 times daily by rare cases of urticaria, angio-oedema, rash, bronchospasm;
for injections. Children 6 - 9 years: 1 teaspoonful 4 times daily oropharyngeal oedema and anaphylaxis.
Children under 6 years: 1/2 - 1 teaspoonful 4 times daily OCULAR COMPLICATIONS:
ALUPENT Sugar Free Syrup OVERDOSAGE: There have been isolated reports of ocular complications (i.e.
Symptoms mydriasis, increased intraocular pressure, narrow-angle glaucoma,
The expected symptoms with overdosage are those of excessive eye pain) when aerosolised ipratropium bromide either alone or
(Orciprenaline Sulfate) in combination with an adrenergic beta2-agonist, has come in
beta-adrenergic-stimulation, including exaggeration of the known
pharmacologic effects, i.e. any of the symptoms listed under side contact with the eyes. Thus patients must be instructed in the
COMPOSITION correct administration of Atrovent metered aerosol. Eye pain
effects, the most prominent being tachycardia, palpitation, tremor,
5 ml syrup (sugar-free) contains 10.0 mg 1-(3,5-dihydroxyphenyl)- or discomfort, blurred vision, visual halos or coloured images
hypertension, hypotension, widening of the pulse pressure, anginal
2-isopropylaminoethanol sulfate (= orciprenaline sulfate) in association with red eyes from conjunctival congestion and
pain, arrhythmias and ushing.
excipients: corneal oedema may be signs of acute narrow-angle glaucoma.
Therapy:
syrup: edetic acid, glycerol, hydrochloric acid, Should any combination of these symptoms develop, treatment
Administration of sedatives, tranquilizers, in severe cases intensive with miotic drops should be initiated and specialist advice sought
hydroxyethylcellulose, methyl parahydroxybenzoate, propyl
parahydroxybenzoate, sorbitol, woodruff avour, water therapy. Beta-receptor blockers, preferably beta1-selective, are immediately.
suitable as specic antidotes; however, a possible increase in
PHARMACOLOGICAL PROPERTIES: bronchial obstruction must be taken into account and the dose INTERACTIONS:
ALUPENT is a beta-adrenergic agonist bronchodilator. When should be adjusted carefully in patients suffering from bronchial Beta-adrenergics and xanthine preparations may intensify the
administered orally or by inhalation, ALUPENT decreases asthma. bronchodilatory effect. The therapeutic effect and adverse
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SPDI
effects of Atrovent N Metered Dose Inhaler may become more (g. 2) Patients must be instructed in the correct administration of
pronounced if other anticholinergic medications, such as those ATROVENT solution for inhalation. Care must be taken not to
containing pirenzepine, are given concomitantly. allow the solution or mist into the eyes. It is recommended that
the nebulized solution be administered via a mouth piece. If this
PREGNANCY AND LACTATION:
is not available and a nebulizer mask is used, it must t properly.
The safety of Atrovent during human pregnancy has not been Patients who may be predisposed to glaucoma should be warned
established. The benets of using ATROVENT during a specically to protect their eyes. ATROVENT should be used
conrmed or suspected pregnancy must be weighed against with caution in patients predisposed to narrow-angle glaucoma, or
possible hazards to the unborn child. Preclinical studies have with prostatic hypertrophy or bladder-neck obstruction.
shown no embryotoxic or teratogenic effects following inhalation The mouthpiece should always be kept clean and can be washed
Patients with cystic brosis may be more prone to gastro-intestinal
or intranasal application at doses considerably higher than those with warm water. If soap or detergent is used, the mouthpiece
motility disturbances. Immediate hypersensitivity reactions
recommended in man. should be thoroughly rinsed in clear water.
may occur after administration of ATROVENT solution for
It is not known whether Atrovent is excreted into breast milk. WARNING: inhalation, as demonstrated by rare cases of urticaria, angioedema,
Although lipid-insoluble quaternary cations pass into breast The plastic mouthpiece has been specially designed for use with rash, bronchospasm and oropharyngeal edema.
milk, it is unlikely that ATROVENT would reach the infant to ATROVENT metered aerosol to ensure that you always get the
DRUG INTERACTIONS:
an important extent, when administered by inhalation. However, right amount of the medicine. The mouthpiece must never be used
because many drugs are excreted into breast milk, caution should with any other metered aerosol nor must the Atrovent metered Beta-adrenergics and xanthine preparations may intensify the
be exercised when ATROVENT is administered to nursing aerosol be used with any mouthpiece other than the one supplied bronchodilatory effect. ATROVENT has been used with other
mothers. with the product. The container is under pressure and should by drugs commonly used in the treatment of reversible airways
no account be opened by force or exposed to temperatures above obstruction, including sympathomimetic bronchodilators,
SIDE EFFECTS: 50C. methylxanthines, steroids and disodium cromoglycate without
The most frequent non-respiratory adverse events reported in evidence of deleterious medical interactions. ATROVENT
clinical trials were gastro-intestinal motility disorders (e.g. OVERDOSE: and disodium cromoglycate inhalation solutions should not be
constipation, diarrhoea and vomiting), dryness of the mouth No symptoms specic to overdose have been encountered. In simultaneously administered in the same nebulizer as precipitation
and headache. Further, the following side effects have been view of the wide therapeutic range and topical administration may occur.
observed with ATROVENT: increased heart rate, palpitations, of ATROVENT, no serious anticholinergic symptoms are to
be expected. Minor systemic manifestations of anticholinergic PREGNANCY AND LACTATION:
supraventricular tachycardia and atrial brillation, ocular
accommodation disturbances, nausea, urinary retention and action, including dry mouth, visual accommodation disturbances Although preclinical studies have shown no hazard, safety during
and increase of heart rate may occur. human pregnancy is not established. The usual precautions
dizziness.
regarding the use of drugs in pregnancy, especially during the
These side effects have been reversible. The risk of urinary AVAILABILITY:
rst trimester should be observed. It is not known whether
retention may be increased in patients with pre-existing outow Metered aerosol ATROVENT is excreted in breast milk. Although lipid-insoluble
tract obstruction. Ocular side effects have been reported (see: quaternary bases pass into breast milk, it is unlikely that Atrovent
STORAGE INSTRUCTIONS
Special warnings and precautions). As with other inhaled therapy would reach the infant to an important extent, especially when
including bronchodilators cough, local irritation and, inhalation Store below 30 C. Store in a safe place out of the reach of
children! taken by inhalation solution. However, because many drugs
induced bronchoconstriction have been observed. Allergic-type are excreted in breast milk, caution should be exercised when
reactions such as skin rash, pruritis, angio-oedema of the tongue, Do not take the medicine after the expiry date printed on the
ATROVENT is administered to a nursing woman.
lips and face, urticaria (including giant urticaria), laryngospasm pack.
and anaphylactic reactions may occur. SIDE EFFECTS:
DOSAGE: ATROVENT 250 mcg Unit Dose Vials The most frequent non-respiratory adverse events in clinical trials
were headache, nausea and dryness of the mouth. Because of the
The dosage should be adapted to the individual requirements. Solution for Inhalation low systemic absorption of ATROVENT (ipratropium bromide),
Unless otherwise prescribed, the following dosages are anticholinergic side effects, such as tachycardia and palpitations,
recommended for adults and school children: 2 metered doses ocular accomodation disturbances, gastro-intestinal motility
(Ipratropium Bromide)
(puffs) 4 times daily. Since a requirement for increasing doses disturbances and urinary retention are rare and reversible, although
suggests that additional therapeutic modalities may be needed, a COMPOSITION: the risk of urinary retention may be increased in patients with pre-
total daily dose of 12 puffs should generally not be exceeded. existing outow tract obstruction. Ocular side effects have been
1 unit dose vial (2 ml) solution for inhalation contains 261 mcg
If therapy does not produce a signicant improvement or if the (8r)-3-hydroxy-8-isopropyl-1H,5H-tropanium bromide ()- reported (see: Special Precautions). As with other inhaled therapy
patients condition gets worse, medical advice must be sought in tropate monohydrate (= ipratropium bromide) corresponding to 250 including bronchodilators, cough, and, less common, paradoxical
order to determine a new plan of treatment. In the case of acute mcg ipratropium bromide anhydrous excipients: sodiumchloride, bronchoconstriction has been observed.
or rapidly worsening dyspnoea (difculty in breathing) a doctor hydrochloric acid DOSAGE & ADMINISTRATION:
should be consulted immediately.
PHARMACOLOGICAL PROPERTIES: The dosage should be adapted to the individual requirements of
For acute exacerbations of chronic obstructive airways disease the patient; patients should also be kept under medical supervision
ATROVENT is a quaternary ammonium compound with
treatment with ATROVENT inhalation solution or unit dose during treatment. Unless otherwise prescribed, the following doses
anticholinergic (parasympatholytic) properties. In preclinical
vials may be indicated. Because of insufcient information in are recommended:
studies, it appears to inhibit vagally mediated reexes by
children Atrovent metered aerosol should only be used on medical antagonizing the action of acetylcholine, the transmitter agent Children 6 - 12 Years:
advice and under the supervision of an adult. released from the vagus nerve. Anticholinergics prevent the increase 1 unit dose vial; repeated doses can be administered until the
ADMINISTRATION: in intracellular concentration of cyclic guanosine monophosphate
patient is stable. The time interval between the doses may be
(cyclic GMP) caused by interaction of acetylcholine with the
The correct administration of the metered aerosol is essential for determined by the physician. ATROVENT can be administered
muscarinic receptor on bronchial smooth muscle.
successful therapy. Depress the valve twice before the apparatus combined with an inhaled beta-agonist.
is used for the rst time. The bronchodilation following inhalation of ATROVENT
Children Under 6 Years Of Age:
is primarily a local, site-specic effect, not a systemic one.
Before each use the following rules should be observed: Preclinical and clinical evidence suggest no deleterious effect of Because there is limited information in this age group the following
1. Remove protective cap. ATROVENT on airway mucous secretion, mucociliary clearance dose recommendation should be given under medical supervision:
(g. 1) or gas exchange. The bronchodilator effect of ATROVENT in 1 unit dose vial; repeated doses can be administered until the
the treatment of acute bronchospasm associated with asthma has patient is stable. The time interval between the doses may be
been shown in studies in children over 6 years of age. In most determined by the physician. ATROVENT can be administered
of these studies ATROVENT was administered in combination combined with an inhaled beta-agonist.
with an inhaled beta-agonist. Although the data are limited, The unit dose vials of 2 ml are to be diluted with physiological
ATROVENT has been shown to have a therapeutic effect in the saline up to a nal volume of 2 - 4 ml or may be combined with
2. Breathe out deeply. treatment of bronchospasm associated with viral bronchiolitis and Berotec solution for inhalation. Daily doses exceeding 1 mg in
3. Hold the metered aerosol as shown in g. 1, and close lips bronchopulmonary dysplasia in infants and very small children. children under 12 years of age should be given under medical
over the mouthpiece. The arrow and the base of the container INDICATIONS: supervision. It is advisable not to greatly exceed the recommended
should be pointing upwards. daily dose.
ATROVENT is indicated, when used concomitantly with inhaled
4. Breathe in as deeply as possible, pressing the base of the beta-agonists in the treatment of reversible airways obstruction as If therapy does not produce a signicant improvement or if the
container rmly at the same time, this releases one metered in acute and chronic asthma. patient`s condition gets worse, medical advice must be sought in
dose. Hold the breath for a few seconds, then remove the order to determine a new plan of treatment. In the case of acute
mouthpiece and breathe out. The same action should be repeated CONTRAINDICATIONS:
or rapidly worsening dyspnea (difculty in breathing) a doctor
for a second inhalation. ATROVENT is contraindicated in patients with known
should be consulted immediately. ATROVENT solution for
hypersensitivity to atropine or its derivatives or to any other
5. Replace the protective cap after use. inhalation can be administered using a range of commercially
component of the product.
6. After not using the metered aerosol for three days the valve has available nebulising devices.
to be actuated once. SPECIAL PRECAUTIONS: Where wall oxygen is available the solution is best admininistered
The container is not transparent. It is not therefore possible to see Ocular complications at a ow rate of 6 - 8 litres per minute. ATROVENT solution
when it is empty. The aerosol will deliver 200 doses. When these There have been isolated reports of ocular complications (i.e. for inhalaltion is suitable for concurrent inhalation with the
have all been used the aerosol may still appear to contain a small mydriasis, increased intraocular pressure, angle-closure glaucoma, secretomucolytics Mucosolvan solution for inhalation and
amount of uid. The aerosol should, however, be replaced because eye pain) when aerosolized ipratropium bromide either alone or in Bisolvon solution for inhalation, and Berotec solutions for
you may not get the right amount of treatment. The amount of combination with an adrenergic beta2-agonist, has escaped into inhalation.
treatment in your aerosol can be checked as follows: the eyes. Eye pain or discomfort, blurred vision, visual halos or
colored images in association with red eyes from conjunctival and INSTRUCTIONS FOR USE:
Remove the aerosol from the plastic mouthpiece and put the The unit dose vials are intended only for inhalation with suitable
corneal congestion may be signs of acute angle-closure glaucoma.
aerosol into a container of water. nebulising devices and should not be taken orally.
Should any combination of these symptoms develop, treatment
The contents of the aerosol can be estimated by observing its with miotic drops should be initiated and specialist advice sought 1. Prepare the nebuliser for lling, according to the instructions
position in the water (see g. 2) immediately. provided by the manufacturer or doctor.
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SPDI
2. Tear one unit dose vial from the strip. CONTRAINDICATIONS: range of commercially available nebulising devices. Where wall
ATROVENT is contraindicated in patients with known oxygen is available the solution is best admininistered at a ow
hypersensitivity to atropine or its derivatives or to any other rate of 6 - 8 litres per minute. ATROVENT inhalation solution
component of the product. is suitable for concurrent inhalation with the secretomucolytics
Mucosolvan inhalation solution and Bisolvon inhalation
SPECIAL PRECAUTIONS solution, and Berotec inhalation solutions.
Ocular complications
3. Open the unit dose vial by rmly twisting the top. INSTRUCTIONS FOR USE
There have been isolated reports of ocular complications (i.e.
4. Squeeze the content of the unit dose vial into the nebuliser The unit dose vials are intended only for inhalation with suitable
mydriasis, increased intraocular pressure, angle-closure glaucoma,
reservoir. nebulising devices and should not be taken orally.
eye pain) when aerosolized ipratropium bromide either alone or in
combination with an adrenergic beta2-agonist, has escaped into 1. Prepare the nebuliser for lling, according instructions provided
the eyes. Eye pain or discomfort, blurred vision, visual halos or by the manufacturer or doctor.
colored images in association with red eyes from conjunctival and 2. Tear one unit dose vial from the strip.
corneal congestion may be signs of acute angle-closure glaucoma.
Should any combination of these symptoms develop, treatment
5. Assemble the nebuliser and use as directed. with miotic drops should be initiated and specialist advice sought
6. After use throw away any solution left in the reservoir and clean immediately.
the nebuliser, following the manufacturers instructions. Patients must be instructed in the correct administration of
ATROVENT inhalation solution. Care must be taken not to
allow the solution or mist into the eyes. It is recommended that 3. Open the unit dose vial by rmly twisting the top.
the nebulized solution be administered via a mouth piece. If this 4. Squeeze the content of the unit dose vial into the nebuliser
is not available and a nebulizer mask is used, it must t properly. reservoir.
Patients who may be predisposed to glaucoma should be warned
specically to protect their eyes.
Since the unit dose vials contain no preservative, it is important ATROVENT should be used with caution in patients predisposed
that the contents are used soon after opening and that a fresh vial to narrow-angle glaucoma, or with prostatic hypertrophy or
is used for each administration to avoid microbial contamination. bladder-neck obstruction. Patients with cystic brosis may be
Partly used, opened or damaged unit dose vials should be more prone to gastro-intestinal motility disturbances. Immediate
discarded. hypersensitivity reactions may occur after administration of 5. Assemble the nebuliser and use as directed.
ATROVENT inhalation solution, as demonstrated by rare cases 6. After use throw away any solution left in the reservoir and clean
OVERDOSAGE:
of urticaria, angioedema, rash, bronchospasm and oropharyngeal the nebuliser, following the manufacturers instructions.
No symptoms specic to overdosage have been encountered. In edema.
view of the wide therapeutic range and topical administration of
ATROVENT solution for inhalation, no serious anticholinergic DRUG INTERACTIONS:
symptoms are to be expected. Minor systemic manifestations of Beta-adrenergics and xanthine preparations may intensify the
anticholinergic action, including dry mouth, visual accommodation bronchodilatory effect. ATROVENT has been concomitantly
disturbances and tachycardia may occur. used with other drugs commonly used in the treatment of chronic
obstructive pulmonary disease, including sympathomimetic
AVAILABILITY: bronchodilators, methylxanthines, steroids and disodium Since the unit dose vials contain no preservative, it is important
Solution for inhalation in unit dose vials cromoglycate without evidence of deleterious medical interactions. that the contents are used soon after opening and that a fresh vial
ATROVENT and disodium cromoglycate inhalation solutions is used for each administration to avoid microbial contamination.
STORAGE INSTRUCTIONS Partly used, opened or damaged unit dose vials should be
should not be simultaneously administered in the same nebulizer
Store in a safe place below 30oC. as precipitation may occur. discarded.
Store in a safe place out of the reach of children!
PREGNANCY AND LACTATION: OVERDOSAGE:
Do not take the medicine after the expiry date printed on the
pack. Although preclinical studies have shown no hazard, safety during No symptoms specic to overdosage have been encountered. In
human pregnancy is not established. The usual precautions regarding view of the wide therapeutic range and topical administration of
the use of drugs in pregnancy, especially during the rst trimester ATROVENT inhalation solution, no serious anticholinergic
ATROVENT 500 mcg Unit Dose Vials should be observed. It is not known whether ATROVENT is symptoms are to be expected. Minor systemic manifestations of
Solution for Inhalation excreted in breast milk. Although lipid-insoluble quaternary bases anticholinergic action, including dry mouth, visual accommodation
pass into breast milk, it is unlikely that ATROVENT would disturbances and tachycardia may occur.
reach the infant to an important extent, especially when taken by
(Ipratropium Bromide) inhalation solution. However, because many drugs are excreted in AVAILABILITY:
breast milk, caution should be exercised when ATROVENT is Solution for inhalation in unit dose vials
COMPOSITION: administered to a nursing woman.
STORAGE INSTRUCTIONS
1 unit dose vial (2 ml) solution for inhalation contains 522 mcg SIDE EFFECTS: Store in a safe place below 30 C.
(8r)-3-hydroxy-8-isopropyl-1H,5H-tropanium bromide ()-
The most frequently non-respiratory adverse events in clinical Store in a safe place out of the reach of children!
tropate monohydrate (= ipratropium bromide) corresponding to
trials were headache, nausea and dryness of the mouth. Because Do not take the medicine after the expiry date printed on the
500 mcg ipratropium bromide anhydrous
of the low systemic absorption of ATROVENT (ipratropium pack.
excipients: sodiumchloride, hydrochloric acid bromide), anticholinergic side effects, such as tachycardia and
palpitations, ocular accomodation disturbances, gastro-intestinal
motility disturbances and urinary retention are rare and reversible, BISOLVON 8mg Tablet
ATROVENT is a quaternary ammonium compound with
although the risk of urinary retention may be increased in patients
anticholinergic (parasympatholytic) properties. In preclinical
studies, it appears to inhibit vagally mediated reexes by
with pre-existing outow tract obstruction. Ocular side effects have (Bromhexine Hydrochloride)
been reported (see: Special Precautions). As with other inhaled
antagonizing the action of acetylcholine, the transmitter agent therapy including bronchodilators, cough, and, less common, BISOLVON Elixir
released from the vagus nerve. Anticholinergics prevent the increase paradoxical bronchoconstriction has been observed.
in intracellular concentration of cyclic guanosine monophosphate
OTC
(cyclic GMP) caused by interaction of acetylcholine with DOSAGE AND ADMINISTRATION: (Bromhexine Hydrochloride)
the muscarinic receptor on bronchial smooth muscle. The The dosage should be adapted to the individual requirements of
bronchodilation following inhalation of ATROVENT is the patient; patients should also be kept under medical supervision BISOLVON Solution
primarily a local, site-specic effect, not a systemic one. In during treatment. Unless otherwise prescribed, the following doses
controlled 90 day studies in patients with bronchospasm associated are recommended:
(Bromhexine Hydrochloride)
with chronic obstructive pulmonary disease (chronic bronchitis Maintenance Treatment:
and emphysema) signicant improvements in pulmonary function Adults (including elderly) and adolescents over 12 years of age: COMPOSITION:
(FEV1 and FEF25-75% increases of 15% or more) occurred 1 unit dose vial 3 to 4 times daily
1 tablet contains............................................... 4mg (N.R) or 8 mg
within 15 minutes, reached a peak in 1-2 hours, and persisted Acute Attacks: 4 ml solution for oral and inhalation use contain................... 8 mg
in the majority of patients up to 6 hours. Preclinical and clinical Adults (including elderly) and adolescents over 12 years of age: 1
evidence suggest no deleterious effect of ATROVENT on 5 ml elixir contain .................................................................. 4 mg
unit dose vial; repeated doses can be administered until the patient
airway mucous secretion, mucociliary clearance or gas exchange. N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)amine
is stable. The time interval between the doses may be determined
The bronchodilator effect of ATROVENT in the treatment of by the physician. ATROVENT can be administered combined
hydrochloride (= bromhexine hydrochloride)
acute bronchospasm associated with asthma has been shown in with an inhaled beta-agonist. The unit dose vials of 2 ml are to be excipients:
studies in adults. In most of these studies ATROVENT was diluted with physiological saline up to a nal volume of 2 - 4 ml or tablets: lactose, maize starch, gelatine, magnesium stearate
administered in combination with an inhaled beta-agonist. may be combined with Berotec inhalation solution. solution: tartaric acid, methyl parahydroxybenzoate
INDICATIONS: Daily doses exceeding 2 mg in adults and children over 12 years elixir 4mg: tartaric acid, benzoic acid, sodium carboxymethylcel-
of age should be given under medical supervision. It is advisable lulose, glycerol, sorbitol solution, pharma avour, ethanol.
ATROVENT is indicated as a bronchodilator for maintenance not to greatly exceed the recommended daily dose during either
treatment of bronchospasm associated with chronic obstructive acute or maintenance treatment. If therapy does not produce a PHARMACOLOGICAL PROPERTIES:
pulmonary disease, including chronic bronchitis and emphysema. signicant improvement or if the patients condition gets worse, Bromhexine is a synthetic derivative of the herbal active
ATROVENT is indicated, when used concomitantly with medical advice must be sought in order to determine a new plan ingredient vasicine. Preclinically, it has been shown to increase the
inhaled beta-agonists in the treatment of acute bronchospasm of treatment. In the case of acute or rapidly worsening dyspnea proportion of serous bronchial secretion. Bromhexine enhances
associated with chronic obstructive pulmonary disease including (difculty in breathing) a doctor should be consulted immediately. mucus transport by reducing mucus viscosity and by activating
chronic bronchitis and asthma. ATROVENT inhalation solution can be administered using a the ciliated epithelium (mucociliary clearance). In clinical studies,
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SPDI
bromhexine showed a secretolytic and secretomotor effect in the The suppositories should be unwrapped and inserted into the
bronchial tract area, which facilitates expectoration and eases BUSCOPAN rectum pointed end rst. Since cases of poisoning with Buscopan
cough. OTC have not been reported so far, the following recommendations are
based on theoretical considerations:
INDICATIONS: (Hyoscine-N-butylbromide) Symptoms:
Secretolytic therapy in acute and chronic bronchopulmonary
COMPOSITION: In the case of overdosage, anticholinergic symptoms as urinary
diseases associated with abnormal mucus secretion and impaired
retention, dry mouth, reddening of the skin, tachycardia, inhibition
mucus transport. 1sugar-coated tablet contains 10.0 mg
of gastrointestinal motility, and transient visual disturbances may
[1suppository contains 10.0 mg(N.R)]
CONTRAINDICATIONS: occur.
[1 suppository for infants and young
BISOLVON should not be used in patients known to be children contains 7.5 mg(N.R)] Therapy:
hypersensitive to bromhexine or other components of the Hyoscine-N-butylbromide In the case of oral poisoning, gastric lavage with medicinal charcoal
formulation. Excipients: should be followed by magnesium sulfate (15 %). Symptoms of
BUSCOPAN overdosage respond to parasympathomimetics.
DRUG INTERACTIONS: s.c. tablets: dibasic calcium phosphate, maize starch, starch soluble,
For patients with glaucoma, pilocarpine should be given locally.
Administration of bromhexine together with antibiotics aerosil 200, tartaric acid, stearic acid, polyvidone, saccharose, talc,
If necessary, parasympathomimetics should be administered, e.g.
(amoxicillin, cefuroxime, erythromycin, doxycycline) leads to acacia, titanium dioxide, polyethylene glycol 6000, carnauba wax,
neostigmine 0.5-2.5 mg i.m. or i.v. Cardiovascular complications
higher antibiotic concentration in the lung tissue. No clinically beeswax white.
should be treated according to usual therapeutic principles.
relevant unfavourable interactions with other medications have Suppositories: Hard fat In case of respiratory paralysis: intubation, articial respiration.
been reported. BUSCOPAN exerts a spasmolytic action on the smooth muscle Catheterisation may be required for urinary retention. In addition,
of the gastrointestinal, biliary and genito-urinary tracts. As a appropriate supportive measures should be used as required.
quarternary ammonium derivative, hyoscine-N-butylbromide does
Available preclinical studies as well as clinical experience to not enter the central nervous system. Therefore, anticholinergic AVAILABILITY:
date have shown no evidence of illeffects during pregnancy. side effects at the central nervous system do not occur. Peripheral Sugar coated tablet containing 10 mg
Nonetheless, the usual precautions regarding the use of drugs anticholinergic action results from a ganglionblocking action [Suppositories containing 10 mg (N.R)]
during pregnancy, especially during the rst trimester, should within the visceral wall as well as from an anti-muscarinic [Pediatric suppositories containing 7.5 mg (N.R)]
be observed. The drug is expected to enter breast milk and thus activity.
should be avoided during lactation. STORAGE INSTRUCTIONS:
PHARMACOKINETICS: Store in a safe place below 30o C
SIDE EFFECTS: As a quaternary ammonium compound, hyoscine-N-butylbromide Suppositories store below 25o C
BISOLVON is generally well tolerated. Mild gastro-intestinal is highly polar and hence only partially absorbed following oral
side effects have been reported. Allergic reactions, including skin (8%) or rectal (3%) administration. The systemic availability was
rashes, bronchospasm, angio-oedema, and anaphylaxis have also found to be less than 1%. COMBIVENT Metered Aerosol
been reported very rarely. Nevertheless, despite the briey measurable low blood levels,
relatively high local concentrations of radio-labelled hyoscine-N- (Ipratropium bromide monohydrate and
butylbromide and/or its metabolites have been observed at the site
ORAL: of action: in the gastrointestinal tract, gall bladder, bile ducts, liver,
Salbutamol sulphate)
Tablets 4 mg and kidneys.
COMPOSITION:
Adults and children over 12 years: 8 mg (2 tablets) 3 times daily Hyoscine-N-butylbromide does not pass the blood-brain barrier
Children 6 - 12 years: 4 mg (1 tablet) 3 times daily and its binding to plasma proteins is low. The total clearance, 1 metered dose contains:
Children 2 - 6 years: 4 mg (1 tablet) 2 times daily determined after i.v. administration, is 1.2 l/min, approximately (8r)-3-Hydroxy-8-isopropyl-1,5-tropanium bromide ()-
half of the clearance is renal. The main metabolites found in urine tropate monohydrate (= ipratropium bromide monohydrate) 21
Tablets 8 mg
bind poorly to the muscarinic receptor. Gastrointestinal tract mcg di[(RS)-2-tert-butylamino-1-(4-hydroxy-3-hydroxymethyl-
Adults and children over 12 years: 8 mg (1 tablet) 3 times daily phenyl)ethanol] sulphate (= salbutamol sulphate) 120 mcg
spasm, spasm and dyskinesia of the biliary system, genito-urinary
Children 6 - 12 years: 4 mg (1/2 tablet) 3 times daily tract spasm. Excipients: CFC (Freon 11, 12, 114), soya Lecithin.
Children 2 - 6 years: 4 mg (1/2 tablet) 2 times daily
Solution 8 mg/4 ml (= 60 drops) CONTRAINDICATIONS: PHARMACOLOGICAL PROPERTIES:
Buscopan is contraindicated in myasthenia gravis and megacolon. Ipratropium bromide is a quaternary ammonium compound with
Adults and children over 12 years: 4 ml 3 times daily
In addition, it should not be used in patients who have anticholinergic (parasympatholytic) properties. In preclinical
Children 6 - 12 years: 2 ml 3 times daily demonstrated prior sensitivity to hyoscine-N-butylbromide or any studies, it appears to inhibit vagally mediated reexes by
Children 2 - 6 years: 20 drops 3 times daily other component of the product. antagonizing the action of acetylcholine, the transmitter agent
Children under 2 years: 10 drops 3 times daily released from the vagus nerve. Anticholinergics prevent the increase
Elixir 4 mg/5 ml (5 ml = 1 teaspoon) in intracellular concentration of cyclic guanosine monophosphate
Long experience has shown no evidence of ill-effects during (cyclic GMP) caused by interaction of acetylcholine with the
Adults and children over 12 years: 10 ml (2 teasp.) 3 times daily
human pregnancy. However, the usual precautions regarding the muscarinic receptor on bronchial smooth muscle.
Children 6 - 12 years: 5 ml (1 teasp.) 3 times daily use of drugs in pregnancy, especially during the rst trimester,
Children 2 - 6 years: 2.5 ml (1/2 teasp.) 3 times daily The bronchodilation following inhalation of ipratropium bromide
should be observed. Safety during lactation has not yet been
is primarily local and site specic to the lung and not systemic in
Children under 2 years: 1.25 ml (1/4 teasp.) 3 times daily established. However, adverse effects on the new born have not
nature. Salbutamol sulphate is a beta2-adrenergic agent which acts
At commencement of treatment, it may be necessary to increase been reported.
on airway smooth muscle resulting in relaxation.
the total daily dose up to 48 mg in adults. The elixir is sugar-free INTERACTIONS: Salbutamol relaxes all smooth muscle from the trachea to the
and therefore suitable for diabetics and small children.
The anticholinergic effect of tricyclic antidepressants, terminal bronchioles and protects against all bronchoconstrictor
Inhalation (with aerosol apparatus) antihistamines, quinidine, amantadine and disopyramide may challenges. COMBIVENT metered aerosol provides the
It is generally recommended to warm inhalant solutions to body be intensied by BUSCOPAN. Concomitant treatment with simultaneous release of ipratropium bromide and salbutamol
temperature before inhalation. Patients with bronchial asthma may dopamine antagonists such as metoclopramide may result in sulphate allowing the additive effect on both muscarinic
be advised to commencing inhalation after they have taken their diminution of the effects of both drugs on the gastrointestinal and beta2- adrenergic receptors in the lung resulting in a
regular bronchospasmolytic therapy. tract. The tachycardic effects of beta-adrenergic agents may be bronchodilation which is superior to that provided by each single
Solution for inhalation enhanced by BUSCOPAN. agent. Controlled studies in patients with reversible bronchospasm
have demonstrated that Combivent metered aerosol has a greater
Adults: 4 ml 2 times daily SIDE EFFECTS:
bronchodilator effect than either of its components and there was
Children over 12 years: 2 ml 2 times daily Anticholinergic side effects including xerostomia, dyshidrosis, no potentiation of adverse events.
Children 6 - 12 years: 1 ml 2 times daily tachycardia and potentially urinary retention may occur but are
Children 2 - 6 years: 10 drops 2 times daily generally mild and self limited. Very rarely hypersensitivity INDICATIONS:
Children under 2 years: 5 drops 2 times daily reactions, particularly skin reactions and, in extremely rare cases, COMBIVENT metered aerosol is indicated for the management
dyspnoea have been reported. Because of the potential risk of of reversible bronchospasm associated with obstructive
The solution may be diluted 1:1 with physiological saline
anticholinergic complications, caution should be used in patients airways diseases in patients who require more than a single
solution. In order to avoid precipitation the solution should be
prone to narrow angle glaucoma as well as in patients susceptible bronchodilator.
inhaled immediately after mixing. The combined administration
to intestinal or urinary outlet obstructions and in those inclined to
of inhalation and oral application intensies the effect and is tachyarrhythmia.
CONTRAINDICATIONS:
especially suited for the commencement of treatment in cases COMBIVENT metered aerosol is contraindicated in patients
where the full effect is to be reached quickly. DOSAGE AND ADMINISTRATION: with hypertrophic obstructive cardiomyopathy or tachyarrhythmia.
Unless otherwise prescribed by the physician, the following COMBIVENT metered aerosol is also contraindicated in
NOTE:
dosages are recommended: patients with a history of hypersensitivity to soya lecithin or
Patients being treated with Bisolvon should be notied of an related food products such as soybean and peanut.
expected increase in the ow of secretions. ORAL:
For such patients COMBIVENT Unit Dose Vials without
Sugar-coated tablets:
OVERDOSAGE: soya lecithin can be used. Combivent should also not be taken by
Adults and children over 6 years: 3 - 5 times daily 1 - 2 s.c. patients with known hypersensitivity to atropine or its derivatives
No symptoms of overdosage have been reported in man to date. If tablets The sugar-coated tablets should be swallowed whole with
they occur, symptomatic treatment should be provided. or to any other component of the product.
adequate uid.
SPECIAL PRECAUTIONS:
AVAILABILITY: RECTAL:
Immediate hypersensitivity reactions may occur after administration
Tablets 4mg (N.R) and 8 mg; Solution for oral and inhalation use Suppositories: of COMBIVENT metered aerosol, as demonstrated by rare cases
8 mg/4 ml; Elixir 4 mg/5 ml
Adults and children over 6 years: 3 - 5 times daily 1 - 2 of urticaria, angioedema, rash, bronchospasm and oropharyngeal
STORAGE INSTRUCTIONS: suppositories oedema.
Store in a safe place below 30 C. Store in a safe place out of the Paediatric suppositories: Ocular complications:
reach of children! Do not take the medicine after the expiry date Children over 1 year: 3 - 5 times daily 1 suppository There have been isolated reports of ocular complications (i.e.
printed on the pack. Infants: 2 - 3 times daily 1 suppository mydriasis, increased intraocular pressure, narrow-angle glaucoma,
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SPDI
eye pain) when aerosolised ipratropium bromide either alone or in Children: Salbutamol sulphate is a beta2-adrenergic agent which acts
combination with an adrenergic beta2-agonist, has escaped into There is no experience of the use of Combivent in children below on airway smooth muscle resulting in relaxation. Salbutamol
the eyes. Eye pain or discomfort, blurred vision, visual halos or the age of 12 years. Patients should be advised to consult a relaxes all smooth muscle from the trachea to the terminal
colored images in association with red eyes from conjunctival doctor or the nearest hospital immediately in the case of acute or bronchioles and protects against all bronchoconstrictor challenges.
congestion and corneal oedema may be signs of acute narrow- rapidly worsening dyspnoea (difculty in breathing) if additional COMBIVENT unit dose vials provide the simultaneous release
angle glaucoma. Should any combination of these symptoms inhalations do not produce an adequate improvement. of ipratropium bromide and salbutamol sulphate allowing the
develop, treatment with miotic drops should be initiated and additive effect on both muscarinic and beta2-adrenergic receptors
specialist advice sought immediately. Patients must be instructed ADMINISTRATION: in the lung resulting in a bronchodilation which is superior to that
in the correct administration of COMBIVENT metered aerosol. The correct operation of the metered aerosol apparatus is essential provided by each single agent. Controlled studies in patients with
Care must be taken not to expose the eyes to the aerosol of for successful therapy. reversible bronchospasm have demonstrated that Combivent unit
COMBIVENT. Patients who may be predisposed to glaucoma Shake the aerosol canister and depress the valve two times before dose vials have a greater bronchodilator effect than either of its
should be warned specically to protect their eyes. the apparatus is initially used. components and there was no potentiation of adverse events.
In the following conditions Combivent should only be used after Before each use the following rules should be observed: INDICATIONS:
careful risk/benet assessment, especially when doses higher 1. Remove protective cap. COMBIVENT unit dose vials are indicated for the management
than recommended are used: insufciently controlled diabetes 2. Shake the metered aerosol well before each use (see g. 1). of reversible bronchospasm associated with obstructive
mellitus, recent myocardial infarction, severe organic heart or (g. 1) (g. 2) airway diseases in patients who require more than a single
vascular disorders, hyperthyroidism, phaeochromocytoma, risk
bronchodilator.
of narrow-angle glaucoma, prostatic hypertrophy or bladder-neck
obstruction. Potentially serious hypokalaemia may result from CONTRAINDICATIONS:
beta2-agonist therapy . Additionally, hypoxia may aggravate Hypertrophic obstructive cardiomyopathy, tachyarrhythmia.
the effects of hypokalaemia on cardiac rhythm. Patients with Hypersensitivity to any of the components of the product, to
cystic brosis may be more prone to gastro-intestinal motility atropine or its derivatives.
disturbances. In the case of acute, rapidly worsening dyspnoea 3. Breathe out deeply.
(difculty in breathing) a doctor should be consulted immediately. 4. Hold the metered aerosol as shown in g. 2, and close lips over SPECIAL PRECAUTIONS:
If higher than recommended doses of COMBIVENT are the mouthpiece. The arrow and the base of the container should Immediate hypersensitivity reactions may occur after
required to control symptoms, the patients therapy plan should be be pointing upwards. administration of COMBIVENT solution for inhalation, as
reviewed by a doctor. 5. Breathe in as deeply as possible, pressing the base of the demonstrated by rare cases of urticaria, angioedema, rash,
container rmly at the same time, this releases one metered bronchospasm and oropharyngeal oedema.
DRUG INTERACTIONS: dose. Hold the breath for a few seconds, then remove the
Ocular Complications:
The concurrent administration of xanthine derivatives as well mouthpiece from the mouth and breathe out. The same action
as other beta-adrenergics and anticholinergics may increase should be repeated for a second inhalation. There have been isolated reports of ocular complications (i.e.
the side effects. Beta-agonist induced hypokalaemia may be mydriasis, increased intraocular pressure, narrow-angle glaucoma,
6. Replace the protective cap after use.
eye pain) when aerosolised ipratropium bromide either alone or in
increased by concomitant treatment with xanthine derivatives, The container is under pressure and should on no account be combination with an adrenergic beta2-agonist, has escaped into
glucocorticosteroids and diuretics. This should be taken into opened by force or exposed to temperatures exceeding 50C. As the eyes. Eye pain or discomfort, blurred vision, visual halos or
account particularly in patients with severe airway obstruction. the container is not transparent it is not possible to see when the colored images in association with red eyes from conjunctival
Hypokalaemia may result in an increased susceptibility to contents are used up, but shaking the container will show if there is congestion and corneal oedema may be signs of acute narrow-
arrhythmias in patients receiving digoxin. It is recommended any remaining uid.The mouthpiece should always be kept clean angle glaucoma. Should any combination of these symptoms
that serum potassium levels are monitored in such situations. and can be washed with warm water. If soap or detergent is used, develop, treatment with miotic drops should be initiated and
A potentially serious reduction in bronchodilator effect may the mouthpiece should be thoroughly rinsed in clear water.
specialist advice sought immediately. Patients must be instructed
occur during concurrent administration of beta-blockers. Beta-
OVERDOSAGE: in the correct administration of COMBIVENT unit dose vials.
adrenergic agonists should be administered with caution to patients
Symptoms: Care must be taken not to expose the eyes to the solution or
being treated with monoamine oxidase inhibitors or tricyclic
aerosol of COMBIVENT. It is recommended that the nebulised
antidepressants, since the action of betaadrenergic agonists may The effects of overdosage are expected to be primarily related to
solution be administered via a mouth piece. If this is not available
be enhanced. Inhalation of halogenated hydrocarbon anaesthetics salbutamol. The expected symptoms with overdosage are those
and a nebuliser mask is used, it must t properly.
such as halothane, trichloroethylene and enurane may increase of excessive beta-adrenergic-stimulation, the most prominent
the susceptibility to the cardiovascular effects of beta-agonists. being tachycardia, palpitation, tremor, hypertension, hypotension, Patients who may be predisposed to glaucoma should be warned
widening of the pulse pressure, anginal pain, arrhythmias, and specically to protect their eyes. In the following conditions
PREGNANCY AND LACTATION: COMBIVENT should only be used after careful risk/benet
ushing. Expected symptoms of overdosage with ipratropium
The safety of Combivent during human pregnancy is not bromide (such as dry mouth, visual accomodation disturbances) assessment, especially when doses higher than recommended
established. The usual precautions regarding the use of drugs in are mild and transient in nature in view of the wide therapeutic are used: insufciently controlled diabetes mellitus, recent
pregnancy, especially during the rst trimester, should be observed. range and topical administration. myocardial infarction, severe organic heart or vascular disorders,
The inhibitory effect of COMBIVENT on uterine contraction Therapy:
hyperthyroidism, phaeochromocytoma, risk of narrow-angle
should be taken into account. Salbutamol sulphate and ipratropium glaucoma, prostatic hypertrophy or bladder-neck obstruction.
Administration of sedatives, tranquillizers, in severe cases Potentially serious hypokalaemia may result from beta2-agonist
bromide are probably excreted in breast milk and their effects on
intensive therapy. Beta-receptor blockers, preferably beta1- therapy. Additionally, hypoxia may aggravate the effects of
the neonate are not known. Although lipidinsoluble quaternary
selective, are suitable as specic antidotes; however, a possible hypokalaemia on cardiac rhythm.
bases pass into breast milk, it is unlikely that ipratropium bromide
increase in bronchial obstruction must be taken into account and
would reach the infant to an important extent, especially when Patients with cystic brosis may be more prone to gastro-intestinal
the dose should be adjusted carefully in patients suffering from
taken by inhalation. However, because many drugs are excreted in motility disturbances. In the case of acute, rapidly worsening
bronchial asthma.
breast milk, caution should be exercised when COMBIVENT is dyspnoea (difculty in breathing) a doctor should be consulted
administered to a nursing woman. AVAILABILITY: immediately. If higher than recommended doses of Combivent are
Metered dose inhaler required to control symptoms, the patientss therapy plan should
SIDE EFFECTS:
be reviewed by a doctor.
In common with other beta-agonist containing products more STORAGE INSTRUCTIONS:
frequent undesirable effects of COMBIVENT are headache, Store in a safe place below 30oC. Store in a safe place out of the DRUG INTERACTIONS:
dizziness, nervousness, tachycardia, ne tremor of skeletal reach of children. The concurrent administration of xanthine derivatives as well
muscles and palpitations, especially in susceptible patients. Do not take the medicine after the expiry date printed on the as other beta-adrenergics and anticholinergics may increase
Potentially serious hypokalaemia may result from beta2-agonist pack. the side effects. Beta-agonist induced hypokalaemia may be
therapy .As with use of other inhalation therapy, cough, local increased by concomitant treatment with xanthine derivatives,
irritation and less common inhalation induced bronchocospasm COMBIVENT Unit Dose Vial Solution glucocorticosteroids and diuretics. This should be taken into
can occur. As with other beta-mimetics, nausea, vomiting, account particularly in patients with severe airway obstruction.
sweating, weakness and myalgia/muscle cramps may occur. In Hypokalaemia may result in an increased susceptibility to
rare cases decrease in diastolic blood pressure, increase in systolic (Ipratropium bromide, Salbutamol sulphate) arrhythmias in patients receiving digoxin. It is recommended that
blood pressure, arrhythmias, particularly after higher doses, may serum potassium levels are monitored in such situations.
occur. In individual cases psychological alterations have been COMPOSITION: A potentially serious reduction in bronchodilator effect may
reported under inhalational therapy with beta-mimetics. The 1 unit-dose vial (2.5 ml) solution for inhalation contains (8r)-3- occur during concurrent administration of beta-blockers. Beta-
most frequently non-respiratory anticholinergic related adverse hydroxy-8-isopropyl-1H,5H-tropanium bromide ()-tropate adrenergic agonists should be administered with caution to patients
events were dryness of the mouth and dysphonia. There have been monohydrate (= ipratropium bromide) corresponding to 0.5 mg being treated with monoamine oxidase inhibitors or tricyclic
isolated reports of ocular complications (i.e. mydriasis, increased ipratropium bromide anhydrous: 0.52 mg antidepressants, since the action of beta-adrenergic agonists may
intraocular pressure, angle-closure glaucoma, eye pain) when be enhanced. Inhalation of halogenated hydrocarbon anaesthetics
di[(RS)-2-tert-butylamino-1-(4-hydroxy-3-hydroxymethyl-
aerosolised ipratropium bromide either alone or in combination phenyl)ethanol] sulphate (= salbutamol sulphate) corresponding to such as halothane, trichloroethylene and enurane may increase
with an adrenergic beta2-agonist, has escaped into the eyes. 2.5 mg salbutamol base: 3.01 mg the susceptibility to the cardiovascular effects of beta-agonists.
Ocular side effects, gastrointestinal motility disturbances and
urinary retention may occur in rare cases and are reversible (see Excipients: sodium chloride, hydrochloric acid, puried water PREGNANCY AND LACTATION:
Special Precautions). Allergic-type reactions such as skin rash, PHARMACOLOGICAL PROPERTIES: The safety of Combivent during human pregnancy is not
angioedema of the tongue, lips and face, urticaria (including giant Ipratropium bromide is a quaternary ammonium compound with established. The usual precautions regarding the use of drugs
urticaria), laryngospasm and anaphylactic reactions have been anticholinergic (parasympatholytic) properties. In preclinical in pregnancy, especially during the rst trimester, should be
reported, with positive rechallenge in some cases. Many of the studies, it appears to inhibit vagally mediated reexes by observed. The inhibitory effect of COMBIVENT on uterine
patients have had a history of allergy to other drugs and/or foods, antagonizing the action of acetylcholine, the transmitter agent contraction should be taken into account. Salbutamol sulphate and
including soybean (see: Contraindications). released from the vagus nerve. Anticholinergics prevent the ipratropium bromide are probably excreted in breast milk and their
increase in intracellular concentration of cyclic guanosine effects on the neonate are not known.
DOSAGE:
monophosphate (cyclic GMP) caused by interaction of Although lipid-insoluble quaternary bases pass into breast milk, it
Adults (including elderly patients): is unlikely that ipratropium bromide would reach the infant to an
acetylcholine with the muscarinic receptor on bronchial smooth
Two inhalations four times a day. muscle. The bronchodilation following inhalation of ipratropium important extent, especially when taken by inhalation. However,
The dose may be increased as required up to a limit of 12 bromide is primarily local and site specic to the lung and not because many drugs are excreted in breast milk, caution should be
inhalations in 24 hours. systemic in nature. exercised when Combivent is administered to a nursing woman.
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SPDI
SIDE EFFECTS: selective, are suitable as specic antidotes; however, a possible For Constipation:
In common with other beta-agonist containing products more increase in bronchial obstruction must be taken into account and Coated Tablets:
frequent undesirable effects of COMBIVENT are headache, the dose should be adjusted carefully in patients suffering from Adults and children over 10 years: 1 - 2 coated tablets (5 - 10 mg)
dizziness, nervousness, tachycardia, ne tremor of skeletal muscles bronchial asthma. Children 4 - 10 years: 1 tablet (5 mg)
and palpitations, especially in susceptible patients. Potentially AVAILABILITY: Children under 4 years: paediatric suppositories are
serious hypokalaemia may result from beta2-agonist therapy. As recommended
Solution for inhalation in unit dose vials
with use of other inhalation therapy, cough, local irritation and The tablets should be taken at night to produce evacuation the
less common inhalation induced bronchocospasm can occur. As STORAGE INSTRUCTIONS: following morning. They should be swallowed whole with
with other beta-mimetics, nausea, vomiting, sweating, muscle Store in a safe place below 30oC. Store in a safe place out of the adequate uid. The tablets should not be taken together with milk
weakness and myalgia/muscle cramps may occur. reach of children. or antacids.
In rare cases decrease in diastolic blood pressure, increase in Do not take the medicine after the expiry date printed on the pack Suppositories:
systolic blood pressure, arrhythmias, particularly after higher
Adults and children over 10 years: 1 suppository (10 mg)
doses, may occur. In rare cases skin reactions or allergic reactions
may occur, especially in hypersensitive patients. In individual cases DULCOLAX Children under 10 years: 1 paediatric suppository
(5 mg)
psychological alterations have been reported under inhalational OTC
therapy with beta-mimetics. The most frequently non-respiratory Suppositories are usually effective in about 30 minutes. They
(Bisacodyl) should be unwrapped and inserted into the rectum pointed end
anticholinergic related adverse events were dryness of the mouth
and dysphonia. rst.
COMPOSITION:
There have been isolated reports of ocular complications (i.e. For preparation for diagnostic procedures and preoperatively
1 coated tablet contains 5 mg
mydriasis, increased intraocular pressure, angle-closure glaucoma, [1 suppository contains 10 mg (N.R)] When using DULCOLAX to prepare the patient for radiographic
eye pain) when aerosolised ipratropium bromide either alone or in examination of the abdomen or preoperatively, tablets should be
[1 paediatric suppository contains 5 mg (N.R)
combination with an adrenergic beta2-agonist, has escaped into combined with the suppositories in order to achieve complete
the eyes. Ocular side effects, gastrointestinal motility disturbances 4,4-diacetoxy-diphenyl-(pyridyl-2)-methane (= bisacodyl)
evacuation of the intestine.
and urinary retention may occur in rare cases and are reversible Excipients:
The dosage recommended for adults is two to four tablets the night
(see Special Precautions) Tablets: lactose, maize starch, glycerol, magnesium stearate,
before and one suppository to be inserted the following morning.
saccharose, talc, acacia, titanium dioxide, eudragit L100 and S100,
DOSAGE AND ADMINISTRATION: In the case of children 4 years of age and over, one tablet in the
dibutylphthalate, polyethylene glycol, iron oxide yellow, beeswax
Combivent inhalation solution in unit dose vials may be white, carnauba wax, shellac evening and one paediatric suppository on the following morning
administered from a suitable nebuliser or an intermittent positive is recommended.
Suppositories: witepsol E76, witepsol E45 (N.R)
pressure ventilator. The following dose is recommended for adults OVERDOSE:
(including elderly patients) and adolescents over 12 years of age: PHARMACOLOGICAL PROPERTIES:
Symptoms:
Treatment of acute attacks: Bisacodyl is a locally acting laxative from the diphenylmethane
derivatives group. As an antiresorptive hydragogue laxative If high doses are taken watery stools (diarrhoea), abdominal
1 unit dose vial is sufcient for prompt symptom relief in many cramps and a clinically signicant loss of potassium and other
cases. In severe cases if an attack has not been relieved by one unit (stimulant laxative) DULCOLAX stimulates, after hydrolysis
in the large intestine, peristalsis of the colon and promotes electrolytes can occur. Chronic overdose with DULCOLAX
dose vial, two unit dose vials may be required. may cause chronic diarrhoea, abdominal pain, hypokalaemia,
accumulation of water and electrolytes in the colonic lumen.
In these cases, patients should consult the doctor or the nearest secondary hyperaldosteronism and renal calculi. Renal tubular
hospital immediately. INDICATIONS / USAGE: damage, metabolic alkalosis and muscle weakness secondary
For use in patients suffering from constipation. In preparation for to hypokalaemia have also been described in association with
Maintenance Treatment:
diagnostic procedures, in pre- and postoperative treatment and in chronic laxative abuse
1 unit dose vial three or four times daily. conditions, which require defecation to be facilitated, Dulcolax
should be used under medical supervision. Therapy:
INSTRUCTIONS FOR USE:
After ingestion of oral forms of DULCOLAX, absorption can
The unit dose vials are intended only for inhalation with suitable CONTRAINDICATIONS: be minimised or prevented by inducing vomiting or gastric lavage.
nebulising devices and should not be taken orally or administered DULCOLAX is contraindicated in patients with ileus, intestinal Replacement of uids and correction of electrolyte imbalance may
parenterally. obstruction, acute surgical abdominal conditions including be required. This is especially important in the elderly and the
1. Prepare the nebuliser for lling, according to the instructions appendicitis, acute inammatory bowel diseases, and in severe young. Administration of antispasmodics may be of value.
provided by the manufacturer or doctor. dehydration. It is also contraindicated in patients with known
2. Tear one unit dose vial from the strip. hypersensitivity to bisacodyl or any other component of the AVAILABILITY:
product. Coated tablets of 5 mg
SPECIAL WARNINGS AND PRECAUTIONS: [Suppositories of 10 mg (N.R)]
[Paediatric suppositories of 5 mg(N.R)]
As with all laxatives, DULCOLAX should not be taken on a
continuous daily basis for long periods. If laxatives are needed STORAGE INSTRUCTIONS:
every day, the cause of constipation should be investigated. Store below 30oC. Store in a safe place and out of reach of
3. Open the unit dose vial by rmly twisting the top. Prolonged excessive use may lead to uid and electrolyte
4. Squeeze the content of the unit dose vial into the nebuliser children.
imbalance and hypokalaemia, and may precipitate onset of
reservoir. Do not take the medicine after the expiry date printed on the
rebound constipation.
pack.
Dizziness and /or syncope have been reported in patients who
have taken DULCOLAX. The details available for these cases
suggest that the events would be consistent with defecation GINCOSAN Capsules
syncope (or syncope attributable to straining at stool), or with a OTC
vasovagal response to abdominal pain which may be related to
the constipation that prompted the patients in question to resort
[Ginkgo biloba tree (Extract GK501)and the
5. Assemble the nebuliser and use as directed.
6. After use throw away any solution left in the reservoir and clean to the use of laxatives and not necessarily to the administration of roots of Panax ginseng(Extract G115)]
the nebuliser, following the manufacturers instructions. DULCOLAX itself.
The use of suppositories may lead to painful sensations and PROPERTIES AND INDICATIONS
local irritation, especially in anal ssure and ulcerative proctitis. GINCOSAN contains standardized extracts from the leaves of
Children should not take Dulcolax without medical advice. the Ginkgo biloba tree (Extract GK501) and the roots of Panax
ginseng (Extract G115).
INTERACTIONS:
The standardized Ginkgo extract GK501 has a positive effect on
The concomitant use of diuretics or adreno-corticosteroids may
the circulation in the brain and the small blood vessels (arterioles
increase the risk of electrolyte imbalance if excessive doses of
Since the unit dose vials contain no preservative, it is important and venules).
DULCOLAX are taken. Electrolyte imbalance may lead to
that the contents are used soon after opening and that a fresh vial increased sensitivity to cardiac glycosides. The standardized Ginseng extract G115 has a stimulant effect on
is used for each administration to avoid microbial contamination. the brain function.
Partly used, opened or damaged unit dose vials should be discarded. PREGNANCY AND LACTATION:
The combination of these two extracts, the effects of which
It is strongly recommended not to mix COMBIVENT solution Long experience has shown no evidence of undesirable or complement each other, make GINCOSAN a product which
for inhalation with other drugs in the same nebuliser. damaging effects during pregnancy. Nevertheless, as with all is indicated for symptoms which point towards circulatory
drugs, DULCOLAX should only be taken during pregnancy on insufciency.
OVERDOSAGE: medical advice. Whether bisacodyl passes into breast milk has not
GINCOSAN may therefore be used in the treatment of declining
Symptoms: been established. Breast feeding during DULCOLAX treatment
vitality in the elderly.
The effects of overdosage are expected to be primarily related to is therefore not recommended.
salbutamol. The expected symptoms with overdosage are those Signs of this condition are poor concentration, loss of memory,
SIDE EFFECTS: impaired perception, forgetfulness, changing mood, irritability,
of excessive beta-adrenergic-stimulation, the most prominent
being tachycardia, palpitation, tremor, hypertension, hypotension, While using DULCOLAX, episodes of abdominal discomfort difculties of adaptation and contact and dizziness.
widening of the pulse pressure, anginal pain, arrhythmias, and including cramps and abdominal pain may occur. Diarrhoea has
been observed. Allergic reactions, including isolated cases of NOTE
ushing. Expected symptoms of overdosage with ipratropium
bromide (such as dry mouth, visual accomodation disturbances) angio-oedema and anaphylactoid reactions have been reported in Heavy smoking, excessive consumption of salt and fats and an
are mild and transient in nature in view of the wide therapeutic association with the administration of DULCOLAX. unbalanced diet can impair the vitality and efciency, and should
range and topical administration. therefore be avoided.
DOSAGE AND ADMINISTRATION /
Therapy: RECOMMENDED INTAKE: CONTRAINDICATIONS
Administration of sedatives, tranquillizers, in severe cases Unless otherwise prescribed by the physician, the following Do not take GINCOSAN if you are hypersensitive or allergic to
intensive therapy. Beta-receptor blockers, preferably beta1- dosages are recommended: any of the ingredients.
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Inform your doctor if you: of life. It unites the active substances of Ginseng (the ginsenosides) PHARMACOKINETICS:
have allergies (to drugs, foods, household dust, or of an in different galenic forms which are easy to take and dose out, IMUKIN is rapidly cleared after intravenous administration and
occupational nature); or readily absorbed, well tolerated, pleasant-tasting. slowly although well absorbed after intramuscular or subcutaneous
are treating the same symptoms with other drugs. GINSANA Capsules are particularly useful for people on the administration. The mean elimination half-lives were 38 minutes,
move: physical and mental workers, students, drivers, travellers, 2.9 hours and 5.9 hours after administration of a single 100 mcg/
DOSAGE sportsmen, housewives. m2 injection by intravenous, intramuscular and subcutaneous
Unless otherwise prescribed, take 1 capsule twice a day after GINSANA Tonic is primarily inteded for persons not on the routes. Peak plasma concentrations occurred approximately 4
breakfast and lunch without chewing and with a little uid. move: elderly people, convalescents and children. hours after i.m. dosing and 7 hours after s.c. dosing. Multiple dose
Generally, the treatment should be continued for at least 4 weeks. subcutaneous pharmacokinetic studies were conducted in healthy
GINSANA Chewable tablets: for persons at every stage of
male subjects.
The duration of treatment should be discussed with your physician. life.
Observe the dosage indicated on the leaet or prescribed by your There was no accumulation of IMUKIN after 12 consecutive
INDICATIONS daily injections of 100 mcg/m2. Interferon gamma was not detected
physician. If you think the effect of the drug is too weak or too
strong, consult your physician or pharmacist. GINSANA is indicated whenever the physical or mental in the urine of healthy male subjects following adminstration
condition necessitates effective support: of 100 mcg/m2 by the intramuscular or subcutaneous injection.
SIDE EFFECTS In vitro hepatic and renal perfusion studies demonstrated that
to combat loss of concentration and to improve mental
In rare cases unspecic side effects (headache, allergic skin efciency these organs are capable of clearing interferon gamma from the
reactions) have been observed. to treat fatigue, weakness, and exhaustion perfusate.
GENERAL NOTICE to improve physical performance INDICATIONS:
The capsules contain no glucose or sucrose and are therefore to alleviate stress caused by nervous debility IMUKIN is indicated as an adjunct for the reduction of
suitable for diabetics. to help overcome menopausal disorders the frequency of serious infections, in patients with Chronic
Keep GINCOSAN in a dry place, at room temperature (15- to retard the degenerative process of ageing Granulomatous Disease (CGD)
25C) and out of the reach of children. to support the cardiovascular system CONTRAINDICATIONS:
The drug may be used only up to the expiry date indicated on the to activate cell metabolism
IMUKIN is contraindicated in patients with hypersensitivity
container with EXP. to induce better sleep to interferon gamma, known hypersensitivity to closely related
to shorten the period of convalescence interferons or to any other component of the product.
COMPOSITION
to improve the bodys resistance to infections
One capsule contains: SPECIAL PRECAUTIONS:
to induce a feeling of well-being and stability
Standardized Ginkgo biloba extract GK501 60 mg adjusted to IMUKIN should be used with care in patients with pre-existing
24% ginkgoavone- glycosides and 6% terpenes (ginkgolides, DOSAGE cardiac disease, including angina pectoris, congestive heart
bilobalide) Standardized Panax ginseng C.A. Meyer extract G115 The doses stated are for adults. Adolescents reduce eventually the failure, or arrhythmias. No direct cardiotoxic effects have been
100 mg adjusted to 4% ginsenosides Excip. pro caps. doses stated according to their age. demonstrated, although it is possible that acute and transient u-
GINSANA Capsules: Normally 2 capsules per day at breakfast like or constitutional symptoms such as fever or chills, produced
PACKAGES
or one each with breakfast and lunch. In severe stress situations the by the administration of IMUKIN may exacerbate pre-existing
There are packs of 30 and 60 capsules. conditions.
daily dosage can be increased up to 4 capsules during the initial
period of treatment. The capsules are taken preferably with some Caution should be exercised when treating patients with known
GINSANA G115 liquid. seizure disorders and/or compromised central nervous system
OTC GINSANA Tonic: Normally 1 measuring cup = 15 ml per day function. Similarly for patients with serious liver disease or
before or after meals, preferably at breakfast. In severe stress severe renal insufciency, as the possibility exists, that with
(Highly concentrated, standardized Ginseng situations the daily dosage can be increased up to 30 ml during the repeated administration, accumulation of interferon gamma may
Extract G115) initial period of treatment. occur. Simultaneous administration of interferon gamma with
GINSANA Chewable tablets: 2 to 6 tablets per day, according other heterologous serum protein preparations or immunological
The unique natural source of energy and vitality at every stage to need. preparations (e.g. vaccines) should be avoided due to the risk of an
of life unexpected, or amplied, immune response.
The onset and the intensity of the therapeutic action depend on
PRESENTATION each individual case and may vary from person to person. As a rule Safety and effectiveness in children under the age of 6 months
it is recommended to take GINSANA as a course of treatment has not been established. Even when given at the recommended
GINSANA is available in the following galenic forms:
for periods of 8 to 12 weeks. dosage of 50 mcg/m2 by subcutaneous injection, IMUKIN
GINSANACapsules: Soft gelatine capsules for oral use. Free may affect the ability to drive a vehicle or to operate machinery.
from calories and sugar, therefore suitable also for diabetics. GENERAL NOTICE This effect may be enhanced by alcohol. Patients treated with
GINSANA Tonic with natural fruit concentrate without Shake GINSANA Tonic well before use. A slight turbidity is Imukin as well as their parents, should be informed regarding the
alcohol: Fruity tonic solution without alcohol. normal with this natural product. potential benets and risks associated with treatment. If home use
GINSANA Chewable tablets: Fruity chewable tablets for is considered to be desirable by the physician, instructions on the
NOTICE FOR COMPETITIVE ATHLETES appropriate use should be given.
persons at every stage of life.
In spite of its stimulant and tonicizing action, GINSANA has In addition to the tests normally required for monitoring patients
COMPOSITION no doping effect proper. In a test carried out according to the with CGD, patients should have the following tests before
GINSANA Capsules (per capsule): ofcial specications of the Swiss National Sports Association it commencing Imukin therapy, at appropriate periods to be dened
Highly concentrated, standardized Ginseng Extract G115 100 mg was proved that GINSANA contains no substances stated in the by the treating physician: hematologic tests, including complete
(corresponding to 500 mg of Ginseng root; made from roots of doping list of the International Olympic Commitee. blood counts, differential and platelet counts; blood chemistries,
best quality of genuine Panax Ginseng C.A. Meyer) Thus GINSANA can be taken also by competitive athletes. including renal and liver function tests; urinalysis.
Excip. q.s. ad 650 mg PACKAGES More than 900 patients treated with Imukin as a single-agent in
GINSANA Tonic with natural fruit concentrate without clinical trials, have been tested for the presence of antibody to
GINSANA Capsules: Packs of 30 and 100 capsules
alcohol (per single dose of 15 ml): interferon gamma, by a sensitive radioimmunoprecipitation assay
GINSANA Tonic with natural fruit concentrate without which detects neutralising as well as non-neutralising antibody.
Highly concentrated, standardized Ginseng Extract G115 140 alcohol: In only one patient the performed assay was positive. None the
mg (corresponding to 700 mg of Ginseng root; made from roots
Bottle of 250 ml less, subsequent samples were negative. Interferon gamma 1b, the
of best quality of genuine Panax Ginseng C.A. Meyer) Sodium
GINSANA Chewable tablets: Packs of 24 tablets active ingredient of IMUKIN, is an exogenous protein, which
benzoate, aromatics, excip. ad solut. 15 ml
may lead to the occurrence of antibodies during the course of
GINSANA Chewable tablets (per tablet): treatment.
Highly concentrated, standardized Ginseng Extract G115 50 mg IMUKIN Injection
(corresponding to 250 mg of Ginseng root; made from roots of PREGNANCY AND LACTATION:
best quality of genuine Panax Ginseng C.A. Meyer) with vitamin There is insufcient information concerning the use of IMUKIN
C and aromatics
(Recombinant human interferon gamma-1b) during pregnancy in humans, to assess the risk, if any. An increased
incidence of abortions has been observed in pregnant primates
PROPERTIES COMPOSITION:
which received the drug in doses approximately 100 times higher
GINSANA is a natural product. It contains the active substances Each vial of 0.5 ml contains 100 micrograms (= 2 million IU) than that recommended for human use. For lower doses there is
(ginsenosides) of the genuine Panax Ginseng C.A. Meyer in form recombinant human interferon gamma-1b no evidence of maternal toxicity, embryotoxictiy, fetotoxicity or
of the highly concentrated Extract G115 which is standardized on Excipients: manitol, sodiumsuccinate hexyhydrate, succinic acid teratogenicity in preclinical studies.
the total content of ginsenosides. anhydrous, polysorbate 20 IMUKIN should therefore be used during pregnancy only if
This extract belongs to the group of adaptogenic substances. the potential benet justies the potential risk to the fetus. It is
PROPERTIES:
These are substances which increase e.g. in stress situations, not known whether Imukin is excreted in human milk; therefore,
Interferons are a family of functionally related proteins, synthesized breast feeding is not recommended.
during convalescence, and generally in cases of reduced physical
by eukaryotic cells in response to viruses and a variety of natural
and mental efciency
and synthetic stimuli. It is presumed that interferon gamma SIDE EFFECTS:
the capacity of the human organism to overcome outside strain increases macrophage cytotoxicity by enhancing the respiratory The clinical and laboratory toxicity associated with multiple dose
by adaptation. burst via generation of toxic oxygen metabolites capable of studies of IMUKIN is dose, route and schedule-dependent. The
GINSANA increases the physical and mental efciency in mediating the lysis of intracellular microorganisms. It increases most common adverse events include constitutional symptoms
states of weakness and exhaustion, and is recommended for HLA-DR expression on macrophages and augements Fc receptor such as fever, headache, chills, myalgia or fatigue which may
symptoms like nervousness, fatigue, listlessness, reduced powers expression which results in increased antibody-dependent cell- decrease in severity as treatment continues.
of concentration and reaction. mediated cytotoxicity. Acetaminophen (paracetamol) may be used to ameliorate
During convalescence or in severe stress situations GINSANA In a placebo-controlled trial in patients with CGD, Imukin reduces these effects. Vomiting, nausea, arthralgia and injection site
helps to regain natural strength and to restore physical and mental the frequency of serious infections during the 12 months trial tenderness have been reported in some patients. Acute serious
balance. period. The overwhelming majority of these patients were also hypersensitivity reactions have not been observed in patients
GINSANA is indicated both for men and women at every stage receiving prophylactic antibiotic therapy. receiving IMUKIN.
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However, transient cutaneous rashes (e.g. dermatitis, maculopapular Lysine belongs to the category of the amino acids, essential Folic Acid 0.1 mg
rash, pustular and vesicular eruptions and erythema at injection components of the proteins, and among other functions it is Biotin 30.0 mcg
site) have occured in some patients following injection but have important for bone formation. Niacinamide (PP) 13.0 mg
rarely necessitated treatment interruption. In children, lysine is the amino acid most often inadequately Manganese 0.5 mg
In some patients treated with gamma interferon an increased supplied. Copper 0.3 mg
production of autoantibodies, including the development of An unbalanced or decient diet may not provide the necessary Calcium 125.0 mg
systemic lupus erythematosus, has been observed. Isolated cases substances which are required. Magnesium 26.5 mg
of confusion which may have been triggered by the administration Iron 2.5 mg
of IMUKIN have been reported in some patients with CNS INDICATIONS
Zinc 2.5 mg
involving diseases other than CGD. KIDDI PHARMATON FIZZ serves as a supplement during the Inactive ingredients:
growth years, for loss of appetite, during periods of convalescence
INTERACTIONS: Aromatics: Orange avor; Sweeteners: Aspartame, Acesulfame,
and to combat physical tiredness.
There is no evidence that Imukin reduces the efcacy of antibiotics Sorbitol; Excip. pro compr. efferv.
or glucocorticoids in CGD patients. Drug interactions seen with NOTE
PACKAGES
Imukin are similar to those seen with other interferons in animal A sufcient and diversied diet is the most important measure to
experiments. It is theoretically possible that hepatotoxic and/ There are packages of 20 effervescent tablets.
avoid as far as possible deciencies of vitamins, minerals and trace
or nephrotoxic drugs might have an effect on the clearance of elements.
IMUKIN. The effects of other agents which are commonly
CONTRAINDICATIONS
METALYSE 10,000U (50 mg)
administered to CGD patients e.g. anti-inammatory drugs,
KIDDI PHARMATON FIZZ should not be taken: Powder and solvent for solution for injection
NSAID`s, theophylline immunosuppressive and cytostatic drugs,
on the acute cellular effects induced by interferon gamma and - In cases of existing disorders of the calcium metabolism, such
therefore on its therapeutic effect in CGD patients, is not known. as increased calcium levels or increased calcium excretion [Tenecteplase (TNK-tPA)]
Theoretically, the concomitant administration of heterologous - In cases of oversupply of the body with vitamin A or D
serum protein preparations or immunological preparations (e.g. - In case of renal malfunctions COMPOSITION:
vaccines) may increase the immunogenicity of IMUKIN. - Concomitantly with other products containing vitamin A or D METALYSE 10,000 units:
IMUKIN potentially can alter the half-lives of simultaneously - In case of hypersensitivity to any of the ingredients
administered drugs which are metabolized by the cytochrome 1 vial contains 10,000 units (50 mg) tenecteplase
P-450 system. Concurrent use of drugs having neurotoxic KIDDI PHARMATON FIZZ contains
1 pre-lled syringe contains 10 ml water for injections
(including effects on the central nervous system), haematotoxic Aspartame, which consist of, among other ingredients, the amino
Excipients:
or cardiotoxic effects may increase the toxicity of interferons in acid phenylalanine.
these systems. IMUKIN should not be mixed with other drugs L-arginine, phosphoric acid, polysorbate 20 The reconstituted
One effervescent tablet contains the equivalent of 11.2 mg
in the same syringe. solution contains 1,000 units (5 mg) tenecteplase per ml. Potency
phenylalanine, which causes problems in patients with
phenylketonuria, a rare metabolic disorder. Therefore, in these of tenecteplase is expressed in units (U) by using a reference
DOSAGE AND ADMINISTRATION: standard which is specic for tenecteplase and is not comparable
patients, use of KIDDI PHARMATON FIZZ is only indicated
The recommended dosage of Imukin for injection, in patients with in the most severe cases of vitamin deciency and under medical with units used for other thrombolytic agents.
CGD is 50 mcg/m2 three times a week, for those patients whose supervision.
body surface area is greater than 0.5 m2 and 1.5 mcg/kg/dose for PHARMACOLOGICAL PROPERTIES:
those, whose body surface area is equal to, or less than 0.5 m2. PRECAUTIONS Tenecteplase is a recombinant brin-specic plasminogen
The actually drawn volume must be controlled before injection. Unless otherwise prescribed by the physician, KIDDI activator that is derived from native t-PA by modications at three
Injection should be administered subcutaneously, preferably in the PHARMATON FIZZ should not be taken for a prolonged sites of the protein structure. It binds to the brin component of the
evening. period of time in a dosage higher than the recommended one. thrombus (blood clot) and selectively converts thrombus-bound
The optimum sites for injection are the right and the left deltoid, Inform your physician or pharmacist, if you plasminogen to plasmin, which degrades the brin matrix of the
and the anterior thigh. Imukin can be administered by a physician, thrombus. Tenecteplase has higher brin specicity and greater
- suffer from other diseases
nurse, family member or the patient themself provided they are resistance to inactivation by its endogenous inhibitor (PAI-1)
- have any allergies
trained in the administration of subcutaneous injections. Although compared to native t-PA.
the most benecial dose of Imukin has not yet been established, - take or use other medications (also self-purchased - be it topic
or systemic) After administration of tenecteplase dose dependent consumption
higher doses than that referred to above are not recommended, as of 2-antiplasmin (the uid-phase inhibitor of plasmin) with
neither the safety nor efcacy has been established for higher or PREGNANCY AND LACTATION consequent increase in the level of systemic plasmin generation
lower doses. If severe reactions occur, the dose should be modied KIDDI PHARMATON FIZZ is specic for children. have been observed. This observation is consistent with the
(50% reduction), or therapy discontinued until adverse reactions
Nevertheless, according to general medical practice, the use of intended effect of plasminogen activation. In comparative studies
abate.
KIDDI PHARMATON FIZZ by pregnant and lactating women a less than 15% reduction in brinogen and a less than 25 %
OVERDOSAGE: should be decided by the prescribing physician. reduction in plasminogen were observed in subjects treated with
IMUKIN has been administered at higher doses (>100 mcg/ the maximum dose of tenecteplase (10,000 U, corresponding to 50
m2) to patients with advanced malignancies by the intravenous mg), whereas alteplase caused an approximately 50% decrease in
or intramuscular route. Central nervous system adverse reactions School-aged children from 6 to 14 years of age: one effervescent brinogen and plasminogen levels.
including decreased mental status, gait disturbance and dizziness tablet per day.
No clinically relevant antibody formation was detected at 30 days.
have been observed, particularly in cancer patients receiving doses KIDDI PHARMATON FIZZ is preferably taken during Patency data from the phase I and II angiographic studies suggest
greater than 100 mcg/m2/day. These abnormalities were reversible breakfast or lunch. that tenecteplase, administered as a single intravenous bolus, is
within a few days upon dose reduction or discontinuation of Dissolve KIDDI PHARMATON FIZZ in a glass of water. effective in dissolving blood clots in the infarct-related artery of
therapy. Reversible neutropenia, elevation of hepatic enzymes and KIDDI PHARMATON is sugar-free. It has a pleasant orange subjects experiencing an AMI on a dose related basis.
of triglycerides and thrombocytopenia have also been observed. taste which comes from orange avoring, and its color is derived A large scale mortality trial (ASSENT II) in approx. 17,000
SPECIAL PRECAUTIONS FOR STORAGE: from the natural ingredient, Beta-carotene. patients showed that tenecteplase is therapeutically equivalent
The formulation does not contain a preservative. Once opened, the Observe the dosage indicated on the leaet or prescribed by our to alteplase in reducing mortality (6.2% for both treatments,
content of a vial should be used immediately. The unused portion physician. at 30 days) and that the use of tenecteplase is associated with a
of any vial should be discarded. As is the case for all parenteral If you think the effect of the drug is too weak or too strong, consult signicantly lower incidence of non-intracranial bleedings (26.4%
drug products Imukin should be inspected visually for particulate your physician or pharmacist. vs. 28.9%, p=0.0003).
matter and discolouration prior to administration. Side-effects This translates into a signicantly lower need of transfusions
Vials of IMUKIN must be placed in a refrigerator (2 - 8C). So far, no signicant side-effects have been observed when KIDDI (4.3% vs. 5.5%, p=0.0002). Intracranial haemorrhage occurred
Avoid subzero temperatures. PHARMATON is used as prescribed. at a rate of 0.93% vs. 0.94% for tenecteplase and alteplase,
Vials of IMUKIN must not be shaken vigorously. respectively. In the 475 patients treated beyond 6 hours numerical
STORAGE CONDITIONS
AVAILABILITY: differences in favour of tenecteplase were observed with regard
Keep in a dry place, at room temperature (15-25C) and out of to 30-day mortality (4.3% vs. 9.6%), stroke (0.4% vs. 3.3%) and
Vials of 100 mcg/0.5 ml the reach of children. ICH (0% vs. 1.7%).
The drug may only be used up to the expiration date indicated on
KIDDI PHARMATON FIZZ eff. tablets the container with EXP. PHARMACOKINETICS:
OTC Further information is available from your physician or Tenecteplase is an intravenously administered, recombinant
pharmacist. protein that activates plasminogen. Tenecteplase is cleared
(Lysine Hydrochloride, Beta-carotene, Vita- from the circulation by binding to specic receptors in the liver
min A, Vitamin B1, Vitamin B2, Vitamin B6, COMPOSITION followed by catabolism to small peptides. Binding to hepatic
One effervescent Tablet contains: receptors is, however, reduced compared to native t-PA, resulting
Vitamin B12, Vitamin C,Vitamin D3 ,Vita-
Active ingredients: in a prolonged halife.
min E, Folic Acid, Biotin, Niacinamide (PP), Lysine hydrochloride 500.0 mg Data on tissue distribution and elimination were obtained in studies
Manganese, Copper, Calcium, Magnesium, Beta-carotene 1.2 mg with radioactively labelled tenecteplase in rats. The main organ
Iron, Zinc) Vitamin A 1665 IU to which tenecteplase distributed was the liver. It is not known
Vitamin B1 1.0 mg whether and to which extent tenecteplase binds to plasma proteins
PROPERTIES Vitamin B2 1.2 mg in humans. After single intravenous bolus injection of tenecteplase
KIDDI PHARMATON FIZZ with lysine is a balanced Vitamin B6 1.4 mg in patients with acute myocardial infarction, tenecteplase antigen
multivitamin product with minerals and trace elements. Vitamin B12 1.4 mcg exhibits biphasic elimination from plasma.
For growing children, one effervescent tablet covers the daily Vitamin C 45.0 mg There is no dose dependence of tenecteplase clearance in the
requirement of 11 essential vitamins, as well as a substantial Vitamin D3 400 IU therapeutic dose range. The initial, dominant half-life is 24 5.5
percentage of the daily requirement of 6 minerals and lysine. Vitamin E 7.0 mg (mean +/-SD) min, which is 5 times longer than native t-PA. The
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SPDI
terminal half-life is 129 87 min, and plasma clearance is 119 Arrhythmias Coronary thrombolysis may result in arrhythmia Patients body weight Tenecteplase Tenecteplase Corresponding
49 ml/min. Increasing body weight resulted in a moderate increase associated with reperfusion. category (kg) (U) (mg) volume of
of tenecteplase clearance, and increasing age resulted in a slight Glyco-ProteinIIb/IIIa antagonists There is no experience with reconstituted
decrease of clearance. the use of GPIIb/IIIa antagonists within the rst 24 hours after solution(ml)
Women exhibit in general lower clearance than men, but this start of treatment. < 60 6,000 30 6
can be explained by the generally lower body weight of women. Thrombo-embolism The use of METALYSE can increase 60 to < 70 7,000 35 7
Because elimination of tenecteplase is through the liver, it is not the risk of thrombo-embolic events in patients with left heart 70 to < 80 8,000 40 8
expected that renal dysfunction will affect the pharmacokinetics of thrombus, e.g., mitral stenosis or atrial brillation.
METALYSE. This is also supported by animal data. However, 80 to < 90 9,000 45 9
Re-administration No antibody formation to the tenecteplase
the effect of renal and hepatic dysfunction on pharmacokinetics of 90 10,000 50 10
molecule has been observed after treatment. However, there is no
tenecteplase in humans has not been specically investigated.
experience with re-administration of METALYSE. The required dose should be administered as a single intravenous
INDICATIONS: bolus over 5 to 10 seconds. A pre-existing intravenous line, which
INTERACTIONS:
has been used for administration of 0.9% sodium chloride solution
METALYSE is indicated for the thrombolytic treatment of acute
No formal interaction studies with METALYSE and medicinal only, may be used for administration of METALYSE.
myocardial infarction (AMI). Treatment should be initiated as
products commonly administered in patients with AMI have
soon as possible after symptom onset. If a line is used, this line should be ushed after METALYSE
been performed. However, the analysis of data from more than
injection for proper delivery. METALYSE is incompatible with
CONTRAINDICATIONS: 12,000 patients treated during phase I, II and III did not reveal
dextrose solution. No other medicinal product should be added to
Thrombolytic therapy is associated with a risk of bleeding. any clinically relevant interactions with medicinal products
the injection solution or infusion line.
Therefore, METALYSE is contraindicated in the following commonly used in patients with AMI and concomitantly used
Adjunctive Therapy:
situations: with METALYSE. Medicinal products that affect coagulation or
those that alter platelet function may increase the risk of bleeding Acetylsalicylic acid (ASA) and heparin should be administered
Signicant bleeding disorder at present or within the past 6 as soon as possible after diagnosis to inhibit the thrombogenic
months, known haemorrhagic diathesis prior to, during or after METALYSE therapy.
process. ASA should be administered as soon as possible after AMI
Patients with current concomitant oral anticoagulant therapy PREGNANCY AND LACTATION: symptom onset and continued at least until hospital discharge.
(INR > 1.3) There is no experience of use of METALYSE in pregnant The recommended initial oral dose is between 150 and 325 mg
Any history of central nervous system damage woman. The benet of treatment must be evaluated against the per day. If the patient is unable to ingest tablets, an initial dose
(i.e. neoplasm, aneurysm, intracranial or spinal surgery) potential risks in case of myocardial infarction during pregnancy. of 100 - 250 mg may be given intravenously if available. The
Severe uncontrolled arterial hypertension It is not known if tenecteplase is excreted into breast milk. ASA dosage during the following days will be at the discretion
of the treating physician. Heparin should be administered as soon
Major surgery, biopsy of a parenchymal organ, or signicant SIDE EFFECTS: as possible after the diagnosis of AMI has been conrmed, and
trauma within the past 2 months (this includes any trauma
The following adverse events which may be causally related to continued for at least 24 hours on a body weight adjusted basis.
associated with the current AMI), recent trauma to the head or
the administration of METALYSE have been reported. As with For patients weighing 67 kg or less, an initial intravenous heparin
cranium
other thrombolytic agents, haemorrhage is the most common bolus not exceeding 4,000 IU is recommended followed initially
Prolonged or traumatic cardiopulmonary resuscitation (> 2
undesirable effect associated with the use of METALYSE. The by not more than an 800 IU/hour infusion.
minutes) within the past 2 weeks
type of haemorrhage associated with thrombolytic therapy can be For patients weighing more than 67 kg, an initial intravenous
Severe hepatic dysfunction, including hepatic failure, cirrhosis, divided into two broad categories: supercial bleeding, normally heparin bolus not exceeding 5,000 IU is recommended followed
portal hypertension (oesophageal varices) and active hepatitis from injection sites internal bleedings into the gastro-intestinal initially by 1,000 IU/hour infusion. For patients already receiving
Diabetic haemorrhagic retinopathy or other haemorrhagic or urinary tract, haemopericardium, pulmonary haemorrhage, heparin treatment, the initial bolus should not be given. The
ophthalmic conditions retroperitoneal bleeding and cerebral haemorrhage (including infusion rate should be adjusted to maintain an aPTT of 50 -75
Active peptic ulceration respective neurological symptoms such as somnolence, aphasia, seconds (1.5 to 2.5 times control or a heparin plasma level of 0.2
Arterial aneurysm and known arterial/venous malformation convulsion). to 0.5 IU/ml).
Neoplasm with increased bleeding risk Death and permanent disability are reported in patients who have INSTRUCTIONS FOR USE / HANDLING:
Acute pericarditis and/or subacute bacterial endocarditis experienced stroke (including intracranial bleeding) and other METALYSE should be reconstituted by adding the complete
Acute pancreatitis serious bleeding episodes. The frequencies given below are based volume of water for injections from the pre-lled syringe to the
Hypersensitivity to the active substance tenecteplase and to any on corresponding occurrences in a clinical trial involving 8,258 vial containing the powder for injection.
of the excipients patients treated with METALYSE for myocardial infarction. 1. Ensure that the appropriate vial size is chosen according to the
The classication of cholesterol crystal embolisation is based on body weight of the patient. (see Dosage and Administration)
SPECIAL WARNINGS AND PRECAUTIONS: the fact that in the largest BI sponsored clinical trials in which >
2. Check that the cap of the vial is still intact.
METALYSE should be prescribed by physicians experienced 14,000 patients were treated no respective case was seen.
in the use of thrombolytic treatment and with the facilities to 3. Remove the ip-off cap from the vial.
Nervous system disorders: 4. Remove the tip-cap from the syringe. Then immediately screw
monitor that use. This does not preclude the prehospital use of
Uncommon: intracranial haemorrhage the pre-lled syringe on the vial adapter and penetrate the vial
METALYSE. As with other thrombolytics, it is recommended
that when METALYSE is administered standard resuscitation Cardiac disorders stopper in the middle with the spike of the vial adapter.
equipment and medication be available in all circumstances. Very common: reperfusion arrhythmias 5. Add the water for injections into the vial by pushing the syringe
plunger down slowly down to avoid foaming.
Bleeding The most common complication encountered during Rare: haemopericardium
6. Reconstitute by swirling gently.
METALYSE therapy is bleeding. The concomitant use of Vascular Disorders:
7. The reconstituted preparation is a colourless to pale yellow,
heparin anticoagulation may contribute to bleeding. As brin Very common: bleeding clear solution. Only clear solution without particles should be
is lysed during METALYSE therapy, bleeding from recent
Common: ecchymosis used.
puncture sites may occur.
Uncommon: thrombotic embolisation 8. Directly before the solution is administered, invert the vial with
Therefore, thrombolytic therapy requires careful attention to the syringe still attached, so that the syringe is below the vial.
all possible bleeding sites (including those following catheter Respiratory, thoracic and mediastinal disorders
Common: epistaxis 9. Transfer the appropriate volume of reconstituted solution of
insertions, arterial and venous puncture, cutdown and needle METALYSE into the syringe, based on the patients
puncture). The use of rigid catheters, intramuscular injections and Uncommon: pulmonary haemorrhage
weight.
non-essential handling of the patient should be avoided during Gastro-intestinal Disorders:
10. Disconnect the syringe from the vial adapter.
treatment with METALYSE. Should serious bleeding occur, Common: bleeding into gastrointestinal tract, nausea, vomiting 11. METALYSE should be administered to the patient,
in particular cerebral haemorrhage, concomitant heparin Uncommon: bleeding into retroperitoneum intravenously over 5 to 10 seconds. It should not be administered
administration should be terminated immediately. Administration Reproductive System and Breastdisorders: into a line containing dextrose.
of protamine should be considered if heparin has been administered 12. Any unused solution should be discarded.
Common: bleeding into urogenital tract
within 4 hours before the onset of bleeding. In the few patients Alternatively the reconstitution can be performed with the
who fail to respond to these conservative measures, judicious use General Disorders and Administration
included needle.
of transfusion products may be indicated. Site Conditions:
Transfusion of cryoprecipitate, fresh frozen plasma, and platelets Very common: supercial bleeding, normally from punctures or OVERDOSE:
should be considered with clinical and laboratory reassessment damaged blood vessels In the event of overdose there may be an increased risk of bleeding.
after each administration. A target brinogen level of 1 g/l is Investigations: In case of severe prolonged bleeding substitution therapy may be
desirable with cryoprecipitate infusion. Antibrinolytic agents considered.
Very common: drop in blood pressure
should also be considered. The use of METALYSE therapy has Common: increased temperature INCOMPATIBILITIES:
to be carefully evaluated in order to balance the potential risks of METALYSE is incompatible with dextrose solution. No other
Injury, Poisoning and Procedural Complications:
bleeding with expected benets under the following conditions: medicinal product should be added to the injection solution or
Uncommon: anaphylactoid reactions (incl. rash, urticaria,
Systolic blood pressure > 160 mm Hg infusion line.
bronchospasm, laryngeal oedema)
Any known or suspected history of stroke or transient ischaemic
Very rare: cholesterol crystal embolisation SPECIAL PRECAUTIONS FOR STORAGE:
attack
Surgical and Medical Procedures: Do not store above 30 C. Keep the container in the outer carton in
Recent gastro-intestinal or genitourinary bleeding (within the
past 10 days) Common: blood transfusion necessary order to protect from light.
Any known recent (within the past 2 days) intramuscular DOSAGE AND ADMINISTRATION: RECONSTITUTED SOLUTION:
injection
METALYSE should be administered on the basis of body weight, Chemical and physical in-use stability has been demonstrated for
Advanced age, i.e. over 75 years with a maximum dose of 10,000 units (50 mg tenecteplase). The up to 24 hours at 2 8 C and 8 hours at 30 C.
Low body weight < 60 kg volume required to administer the correct dose can be calculated From a microbiological point of view, the product should be used
Cerebrovascular disease from the following scheme: immediately after reconstitution. If not used immediately, in-use
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SPDI
storage times and conditions prior to use are the responsibility of (AUC) increase disproportionately with dose. There is no evidence SPECIAL WARNINGS AND PRECAUTIONS:
the user and would normally not be longer than 24 hours at 2 - 8 of clinically relevant accumulation of telmisartan. After oral (and Renovascular hypertension: There is an increased risk of severe
C or 8 hours at 30 C. intravenous) administration telmisartan is nearly exclusively hypotension and renal insufciency when patients with bilateral
excreted with the faeces, exclusively as unchanged compound. renal artery stenosis or stenosis of the artery to a single functioning
AVAILABILITY: Cumulative urinary excretion is < 2% of dose. kidney are treated with medicinal products that affect the renin-
Vial with 50 mg powder for solution for injection + pre-lled Total plasma clearance (CLtot) is high (approximately 900 ml/min angiotensin-aldosterone system.
syringe with 10 ml water for injection. compared with hepatic blood ow (about 1500 ml/min). Renal impairment and kidney transplant: When MICARDIS
Elderly patients: The pharmacokinetics of telmisartan do not is used in patients with impaired renal function, a periodic moni-
MICARDIS Tablet. differ between younger and elderly patients. toring of potassium and creatinine serum levels is recommended.
Patients with renal impairment: Lower plasma concentrations There is no experience regarding the administration of Micardis in
(Telmisartan) were observed in patients with renal insufciency undergoing patients with a recent kidney transplant.
dialysis. Telmisartan is highly bound to plasma protein in
Intravascular volume depletion: Symptomatic hypotension,
COMPOSITION: renal-insufcient subjects and cannot be removed by dialysis.
especially after the rst dose, may occur in patients who are volume
The elimination half-life is not changed in patients with renal
1 tablet contains 40 or 80 mg [1,1-biphenyl]-2-carboxylic and/or sodium depleted by vigorous diuretic therapy, dietary salt
impairment.
acid, 4-[(1,4dimethyl-2-propyl[2,6-bi-1Hbenzimidazole]- 1- restriction, diarrhoea or vomiting. Such conditions should be
Patients with hepatic impairment: corrected before the administration of Micardis. Volume and/or
yl)methyl] (= telmisartan)
Pharmacokinetic studies in patients with hepatic impairment sodium depletion should be corrected prior to administration of
Excipients: povidone, meglumine, sodium hydroxide, sorbitol,
showed an increase in absolute bioavailability up to nearly 100%. MICARDIS.
magnesium stearate.
The elimination half-life is not changed in patients with hepatic
Other conditions with stimulation of the reninangiotensinaldos
PHARMACOLOGICAL PROPERTIES: impairment.
terone system: In patients whose vascular tone and renal function
Telmisartan is an orally effective and specic angiotensin II INDICATIONS: depend predominantly on the activity of the reninangiotensin-
receptor (type AT1) antagonist. Telmisartan displaces angiotensin aldosterone system (e.g. patients with severe congestive heart
Treatment of essential hypertension.
II with very high afnity from its binding site at the AT1 receptor failure or underlying renal disease, including renal artery stenosis),
subtype, which is responsible for the known actions of angiotensin CONTRAINDICATIONS: treatment with other medicinal products that affect this system has
II. Telmisartan does not exhibit any partial agonist activity at the Hypersensitivity to the active ingredient or any of the been associated with acute hypotension, hyperazotaemia, oliguria,
AT1 receptor. Telmisartan selectively binds the AT1 receptor. The excipients or rarely acute renal failure.
binding is long lasting. Telmisartan does not show afnity for Second and third trimesters of pregnancy and lactation Primary Aldosteronism:
other receptors, including AT2 and other less characterised AT Biliary obstructive disorders
receptors. Patients with primary aldosteronism generally will not respond to
Severe hepatic impairment antihypertensive medicinal products acting through inhibition of
The functional role of these receptors is not known, nor is the Severe renal impairment
effect of their possible overstimulation by angiotensin II, whose the reninangiotensin system. Therefore, the use of telmisartan is
levels are increased by telmisartan. Plasma aldosterone levels SIDE EFFECTS: not recommended.
are decreased by telmisartan. Telmisartan does not inhibit human The overall incidence of adverse events reported with telmisartan Aortic and mitral valve stenosis, obstructive hypertrophic
plasma renin or block ion channels. Telmisartan does not inhibit (41.4%) was usually comparable to placebo (43.9%) in cardiomyopathy: As with other vasodilators, special caution is
angiotensin converting enzyme (kininase II), the enzyme which placebocontrolled trials. The incidence of adverse events was indicated in patients suffering from aortic or mitral stenosis, or
also degrades bradykinin. not dose related and showed no correlation with gender, age obstructive hypertrophic cardiomyopathy.
Therefore it is not expected to potentiate bradykinin-mediated or race of the patients. The adverse drug reactions listed below Hyperkalaemia:
adverse effects. In man, an 80 mg dose of telmisartan almost have been accumulated from all clinical trials including 5788 During treatment with other medicinal products that affect the
completely inhibits the angiotensin II evoked blood pressure hypertensive patients treated with telmisartan. Adverse reactions renin-angiotensin-aldosterone system hyperkalaemia may occur,
increase. The inhibitory effect is maintained over 24 hours and have been ranked under headings of frequency using the following
especially in the presence of renal impairment and/or heart failure.
still measurable up to 48 hours. convention:
Monitoring of serum potassium in patients at risk is recommended.
very common ( 1/10); common ( 1/100, < 1/10); uncommon Based on experience with the use of other medicinal products
After the rst dose of telmisartan, the antihypertensive activity
( 1/1.000, < 1/100); rare ( 1/10.000, < 1/1.000); very rare (< that affect the renin-angiotensin system, concomitant use
gradually becomes evident within 3 hours. The maximum
1/10.000)
reduction in blood pressure is generally attained 4 weeks after the with potassium-sparing diuretics, potassium supplements, salt
start of treatment and is sustained during long-term therapy. Body as a whole , general: substitutes containing potassium or other medicinal products
The antihypertensive effect persists constantly over 24 hours after Common: Back pain (eg. Sciatica), chest pain, that may increase the potassium level (heparin, etc.) may lead
dosing and includes the last 4 hours before the next dose as shown inuenza-like symptoms, symptoms to an increase in serum potassium and should therefore be co-
by ambulatory blood pressure measurements. This is conrmed of infection (eg. Urinary tract administered cautiously with MICARDIS.
by trough to peak ratios consistently above 80 % seen after doses infections including cystitis) Hepatic Impairment:
of 40 and 80 mg of telmisartan in placebo controlled clinical Uncommon: Abnormal vision, sweating increased. Telmisartan is mostly eliminated in the bile. Patients with biliary
studies. There is an apparent trend to a dose relationship to a time Central and peripheral nervous system: obstructive disorders or hepatic insufciency can be expected to
to recovery of baseline SBP. In this respect data concerning DBP Uncommon Vertigo have reduced clearance. Telmisartan should be used with caution
are inconsistent. in these patients.
Gastro-intestinal system:
In patients with hypertension telmisartan reduces both systolic Sorbitol:
Common: Abdominal pain, diarrhea, dyspepsia,
and diastolic blood pressure without affecting pulse rate. The
Gastrointestinal Disorders A recommended daily dose of MICARDIS 40 mg tablets
antihypertensive efcacy of telmisartan is comparable to that
Uncommon: Dry mouth, atulence contains 169 mg sorbitol. MICARDIS is therefore unsuitable
of agents representative of other classes of antihypertensive
drugs (demonstrated in clinical trials comparing telmisartan to Musculo-skeletal System: for patients with hereditary fructose intolerance.
amlodipine, atenolol , enalapril, hydrochlorothiazide, losartan and Common: Arthralgia,cramps in legs or leg pain, Other:
lisinopril. myalgia As observed for angiotensin converting enzyme inhibitors,
Upon abrupt cessation of treatment with telmisartan, blood Uncommon: Tendinitis like symptoms telmisartan and the other angiotensin antagonist are apparently
pressure gradually returns to pre-treatment values over a period Psychiatric system: less effective in lowering blood pressure in black people than
of several days without evidence of rebound hypertension. The Uncommon Anxiety in non-blacks, possibly because of higher prevalence of low-
incidence of dry cough was signicantly lower in patients treated renin states in the black hypertensive population. As with any
Respiratory System antihypertensive agent, excessive reduction of blood pressure in
with telmisartan than in those given angiotensin converting
enzyme inhibitors in clinical trials directly comparing the two Uncommon: Upper respiratory tract infections patients with ischaemic cardiopathy or ischaemic cardiovascular
antihypertensive treatments. Benecial effects of telmisartan on including pharyngitis and sinusitis disease could result in a myocardial infarction or stroke.
mortality and cardiovascular morbidity are currently unknown. Skin And Appendages System:
INTERACTIONS:
Common: Skin disorders like eczema
PHARMACOKINETICS: Telmisartan may increase the hypotensive effect of other
In addition, since the introduction of telmisartan in the market,
Absorption of telmisartan is rapid although the amount absorbed antihypertensive agents. Other interactions of clinical signicance
cases of erythema, pruritus, faintness, insomnia, depression,
varies. The mean absolute bioavailability for telmisartan is about have not been identied. Compounds, which have been
stomach upset, vomiting, hypotension, bradycardia, tachycardia,
50%. When telmisartan is taken with food, the reduction in the area studied in pharmacokinetic trials, include digoxin, warfarin,
dyspnoea, eosinophilia, thrombocytopenia, weakness and lack
under the plasma concentrationtime curve (AUC) of telmisartan hydrochlorothiazide , glibenclamide, ibuprofen, paracetamol,
of efcacy have been reported rarely. As with other angiotensin
varies from approximately 6% (40 mg dose) to approximately simvastatin and amlodipine. For digoxin a 20% increase in median
II antagonists isolated cases of angioedema, urticaria and other
19% (160 mg dose). By 3 hours after administration plasma plasma digoxin trough concentration has been observed (39%
related events have been reported.
concentrations are similar whether telmisartan is taken fasting or in a single case), monitoring of plasma digoxin levels should be
with food. Laboratory ndings: considered.
The small reduction in AUC is not expected to cause a No signicant differences in changes in laboratory test parameters Reversible increases in serum lithium concentrations and toxicity
reduction in the therapeutic efcacy. Gender differences in were observed in clinical studies with telmisartan.
have been reported during concomitant administration of lithium
plasma concentrations were observed, Cmax and AUC being Infrequently, a decrease in haemoglobin or an increase in uric with angiotensin converting enzyme inhibitors. Very rare cases
approximately 3-and 2-fold higher, respectively, in females acid have been observed which occur more often during treatment have also been reported with angiotensin II receptor antagonists.
compared to males without relevant inuence on efcacy. with telmisartan than with placebo. Increases in creatinine or liver Therefore, serum lithium level monitoring is advisable during
Telmisartan is largely bound to plasma protein (> 99.5 %), mainly enzymes have been observed during treatment with telmisartan concomitant use.
albumin and alpha-1 acid glycoprotein. The mean steady state but these changes in laboratory ndings occurred with a frequency
apparent volume of distribution (Vss) is approximately 500 L. similar to or lower than placebo. PREGNANCY AND LACTATION:
Telmisartan is metabolised by conjugation to the glucuronide of the In addition, the following adverse events occurred in more than There are no adequate data on the use of telmisartan in pregnant
parent compound . No pharmacological activity has been shown 1 % of the 3,445 patients treated in all trials with telmisartan: women. Preclinical studies do not indicate teratogenic effect, but
for the conjugate. Telmisartan is characterised by biexponential bronchitis, insomnia, arthralgia, anxiety, depression, palpitation, have shown fetotoxicity. Therefore as a precautionary measure,
decay pharmacokinetics with a terminal elimination half-life of cramps (legs), rash. Causal association of these events with telmisartan should preferably not be used during the rst trimester
>20 hours. The maximum plasma concentration (Cmax) and, to telmisartan could not be established. A single case of angioedema of pregnancy. A switch to a suitable alternative treatment should be
a smaller extent, area under the plasma concentration-time curve was reported. carried out in advance of a planned pregnancy.
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In the second and third trimesters, substances that act directly on Therefore it is not expected to potentiate bradykininmediated Elderly patients:
the reninangiotensin- system can cause injury and even death in adverse effects. In man, an 80 mg dose of telmisartan almost Pharmacokinetics of telmisartan do not differ between the elderly
the developing foetus; therefore, telmisartan is contraindicated completely inhibits the angiotensin II evoked blood pressure
and those younger than 65 years.
in the second and third trimesters of pregnancy. If pregnancy is increase. The inhibitory effect is maintained over 24 hours and
diagnosed telmisartan should be discontinued as soon as possible. still measurable up to 48 hours. After the rst dose of telmisartan, Patients with renal impairment: Renal excretion does not
the antihypertensive activity gradually becomes evident within 3 contribute to the clearance of telmisartan. Based on modest
Telmisartan is contraindicated during lactation since it is not
known whether it is excreted in human milk. hours. experience in patients with mild to moderate renal impairment
The maximum reduction in blood pressure is generally attained (creatinine clearance of 30 60 ml/min, mean about 50 ml/min)
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: no dosage adjustment is necessary in patients with decreased
4 weeks after the start of treatment and is sustained during long-
No studies on the effect on the ability to drive and use machines term therapy. The antihypertensive effect persists constantly over renal function. Telmisartan is not removed from blood by
have been performed. However, when driving vehicles or operating 24 hours after dosing and includes the last 4 hours before the next haemodialysis. In patients with impaired renal function the rate
machinery it must be borne in mind that dizziness or drowsiness dose as shown by ambulatory blood pressure measurements. This of hydrochlorothiazide elimination is reduced. In a typical study
may occasionally occur when taking antihypertensive therapy. is conrmed by trough to peak ratios consistently above 80% seen in patients with a mean creatinine clearance of 90 ml/min the
after doses of 40 and 80 mg of telmisartan in placebo controlled elimination halife of hydrochlorothiazide was increased. In
clinical studies. functionally anephric patients the elimination half-life is about 34
Adults: hours.
In patients with hypertension telmisartan reduces both systolic
The recommended dose is 40 mg once daily. Some patients may Patients with hepatic impairment: Pharmacokinetic studies in
and diastolic blood pressure without affecting pulse rate. The
already benet at a daily dose of 20 mg. In cases where the target patients with hepatic impairment showed an increase in absolute
antihypertensive efcacy of telmisartan is comparable to that
blood pressure is not achieved, telmisartan dose can be increased
of agents representative of other classes of antihypertensive bioavailability up to nearly 100%. The elimination half-life is not
to a maximum of 80 mg once daily. Alternatively, telmisartan
drugs (demonstrated in clinical trials comparing telmisartan to changed in patients with hepatic impairment.
may be used in combination with thiazide-type diuretics such as
amlodipine, atenolol, enalapril, hydrochlorothiazide , losartan ,
hydrochlorothiazide, which has been shown to have an additive INDICATIONS:
and lisinopril).
blood pressure lowering effect with telmisartan. When considering Treatment of essential hypertension. As xed dose combination
raising the dose, it must be borne in mind that the maximum Upon abrupt cessation of treatment with telmisartan, blood
MICARDIS PLUS is indicated in patients whose blood pressure
antihypertensive effect is generally attained four - eight weeks pressure gradually returns to pre-treatment values over a period
is not adequately controlled on telmisartan or hydrochlorothiazide
after the start of treatment. of several days without evidence of rebound hypertension. The
alone.
In patients with severe hypertension treatment with telmisartan incidence of dry cough was signicantly lower in patients treated
at doses up to 160 mg alone and in combination with with telmisartan than in those given angiotensin converting CONTRAINDICATIONS
hydrochlorothiazide 12.5 - 25 mg daily was well tolerated and enzyme inhibitors in clinical trials directly comparing the two Hypersensitivity to the active ingredient, to any of the
effective . MICARDIS may be taken with or without food. antihypertensive treatments. excipients, or to other sulphonamide-derived substances
Renal Impairment: Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic. (hydrochlorothiazide is a sulphonamidederived substance).
The mechanism of the antihypertensive effect of thiazide diuretics Second and third trimesters of pregnancy and lactation
No posology adjustment is required for patients with mild to is not fully known. Thiazides effect the renal tubular mechanisms
moderate renal impairment. Telmisartan is not removed from Choleastasis and biliary obstructive disorders
of electrolyte re-absorption, directly increasing excretion of
blood by hemoltration. Severe hepatic impairment
sodium and chloride in approximately equivalent amounts. The
Hepatic Impairment: diuretic action of hydrochlorothiazide reduces plasma volume, Severe renal impairment (creatinine clearance < 30 ml/min)
In patients with mild to moderate hepatic impairment the posology increases plasma renin activity, increases aldosterone secretion, Refractory hypokalaemia, hypercalcaemia
should not exceed 40 mg once daily. with consequent increases in urinary potassium and bicarbonate
SPECIAL WARNINGS AND PRECAUTIONS:
Elderly: loss, and decreases in serum potassium.
Hepatic impairment:
No dosing adjustment is necessary. Presumably through blockade of the renin-angiotensin-
Telmisartan is mostly eliminated in the bile. Patients with biliary
aldosterone system, co-administration of telmisartan tends to
Children And Adolescents: obstructive disorders or severe hepatic insufciency can be
reverse the potassium loss associated with these diuretics. With
There are no data on the safety and efcacy of MICARDIS in expected to have reduced clearance. Therefore, MICARDIS
hydrochlorothiazides, onset of diuresis occurs in 2 hours, and
children and adolescents. PLUS should not be given to these patients. MICARDIS PLUS
peak effect occurs at about 4 hours, while the action persists for
approximately 6 - 12 hours. Epidemiological studies have shown should be used with caution in patients with impaired hepatic
OVERDOSE:
that long-term treatment with hydrochlorothiazide reduces the risk function or progressive liver disease, since minor alterations of
No data are available with regard to overdose in humans. If
of cardiovascular mortality and morbidity. uid and electrolyte balance may precipitate hepatic coma. There
symptomatic hypotension should occur, supportive treatment should
is no clinical experience with MICARDIS PLUS in patients
be instituted. Telmisartan is not removed by haemodialysis. PHARMACOKINETICS: with hepatic impairment.
STORAGE INSTRUCTIONS: Concomitant administration of hydrochlorothiazide and telmisartan Renovascular hypertension: There is an increased risk of severe
Store in a safe place below 30 C has no effect on the pharmacokinetics of either drug.
hypotension and renal insufciency when patients with bilateral
Absorption: renal artery stenosis or stenosis of the artery to a single functioning
AVAILABILITY:
Telmisartan: Following oral administration peak concentrations kidney are treated with medicinal products that affect the renin-
Tablets of 40 and 80 mg of telmisartan are reached in 0.5 1.5 h after dosing. The angiotensin-aldosterone system.
absolute bioavailability of telmisartan at 40 mg and 160 mg Renal impairment and kidney transplant:
MICARDIS PLUS Tablets was 42% and 58%, respectively. Food slightly reduces the
Experience with MICARDIS PLUS is modest and therefore
bioavailability of telmisartan with a reduction in the area under
the plasma concentration time curve (AUC) of about 6% with periodic monitoring of potassium, creatinine and uric acid serum
(Telmisartan and Hydrochlorothiazide) the 40 mg tablet and about 19% after a 160 mg dose. By 3 hours levels is recommended. MICARDIS PLUS should not be used
after administration plasma concentrations are similar whether in patients with severe renal impairment (creatinine clearance <
COMPOSITION: telmisartan is taken fasting or with food. The small reduction 30 ml/min). Thiazide diuretic-associated azotaemia may occur
in AUC is not expected to cause a reduction in the therapeutic in patients with impaired renal function. There is no experience
1 tablet contains: [1,1-biphenyl]-2-carboxylic acid, 4-
efcacy. The pharmacokinetics of orally administered telmisartan regarding the administration of MICARDIS PLUS in patients
[(1,4dimethyl-2-propyl[2,6-bi- 1H-benzimidazole]-1-yl)methyl]
are non-linear over doses from 20 160 mg with greater than with a recent kidney transplant.
(= telmisartan) 40 or 80 mg Hydrochlorothiazide 12.5 mg
Excipients: proportional increases of plasma concentrations (Cmax and Intravascular volume depletion: Symptomatic hypotension,
AUC) with increasing doses. Telmisartan does not accumulate especially after the rst dose, may occur in patients who are
povidone, meglumine, sodium hydroxide, sorbitol, magnesium signicantly in plasma on repeated administration. volume and/or sodium depleted by vigorous diuretic therapy,
stearate, microcristalline cellulose, iron oxide red, sodium starch
Hydrochlorothiazide: Following oral administration of dietary salt restriction, diarrhoea or vomiting. Such conditions
glycolate, lactose monohydrate, maize starch
MICARDIS PLUS peak concentrations of hydrochlorothiazide should be corrected before the administration of MICARDIS
PHARMACOLOGICAL PROPERTIES: are reached in approximately 1.0 3.0 hours after dosing. Based PLUS.
MICARDIS PLUS is a combination of an angiotensin on cumulative renal excretion of hydrochlorothiazide the absolute Other conditions with stimulation of the renin-angiotensin-
II receptor antagonist, telmisartan, and a thiazide diuretic, bioavailability was about 60%. aldosterone system: In patients whose vascular tone and renal
hydrochlorothiazide. The combination of these ingredients has Distribution: function depend predominantly on the activity of the renin-
an additive antihypertensive effect, reducing blood pressure to a Telmisartan: Telmisartan is highly bound to plasma proteins angiotensin-aldosterone system (e.g. patients with severe
greater degree than either component alone. Micardis Plus once (> 99.5%) mainly albumin and alpha1-acid glycoprotein. The congestive heart failure or underlying renal disease, including
daily produces effective and smooth reductions in blood pressure apparent volume of distribution for telmisartan is approximately renal artery stenosis), treatment with other medicinal products
across the therapeutic dose range. 500 litres indicating additional tissue binding. that affect this system has been associated with acute hypotension,
Telmisartan: Telmisartan is an orally effective and specic Hydrochlorothiazide: hyperazotaemia, oliguria, or rarely acute renal failure.
angiotensin II receptor (type AT1) antagonist. Telmisartan Primary aldosteronism:
Hydrochlorothiazide is 64% protein bound in the plasma and its
displaces angiotensin II with very high afnity from its binding
apparent volume of distribution is 0.8 0.3 l/kg. Patients with primary aldosteronism generally will not respond to
site at the AT1 receptor subtype, which is responsible for the
known actions of angiotensin II. Telmisartan does not exhibit any Biotransformation And Elimination: antihypertensive medicinal products acting through inhibition of
partial agonist activity at the AT1 receptor. Telmisartan: the renin-angiotensin system. Therefore, the use of telmisartan is
not recommended.
Telmisartan selectively binds the AT1 receptor. The cytochrome P450 isoenzymes are not involved in the
metabolism of telmisartan. Total plasma clearance of telmisartan Aortic and mitral valve stenosis, obstructive hypertrophic
The binding is long lasting. Telmisartan does not show afnity
for other receptors, including AT2 and other less characterised after oral administration is > 1500 ml/min. Terminal elimination cardiomyopathy: As with other vasodilators, special caution is
AT receptors. The functional role of these receptors is not known, half-life was > 20 hours. indicated in patients suffering from aortic or mitral stenosis, or
nor is the effect of their possible overstimulation by angiotensin Hydrochlorothiazide: obstructive hypertrophic cardiomyopathy.
II, whose levels are increased by telmisartan. Plasma aldosterone Hydrochlorothiazide is not metabolised in man and is excreted Metabolic and endocrine effects:
levels are decreased by telmisartan. Telmisartan does not inhibit almost entirely as unchanged drug in urine. About 60% of the oral Thiazide therapy may impair glucose tolerance. In diabetic patients
human plasma renin or block ion channels. dose are eliminated as unchanged drug within 48 hours. Renal dosage adjustments of insulin or oral hypoglycaemic agents may
Telmisartan does not inhibit angiotensin converting enzyme clearance is about 250 300 ml/min. The terminal elimination be required. Latent diabetes mellitus may become manifest during
(kininase II), the enzyme which also degrades bradykinin. half-life of hydrochlorothiazide is 10 15 hours. thiazide therapy. Increase in cholesterol and triglyceride levels
169
Book_01.indd 169 6/4/2008 2:20:45 PM

SPDI
have been associated with thiazide diuretic therapy; however, at by serum potassium disturbances (e.g. digitalis glycosides, SIDE EFFECTS:
the 12.5 mg dose contained in MICARDIS PLUS, minimal or antiarrhythmics) and the following torsades de pointes inducing Fixed Dose Combination
no effects were reported. Hyperuricaemia may occur or frank gout drugs (which include some antiarrhythmics), hypokalaemia being
The overall incidence of adverse events reported with
may be precipitated in some patients receiving thiazide therapy. a predisposing factor to torsades de pointes.
MICARDIS PLUS was comparable to those reported with
Electrolyte imbalance: Class Ia antiarrythmics (e.g. quinidine, hydroquinidine, telmisartan alone in randomised controlled trials involving 1471
As for any patient receiving diuretic therapy, periodic determination disopyramide) patients receiving telmisartan plus hydrochlorothiazide (835)
of serum electrolytes should be performed at appropriate intervals. Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, or telmisartan alone (636). There was no dose-relationship to
Thiazides, including hydrochlorothiazide, can cause uid or ibutilide) undesirable effects and there was no correlation with gender, age
electrolyte imbalance (hypokalaemia, hyponatraemia, and Some antipsychotics:(e.g. thioridazine, chlorpromazine, or race of the patients.
hypochloraemic alkalosis). Warning signs of uid or electrolyte levomepromazine, triuoperazine, cyamemazine, sulpiride, Adverse reactions reported in all clinical trials and occurring more
imbalance are dryness of mouth, thirst, weakness, lethargy, sultopride, amisulpride, tiapride, pimozide, haloperidol, frequently (p 0.05) with telmisartan plus hydrochlorothiazide
drowsiness, restlessness, muscle pain or cramps, muscular droperidol) than with placebo are shown below according to system organ
fatigue, hypotension, oliguria, tachycardia, and gastro-intestinal Others: (e.g. bepridil, cisapride, diphemanil, erythromycin class. Adverse reactions known to occur with each component
disturbances such as nausea or vomiting. Although hypokalaemia IV, halofantrin, mizolastin, pentamidine, sparoxacine, given singly but which have not been seen in clinical trials may
may develop with the use of thiazide diuretics, concurrent therapy terfenadine, vincamine IV.) occur during treatment with MICARDIS PLUS.
with telmisartan may reduce diuretic-induced hypokalaemia. Digitalis glycosides: INFECTIONS AND INFESTATIONS:
The risk of hypokalaemia is greatest in patients with cirrhosis of Thiazide-induced hypokalaemia or hypomagnesaemia favours
liver, in patients experiencing brisk diuresis, in patients who are Bronchitis, pharyngitis, sinusitis, upper respiratory tract infections,
receiving inadequate oral intake of electrolytes and in patients the onset of digitalis-induced cardiac arrhythmias (see Special urinary tract infections
receiving concomitant therapy with corticosteroids or ACTH. warnings and precautions). Immune System Disorders:
Conversely, due to the antagonism of the angiotensin II (AT1) Other antihypertensive agents: Telmisartan may increase the Allergy
receptors by the telmisartan component of MICARDIS PLUS, hypotensive effect of other antihypertensive agents.
Endocrine Disorders:
hyperkalaemia might occur. Alcohol, barbiturates, narcotics, or antidepressants: potentia-
tion of orthostatic hypotension may occur. Baclofen, Loss of diabetic control
Although clinically signicant hyperkalaemia has not been
documented with MICARDIS PLUS, risk factors for the Amifostine: Metabolism And Nutrition Disorders:
development of hyperkalaemia include renal insufciency and/or Potentiation of antihypertensive effect may occur. Hypercholesterolaemia, hyperuricaemia, hypokalaemia
heart failure, and diabetes mellitus. Potassium-sparing diuretics, Psychiatric Disorders:
Antidiabetic drugs (oral agents and insulin): dosage adjustment
potassium supplements or potassium-containing salt substitutes of the antidiabetic drug may be required (see Special warnings and Anxiety
should be coadministered cautiously with MICARDIS. There is precautions); Nervous System Disorders:
no evidence that MICARDIS PLUS would reduce or prevent
diuretic-induced hyponatraemia. Chloride decit is generally mild Metformin: Metformin should be used with precaution: risk of Dizziness
and usually does not require treatment. lactic acidosis induced by a possible functional renal failure linked Ear And Labyrinth Disorders:
to hydrochlorothiazide.
Thiazides may decrease urinary calcium excretion and cause an Vertigo
intermittent and slight elevation of serum calcium in the absence of Cholestyramine and colestipol resins: absorption of hydrochlo-
Gastro-intestinal Disorders:
known disorders of calcium metabolism. Marked hypercalcaemia rothiazide is impaired in the presence of anionic exchange resins;
Non-steroidal anti-inammatory drugs: the administration of Abdominal pain, diarrhoea, dyspepsia, gastritis, gastro-intestinal
may be evidence of hidden hyperparathyroidism. Thiazides should disorders
be discontinued before carrying out tests for parathyroid function. a non-steroidal anti-inammatory drug may reduce the diuretic,
natriuretic and antihypertensive effects of thiazide diuretics in some Skin And Subcutaneous Tissue Disorders:
Thiazides have been shown to increase the urinary excretion of
magnesium, which may result in hypomagnesaemia. patients; In elderly patients and patients which may be dehydrated Eczema, skin disorders
there is a risk of acute renal failure, therefore monitoring of renal Musculoskeletal, Connective Tissue
Sorbitol: A recommended daily dose of MICARDIS PLUS function at the initiation of treatment is recommended.
40/12.5 mg tablets contains 169 mg sorbitol. MICARDIS And Bone Disorders:
PLUS is therefore unsuitable for patients with hereditary fructose Pressor amines (e.g. noradrenaline): the effect of pressor amines
Arthralgia, arthrosis, back pain, leg pain, myalgia
intolerance. may be decreased.
Reproductive System And Breast Disorders:
Other: Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine):
the effect of nondepolarizing skeletal muscle relaxants may be Impotence
As with any antihypertensive agent, excessive reduction blood
potentiated by hydrochlorothiazide; General Disorders And Administration
pressure in patients with ischaemic cardiopathy or ischaemic
cardiovascular disease could result in a myocardial infarction or Medicinal products used in the treatment for gout probenecid, Site Conditions: Inuenza-like symptoms, pain As with other
stroke. sulnpyrazone and allopurinol: dosage adjustment of uricosuric angiotensin II antagonists isolated cases of angio-oedema, urticaria
medications may be necessary as hydrochlorothiazide may raise and other related reactions have been reported.
General:
the level of serum uric acid. Increase in dosage of probenecid or Laboratory ndings:
Hypersensitivity reactions to hydrochlorothiazide may occur in sulnpyrazone may be necessary. Coadministration of thiazide
patients with or without a history of allergy or bronchial asthma, Changes in laboratory ndings that were seen in clinical trials of
may increase the incidence of hypersensitivity reactions of
but are more likely in patients with such a history. Exacerbation or telmisartan plus hydrochlorothiazide are included above.
allopurinol.
activation of systemic lupus erythematosus has been reported with ADDITIONAL INFORMATION ON INDIVIDUAL COM-
Calcium salts: Thiazide diuretics may increase serum calcium
the use of thiazide diuretics. PONENTS
levels due to the decreased excretion. If calcium supplements
INTERACTIONS: must be prescribed, serum calcium levels should be monitored and Undesirable effects previously reported with one of the individual
Lithium: calcium dosage adjusted accordingly; components are potential undesirable effects with MICARDIS
Beta-blockers and diazoxide: The hyperglycaemic effect of beta- PLUS, even if not observed thus far in clinical trials.
Reversible increases in serum lithium concentrations and toxicity
have been reported during concomitant administration of lithium blockers and diazoxide may be enhanced by thiazides. TELMISARTAN:
with angiotensin converting enzyme inhibitors. Very rare cases Anticholinergic agents (e.g. atropine, biperiden) may increase
Undesirable effects occurred with similar frequency in placebo
have also been reported with angiotensin II receptor antagonists. the bioavailability of thiazide-type diuretics by decreasing
and telmisartan treated patients. The overall incidence of adverse
In addition, renal clearance of lithium is reduced by thiazides gastrointestinal motility and stomach emptying rate.
events reported with telmisartan (41,4%) was comparable to
as a consequence the risk of lithium toxicity may be increased Amantadine: Thiazides may increase the risk of adverse effects placebo (43,9%) in placebo controlled trials. The adverse drug
with MICARDIS PLUS. Coadministration of lithium and caused by amantadine. reactions listed below have been accumulated from all clinical trials
MICARDIS PLUS should only be allowed under strict medical Cytotoxic agents (e.g. cyclophosphamide, methotrexate): including 5788 hypertensive patients treated with telmisartan:
supervision and should not be recommended. If this combination Thiazides may reduce the renal excretion of cytotoxic drugs and
proves essential, serum lithium level monitoring is recommended Infections And Infestations:
potentiate their myelosuppressive effects.
during concomitant use. Symptoms of infection (e.g. urinary tract infections including
Medicinal products associated with potassium loss and PREGNANCY AND LACTATION: cystitis), upper respiratory tract infections including pharyngitis
hypokalaemia (e.g. other kaliuretic diuretics, laxatives, There are no adequate data on the use of telmisartan in pregnant and sinusitis
corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G women. Preclinical studies do not indicate teratogenic effect, but Psychiatric Disorders:
sodium, salicylic acid and derivatives): have shown fetotoxicity. Therefore as a precautionary measure, Anxiety
If these drugs are to be prescribed with the hydrochlorothiazide- telmisartan should preferably not be used during the rst trimester Eye Disorders:
telmisartan combination, monitoring of potassium plasma levels of pregnancy. A switch to a suitable alternative treatment should
be carried out in advance of a planned pregnancy. In the second Abnormal vision
is advised. These medicinal products may potentiate the effect of
hydrochlorothiazide on serum potassium (see Special warnings and third trimesters, substances that act directly on the renin- Ear And Labyrinth Disorders:
and precautions). angiotensin-system can cause injury and even death in the Vertigo
Medicinal products that may increase potassium levels or developing foetus; therefore, telmisartan is contraindicated in the Gastro-intestinal Disorders:
induce hyperkalaemia (e.g. ACE inhibitors, potassium-sparing second and third trimesters of pregnancy.
Abdominal pain, diarrhoea, dry mouth, dyspepsia, atulence,
diuretics, potassium supplements, salt substitutes containing If pregnancy is diagnosed telmisartan should be discontinued as gastro-intestinal disorders
potassium, cyclosporin or other medicinal products such as soon as possible. Thiazides cross the placental barrier and appear
in cord blood. They may cause foetal electrolyte disturbances and Skin and subcutaneous tissue disorders:
heparin sodium):
possibly other reactions that have occurred in the adults. Cases Skin disorders like eczema, sweating increased
If these medicinal products are to be prescribed with the
hydrochlorothiazide-telmisartan combination, monitoring of of neonatal thrombocytopenia, of foetal or neonatal jaundice Musculoskeletal, connective tissue and bone disorders:
potassium plasma levels is advised. Based on the experience with have been reported with maternal thiazide therapy. Telmisartan is Arthralgia, back pain (e.g.sciatica), cramps in legs or leg pain,
the use of other medicinal products that blunt the reninangiotensin contraindicated during lactation since it is not known whether it myalgia, tendinitis like symptoms
system, concomitant use of the above medicinal products may is excreted in human milk. Thiazides appear in human milk and
General Disorders And Administration Site Conditions:
lead to increases in serum potassium (see Special warnings and may inhibit lactation.
Chest pain, inuenza-like symptoms In addition, since
precautions). EFFECTS ON ABILITY TO DRIVE AND USE MACHINES the introduction of telmisartan in the market, cases of
Medicinal products affected by serum potassium No studies on the effect on the ability to drive and use machines erythema, pruritus, faintness, insomnia, depression, vomiting,
disturbances: have been performed. However, when driving vehicles or operating hypotension, bradycardia, tachycardia, dyspnoea, eosinophilia,
Periodic monitoring of serum potassium and ECG is recommended machinery it must be borne in mind that dizziness or drowsiness thrombocytopenia, weakness, and lack of efcacy have been
when MICARDIS PLUS is administered with drugs affected may occasionally occur when taking antihypertensive therapy. reported rarely.
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SPDI
Laboratory ndings: Elderly: - Symptomatic treatment of painful osteoarthritis (arthrosis,
Infrequently, a decrease in haemoglobin or an increase in uric No dosage adjustment is necessary . degenerative joint disease).
acid have been observed which occur more often during treatment - Symptomatic treatment of rheumatoid arthritis.
Children and adolescents: - Symptomatic treatment of ankylosing spondylitis.
with telmisartan than with placebo. Increases in creatinine or liver
enzymes have been observed during treatment with telmisartan but Safety and efcacy of MICARDIS PLUS have not been
established in children and in adolescents up to 18 years. CONTRAINDICATIONS:
these occurred with a frequency similar to or lower than placebo.
Known hypersensitivity to meloxicam or any excipient of the
HYDROCHLOROTHIAZIDE: OVERDOSE: product. There is a potential for cross sensitivity to acetylsalicylic
Hydrochlorothiazide may cause or exacerbate volume depletion No specic information is available on the treatment of overdose acid and other non-steroidal anti-inammatory drugs (NSAIDs).
which could lead to electrolyte imbalance. Adverse events reported with MICARDIS PLUS. The patient should be closely Mobic should not be given to patients who have developed signs
with the use of hydrochlorothiazide alone include: monitored, and the treatment should be symptomatic and of asthma, nasal polyps, angio-oedema or urticaria following the
supportive. Management depends on the time since ingestion administration of acetylsalicylic acid or other NSAIDs.
Infections And Infestations:
and the severity of the symptoms. Suggested measures include - Active peptic ulceration
Sialadenitis induction of emesis and/or gastric lavage. Activated charcoal may - Severe hepatic insufciency
Blood and the lymphatic system disorders: be useful in the treatment of overdose. - Non-dialysed severe renal insufciency
Aplastic anaemia, haemolytic anaemia, bone marrow depression, Serum electrolytes and creatinine should be monitored frequently. - Children and adolescents aged less than 15 years
leukopenia, neutropenia/agranulocytosis, thrombocytopenia If hypotension occurs, the patient should be placed in a supine - Pregnancy or breastfeeding.
Immune system disorders: position, with salt and volume replacements given quickly. The
most likely manifestations of telmisartan overdose are expected SPECIAL PRECAUTIONS:
Anaphylactic reactions
to be hypotension and tachycardia; bradycardia might also occur. As with other NSAIDs caution should be exercised when treating
Metabolism and nutrition disorders:
Overdose with hydrochlorothiazide is associated with electrolyte patients with a history of gastrointestinal disease and in patients
Anorexia, loss of appetite depletion (hypokalaemia, hypochloraemia) and dehydration receiving treatment with anticoagulants. Patients with gastro-
Psychatric disorders: resulting from excessive diuresis. intestinal symptoms should be monitored. Mobic should be
Depression, restlessness, sleep disturbances The most common signs and symptoms of overdose are nausea withdrawn if peptic ulceration or gastrointestinal bleeding occurs.
Nervous system disorders: and somnolence. Hypokalaemia may result in muscle spasm and/ Gastro-intestinal bleeding, ulceration or perforation can occur at
or accentuate cardiac arrhythmias associated with the concomitant any time during treatment, with or without warning symptoms or a
Light-headedness, paraesthesia
use of digitalis glycosides or certain anti-arrhythmic drugs. No previous history of serious gastro-intestinal events.
Eye disorders:
data are available for telmisartan with regard to overdose in The consequences of such events are generally more serious in
Transient blurred vision, xanthopsia the elderly. Special attention should be paid in patients reporting
humans. Telmisartan is not removed by haemodialysis. The degree
Ear and labyrinth disorders: to which hydrochlorothiazide is removed by haemodialysis has not mucocutaneous adverse events and consideration given to
Vertigo been established. discontinuing MOBIC. NSAIDs inhibit the synthesis of renal
Cardiac disorders: prostaglandins which play a supportive role in the maintenance
STORAGE INSTRUCTIONS: of renal perfusion. In patients whose renal blood ow and
Cardiac arrhythmias
Store in a safe place below 30C blood volume are decreased, administration of an NSAID may
Vascular disorders: precipitate overt renal decompensation which is typically followed
Necrotizing angiitis (vasculitis), postural hypotension AVAILABILITY: by recovery to pretreatment state upon discontinuation of non-
Respiratory disorders: Tablets of 40/12.5mg and 80 mg/12.5mg steroidal anti-inammatory therapy.
Respiratory distress (including pneumonitis and pulmonary Patients at greatest risk of such a reaction are dehydrated patients,
oedema) MOBIC those with congestive heart failure, liver cirrhosis, nephrotic
Gastro-intestinal disorders: syndrome and overt renal disease, those receiving a diuretic or
Constipation, diarrhoea, gastric irritation, pancreatitis those having undergone major surgical procedures which led to
Hepato-biliary disorders:
(Meloxicam) hypovolaemia. In such patients the volume of diuresis and the
renal function should be carefully monitored at the beginning of
Jaundice (intrahepatic cholestatic jaundice) COMPOSITION: therapy.
Skin and subcutaneous tissue disorders: 1 tablet contains 7.5 mg or 15 mg [1 suppository contains 7.5 In rare instances NSAIDs may be the cause of interstitial nephritis,
Cutaneous lupus erythematosus-like reactions, cutaneous vasculitis, mg(N.R) or 15 mg 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)- glomerulonephritis, renal medullary necrosis or nephrotic
photosensitivity reactions, rash, reactivation of cutaneous lupus 2H-1,2-benzothiazine-3-carboxamide-1,1- dioxide (= meloxicam) syndrome. The dose of MOBIC in patients with end-stage
erythematosus, urticaria, toxic epidermal necrolysis. renal failure on haemodialysis should not be higher than 7.5 mg.
Excipients:
Musculoskeletal, connective tissue and bone disorders: No dose reduction is required in patients with mild or moderate
Tablets: sodium citrate, lactose, microcrystalline cellulose, renal impairment (i.e. in patients with a creatinine clearance of
Muscle spasm, weakness polyvidone, anhydrous colloidal silica, crospolyvidone, greater than 25 ml/min). As with most other NSAIDs, occasional
Renal and urinary disorders: magnesium stearate elevations of serum transaminases or other parameters of liver
Interstitial nephritis, renal dysfunction [Suppositories: hard fat, polyoxyethylenated hydrogenated castor function have been reported. In most cases these have been small
General disorders and administration site conditions: oil.(N.R)] and transient increases above the normal range.
Fever If the abnormality is signicant or persistent, MOBIC should
Laboratory ndings: be stopped and follow up tests carried out. No dose reduction is
MOBIC is a non-steroidal anti-inammatory drug (NSAID) of required in patients with clinically stable liver cirrhosis. Frail or
Hyperglycaemia, glycosuria, hyperuricaemia, electrolyte
the enolic acid class which has shown anti-inammatory, analgesic debilitated patients may tolerate side effects less well and such
imbalance (including hyponatraemia and hypokalaemia), increases
and antipyretic properties in animals. Meloxicam showed potent patients should be carefully supervised. As with other NSAIDs,
in cholesterol and triglycerides.
anti-inammatory activity in all standard models of inammation. caution should be used in the treatment of elderly patients who are
DOSAGE AND ADMINISTRATION: A common mechanism for the above effects may exist in the more likely to be suffering from impaired renal, hepatic or cardiac
Adults: ability of meloxicam to inhibit the biosynthesis of prostaglandins, function. Induction of sodium, potassium and water retention and
known mediators of inammation. Comparison of the ulcerogenic interference with the natriuretic effects of diuretics may occur with
MICARDIS PLUS should be taken once daily. The dose of
dose and the anti-inammatory effective dose in the rat adjuvant NSAIDs. Cardiac failure or hypertension may be precipitated or
telmisartan could be up-titrated before switching to MICARDIS
arthritis model conrmed a superior therapeutic margin in animals exacerbated in susceptible patients as a result.
PLUS. Direct change from monotherapy to the xed combinations
may be considered. MICARDIS PLUS 40/12.5 mg may be
over standard NSAIDs. In vivo, meloxicam inhibited prostaglandin MOBIC suppositories should not be used in patients with any
biosynthesis more potently at the site of inammation than in the inammatory lesions of the rectum or anus, or in patients with
administered in patients whose blood pressure is not adequately
gastric mucosa or the kidney. a recent history of rectal or anal bleeding. There are no specic
controlled by MICARDIS 40 mg or hydrochlorothiazide.
These differences are thought to be related to a selective inhibition studies about effects on the ability to drive vehicles and to
MICARDIS PLUS 80/12.5 mg may be administered in
of COX-2 relative to COX-1 and it is believed that COX-2 use machinery. Patients who experience visual disturbances,
patients whose blood pressure is not adequately controlled by
inhibition provides the therapeutic effects of NSAIDs whereas drowsiness or other central nervous system disturbances should
MICARDIS 80 mg or by MICARDIS PLUS 40/12.5 mg.
inhibition of constitutive COX-1 may be responsible for gastric refrain from these activities.
The maximum antihypertensive effect is generally attained with
MICARDIS PLUS 4 8 weeks after the start of treatment. and renal side effects. The COX-2 selectivity of meloxicam has DRUG INTERACTIONS:
been conrmed both in vitro and ex vivo in a number of test
When necessary, MICARDIS PLUS may be administered with - Other NSAIDs including salicylates: Concomitant
systems. In the human whole blood assay, meloxicam has been administration of more than one NSAID may increase the risk
another antihypertensive drug. In patients with severe hypertension
shown in vitro to inhibit COX-2 selectively. of gastrointestinal ulceration and bleeding through synergistic
treatment with telmisartan at doses up to 160 mg alone and in
combination with hydrochlorothiazide 12.5 - 25 mg daily was well Meloxicam (7.5 and 15 mg) demonstrated a greater inhibition action.
tolerated and effective . MICARDIS PLUS may be taken with of COX-2 ex vivo, as demonstrated by a greater inhibition - Oral anticoagulants, ticlopidine, systemically administered
or without food. of lipopolysaccharide-stimulated PGE2 production (COX-2) as heparin, thrombolytics: increased risk of bleeding. If such co-
Renal Impairment: compared with thromboxane production in clotting blood (COX-1). prescribing cannot be avoided, close monitoring of the effects
These effects were dose-dependent. Meloxicam has been demonstrated of anticoagulants is required.
Due to the hydrochlorothiazide component, MICARDIS PLUS to have no effect on either platelet aggregation or bleeding time - Lithium: NSAIDs have been reported to increase lithium
should not be used by patients with severe renal dysfunction at recommended doses ex vivo, while indomethacin, diclofenac, plasma levels. It is recommended that plasma lithium levels
(creatinine clearance < 30 ml/min). Loop diuretics are preferred to ibuprofen and naproxen signicantly inhibited platelet aggregation be monitored when initiating, adjusting and discontinuing
thiazides in this population. MOBIC.
and prolonged bleeding.
Experience in patients with mild to moderate renal impairment
In clinical trials, gastro-intestinal adverse events overall were - Methotrexate: As other NSAIDs. MOBIC may increase the
is modest but has not suggested adverse renal effects and dose
reported less frequently with meloxicam 7.5 mg and 15 mg haematologic toxicity of methotrexate. In this situation, strict
adjustment is not considered necessary. Periodic monitoring of monitoring of blood cell count is recommended.
renal function is advised. than with the NSAIDs with which it has been compared, due
predominantly to a lower reporting incidence of events such as - Contraception: NSAIDs have been reported to decrease the
Hepatic Impairment: efcacy of intrauterine devices.
dyspepsia, vomiting, nausea and abdominal pain. The incidence
In patients with mild to moderate hepatic impairment the posology of upper gastro-intestinal perforation, ulcers, and bleeds reported - Diuretics: Treatment with NSAIDs is associated with the
should not exceed MICARDIS PLUS 40/12.5 mg once daily. in association with meloxicam is low and dose dependent. potential for acute renal insufciency in patients who are
MICARDIS PLUS is not indicated in patients with severe dehydrated. Patients receiving MOBIC and diuretics should
hepatic impairment. Thiazides should be used with caution in INDICATIONS: be adequately hydrated and be monitored for renal function
patients with impaired hepatic function. MOBIC is a non-steroidal anti-inammatory drug indicated for prior to initiating treatment.
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SPDI
- Antihypertensives (e.g. beta-blockers, ACE-inhibitors, Rectal administration: INTERACTIONS:
vasodilators, diuretics): A reduced effect of the antihypertensive 7.5 mg in rectum once a day are recommended. For more severe Administration of ambroxol together with antibiotics (amoxicilline,
drug by inhibition of vasodilating prostaglandins has been cases a 15 mg suppository is available. Rectal administration cefuroxime, erythromycin, doxycycline) leads to higher antibiotic
reported during treatment with NSAIDs. should be used for the shortest time possible, in view of the risk of concentration in the lung tissue. No clinically relevant unfavourable
- Cholestyramine binds meloxicam in the gastrointestinal tract local toxicity added to the risks of oral administration. interaction with other medications have been reported.
leading to a faster elimination of meloxicam.
Combined administration: DOSAGE AND ADMINISTRATION:
- Nephrotoxicity of cyclosporin may be enhanced by NSAIDs via
renal prostaglandin mediated effects. The total daily dosage of MOBIC administered as tablets, Tablets 30 mg:
During combined treatment renal function is to be measured. suppositories, oral suspension and injections should not exceed
Adults 1 tablet 3 times daily
15 mg.
Meloxicam is eliminated almost entirely by hepatic metabolism, of The therapeutic effect may be enhanced by administering 2 tablets
which approximately two thirds are mediated by cytochrome (CYP) OVERDOSAGE: 2 times daily. The tablets should be taken after meals with liquid.
P450 enzymes (CYP 2C9 major pathway and CYP 3A4 minor In case of overdose the standard measures of gastric evacuation and Liquid (5 ml = 1 teaspoonful)
pathway) and one-third by other pathways, such as peroxidase general supportive measures should be used as there is no known
oxidation. The potential for a pharmacokinetic interaction should Adults and children over 12 years:
antidote. It has been shown in a clinical trial that cholestyramine
be taken into account when meloxicam and drugs known to accelerates the elimination of meloxicam. Liquid 15 mg/5ml 10 ml (2 tsps.) 3 times daily
inhibit, or to be metabolised by, CYP 2C9 and/or CYP 3A4 are For the therapy of acute respiratory tract disorders and for the
administered concurrently. No relevant pharmacokinetic drug- AVAILABILITY: initial treatment of chronic conditions up to 14 days, the dose
drug interactions were detected with respect to the concomitant Tablets 7.5 mg and 15 mg maybe increased to 30ml (2 tablespoons) 2 times daily.
administration of antacids, cimetidine, digoxin and furosemide.
[Suppositories 7.5 mg and 15 mg(N.R)] For the treatment of children under the age of 12 the following
Interactions with oral antidiabetics cannot be excluded.
dosage regimen is recommended depending on the severity of the
STORAGE INSTRUCTIONS:
PREGNANCY AND LACTATION: disease:
Although no teratogenic effects were seen in preclinical Store in a safe place below 30 C. Store in a safe place out of the
Liquid 15 mg/5 ml
testing, MOBIC should not be used during pregnancy and reach of children.
Children 6 - 12 years 5 ml (1 tsp.) 2 - 3 times daily
breastfeeding. Do not take the medicine after the expiry date printed on the
pack. Children 2 - 6 years 2.5 ml (1/2 tsp.) 3 times daily
SIDE EFFECTS: Children under 2 years 2.5 ml (1/2 tsp.) 2 times daily
The following adverse events which may be causally related MUCOSOLVAN liquid should be taken at mealtimes.
with the administration of MOBIC have been reported. The MUCOSOLVAN Tablet Solution 15 mg/2 ml for oral and inhalation use
frequencies given below are based on corresponding occurrences Oral (1 ml = 25 drops)
in clinical trials, regardless of any causal relationship. The
information is based on clinical trials involving 3750 patients who
(Ambroxol Hydrochloride) Adults at the initiation of treatment, 4 ml 3 times
daily.
have been treated with daily oral doses of 7.5 or 15 mg MOBIC
tablets or capsules over a period of up to 18 months (mean duration
MUCOSOLVAN Liquid Children over 6 years 2 ml (= 50 drops) 2 - 3 times daily
of treatment 127 days): OTC Children 2 - 6 years 1 ml (= 25 drops) 3 times daily
Gastrointestinal: (Ambroxol Hydrochloride) Children under 2 years 1 ml (= 25 drops) 2 times daily
Dyspepsia, nausea, vomiting, abdominal pain, constipation, The drops should be taken with meals diluted with tea, fruit juice,
atulence, diarrhea (more frequent than 1%). Transitory COMPOSITION milk or water.
abnormalities of liver function parameters e.g. raised transaminases 1 tablet contains 30 mg Inhalation:
or bilirubin eructation, oesophagitis, gastroduodenal ulcer, occult 5 ml liquid contains 15 mg Adults and children over 6 years 1 - 2 inhalations of 2 - 3 ml
or macroscopic gastrointestinal bleeding (between 0.1 and 1%).
[2 ml solution for oral or inhalation use contains 15 mg trans-4-[(2- solution daily
Gastrointestinal perforation: colitis, hepatitis, gastritis (less
frequent than 0.1%). amino-3,5-dibromo-benzyl)amino]cyclohexanol hydrochloride Children under 6 years 1 - 2 inhalations of 2 ml
(=ambroxol hydrochloride)(N.R)] solution daily
Hematological:
Excipients: MUCOSOLVAN inhalant solution can be used in all modern
Anemia (more frequent than 1%). Disturbances of blood
count, including differential white cell count, leukopenia and Tablets: inhalation devices (excluding steam inhalers). It is miscible with
thrombocytopenia. Concomitant administration of a potentially lactose, maize starch, colloidal silica, magnesium stearate. physiological saline solution and may be diluted 1 : 1 in order to
myelotoxic drug, in particular methotrexate, appears to be a obtain optimal moisturisation of the air released by a respirator.
Liquid:
predisposing factor to the onset of a cytopenia (between 0.1 and Since deep inhalation may provoke cough, the patient should
Hydroxyethylcellulose, sorbitol solution 70%, glycerin, benzoic
1%). breathe normally during the inhalation treatment. It is generally
acid, propyleneglycol, tartaric acid.
Dermatological: recommended to warm inhalant solutions to body temperature
[Solution: (N.R)] before inhalation.
Pruritus, skin rash (more frequent than 1%); stomatitis, urticaria
Citric acid, dibasic sodium phosphate, sodium chloride, Patients with bronchial asthma may be advised to commencing
(between 0.1 and 1%) ; photosensitisation, on rare occasions
benzalkonium chloride. inhalation after they have taken their regular bronchospasmolytic
bullous reactions, erythema multiforme, Stevens Johnson
Syndrome, Toxic Epidermal Necrolysis may develop. (less PROPERTIES: therapy.
frequent than 0.1%). Preclinically, ambroxol, the active ingredient of OVERDOSAGE:
Respiratory: MUCOSOLVAN, has been shown to increase respiratory
No symptoms of overdosage have been reported in man to date. If
Onset of acute asthma has been reported (less frequent than 0.1%) tract secretion. It enhances pulmonary surfactant production and
they occur, symptomatic treatment should be provided.
in certain individuals following the administration of aspirin or stimulates ciliary activity. These actions result in improved mucus
other NSAIDs, including MOBIC. ow and transport (mucociliary clearance). Improvement of AVAILABILITY:
Central nervous system : mucociliary clearance has been shown in clinical pharmacological Tablets 30 mg
studies. Enhancement of uid secretion and mucociliary clearance Liquid 15 mg/5 ml
Lightheadedness, headache (more frequent than 1%); vertigo,
facilitates expectoration and eases cough.
tinnitus, drowsiness (between 0.1 and 1%); confusion, [Solution for oral or inhalation use 15 mg/2 ml(N.R)]
disorientation, alteration of mood (less frequent than 0.1%). INDICATIONS:
Cardiovascular: Secretolytic therapy in acute and chronic bronchopulmonary
Store in a safe place out of the reach of children.
Oedema (more frequent than 1%); increase of blood pressure, diseases associated with abnormal mucus secretion and impaired
mucus transport. Do not take the medicine after the expiry date printed on the
palpitations, ushes (between 0.1 and 1%).
pack.
Genitourinary: CONTRAINDICATIONS:
Abnormal renal function parameters increased serum MUCOSOLVAN should not be used in patients known to
creatinineand/or serum urea (between 0.1 and 1%), acute renal be hypersensitive to ambroxol or other components of the
PHARMATON CAPSULES
failure (less frequent than 0.1%). formulation. OTC
Vision disorders: (Highly concentrated standardised Ginseng
SPECIAL PRECAUTIONS:
Conjunctivitis, visual disturbances including blurred vision (less
frequent than 0.1%) MUCOSOLVAN solution contains the preservative extract G115, Vitamin A, Vitamin D3, Vitamin
benzalkonium chloride. When inhaled this preservative may E, Vitamin B1, Vitamin B2, Vitamin B6,
Hypersensitivity reactions: cause bronchoconstriction in sensitive patients with hyperreactive
Angio-oedema and immediate hypersensitivity reactions, including airways. Vitamin B12, Biotin, Nicotinamide,Vitamin,
anaphylactoid / anaphylactic reactions (less frequent than 0.1%). Folic acid, Copper Selenium, Manganese,
SIDE EFFECTS:
DOSAGE AND ADMINISTRATION: Magnesium, Iron, Zinc, Calcium, Lecithin)
MUCOSOLVAN is generally well tolerated. Mild upper
Osteoarthritis: gastro-intestinal side effects (primarily pyrosis, dyspepsia, and
7.5 mg/day . If necessary, the dose may be increased to 15 mg/ occasionally nausea, vomiting) have been reported, principally PROPERTIES
day. following parenteral administration. Allergic reactions have PHARMATON CAPSULES is a combination preparation
Rheumatoid arthritis: occured rarely, primarily skin rashes. There have been extremely containing Ginseng extract G115, Lecithin, vitamins, minerals and
15 mg/day. According to the therapeutic response, the dose may be rare case reports of severe acute anaphylactic-type reactions but trace elements.
reduced to 7.5 mg/day. their relationship to ambroxol is uncertain. Some of these patients The Ginseng extract G115 used is prepared from roots of the
have also shown allergic reactions to other substances. genuine Ginseng (Panax ginseng C.A. Meyer) according to a
Ankylosing spondylitis:
PREGNANCY AND LACTATION: specic procedure, and contains a constant (= standardized)
15 mg/day. In patients with increased risks of adverse reactions:
start treatment at the dose of 7.5 mg/day. In dialysis patients with Preclinical studies as well as extensive clinical experience after the amount of active ingredients.
severe renal failure: the dose should not exceed 7.5 mg/day. The 28th week have shown no evidence of ill-effects during pregnancy. The included vitamins, minerals and trace elements are essential
maximum recommended daily dose of MOBIC is 15 mg. As a Nonetheless, the usual precautions regarding the use of drugs substances which generally cannot be produced by the body
dosage for use in children has yet to be established, usage should during pregnancy, espcially during the rst trimester, should be itself. The dosage of the active ingredients in PHARMATON
be restricted to adults. Tablets should be swallowed with water or observed. The drug enters breast milk, but is not likely to affect CAPSULES is adapted to the daily requirements of the human
other uid in conjunction with food. the infant when therapeutic doses are used. organism.
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SPDI
INDICATIONS Vitamin C 60.0 mg Calcium builds and maintains bones and teeth; regulates heart
PHARMATON CAPSULES is a food supplement. Folic acid 0.1 mg rhythm;eases insomnia; helps regulate the passage of nutrients in
Copper 2.0 mg and out of the cell walls; assists in normal blood clotting; helps
The preparation may, be used for convalescence after illness, as
well as for compensation for an insufcient supply of vitamins, Selenium 50.0 mcg maintain proper nerve and muscle function; and it is important to
minerals and trace elements. Manganese 2.5 mg normal kidney function.
NOTE
Magnesium 10.0 mg IS PHARMATON KIDDI SYRUP SUITABLE FOR
Iron 10.0 mg DIABETICS?
A sufcient and diversied diet is the most important measure to
Zinc 1.0mg PHARMATON KIDDI SYRUP is suitable for diabetics (5 ml
avoid as far as possible deciencies of vitamins, minerals and trace
elements which generally cannot be produced by the body itself. Calcium 100.0 mg syrup contains 1.2 g carbohydrates, equivalent to 0.1 carbohydrate
Lecithin 100.0 mg units).
CONTRAINDICATIONS Inactive ingredients: IS PHARMATON KIDDI SYRUP GMO AND ARTIFICIAL
You should not use PHARMATON CAPSULES in the Aromatic: Ethylvanillin; COLORANTS FREE?
following cases:
Excip. pro caps. PHARMATON KIDDI SYRUP does not contain ingredients
In case of existing disturbances of the calcium metabolism, derived from Genetically Modied Organisms (GMO).
such as increased calcium level or increased calcium excretion PACKAGES
PHARMATON KIDDI SYRUP does not contain articial
In case of oversupply of the body with vitamins A or D There are packages of 30 and 100 capsules. colorants.
In case other drugs containing vitamin A or D are taken
WHEN MUST PHARMATON KIDDI SYRUP NOT BE
In case of renal malfunction PHARMATON KIDDI SIROP USED?
During a therapy with retinoids (certain acne remedies) OTC PHARMATON KIDDI SYRUP should not be used
In case of hypersensitivity to one or several ingredients (Lysine hydrochloride, Vitamin B1 In disorders of the calcium metabolism, such as raised calcium
PRECAUTIONS hydrochloride, Vitamin B2 sodium phosphate, blood levels or increased calcium excretion
If the preparation is taken according to the prescriptions in respect In the presence of excessive supply of the body with vitamin D
Vitamin B6 hydrochloride, Vitamin D3, energy;
of intake, no special precautionary measures are necessary.
Vitamin E, Nicotinamide, Dexpanthenol, In patients with impairment of renal function
Nevertheless, inform your physician or pharmacist if you:
Suffer from other diseases
Calcium) With other drugs containing vitamin D
Have any allergies In case of known hypersensitivity to one of the ingredients
The multivitamin preparation with lysine for children and
Take other (also self-purchased) drugs adolescents WHEN IS CAUTION INDICATED WITH THE USE OF
PHARMATON KIDDI SYRUP?
PREGNANCY AND LACTATION WHAT IS CONTAINED IN PHARMATON KIDDI
SYRUP? PHARMATON KIDDI SYRUP should not be taken in more
Vitamins, minerals and trace elements may always be taken in
than the recommended dosage for long periods, except under
amounts corresponding to the daily requirement. 5 ml Syrup contain:
medical supervision.
However, in view of the daily doses provided in PHARMATON Active ingredients:
Inform your doctor, your pharmacist or your druggist if
CAPSULES, you should take this drug only after consulting your Lysine hydrochloride 100.00 mg
physician. you are suffering from other diseases,
Vitamin B1 hydrochloride 1.00 mg
Among other things, PHARMATON CAPSULES contains (Vit. B1: 0.76 mg) have any allergies or
vitamin A. Vitamin B2 sodium phosphate 1.17 mg are taking or applying externally other drugs (including drugs
It has to be taken into account that, with a balanced diet, the (Vit. B2: 0.82 mg) you have purchased yourself!).
daily requirement of vitamin A (contained, for example, in liver, Vitamin B6 hydrochloride 1.00 mg
liver products, milk, dairy products, margarine, eggs, cooking MAY PHARMATON KIDDI SYRUP BE USED / TAKEN
Vitamin D3 133 IU DURING PREGNANCY OR LACTATION?
oil) is covered, or (in the case of liver and liver products) even
exceeded. Vitamin E 5.00 mg PHARMATON KIDDI SYRUP is intended for children and
With a daily intake of high doses of vitamin A during pregnancy, Nicotinamide (Vit. PP) 6.67 mg adolescents.
it has been established that the risk of certain malformations in Dexpanthenol 3.33 mg On the basis of the actual experience no risk for the unborn child
newborns is increased. Calcium 43.33 mg is known when the medication is taken as prescribed. However,
systematic scientic investigations have never been carried out.
DOSAGE AND ADMINISTRATION WHAT IS PHARMATON KIDDI SYRUP AND WHEN IS IT As a precaution you should abstain from using medicines during
Adults: Normally one capsule per day, preferably taken at USED? pregnancy and lactation or ask your physician, your pharmacist or
breakfast. PHARMATON KIDDI SYRUP contains vitamins,calcium your druggist for advice.
Children below 12 years: Not recommended. and lysine. PHARMATON KIDDI SYRUP serves as a tonic
for children and adolescents during the growing phase, in loss of HOW DO YOU USE PHARMATON KIDDI SYRUP?
The capsules are to be swallowed in total with some liquid, Children between 1 and 5 years: 5 ml daily.
appetite, during convalescence and in physical fatigue, as well as
without chewing.
to strengthen the resistance, the performance and the powers of Children over 6 years and adolescents: 10 ml daily.
In case of difculty in swallowing: cut the capsule open, squeeze concentration.
the contents onto a spoon and mix with some marmalade, honey, The dosage of the syrup, in ml, is measured out with the measuring
Lysine is one of the so-called amino acids, which are the building device provided. PHARMATON KIDDI SYRUP is taken
or other food before taking.
blocks of the proteins. Lysine is important for the formation preferably with breakfast. It can also be diluted with water or mixed
Observe the dosage indicated on the leaet or prescribed by your of bone, among other things. The most frequent amino-acid with the food. The taste comes from the orange avouring. Keep
physician. deciency in children concerns lysine.An unbalanced or decient to the dosage indicated in the package insert or that prescribed by
If you think the effect of the drug is too weak or too strong, consult diet can mean that the bodys needs for all these substances cannot your doctor.
your physician or pharmacist. always be covered.
Vitamin B1 plays a key role in the bodys metabolic cycle for WHAT SIDE EFFECTS CAN PHARMATON KIDDI
SIDE-EFFECTS SYRUP HAVE?
generating aids in the digestion of carbohydrates; is essential for
Occasionally, gastro-intestinalside-effects may appear on taking the normal functioning of the nervous system, muscles and heart; Up till now there are no known side effects.If you do notice any
PHARMATON CAPSULES. stabilizes the appetite; promotes growth and good muscle tone. side effects, you should inform your doctor, your pharmacist or
Vitamin B2 is necessary for carbohydrate,fat and protein your druggist.
GENERAL NOTICE
metabolism;aids in the formation of antibodies and red blood cells; WHAT ELSE HAS TO BE CONSIDERED?
PHARMATON CAPSULES do not contain sugar and are it enables cell respiration, and is necessary for the maintenance of
suitable for diabetics. good vision, skin, nails and hair. The yellow colouration of the urine after taking PHARMATON
Keep PHARMATON CAPSULES in a dry place, at room KIDDI SYRUP is due to the vitamin B2 content (natural colour)
Vitamin B6 is necessary for the synthesis and breakdown of amino and is harmless. PHARMATON KIDDI SYRUP can take on
temperature (15-25C), out of the reach of children. acids,the building blocks of proteins; aids in fat and carbohydrate
a natural cloudiness, which however does not impair the efcacy
The drug may only be used to the expiration date indicated on the metabolism and in the formation of antibodies.
of the product.
container with EXP. It maintains appropriate functioning of the central nervous system;
Shake well before use.
Further information is available from your physician or promotes healthy skin; reduces muscle spasms, leg cramps.
Moreover it helps maintain a proper balance of sodium and Store PHARMATON KIDDI SYRUP at room temperature
pharmacist.
phosphorous in the body. (between 15 and 25C) and out of the reach of children.
COMPOSITION The drug must not be used after the date indicated with EXP
Vitamin D improves absorption and utilization of Calcium and
One capsule contains: Phosphorous; it is required for bone and teeth formation; maintains on the container.
Active ingredients: a stable nervous system and normal heart action. WHAT PRESENTATIONS ARE AVAILABLE?
Highly concentrated, standardized Ginseng 40.0 mg Vitamin E is a major anti-oxidant nutrient; it retards cellular aging
Bottles of 200 ml syrup.
extract G115 (made from roots of best quality due to oxidation; aids in bringing nourishment to cells; strengthens
of genuine Panax ginseng C.A. Meyer) the capillary walls and protects the red blood cells from destructive
Vitamin A 2667 IU poisons; prevents and dissolves blood clots. SIFROL Tablet.
Vitamin D3 200 IU Vitamin PP improves blood circulation; it maintains the nervous
system; helps metabolize protein, sugar and fat; increases energy
Vitamin E 10.0 mg
through proper utilization of food; prevents pellagra; helps
(Pramipexole dihydrochloride monohydrate)
Vitamin B1 1.4 mg
maintain a healthy skin, tongue and digestive system.
Vitamin B2 1.6 mg COMPOSITION:
Dexpanthenol participates in the release of energy from
Vitamin B6 2.0 mg carbohydrates,fats and protein, aids in the utilization of vitamins; 1 tablet contains 0.088, 0.18, 0.7 mg.
Vitamin B12 1.0 mcg improves the bodys resistance to stress; helps in cell building and (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (=
Biotin 150.0 mcg the development of the central nervous system; helps theadrenal pramipexole base) equivalent to 0.125, 0.25, 1.0 mg of pramipexole
Nicotinamide 18.0 mg glands, ghts infections by building antibodies. dihydrochloride monohydrate respectively
173
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SPDI
Excipients: and may adversely affect their ability to drive. Patients should be days. Providing patients do not experience intolerable side-effects,
Mannitol, maize starch, anhydrous colloidal silica, polyvidone, alerted to the potential sedating effects associated with SIFROL, the dosage should be titrated to achieve a maximal therapeutic
magnesium stearate including somnolence and the possibility of falling asleep while effect.
engaged in activities of daily living. Ascending-Dose Schedule of SIFROL
PROPERTIES:
Since somnolence is a frequent adverse event with potentially Week Dosage (mg) Total daily dose (mg)
Pharmacodynamic properties: serious consequences, patients should neither drive a car nor 1 3 x 0.125 0.375
Pharmacotherapeutic group: dopamine agonists operate other complex machinery until they have gained sufcient 2 3 x 0.25 0.75
Pramipexole, the active ingredient of Sifrol is a dopamine agonist experience with SIFROL to gauge whether or not it affects their 3 3 x 0.5 1.50
and binds with high selectivity and specicity to the dopamine D2 mental and/or motor performance adversely.
If a further dose increase is necessary the daily dose should be
subfamily receptors and has a preferential afnity to D3 receptors; Patients should be advised that if increased somnolence or
increased by 0.75 mg at weekly intervals up to a maximum dose
it has full intrinsic activity. SIFROL alleviates Parkinsonian episodes of falling asleep during activities of daily living (e.g.
of 4.5 mg per day.
motor decits by stimulation of dopamine receptors in the striatum. conversations, eating etc) are experienced at any time during
Animal studies have shown that pramipexole inhibits dopamine treatment, they should not drive or participate in potentially Maintenance Treatment:
synthesis, release, and turnover. dangerous activities and should contact their physician. The individual dose should be in the range of 0.375 mg to a
Pramipexole protects dopamine neurons from degeneration in maximum of 4.5 mg per day. During dose escalation in three pivotal
INTERACTIONS:
response to ischemia or metamphetamine neurotoxicity. In vitro studies both, in early and advanced disease efcacy was observed
Pramipexole is bound to plasma proteins to a very low (< 20%) starting at a daily dose of 1.5 mg. Further dose adjustments should
studies demonstrate that pramipexole protects neurons from
extent and little biotransformation is seen in man. Therefore, be done based on clinical response and tolerability. In clinical
levodopa neurotoxicity. In human volunteers a dose-dependent
interactions with other medications affecting plasma protein trials approximately 5% of patients were treated at doses below
decrease in prolactin was observed. Efcacy of SIFROL in
binding or elimination by biotransformation are unlikely. 1.5 mg of salt per day.
the controlled clinical trials was maintained for the duration of
Medications that inhibit the active renal tubular secretion of basic
the trials, approximately six months. In open continuation trials Doses higher than 1.5 mg per day can be useful in patients where a
(cationic) drugs, such as cimetidine, or are themselves eliminated
lasting for more than three years there were no signs of decreasing reduction of the levodopa therapy is intended. It is recommended
by active renal tubular secretion, may interact with SIFROL
efcacy. that the dosage of levodopa is reduced during both the dose
resulting in reduced clearance of either or both medications.
Pharmacokinetic Properties: escalation and the maintenance treatment with SIFROL,
Drugs included in this category are Cimetidine, Diltiazem, dependent on reactions in individual patients.
Pramipexole is rapidly and completely absorbed following oral Quinidine, Quinine, Ranitidine, Triamterene, Verapamil, Digoxin,
administration. The absolute bioavailability is greater than 90 % Treatment Discontinuation:
Procainamide and Trimethoprim. In case of concomitant treatment
and the maximum plasma concentrations occur between 1 and 3 with these kind of drugs (incl. amantadine) attention should be Abrupt discontinuation of dopaminergic therapy can lead to the
hours. The rate of absorption is reduced by food intake but not paid to signs of dopamine overstimulation, such as dyskinesias, development of a neuroleptic malignant syndrome. Therefore
the overall extent of absorption. Pramipexole shows linear kinetics agitation or hallucinations. In such cases a dose reduction is pramipexole should be tapered off at a rate of 0.75 mg of salt per
and a relatively small inter-patient variation of plasma levels. In necessary. day until the daily dose has been reduced to 0.75 mg. Thereafter
humans the protein binding of pramipexole is very low (< 20 %) the dose should be reduced by 0.375mg of salt per day.
Selegeline and levodopa do not inuence the pharmacokinetics
and the volume of distribution is large (400L).
of pramipexole. The overall extent of absorption or elimination Dosing in patients with concomitant levodopa therapy:
High brain tissue concentrations were observed in the rat (approx. of levodopa is not changed by pramipexole. The interaction with
8-fold compared to plasma). Pramipexole is metabolised in man In patients with concomitant levodopa therapy it is recommended
anticholinergics and amantadine has not been examined. As that the dosage of levodopa is reduced during both dose escalation
only to a small extent. Renal excretion of unchanged pramipexole anticholinergics are mainly eliminated by metabolism, a potential
is the major route of elimination and accounts for about 80% of and maintenance treatment with SIFROL. This may be necessary
role of interaction is limited. With amantadine, an interaction is in order to avoid excessive dopaminergic stimulation.
dose. Approx. 90% of a 14C-labelled dose is excreted through possible via the same system of excretion in the kidney.
the kidneys while less than 2% is found in the feces. The total Dosing in patients with renal impairment:
While increasing the dose of SIFROL it is recommended that
clearance of pramipexole is approx. 500 ml/min and the renal The elimination of pramipexole is dependent on renal function.
the dosage of levodopa is reduced and the dosage of other anti-
clearance is approx. 400 ml/min. The elimination half-life (t ) The following dosage schedule is suggested for initiation of
parkinsonian medication kept constant. Because of possible
varies from 8 hours in the young to 12 hours in the elderly. therapy: Patients with a creatinine clearance above 50 ml/min
additive effects, caution should be advised when patients are
INDICATION: taking other sedating medication or alcohol in combination with require no reduction in daily dose. In patients with a creatinine
SIFROL and when taking concomitant medication that increase clearance between 20 and 50 ml/min, the initial daily dose of
SIFROL is indicated in the treatment of signs and symptoms of
plasma levels of pramipexole (e.g. cimetidine). SIFROL should be administered in two divided doses, starting
idiopathic Parkinsons disease. It may be used as monotherapy or
at 0.125 mg twice a day (0.25 mg daily).
in combination with Levodopa. PREGNANCY AND LACTATION: In patients with a creatinine clearance less than 20 ml/min, the
CONTRAINDICATIONS: The effect on pregnancy and lactation has not been investigated daily dose of SIFROL should be administered in a single
in humans. Pramipexole was not teratogenic in rats and rabbits,
Hypersensitivity to pramipexole or any other component of the dose, starting at 0.125 mg daily. If renal function declines during
but was embryotoxic in the rat at maternotoxic doses. SIFROL
product. maintenance therapy, reduce SIFROL daily dose by same
should be used during pregnancy only if the potential benet
percentage as decline in creatinine clearance, ie. if creatinine
SPECIAL WARNINGS AND PRECAUTIONS: justies the potential risk to the foetus. The excretion of SIFROL
clearance declines by 30%, then reduce SIFROL daily dose by
When prescribing SIFROL tablets in a patient with renal into the breast milk has not been studied in women. In rats, the
30%. The daily dose can be administered in two divided doses if
impairment a reduced dose is suggested in line with section Dosage concentration of drug was higher in the breast milk than in plasma.
creatinine clearance is between 20 and 50 ml/min, and as a single
and Administration. Hallucinations and confusion are known As SIFROL treatment inhibits secretion of prolactin in humans
daily dose if creatinine clearance is less than 20 ml/min.
side-effects of treatment with dopamine agonists and levodopa. inhibition of lactation is expected. In consequence, SIFROL
should not be used during breast-feeding. Dosing in patients with hepatic impairment:
Hallucinations were more frequent when SIFROL was given in
Dose reduction is not considered necessary in patients with hepatic
combination with levodopa in patients with advanced disease than SIDE EFFECTS: impairement.
in monotherapy in patients with early disease.
The following adverse events have been reported more frequently
Patients should be informed that (mostly visual) hallucinations OVERDOSAGE:
during the use of SIFROL than under placebo: nausea,
can occur. Dyskinesias can occur during the initial titration of constipation, somnolence, hallucinations, confusion and dizziness. Symptoms:
SIFROL. The incidence of initial dyskinesias may be higher in More frequent adverse reactions in early disease were somnolence There is no clinical experience with massive overdosage.
women. If they occur, the dose of levodopa should be decreased. and constipation and in advanced disease, in combination with The expected adverse events should be those related to the
Pathologic changes (degeneration and loss of photoreceptor levodopa treatment, dyskinesias and hallucinations. These adverse pharmacodynamic prole of a dopamine agonist including nausea,
cells) were observed in the retina of albino rats in the 2-years events decreased with continued therapy; constipation, nausea and vomiting, hyperkinesia, hallucinations, agitation and hypotension.
carcinogenicity study. dyskinesia tended to disappear. Therapy: There is no established antidote for overdosage of a
Evaluation of the retinas of albino mice, pigmented rats, monkeys, The incidence of hypotension under SIFROL, compared to dopamine agonist. If signs of central nervous system stimulation
and minipigs did not reveal similar changes. The potential placebo treatment, was not increased. However, in individual are present, a neuroleptic agent may be indicated.
signicance of this effect in humans has not been established, patients, hypotension may occur at the beginning of treatment,
but cannot be disregarded because disruption of a mechanism Management of the overdose may require general supportive
especially if SIFROL is titrated too fast. measures along with gastric lavage, intravenous uids, and
that is universally present in vertebrates (ie. disk shedding) may
Insomnia and peripheral oedema have been reported. electrocardiogram monitoring. Haemodialysis has not been shown
be involved. In case of severe cardiovascular disease, care should
be taken. It is recommended to monitor blood pressure, especially Patients treated with pramipexole tablets have reported falling to be helpful.
at the beginning of treatment, due to the general risk of postural asleep during activities of daily living, including the operation of
hypotension associated with dopaminergic therapy. motor vehicles, which sometimes resulted in accidents. Some of
them did not report a warning sign such as somnolence, which is Store below 30 C. Store in a safe place out of reach of children.
Patients should be aware of the fact that hallucinations can occur
common occurrence in patients receiving pramipexole tablets at AVAILABILITY:
and may adversely affect their ability to drive. Sudden onset of
doses above 1.5 mg (salt)/day, and which, according to the current
sleep during daily activities has been reported in rare cases. This Tablets of 0.125, 0.25, 1.0 mg
knowledge of sleep physiology, always proceeds falling asleep.
can be life threatening to the patient or others depending on the
There was no clear relation to the duration of treatment.
circumstances. These episodes have been reported in some cases
Some patients were taking other medication with potentially SILOMAT
without awareness of warning signs. If this occurs, reduction of
dosage or termination of therapy should be considered. Patients sedative properties. In most cases where information was OTC
available, there were no further episodes following reduction of
being treated with pramipexole must be informed not to drive
dosage or termination of therapy.
(Clobutinol Hydrochloride)
or engage in other activities where impaired alertness could
put themselves or others at risk of serious injury or death (e.g. DOSAGE AND ADMINISTRATION: COMPOSITION:
operating machines). Because of possible additive effects, caution (all dose information refers to pramipexole salt form) The tablets [1 sugar-coated tablet contains 40 mg(N.R)]
should be advised when patients are taking other sedating should be taken orally, swallowed with water, and can be taken 10 ml syrup contains 40 mg
medication or alcohol in combination with pramipexole either with or without food. The daily dosage is administered in 1-p-chlorophenyl-2,3-dimethyl-4-dimethylaminobutanol-(2)-
Symptoms suggestive of a neuroleptic malignant syndrome have equally divided doses 3x per day. hydrochloride (= clobutinol hydrochloride)
been reported with abrupt withdrawal of dopaminergic therapy. Initial treatment: [Excipients:(N.R)]
Effects on ability to drive and use machines: As shown below dosages should be increased gradually from a s.-c. tablets (N.R.): dibasic calcium phosphate, lactose, polyvidone
Patients should be aware of the fact that hallucinations can occur starting-dose of 0.375 mg per day and then increased every 5 - 7 25, starch soluble , maize starch, magnesium stearate, shellack,
174
Book_01.indd 174 6/4/2008 2:20:48 PM

SPDI
talc, sucrose, acacia, erythrosine lacquer, titanium dioxide, AVAILABILITY: was shown with human and animal origin receptors and isolated
polyethylenglycol, carnauba wax. Tablets(N.R), Syrup organ preparations.
Syrup: In preclinical in vitro as well as in vivo studies bronchoprotective
STORAGE INSTRUCTIONS: effects were dosedependent and lasted longer than 24 hours . The
sodiumbenzoate, saccharine sodium, natrosol , sorbitol, macrogol,
Store in a safe place below 30oC. Store in a safe place out of the long duration of effect is likely to be due to its very slow dissocia-
hydrochloric acid,contramarum aroma, peppermint naefo.
reach of children! tion from M3-receptors, exhibiting a signicantly longer dissocia-
PHARMACOLOGICAL PROPERTIES: Do not take the medicine after the expiry date printed on the tion half-life than that seen with ipratropium. As an N-quaternary
Clobutinol is an orally-active non-opioid antitussive drug with a pack. anticholinergic tiotropium is topically (broncho-) selective when
central site of action. In various animal models of cough, its potency administered by inhalation, demonstrating an acceptable therapeu-
is similar to that of codeine. In contrast to codeine, however, it has tic range before giving rise to systemic anticholinergic effects.
SONGHA NIGHT Tablets Dissociation from M2-receptors is faster than from M3, which in
no analgesic activity, does not inhibit intestinal peristalsis, and
does not induce respiratory depression at antitussive doses. OTC functional in vitro studies, elicited (kinetically controlled) receptor
(Extracts of valerian root and melissa leaves) subtype selectivity of M3 over M2. The high potency and slow
Clinical pharmacological studies in volunteers and patients
receptor dissociation found its clinical correlate in signicant
have conrmed the similarity of the cough-suppressing effect
and long-acting bronchodilation in patients with COPD. The
of clobutinol and codeine. Following oral administration of Herbal Medicine
bronchodilation following inhalation of tiotropium is primarily
clobutinol, the onset of cough-relief is after 15-30 minutes, after a local effect (on the airways) not a systemic one. The clinical
PROPERTIES AND INDICATIONS
i.v. administration within 2-4 minutes, and lasts for 4-6 hours. development program included four one-year and two six-month
SONGHA NIGHT is a medicine based on herbal principles. Its
INDICATIONS: active constituents are extracts of valerian root and melissa leaves, randomised, double-blind studies in 2663 patients with COPD
Symptomatic treatment of irritable, non-productive cough which are regarded as mild sedatives. (1308 receiving SPIRIVA).
In inammatory disorders of the airways due to infection and SONGHA NIGHT is used when there is difculty in getting The one-year program consisted of two placebo-controlled and
other causes; to sleep. two ipratropium-controlled trials. The six-month trials were
both salmeterol- and placebocontrolled. These studies included
Before, during or after diagnostic or therapeutic procedures on
ADVICE evaluation of lung function, dyspnoea, exacerbations of COPD
the thorax, bronchi or pleura;
If the trouble lasts for more than a month, consult your doctor. and patients assessments of their health-related quality of
After anaesthesia, especially after intubation. life. In the aforementioned studies, SPIRIVA administered
CONTRAINDICATIONS AND PRECAUTIONS once daily, providedsignicant improvement in lung function
CONTRAINDICATIONS:
SONGHA NIGHT should not be used if you are known to be (forced expiratory volume in one second, FEV1 and forced vital
Use of SILOMAT is contraindicated in pregnancy and during
hypersensitive to one of its constituents (see Composition). capacity, FVC) within 30 minutes following the rst dose and
lactation. SILOMAT should not be taken in the case of known
was maintained for 24 hours. Pharmacodynamic steady state was
hypersensitivity to clobutinol or any other excipient of the drug. Inform your doctor, pharmacist or druggist if you
reached within one week with the majority of bronchodilation
SPECIAL PRECAUTIONS: Have any allergies (medicines, food, household, occupational), observed by the third day.
In conditions, in which cough clearance plays an important role Are continuing treatment of the same complaint with other SPIRIVA signicantly improved morning and evening peak
medicines. expiratory ow rate (PEFR) as measured by patients daily
as the clearing mechanism of the airways, SILOMAT should
recordings. A randomised, placebo-controlled clinical study in
be used with caution and after risk-/benet assessment. There PREGNANCY AND LACTATION 105 patients with COPD demonstrated that bronchodilation was
have been isolated reports of epileptic convulsions in association
Experience so far indicates that there is no risk to the child. maintained throughout the 24 hour dosing interval in comparison
with overdosage. A causal relationship to the use of Silomat in
However, systematic scientic investigations have never been to placebo regardless of whether SPIRIVA was administered
recommended doses has not been established. in the morning or in the evening. The following health outcome
carried out. As a precaution, you should refrain as far as possible
Nevertheless, caution should be observed in patients with a from taking medicines when you are pregnant or breast-feeding, or effects were demonstrated in the long-term (6 month and 1 year)
personal or family history of epilepsy. Patients should not exceed ask your doctor for advice. trials:
the recommended dose. As the elimination of clobutinol is SPIRIVA Signicantly improved dyspnoea (as evaluated
principally via the kidney, caution should be observed in patients DOSAGE AND ADMINISTRATION using the Mahler Transitional Dyspnoea Index). This
with impaired renal function. The ability to drive or operate Adults aged 18 years and over: improvement was maintained throughout the treatment period.
machinery may be impaired by SILOMAT. If there is difculty in getting to sleep, swallow a single dose of SPIRIVA Signicantly reduced the number of COPD
2-3 coated tablets, whole, with a little water between half and one exacerbations and delayed the time to rst exacerbation in
DRUG INTERACTIONS:
hour before going to bed. comparison to placebo.
No specic interactions have been identied; nonetheless, centrally
Keep to the dose given in the package insert or prescribed by a SPIRIVA signicantly improved health-related quality of life
active drugs may interact with each other.
doctor. as demonstrated by the disease-specic St. Georges Respiratory
PREGNANCY AND LACTATION: Questionnaire. This improvement was maintained throughout
If you think the medicine is too weak or too strong, consult your the treatment period.
Embryotoxic and teratogenic effects have been shown in some
doctor, pharmacist or druggist. Additionally, in the one-year placebo controlled trials
preclinical studies, in dosages equivalent to more than 10 times
the maximum recommended dose. The signicance of these SIDE EFFECTS SPIRIVA signicantly reduced the number of hospitalisations
ndings to humans is not known. There is no information on the associated with COPD exacerbations and delayed the time to
When SONGHA NIGHT is used as directed, no side effects
passage of Silomat into the breast milk. Silomat is contraindicated rst hospitalisation.
have so far been observed.
in pregnancy and during lactation. PHARMACOKINETICS:
If allergic symptoms (skin rashes) should occur, the medicine must
SIDE EFFECTS: be discontinued and, if necessary, a doctor consulted. Absorption:
Agitation, tremor, pruritic rash, nausea, vomiting, dizziness, Following dry powder inhalation by young healthy volunteers,
STORAGE CONDITIONS
drowsiness and gastrointestinal complaints have been reported. the absolute bioavailability of 19.5% suggests that the fraction
SONGHA NIGHT should be kept in a dry place at room reaching the lung is highly bioavailable. It is expected from the
There have been rare reports of dyspnoea, muscular hypertonia and
temperature (15-25C), out of reach of children. chemical structure of the compound (quaternary ammonium
convulsions. In rare cases allergic reactions including angioedema,
urticaria, and isolated cases of anaphylaxis have been reported. The medicine must only be used up to the date shown by EXP compound) that tiotropium is poorly absorbed from the gastro-
on the pack. intestinal tract. Food is not expected to inuence the absorption of
DOSAGE AND ADMINISTRATION: tiotropium for the same reason. Oral solutions of tiotropium have
Further information is available from your doctor, pharmacist or
The dosage should be adapted to individual requirements. Unless an absolute bioavailability of 2-3%. Maximum tiotropium plasma
druggist.
otherwise prescribed by the physician, the following doses are concentrations were observed ve minutes after inhalation.
recommended COMPOSITION Distribution:
Sugar-coated tablets 40 mg Each coated tablet contains: The drug is bound by 72% to plasma proteins and shows a volume
Adults and children over 12 years of age: 1 - 2 tablets 3 times Dry extract of valerian root 120.0 mg of distribution of 32 L/kg. At steady state, tiotropium plasma levels
daily. in COPD patients at peak were 17 19 pg/ml when measured 5
Dry extract of melissa leaves 80.0 mg
minutes after dry powder inhalation of a 18 microgram dose and
Syrup (10 ml = 2 teaspoonsful = 40 mg) Indigotine colorant (E 132) and other excipients. decreased rapidly in a multi-compartmental manner. Steady state
Adults and children over 2 - 4 teaspoonsful 3 times daily trough plasma concentrations were 3-4 pg/ml. Local concentrations
12 years of age: PACKAGES
in the lung are not known, but the mode of administration suggests
children 6 - 12 years of age: 1 - 2 teaspoonsful 3 times Blister packs of 30 and 60 coated tablets. substantially higher concentrations in the lung.
daily Biotransformation:
Children 3 - 6 years of age: 1 - 1 teaspoonsful 3 times SPIRIVA 18 mcg Capsule for Inhalation The extent of biotransformation is small. This is evident from
daily a urinary excretion of 74% of unchanged substance after an
Young children 1 - 3 years of age: 1 teaspoonful 3 times daily intravenous dose to young healthy volunteers. Tiotropium, an ester,
(Tiotropium) is nonenzymatically cleaved to the alcohol N-methylscopine and
Infants under 1 year of age: - 1 teaspoonful 3 times daily
dithienylglycolic acid, both not binding to muscarinic receptors.
SILOMAT syrup is sugar-free and therefore suitable for COMPOSITION: Elimination:
diabetics. 1 capsule for inhalation contains tiotropium 18 mcg equivalent The terminal elimination half-life of tiotropium is between 5
OVERDOSAGE: to 22.5 mcg tiotropium bromide monohydrate (INN = tiotropium and 6 days following inhalation. Total clearance was 880 ml/min
bromide) after an intravenous dose in young healthy volunteers with an
Symptoms:
Excipients: interindividual variability of 22%. Intravenously administered
Miosis, vomiting, dizziness, labile blood pressure, exaggerated
lactose monohydrate tiotropium is mainly excreted unchanged in urine (74 %). After
reexes, anxiety, excitation, confusion and convulsions.
dry powder inhalation urinary excretion is 14% of the dose,
Occasionally paradoxical central depression may occur. PHARMACOLOGICAL PROPERTIES: the remainder being mainly non-absorbed drug in gut that is
Therapy Tiotropium is a long-acting, specic antimuscarinic agent, in eliminated via the faeces.
Following oral ingestion of high doses, gastric lavage followed clinical medicine often called an anticholinergic. It has a similar The renal clearance of tiotropium exceeds the creatinine clearance,
by instillation of activated charcoal. Airway maintenance may be afnity to the subtypes of muscarinic receptors M1 to M5. In the indicating secretion into the urine. After chronic once daily
required, with intubation if necessary. In the event of convulsions, airways, inhibition of M3-receptors at the smooth muscle results inhalation by COPD patients, pharmacokinetic steady state was
administration of diazepam i.v. is recommended. in relaxation. The competitive and reversible nature of antagonism reached after 2-3 weeks with no accumulation thereafter.
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Book_01.indd 175 6/4/2008 2:20:49 PM

SPDI
Elderly Patients: any individual case. The information is based on four clinical trials
involving 906 patients who have been treated with SPIRIVA over Open the mouthpiece again. Tip out the used
As expected for all predominantly renally excreted drugs,
a period of up to one year. capsule and dispose.
advanced age was associated with a decrease of tiotropium renal
clearance (326 ml/min in COPD patients < 58 years to 163 ml/ Gastro-intestinal tract: Close the mouthpiece and dust cap for
min in COPD patients > 70 years) which may be explained by 14%: dry mouth usually mild, which often resolved with continued storage of your HandiHaler device.
decreased renal function. Tiotropium excretion in urine after treatment >1% and < 10%: constipation
inhalation decreased from 14% (young healthy volunteers) to Respiratory system: Clean the HandiHaler device once a month.
about 7% (COPD patients), however plasma concentrations did Open the dust cap and mouthpiece. Then
>1% and < 10%: cough and local irritation including throat
not change signicantly with advancing age within COPD patients irritation (as with other inhaled treatment) open the base by lifting the piercing button.
if compared to inter- and intra-individual variability (43% increase Rinse the complete inhaler with warmwater
Cardiovascular system: to remove any powder.
in AUC0-4h after dry powder inhalation).
>0.1% and < 1%: tachycardia Dry the HandiHaler device thoroughly by
Renally Impaired Patients:
In addition isolated cases of supraventricular tachycardia and atrial tipping excess of water out on a paper towel
In common with all other drugs that undergo predominantly renal brillation were reported in association with the use of tiotropium, and air-dry afterwards, leaving the dust cap,
excretion, renal impairment was associated with increased plasma usually in susceptible patients. mouthpiece and base open.
drug concentrations and reduced renal drug clearance after both
Urinary system: It takes 24 hours to air dry, so clean it right
intravenous infusion and dry powder inhalations. Mild renal
>0.1% and < 1%: difculty urinating and urinary retention (in men after you used it and it will be ready for your
impairment (CLCR 50-80 ml/min) which is often seen in elderly
with predisposing factors) next dose.
patients increased tiotropium plasma concentrations slightly (39%
Allergic reactions: Outside of the mouthpiece may be cleaned
increase in AUC0-4h after intravenous infusion).
with a moist but not wet tissue if needed.
In COPD patients with moderate to severe renal impairment >0.1% and < 1%: hypersensitivity reactions including isolated
(CLCR <50 ml/min) the intravenous administration of tiotropium cases of angio-oedema Most of the above mentioned adverse
resulted in doubling of the plasma concentrations (82% increase in reactions can be attributed to the anticholinergic properties of Blisterhandling
AUC0-4h ), which was conrmed by plasma concentrations after SPIRIVA. Other anticholinergic effects such as blurred vision Separate the blister strips by tearing along
and acute glaucoma may occur. As with other inhaled therapy, the perforation.
dry powder inhalation.
inhalation-induced bronchospasm may occur.
Hepatically Impaired Patients:
Liver insufciency is not expected to have any relevant inuence
on tiotropium pharmacokinetics. Tiotropium is predominantly The recommended dosage of SPIRIVA is inhalation of the
contents of one capsule once daily with the HandiHaler Peel back (only immediately before use)
cleared by renal elimination (74% in young healthy volunteers ) using the tab until one capsule is fully
and simple non-enzymatic ester cleavage to pharmacologically inhalation device at the same time of day (see Instructions for use).
SPIRIVA capsules must not be swallowed. visible.
inactive products.
Elderly patients can use SPIRIVA at the recommended dose.
INDICATIONS: Renally impaired patients can use SPIRIVA at the recommended
SPIRIVA is indicated for the maintenance treatment of patients dose.
with COPD (including chronic bronchitis and emphysema), the However, as with all predominantly renally excreted drugs, Remove capsule.
maintenance treatment of associated dyspnoea and for prevention SPIRIVA use should be monitored closely in patients with
of exacerbations. moderate to severe renal impairment . Hepatically impaired
patients can use SPIRIVA at the recommended dose. There is no
CONTRAINDICATIONS:
experience with SPIRIVA in infants and children and therefore
SPIRIVA inhalation powder is contraindicated in patients with should not be used in this age group. The capsules should not be exposed, neither packed nor in the
a history of hypersensitivity to atropine or its derivatives, e.g. inhaler, to extreme temperatures i.e. they should not be exposed
ipratropium or oxitropium or to any component of this product. INSTRUCTIONS FOR USE:
to sunlight or to heating.
The HandiHaler device is especially designed for SPIRIVA. It
SPECIAL WARNINGS AND PRECAUTIONS: must not be used to take any other medication. You can use your OVERDOSE:
SPIRIVA, as a once daily maintenance bronchodilator, HandiHaler device for up to one year to take your medication. High doses of SPIRIVA may lead to anticholinergic signs and
should not be used for the initial treatment of acute episodes of 1. Dust cap symptoms. However, there were no systemic anticholinergic
bronchospasm, i.e. rescue therapy. Immediate hypersensitivity 2. Mouthpiece adverse effects following a single inhaled dose of up to 282
reactions may occur after administration of SPIRIVA inhalation 3. Base micrograms tiotropium in healthy volunteers.
powder.
4. Piercing button Bilateral conjunctivitis in addition to dry mouth was seen in
As with other anticholinergic drugs, SPIRIVA should be used 5. Centre chamber healthy volunteers following repeated once daily inhalation of
with caution in patients with narrow-angle glaucoma, prostatic 141 micrograms in healthy volunteers, which resolved while still
hyperplasia or bladder-neck obstruction. Inhaled medicines may under treatment. In a multiple dose study in COPD patients with
cause inhalation-induced bronchospasm. As with all predominantly a maximum daily dose of 36 micrograms tiotropium over four
renally excreted drugs, SPIRIVA use should be monitored Open the dust cap by pulling it upwards. weeks dry mouth was the only observed adverse event attributable
closely in patients with moderate to severe renal impairment Then open the mouthpiece. to tiotropium. Acute intoxication by oral ingestion of tiotropium
(creatinine clearance of 50 ml/min). Patients must be instructed capsules is unlikely due to low oral bioavailability.
in the correct administration of SPIRIVA capsules.
Care must be taken not to allow the powder to enter into the eyes. AVAILABILITY:
Eye pain or discomfort, blurred vision, visual halos or coloured Remove a SPIRIVA capsulefrom the Capsules for inhalation
images in association with red eyes from conjunctival congestion blister (only immediate before use) and
and corneal oedema may be signs of acute narrow-angle glaucoma. place it in the centre chamber, as illustrated. VIRAMUNE 200 mg Tablets
Should any combination of these symptoms develop specialist It does not matter which way the capsule is
advice should be sought immediately. Miotic eye drops are not placed in the chamber.
considered to be effective treatment. (Nevirapine anhydrate)
SPIRIVA should not be used more frequently than once daily.
SPIRIVA capsules are to be used only with the HandiHaler
VIRAMUNE 50 mg/5 ml
Close the mouthpiece rmly until you hear a
device. click, leaving the dust cap open.
Oral Suspension (N.R.)
INTERACTIONS: (Nevirapine Hemihydrate)
The co-administration of SPIRIVA with other anticholinergic-
containing drugs has not been studied and is therefore not Hold the HandiHaler device with the COMPOSITION:
recommended. Although no formal drug interaction studies mouthpiece upwards and press the piercing 1 tablet contains: 200 mg
have been performed, tiotropium inhalation powder has been button completely in once, and release. This
11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2,3-
used concomitantly with other drugs without adverse drug makes holes in the capsule and allows the
e][1,4]diazepin-6-one (= nevirapine anhydrate)
reactions. These include sympathomimetic bronchodilators, medication to be released when you breathe
methylxanthines, oral and inhaled steroids, commonly used in the in. Excipients:
treatment of COPD. avicel, lactose, polyvidone 25, primojel, aerosil 200, magnesium
Breathe out completely.
stearate
PREGNANCY AND LACTATION: Important:
Please avoid breathing into the mouthpiece 1 ml oral suspension contains: 10 mg 11-cyclopropyl-5, 11-
For SPIRIVA, no clinical data on exposed pregnancies are
at any time. dihydro-4-methyl-6H-dipyrido[3,2-b:2,3-e][1,4]diazepin-6-one
available. Preclinical studies do not indicate direct or indirect
(nevirapine; as 10.35 mg nevirapine hemihydrate)
harmful effects with respect to pregnancy, embryonal / foetal
development, parturition or postnatal development. Clinical data Raise the HandiHaler device to your Excipients:
from nursing women exposed to tiotropium are not available. mouth and close your lipstightly around carbomer, methyl parahydroxybenzoate, propyl
Based on lactating rodent studies, a small amount of tiotropium the mouthpiece. Keep your head in an parahydroxybenzoate, sorbitol, sucrose, polysorbate 80, sodium
is excreted into breast milk. Therefore, SPIRIVA should not be uprightposition and breathe in slowly and hydroxide and puried water
used in pregnant or nursing women unless the expected benet deeply but at a rate sufcient to hear the
capsule vibrate. Breathe until your lungs PROPERTIES:
outweighs any possible risk to the unborn child or the infant.
are full; then hold your breath as long as Nevirapine is a non-nucleoside reverse transcriptase inhibitor
SIDE EFFECTS: comfortable and at the same time take the (NNRTI) of HIV-1. Nevirapine binds directly to reverse
The undesirable effects listed below were attributed to the HandiHaler device out of your mouth. transcriptase and blocks the RNA-dependent and DNA-dependent
administration of SPIRIVA based on reasonable grounds to Resume normal breathing. DNA polymerase activities by causing disruption of the enzymes
suggest a causal relationship. The frequencies given below are Repeat step 5 and 6 once, this will empty the catalytic site. The activity of nevirapine does not compete with
reporting incidences regardless of the assessment of causality in capsule completely. template or nucleoside triphosphates. HIV-2 reverse transcriptase
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SPDI
and eukaryotic DNA polymerases (such as human DNA isolates were susceptible to ZDV and ddI. Cross-resistance between characteristics: male (54%), racial minority groups (73%), median
polymerases ,, or ) are not inhibited by nevirapine. nevirapine and HIV protease inhibitors is unlikely because the age of 11 months (range: 2 months 15 years). These patients
Resistance: enzyme targets involved are different. received 120 mg/m2/day of nevirapine for approximately 4 weeks
HIV isolates with reduced susceptibility (100-250-fold) to followed by 120 mg/m2/b.i.d. (patients >9 years of age) or 200
PHARMACOKINETICS IN ADULT PATIENTS:
nevirapine emerge in vitro. Genotypic analysis showed mutations mg/m2/b.i.d. (patients 9 years of age). Nevirapine clearance
Nevirapine is readily absorbed (>90%) after oral administration adjusted for body weight reached maximum values by age 1 to 2
in the HIV RT gene at amino acid positions 181 and/or 106 in healthy volunteers and in adults with HIV-1 infection. Absolute
depending upon the virus strain and cell line employed. Time to years and then decreased with increasing age.
bioavailability in 12 healthy adults following single-dose
emergence of nevirapine resistance in vitro was not altered when administration was 93 9% (mean SD) for a 50 mg tablet and Nevirapine apparent clearance adjusted for body weight was
selection included nevirapine in combination with several other 91 8% for an oral solution. approximately two-fold greater in children younger than 8 years
NNRTIs. compared to adults. Nevirapine half-life for the study group as a
Peak plasma nevirapine concentrations of 2 0.4 mcg/ml (7.5
Phenotypic and genotypic changes in HIV1 isolates from patients whole after dosing to steady state was 25.9 9.6 hours. With long
mcM) were attained by 4 hours following a single 200 mg dose.
treated with either VIRAMUNE (n=24) or VIRAMUNE+ZDV term drug administration, the mean values for nevirapine terminal
Following multiple doses, nevirapine peak concentrations appear
(n=14) were monitored in Phase I/II trials over 1 to 12 weeks. half-life changed with age as follows: 2 months to 1 year (32
to increase in a linear fashion in the dose range of 200 to 400 mg/ hours), 1 to 4 years (21 hours), 4 to 8 years (18 hours), greater than
After 1 week of VIRAMUNE monotherapy, isolates from 3/3 day. Steady state trough nevirapine concentrations of 4.5 1.9 8 years (28 hours).
patients had decreased susceptibility to nevirapine in vitro; one mcg/ml (17 7 mcM), (n = 242) were attained at 400 mg/day.
or more of the RT mutations at amino acid positions 103, 106, Patients without Prior History of Anti Retroviral Therapy:
The absorption of nevirapine is not affected by food, antacids or
108, 181, 188 and 190 were detected in some patients as early as A durable response for at least one year was documented in BI
medicinal products that are formulated with an alkaline buffering
2 weeks after therapy initiation. By week eight of VIRAMUNE trial 1046 (INCAS) for the triple therapy arm with nevirapine,
agent (e.g., didanosine).
monotherapy, 100% of the patients tested (n=24) had HIV isolates zidovudine and didanosine compared to zidovudine+didanosine
with >100-fold decrease in susceptibility to nevirapine in vitro Nevirapine is highly lipophilic and is essentially nonionised at or nevirapine+zidovudine in 151 HIV-1 infected, treatment-naive
physiologic pH. Following intravenous administration to healthy
compared to baseline, and had one or more of the nevirapine- patients with CD4+ cell counts of 200-600 cells/mm3 (mean 376
associated RT resistance mutations; 19 of 24 patients (80%) adults, the apparent volume of distribution (Vdss) of nevirapine
cells/mm3) and a mean baseline plasma HIV-1 RNA concentration
had isolates with a position 181 mutation regardless of dose. was 1.21 0.09 L/kg, suggesting that nevirapine is widely
of 4.41 log10 copies/ml (25,704 copies/ml)
VIRAMUNE + ZDV combination therapy did not alter the distributed in humans. Nevirapine readily crosses the placenta
and is found in breast milk. Nevirapine is about 60% bound to Patients With A Prior History Of Anti Retroviral Therapy:
emergence rate of nevirapine-resistant virus or the magnitude of
plasma proteins in the plasma concentration range of 1-10 mcg/ ACTG 241 compared treatment with VIRAMUNE+ZDV+ddI
nevirapine resistance in vitro; however, a different RT mutation
pattern, predominantly distributed amongst amino acid positions ml. Nevirapine concentrations in human cerebrospinal uid (n=6) versus ZDV+ddI in 398 HIV-1 infected patients with CD4+ cell
103, 106, 188 and 190 was observed. In patients (6 of 14) whose were 45% ( 5%) of the concentrations in plasma; this ratio is counts 350 cells/mm3 (mean 153 cells/mm3) and a mean baseline
baseline isolates possessed a wild type RT gene, VIRAMUNE approximately equal to the fraction not bound to plasma protein. plasma HIV-1 RNA concentration of 4.59 log10 copies/ml (38,905
+ ZDV combination therapy did not appear to delay emergence Nevirapine has been shown to be an inducer of hepatic cytochrome copies/ml), who had received at least 6 months of nucleoside
of ZDV-resistant RT mutations. Genotypic and phenotypic P450 metabolic enzymes. therapy prior to enrolment (median 115 weeks).
resistance was examined for patients receiving VIRAMUNE The pharmacokinetics of autoinduction are characterised by an A signicant benet of triple therapy with VIRAMUNE
in triple and double therapy drug combination therapy, and in the approximately 1.5 to 2 fold increase in the apparent oral clearance compared to double therapy was observed throughout a 48 week
non- VIRAMUNE comparative group from the INCAS study of nevirapine as treatment continues from a single dose to two-to- treatment period in terms of CD4 cell count, % CD4, quantitative
Antiretroviral naive subjects with CD4 cells counts of 200-600/ four weeks of dosing with 200-400 mg/day. Autoinduction also PBMC microculture and plasma viral DNA. Favourable responses
mm3 were treated with either VIRAMUNE + ZDV (N=46), results in a corresponding decrease in the terminal phase half-life to the triple therapy with VIRAMUNE were seen at all CD4
ZDV + ddI (N=51) or VIRAMUNE + ZDV + ddI (N=51) and of nevirapine in plasma from approximately 45 hours (single dose) count levels.
followed for 52 weeks or longer on therapy. to approximately 25-30 hours following multiple dosing with 200- Clinical endpoint trial:
Virologic evaluations were performed at baseline, six months and 400 mg/day.
ACTG 193a was a placebo controlled trial which compared
12 months. The phenotypic resistance test performed required Although a slightly higher weight adjusted volume of distribution
treatment with VIRAMUNE+ZDV+ddI versus ZDV+ddI,
a minimum of 1000 copies/ml HIV RNA in order to be able to of nevirapine was found in female subjects compared to males, no
as well as studying ZDV+ddC and ZDV alternating with ddI
amplify the virus. Of the three study groups, 16, 19 and 28 patients signicant gender differences in nevirapine plasma concentrations
monthly, in 1298 HIV-1-infected patients (mean age 37 years,
respectively had evaluable baseline isolates and subsequently following single or multiple dose administrations were seen.
51% Caucasian, 87% male) with CD4+ cell counts 50 cells/
remained in the study for at least 24 weeks. At baseline, there Nevirapine pharmacokinetics in HIV-1 infected adults do not
mm3 (mean 25 cells/mm3). Eighty-four percent (84%) of patients
were ve cases of phenotypic resistance to NVP; the IC50 values appear to change with age (range 18-68 years) or race (Black,
had received nucleoside therapy prior to enrolment (median 15
were 5 to 6.5-fold increased in three and >100 fold in two. At 24 Hispanic, or Caucasian). This information is derived from an
months). Treatment doses were VIRAMUNE, 200 mg daily for
weeks, all available isolates recoverable from patients receiving evaluation of pooled data derived from several clinical trials.
two weeks, followed by 200 mg twice daily, or placebo; ZDV, 200
VIRAMUNE were resistant to this agent, while 18/21 (86%) Renal Dysfunction: mg three times daily; ddC, 0.75 mg three times daily; ddI, 200 mg
patients carried such isolates at 30-60 weeks. The single-dose pharmacokinetics of VIRAMUNE have been twice daily (or 125 mg twice daily for patients weighing less than
In 16 subjects viral suppression was below the limits of compared in 23 subjects with either mild (50 CLcr < 80 ml/min), 60 kg). The median time to HIV progression event or death was
detection (<20 copies/ml = 14, <400 copies/ml = 2). Assuming moderate (30 CLcr < 50 ml/min) or severe renal dysfunction signicantly delayed in the VIRAMUNE +ZDV+ddI treatment
that suppression below <20 copies/ml implies VIRAMUNE (CLcr < 30 ml/min), renal impairment or end-stage renal disease group as compared to the ZDV+ddI group (82 weeks versus 62
susceptibility of the virus, 45% (17/38) of patients had virus (ESRD) requiring dialysis, and 8 subjects with normal renal weeks). Mortality was similar for the two groups, throughout the
measured or imputed to be susceptible to VIRAMUNE. All function (CLcr > 80 ml/min). trial. The median time to HIV progression event or death was
11 subjects receiving VIRAMUNE + ZDV who were tested Renal impairment (mild, moderate and severe) resulted in no shorter for ZDV+ddC (53 weeks) and alternating ZDV and ddI
for pheotypic resistance were resistant to VIRAMUNE by signicant change in the pharmacokinetics of VIRAMUNE. (57 weeks) groups.
six months. Over the entire period of observation, one case of However, subjects with ESRD requiring dialysis exhibited a 43.5 Perinatal transmission:
didanosine resistance was seen. zidovudine resistance emerged as % reduction in VIRAMUNE AUC over a one-week exposure
more frequent after 30-60 weeks, especially in patients receiving HIVNET 012 compared prevention of vertical transmission of
period. There was also accumulation of nevirapine hydroxy-
double combination therapy. HIV-1 infection from 618 pregnant women to their neonates using
metabolites in plasma. The results suggest that supplementing
VIRAMUNE therapy with an additional 200 mg dose of VIRAMUNE or ZDV. Mothers received nevirapine 200 mg
Based on the increase in IC50, ZDV resistance appeared lower in
VIRAMUNE following each dialysis treatment would help offset orally at onset of labour and 2 mg/kg to babies within 72 hours
the VIRAMUNE + ZDV + ddI group than the other treatment
the effects of dialysis on VIRAMUNE clearance. Otherwise of birth, or zidovudine 600 mg orally to the mother at onset of
groups. With respect to VIRAMUNE resistance, all isolates
patients with CLcr 20 ml/min do not require an adjustment in labour and 300 mg every 3 hours until delivery, and 4 mg/kg orally
that were sequenced carried at least one mutation associated with
resistance, the most common single changes being K103N and VIRAMUNE dosing. twice daily to babies for 7 days after birth. No other antiretroviral
Y181C. In summary, the use of highly active drug therapies is therapy was given.
Hepatic dysfunction: The single-dose pharmacokinetics of
associated with a delay in the development of antiretroviral drug VIRAMUNE have been compared in 10 subjects with hepatic The mothers median age was 24 years, the media CD4 cell count
resistance. The genotypic correlates of phenotypic VIRAMUNE dysfunction and 8 subjects with normal hepatic function. Overall, was 448 cells/L, and the median plasma HIV-1 RNA level was
resistance were identied in 12 plasma isolates from 11 triple the results suggest that patients with mild to moderate hepatic 26,943 copies/mL. The primary endpoint of HIV infection was
therapy patients. Treatment-emergent, VIRAMUNE resistance- dysfunction, dened as Child-Pugh Classication Score 7, do based on HIV RNA PCR assay, conrmed by either a second HIV
associated mutations were: not require an adjustment in VIRAMUNE dosing. However, RNA assay or HIV culture. Outcomes are summarised for the rates
the pharmacokinetics of VIRAMUNE in one subject with a of HIV RNA PCR conrmed infection (Table 1.) and infection or
Mutation Frequency death (Table 2).
Child-Pugh score of 8 and moderate to severe ascites suggests
K101E 2 that patients with worsening hepatic function may be at risk of Table 1:
K103N 8 accumulating nevirapine in the systemic circulation. Therefore Cumulative HIV-1 Infection Rates According to Time After
caution should be exercised when VIRAMUNE is administered Delivery
V106A 2
to patients with moderate to severe hepatic dysfunction. Zidovudine Nevirapine p
Y181C 5
(n = 308) (n = 310)
PHARMACOKINETICS IN PAEDIATRIC PATIENTS
G190A 6 Time after Probability Probability
The pharmacokinetics of nevirapine have been studied in two delivery of endpoint of endpoint
Combinations of mutations were observed in nine of the 12 open-label studies in children with HIV-1 infection. In one study, Week 6-8 21.3% 11.9% 0.0027
patients. These data from INCAS illustrate that the use of highly nine HIV-infected children ranging from 9 months to 14 years of Week 14-16 25.1% 13.1% 0.00063
active drug therapies is associated with a delay in the development age were administered single doses (7.5 mg, 30 mg, or 120 mg per
of antiretroviral drug resistance. The clinical relevance of m2, n=3 per dose) of nevirapine suspension after an overnight fast. Table 2:
phenotypic and genotypic changes associated with nevirapine Nevirapine AUC and peak concentration increased in proportion Cumulative HIV-1 Infection or Death According to Time After
therapy has not been established. with dose. Following absorption nevirapine mean plasma Delivery
Cross-resistance: Rapid emergence of HIV strains, which are concentrations declined on a log linear basis with time. Zidovudine Nevirapine p
cross-resistant to NNRTIs, has been observed in vitro. Data on Nevirapine terminal phase half-life following a single dose was (n = 308) (n = 310)
cross-resistance between the NNRTI nevirapine and nucleoside 30.6 10.2 hours. In a second multiple dose study, nevirapine Time after Probability Probability
analogue RT inhibitors are very limited. suspension or tablets (240 to 400 mg/m2/day) were administered delivery of endpoint of endpoint
In four patients, ZDV-resistant isolates tested in vitro retained as monotherapy or in combination with ZDV or ZDV and ddI to 37 Week 6-8 23.1% 12.8% 0.0012
susceptibility to nevirapine and in six patients, nevirapine-resistant HIV-1-infected paediatric patients with the following demographics Week 14-16 27.6% 14.4% 0.00021
177
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SPDI
INDICATIONS: Patients should be informed that hepatic reactions are a major In one crossover study, nevirapine had no effect on the steady-
For treatment of HIV infection, VIRAMUNE is indicated for use toxicity of VIRAMUNE requiring close monitoring during state pharmacokinetics of either didanosine (n=18) or zalcitabine
in combination with other antiretroviral agents for the treatment of the rst 2 months. They should be informed that occurrence of (n=6).
HIV-1 infection. Resistant virus emerges rapidly and uniformly symptoms suggestive of hepatitis should lead them to contact Results from a 36 day study in HIV infected patients (n = 25)
when VIRAMUNE is administered as monotherapy. Therefore, promptly their physician. administered VIRAMUNE, nelnavir (750 mg t.i.d.) and
VIRAMUNE should always be administered in combination Liver monitoring: stavudine (30-40 mg bid) showed no statistically signicant
with at least two additional antiretroviral agents. Abnormal liver function tests have been reported with changes in the AUC or Cmax of stavudine. Furthermore a
For the prevention of mother to child transmission of HIV-1 in VIRAMUNE, some in the rst few weeks of therapy. population pharmacokinetic study of 90 patients assigned to
pregnant women who are not taking antiretroviral therapy at time Asymptomatic elevations of liver enzymes are frequently described receive lamivudine with VIRAMUNE or placebo revealed
of labour, VIRAMUNE is indicated and may be used alone, as a and are not necessarily a contraindication to use VIRAMUNE no changes to lamivudine apparent clearance and volume of
single oral dose to the mother during labour and a single oral dose Asymptomatic GGT elevations are not a contraindication to distribution, suggesting no induction effect of VIRAMUNE on
to the infant within 72 hours after birth. continuing therapy. lamivudine clearance.
Monitoring of liver function tests is strongly recommended at Protease Inhibitors:
CONTRAINDICATIONS:
frequent intervals, appropriate to the patients clinical needs, In the following studies, VIRAMUNE was given 200 mg once
VIRAMUNE is contraindicated in patients with clinically daily for two weeks followed by 200 mg twice daily for 28 days.
especially during the rst 2 to 3 months of treatment. Less
signicant hypersensitivity to the active ingredient or any Saquinavir: Results from a clinical trial (n=31) with HIV infected
frequent monitoring is needed thereafter. Physicians and patients
of the excipients of the product. VIRAMUNE should not patients administered nevirapine and saquinavir (hard gelatine
should be vigilant for prodromal signs or ndings of hepatitis,
be readministered to patients who have required permanent capsules; 600 mg t.i.d.) indicated that their co-administration leads
such as anorexia, nausea, jaundice, bilirubinuria, acholic stools,
discontinuation for severe rash, rash accompanied by constitutional to a mean reduction of 24% (p=0.041) in saquinavir AUC and no
hepatomegaly or liver tenderness. Patients should be instructed
symptoms, hypersensitivity reactions, or clinical hepatitis due signicant change in nevirapine plasma levels.
to seek medical attention if these occur. If ASAT or ALAT > 2X
to nevirapine. VIRAMUNE should not be readministered in
ULN, then liver tests should be monitored more frequently during The reduction in saquinavir levels due to this interaction may
patients who previously had ASAT or ALAT > 5X
regular clinic visits. further reduce the plasma levels of saquinavir, which are
Upper Limit of Normality (ULN) during nevirapine therapy achieved with the hard gelatine capsule formulation. The clinical
and had rapid recurrence of liver function abnormalities upon If ASAT or ALAT increase to > 5X ULN, nevirapine should signicance of this interaction is not known. Co-administration
readministration of nevirapine, (see section Special Warnings and be immediately stopped. If ASAT and ALAT return to baseline did not affect the pharmacokinetics of nevirapine.
Precautions). values it may be possible to reintroduce VIRAMUNE, on
Ritonavir:
a case by case basis, at the starting dosage regimen of 200
SPECIAL WARNINGS AND PRECAUTIONS: mg/day for 14 days followed by 400 mg/day. If liver function No dosage adjustments are required when VIRAMUNE is
The rst 8 weeks of therapy with nevirapine therapy are a critical abnormalities rapidly recur, nevirapine should be permanently taken in combination with ritonavir. Results from a clinical trial
period which require close monitoring of patients to disclose discontinued. (n=25) with HIV infected patients administered nevirapine and
the potential appearance of severe and life-threatening skin If clinical hepatitis occurs, characterised by anorexia, nausea, ritonavir (600 mg b.i.d. [using a gradual dose escalation regimen])
reactions (including cases of Stevens-Johnson syndrome and vomiting, icterus AND laboratory ndings (such as moderate indicated that their coadministration leads to no signicant change
toxic epidermal necrolysis) or serious hepatitis/hepatic failure. In or severe liver function test abnormalities (excluding GGT), in ritonavir or nevirapine plasma concentrations.
addition the dosage must be strictly adhered to, especially the 14- nevirapine must be permanently stopped. Nevirapine should Indinavir: Results from a clinical trial (n=25) with HIV infected
days lead-in period (see section Dosage and Administration). not be readministered to patients who have required permanent patients administered nevirapine and indinavir (800 mg q8H)
Severe and life threatening skin reactions, including fatal cases, discontinuation for clinical hepatitis due to nevirapine. indicated that their co-administration leads to a 28% mean decrease
have occurred in patients treated with VIRAMUNE. These (p<0.01) in indinavir AUC and no signicant change in nevirapine
OTHER WARNINGS: plasma levels. No denitive clinical conclusions have been reached
have included cases of Stevens Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN) and hypersensitivity reactions The following events have also been reported when regarding the potential impact of co-administration of nevirapine
characterised by rash, constitutional ndings, and visceral VIRAMUNE has been used in combination with other anti- and indinavir. A dose increase of indinavir to 1000 mg q8h should
involvement. Patients should be carefully monitored during the retroviral agents: anaemia, pancreatitis, peripheral neuropathy and be considered when indinavir is given with nevirapine 200 mg
rst 8 weeks of treatment. thrombocytopenia. These events are commonly associated with b.i.d.; however, there are no data currently available to establish
other anti-retroviral agents and may be expected to occur when that the short term or long term antiviral activity of indinavir 1000
Patients should be closely monitored if an isolated rash occurs.
VIRAMUNE is used in combination with other agents; however mg q8h with nevirapine 200 mg b.i.d. will differ from that of
VIRAMUNE must be permanently discontinued in any patient
it is unlikely that these events are due to nevirapine treatment. indinavir 800 mg q8h with nevirapine 200 mg b.i.d.
experiencing severe rash or a rash accompanied by constitutional
symptoms (such as fever, blistering, oral lesions, conjunctivitis, Patients receiving VIRAMUNE or any other antiretroviral Nelnavir:
swelling, muscle or joint aches, or general malaise), including therapy may continue to develop opportunistic infections and Results from a 36 day study in HIV infected patients (n=25)
Stevens-Johnson syndrome, or toxic epidermal necrolysis. other complications of HIV infection, and therefore should remain administered VIRAMUNE,
VIRAMUNE must be permanently discontinued in any patient under close clinical observation by physicians experienced in the nelnavir (750 mg t.i.d.) and d4T (30-40 mg b.i.d.) showed no
experiencing hypersensitivity reactions, characterised by rash treatment of patients with associated HIV diseases. The long-term statistically signicant changes in nelnavir pharmacokinetic
with constitutional symptoms, plus visceral involvement, such as effects of VIRAMUNE are unknown at this time. parameters after the addition of VIRAMUNE (AUC +4%,
hepatitis, eosinophilia, granulocytopenia, and renal dysfunction or VIRAMUNE therapy has not been shown to reduce the risk of Cmax + 14%, and Cmin -2%). Compared to historical controls
signs of other visceral involvement. (see Side Effects). transmission of HIV-1 to others. VIRAMUNE is extensively VIRAMUNE levels appeared to be unchanged. There were
metabolised by the liver and nevirapine metabolites are eliminated no increased safety concerns noted when the administration of
Patients should be advised that the major toxicity of VIRAMUNE VIRAMUNE with any of the protease inhibitors when used in
is rash. The lead-in period should be used because it has been found largely by the kidney. Pharmacokinetic results suggest caution
should be exercised when VIRAMUNE is administered to patients combination.
to lessen the frequency of rash (see Dosage and Administration).
The majority of rashes associated with VIRAMUNE occur with moderate to severe hepatic dysfunction. In patients with Ketoconazole:
within the rst six weeks of therapy therefore patients should be renal dysfunction who are undergoing dialysis pharmacokinetic Administration of nevirapine 200 mg b.i.d. with ketoconazole 400
monitored carefully for the appearance of rash during this period. results suggest that supplementing VIRAMUNE therapy with mg q.d. resulted in a signicant reduction (63% median reduction
Patients should be instructed that the dose escalation is not to an additional 200 mg dose of VIRAMUNE following each in ketoconazole AUC and a 40% median reduction in ketoconazole
occur if any rash occurs during the lead-in period until the rash dialysis treatment would help offset the effects of dialysis on Cmax). In the same study, ketoconazole administration resulted in
has resolved. VIRAMUNE clearance. a 15-28% increase in the plasma levels of nevirapine compared
Otherwise patients with CLcr 20 ml/min do not require an to historical controls. Ketoconazole and nevirapine should not be
Concomitant prednisone use (40 mg/day for the rst 14 days of
adjustment in VIRAMUNE dosing (see Pharmacokinetics given concomitantly. The effects of nevirapine on itraconazole are
VIRAMUNE administration) has been shown not to decrease
in Adult Patients). Oral contraceptives and other hormonal not known.
the incidence of VIRAMUNE-associated rash, and may be
associated with an increase in rash during the rst 6 weeks of methods of birth control should not be used as the sole method of Although interaction studies have not been performed, antifungal
VIRAMUNE therapy. Risk factors for developing serious contraception in women taking VIRAMUNE, since nevirapine medicinal products, which are eliminated renally (e.g. uconazole)
cutaneous reactions include failure to follow the initial dosing of may lower the plasma concentrations of these medications. might be substituted for ketoconazole. CYP Isoenzyme Inducers:
200 mg daily during the lead-in period. A long delay between the Additionally, when oral contraceptives are used for hormonal An open label study (n = 14) on the effects of VIRAMUNE
initial symptoms and medical consultation may increase the risk of regulation during VIRAMUNE therapy, the therapeutic effect of on the steady state pharmacokinetics of rifampin resulted in no
a more serious outcome of cutaneous reactions. the hormonal therapy should be monitored. signicant change in rifampin Cmax and AUC. In contrast rifampin
produced a signicant lowering of nevirapine AUC (-58%), Cmax
Any patient experiencing severe rash or a rash accompanied by INTERACTIONS:
(-50%) and Cmin (-68%) compared to historical data. At present
constitutional symptoms such as fever, blistering, oral lesions, VIRAMUNE has been shown to be an inducer of hepatic there are insufcient data to assess what dosage adjustments are
conjunctivitis, swelling, muscle or joint aches, or general cytochrome P450 metabolic enzymes (CYP3A, CYP2B) and required when nevirapine and rifampin are co-administered.
malaise should discontinue medication and consult a physician. may result in lower plasma concentrations of other concomitantly Rifabutin:
In these patients VIRAMUNE must not be restarted. If a administered drugs that are extensively metabolised by CYP3A
hypersensitivity reaction occurs, characterised by rash with or CYP2B (see pharmacokinetics). Thus, if a patient has been Administration of nevirapine 200 mg b.i.d. with rifabutin 300 mg
constitutional symptoms such as fever, arthralgia, myalgia and stabilised on a dosage regimen for a drug metabolised by CYP3A q.d (or 150 mg q.d if concomitantly receiving ZDV or protease
lymphadenopathy, plus visceral involvement, such as hepatitis, inhibitors), resulted in non-signicant changes to rifabutin
or CYB2B and begins treatment with VIRAMUNE, dose
eosinophilia, granulocytopenia, and renal dysfunction, nevirapine concentrations (12% median increase in rifabutin AUC and a 3%
adjustments may be necessary.
should be permanently stopped and not be re-introduced. median decrease in rifabutin Cminss), and a signicant increase
Nucleoside Analogues: (20%) in median Cmaxss. There were no signicant changes in
Hepatic reactions: No dosage adjustments are required when nevirapine is taken in the active metabolite 25-O-desacetyl-rifabutin concentrations. In
Severe or life threatening hepatotoxicity, including fatal fulminant combination with zidovudine, didanosine or zalcitabine. When the same study, rifabutin administration resulted in an apparent
hepatitis has occurred in patients treated with VIRAMUNE. zidovudine data were pooled from two studies (n=33) in which signicant increase in systemic clearance of nevirapine by 9%
Serious hepatitis and hepatic failure events in VIRAMUNE HIV-1 infected patients received nevirapine 400 mg/day either compared to historical controls. None of these changes are
treated patients have been reported to occur in the rst 8 weeks of alone or in combination with 200-300 mg/day didanosine or considered to be clinically important. Nevirapine and rifabutin
therapy, but some have occurred later. 0.375 to 0.75 mg/day zalcitabine on a background of zidovudine can safely be administered concurrently with no dose adjustments
Increased ASAT or ALAT levels prior to the start of antiretroviral therapy, nevirapine produced a non-signicant decline of 13% required.
therapy is associated with greater risk of hepatic adverse events in zidovudine area under the curve (AUC) and a non-signicant Concomitant use of VIRAMUNE and St. Johns wort
during antiretroviral therapy in general, including VIRAMUNE- increase of 5.8% in zidovudine Cmax. Paired data suggest that (hypericum perforatum) or St. Johns wort containing products
containing regimens. zidovudine had no effect on the pharmacokinetics of nevirapine. is not recommended, based on a reported interaction between St.
178
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SPDI
Johns wort and another antiretroviral. Coadministration of Non- SIDE EFFECTS: Rash occurred in 2.9% of the zidovudine group, and 2.9% of the
Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), including Adults: nevirapine group. The rates of serious adverse events of any cause
VIRAMUNE, with St. Johns wort is expected to decrease were similar in the two groups of infants (19.8% in the zidovudine
Apart from rash and abnormal LFTs, the most frequently reported
NNRTI concentrations and may result in sub-optimal levels of group, 20.5% in the nevirapine group). Thirty-eight (6.8%) infants
adverse events related to VIRAMUNE therapy across all
VIRAMUNE and lead to loss of virologic response and possible died (22 [7.9%] in the zidovudine group 16 [5.7%] in the nevirapine
clinical trials were nausea, fatigue, fever, headache, somnolence,
resistance to VIRAMUNE or to the class of NNRTIs. group). The most frequent causes of death were pneumonia,
vomiting, diarrhoea, abdominal pain and myalgia.
CYP Isoenzyme Inhibitors: gastroenteritis, diarrhoea, dehydration, and sepsis. Maculopapular
The postmarketing experience has shown that the most rash occurred in 1.3% of the zidovudine group, and 1.6% of the
The results of a nevirapine - clarithromycin drug-drug interaction
serious adverse reactions are Stevens- Johnson syndrome, nevirapine group. No mothers or infants experienced serious rash.
study (n = 18) resulted in a signicant reduction in clarithromycin
toxic epidermal necrolysis, serious hepatitis/hepatic failure In summary the list of side effects, which can be expected with v
AUC (30%), Cmax (-21%) and Cmin (- 46%) but a signicant
and hypersensitivity reactions, characterised by rash with treatment, includes
increase in the AUC (58%) and Cmax (62%) of the active
constitutional symptoms such as fever, arthralgia, myalgia and
metabolite 14-OH clarithromycin. There was a signicant increase - Rash(includingSJS/TEN) - Hypersensitivity reactions
lymphadenopathy, plus visceral involvement, such as hepatitis,
in the nevirapine Cmin (28%) and a non-signicant increase in characterisedby rash
eosinophilia, granulocytopenia, and renal dysfunction. The rst
nevirapine AUC (26%) and Cmax (24%). These results would associated with constitutional
8 weeks of treatment is a critical period which requires close
suggest that no dose adjustment is necessary in either drug when symptoms such as fever,
the two drugs are co-administered. monitoring (see section Special Warnings and Precautions).
arthalgia, myalgia and
In a subpopulation analysis of patients in VIRAMUNE clinical Skin and subcutaneous Tissues: lymphadenopathy plus one
trials, the monitoring of steady-state nevirapine trough plasma The most common clinical toxicity of nevirapine is rash. or more of the following:
concentrations were elevated in patients who received cimetidine Nevirapine attributable rash occurred in 16% of patients in hepatitis, eosinophilia,
(+7%, n = 13). combination regimens in Phase II/III controlled studies. In these granulocytopaenia, renal
Oral Contraceptives: dysfunction or other visceral
clinical trials 35% of patients treated with nevirapine experienced
involvement has also
Nevirapine 200 mg b.i.d. was co-administered with a single rash compared with 19% of patients treated in control groups
been reported.
dose of an oral contraceptive containing ethinyl estradiol (EE) of either zidovudine+didanosine or zidovudine alone. Severe or
0.035mg and norethindrone (NET) 1.0 mg (Ortho-Novum 1/35). life-threatening skin reactions occurred in 6.6% of nevirapine- - Abnormal LFTs, (ASAT, ALAT, - jaundice
Compared to plasma concentrations observed prior to nevirapine treated patients compared with 1.3% of patients treated in the GGT, total bilirubin, alkaline
administration, the median AUC for 17-EE was signicantly control groups. Overall, 7% of patients discontinued nevirapine phosphatase)
decreased by 29% after 28 days of nevirapine due to rash. Rashes are usually mild to moderate, maculopapular - hepatitis - nausea
dosing. There was a signicant reduction in EE mean resident time erythematous cutaneous eruptions, with or without pruritus, - fatigue - fever
and half-life. There was a signicant reduction (18%) in median located on the trunk, face and extremities. - headache - somnolence
AUC for NET, without changes in mean resident time or half- Allergic reactions (anaphylaxis, angio-oedema and urticaria) have - vomiting - diarrhoea
life. The magnitude of the effect suggests that the dose of the oral been reported. Severe and life-threatening skin reactions have - abdominal pain - myalgia
contraceptive could be adjusted to allow adequate treatment for occurred in patients treated with nevirapine, including Stevens- - granulocytopenia (paediatric) - allergic reaction (anaphylaxis,
indications other than contraception (e.g., endometriosis), if used Johnson syndrome (SJS) and, rarely toxic epidermal necrolysis angioedema, urticaria)
with nevirapine. However, the risk of oral contraceptive failure is a (TEN). Fatal cases of SJS, TEN and hypersensitivity reactions
possibility if estrogen/progesterone-containing oral contraceptives DOSAGE AND ADMINISTRATION:
have been reported. Based on a denominator of 2861 nevirapine-
are used. treated clinical trial patients, the overall incidence of SJS was Adults:
Other means of contraception (such as barrier methods) are 0.3% (9/2861). The recommended dose for VIRAMUNE is one 200 mg tablet
recommended, when nevirapine is administered to women of Rashes occur alone or in the context of hypersensitivity reactions daily for the rst 14 days (this lead-in period should be used
child-bearing potential. For other therapeutic uses requiring because it has been found to lessen the frequency of rash), followed
characterised by rash with constitutional symptoms such as
hormonal regulation, the therapeutic effect in patients being by one 200 mg tablet twice daily, in combination with at least two
fever, arthralgia, myalgia and lymphadenopathy plus visceral
treated with nevirapine should be monitored. additional antiretroviral agents. For concomitantly administered
involvement, such as hepatitis, eosinophilia, granulocytopenia
Other Information: and renal dysfunction. The majority of severe rashes occur therapy, the manufacturers recommended dosage and monitoring
In vitro studies using human liver microsomes indicated that the within the rst 6 weeks of treatment. In conjunction with a team should be followed.
formation of nevirapine hydroxylated metabolites was not affected of international experts, Boehringer Ingelheim has developed Paediatric Patients:
by the presence of dapsone, rifabutin, rifampin, and trimethoprim/ a classication scheme and rash management algorithm. These The recommended oral dose of VIRAMUNE for paediatric
sulfamethoxazole. Ketoconazole and erythromycin signicantly guidelines have been used in clinical studies with VIRAMUNE patients 2 months up to 8 years of age is 4 mg/kg once daily for
inhibited the formation of nevirapine hydroxylated metabolites. since 1994 and have been helpful in managing the treatment of two weeks followed by 7 mg/kg twice daily thereafter. For patients
Clinical studies have not been performed. patients with rash. 8 years and older the recommended dose is 4 mg/kg once daily for
It should be noted that other compounds that are substrates of Hepato-biliary: two weeks followed by 4 mg/kg twice daily thereafter. The total
CYP3A or CYP2B6 might have decreased plasma concentrations daily dose should not exceed 400 mg for any patient.
The most frequently observed laboratory test abnormalities are
when co-administered with VIRAMUNE. Based on the known Prevention of Mother to Child HIV Transmission:
metabolism of methadone, nevirapine may decrease plasma elevations in liver function tests (LFTs), including ALAT, ASAT,
GGT, total bilirubin and alkaline phosphatase. Asymptomatic The recommended dosing for administration to pregnant women
concentrations of methadone by increasing its hepatic metabolism.
elevations of GGT levels are the most frequent. Cases of jaundice in labour is a single 200 mg dose followed by a neonatal single
Narcotic withdrawal syndrome has been reported in patients
treated with VIRAMUNE and methadone concomitantly. have been reported. Cases of hepatitis, severe and life-threatening dose of 2 mg/kg orally within 72 hours after birth. Patients should
Methadonemaintained patients beginning nevirapine therapy hepatoxicity, and fatal fulminant hepatitis, have been reported in be advised of the need to take VIRAMUNE every day as
should be monitored for evidence of withdrawal and methadone patients treated with nevirapine. In a large clinical trial, the risk of prescribed. If a dose is missed the patient should not double the
dose should be adjusted accordingly. a serious hepatic event among 1121 patients receiving nevirapine next dose but should take the next dose as soon as possible.
for a median duration of greater than one year was 1.2 % (versus Clinical chemistry tests, including liver function tests, should
PREGNANCY AND LACTATION: 0.6 % in placebo group). The best predictor of a serious hepatic be performed prior to initiating VIRAMUNE therapy and at
No observable teratogenicity was detected in reproductive studies event was elevated baseline liver function tests. The rst 8 weeks appropriate intervals during therapy (see Special Warnings and
performed in pregnant rats and rabbits. In rats, a signicant of treatment is a critical period which requires close monitoring, Precautions).
decrease in foetal body weight occurred at doses providing but such events may also occur later (see section Special Warnings VIRAMUNE administration should be discontinued if patients
systemic exposure approximately 50% higher, based on AUC, than and Precautions). experience severe rash or a rash accompanied by constitutional
that seen at the recommended human clinical dose. The maternal
For liver function test monitoring see section Special Warnings symptoms. Patients experiencing rash during the 14 day lead-in
and development no-observable-effect level dosages in rats and
and Precautions. period of 200 mg daily should not have their dose increased until
rabbits produced systemic exposures approximately equivalent to
Paediatric Patients: the rash has resolved (see Special Warnings and Precautions).
or approximately 50% higher, respectively, than those seen at the
recommended daily human dose, based on AUC. Safety has been assessed in 361 HIV-1-infected paediatric patients VIRAMUNE administration should be interrupted in patients
between the ages of 3 days to 19 years. The majority of these experiencing moderate or severe liver function test abnormalities
There are no adequate and well-controlled studies in pregnant
patients received VIRAMUNE in combination with ZDV or ddI, (excluding GGT) until liver function tests have returned to
women for the treatment of HIV-1 infection. VIRAMUNE
should be used during pregnancy only if the potential benet or ZDV + ddI in two studies. In an open-label trial BI 882 (ACTG baseline. VIRAMUNE may then be restarted at 200 mg daily
justies the potential risk to the foetus. 180) 37 patients were followed for a mean duration of 33.9 months increasing to 200 mg twice daily with caution, after extended
(range: 6.8 months to 5.3 years, including long-term follow-up observation. VIRAMUNE should be permanently discontinued
VIRAMUNE for the prevention of mother to child transmission
of HIV-1 has been demonstrated to be safe and effective when trial BI 892). In ACTG 245, a double-blind placebo controlled if moderate or severe liver function test abnormalities recur (see
given as part of a regimen that includes a single 200 mg oral dose study, 305 patients with a mean age 7 years (range: 10 months to Special Warnings and Precautions).
to mothers during labour followed by a single 2 mg/kg dose to 19 years) received combination treatment with VIRAMUNE for Patients who interrupt VIRAMUNE dosing for more than 7 days
the infant within 72 hours after birth. Preliminary results from an at least 48 weeks at a dose of 120 mg/m2 once daily for two weeks should restart the recommended dosing regimen, using 200 mg
ongoing pharmacokinetic study (ACTG 250) of 10 HIV-1-infected followed by 120 mg/m2 twice daily thereafter. once daily (lead-in) followed by one 200 mg tablet twice daily.
pregnant women who were administered a single oral dose of The most frequently reported adverse events related to OVERDOSE:
100 or 200 mg VIRAMUNE at a median of 5.8 hours before VIRAMUNE were similar to those observed in adults, with There is no known antidote for VIRAMUNE overdose. Cases
delivery, indicated that nevirapine readily crosses the placenta and the exception of granulocytopenia, which was more commonly of VIRAMUNE overdose at doses ranging from 800 to 1800
is found in breast milk. observed in children. Two VIRAMUNEtreated patients mg per day for up to 15 days have been reported. Patients have
Consistent with the recommendation that HIV-infected mothers experienced SJS or Stevens- Johnson/toxic epidermal necrolysis experienced oedema, erythema nodosum, fatigue, fever, headache,
not breast-feed their infants to avoid risking postnatal transmission transition syndrome. Both patients recovered after VIRAMUNE insomnia, nausea, pulmonary inltrates, rash vertigo, vomiting
of HIV, mothers should discontinue breast-feeding if they are treatment was discontinued. and weight decrease. All subsided following discontinuation of
receiving VIRAMUNE. Prevention Of Vertical Transmission: VIRAMUNE.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Based on trial HIVNET 012 (see Clinical Trials), the rates of AVAILABILITY:
There are no specic studies about the ability to drive vehicles maternal serious adverse events of any cause were similar in the
Tablets of 200 mg
and use machinery. However somnolence has been reported in Viramune and zidovudine groups (4.7% versus 4.4%, respectively).
[Oral suspension 10 mg/ml(N.R)]
association with VIRAMUNE therapy and if this occurs during The occurrence of clinical or laboratory abnormalities in mothers
VIRAMUNE administration it is advisable to refrain from such was similar in the two groups (82.2% in the zidovudine group and STORAGE INSTRUCTIONS:
activities. 80.7% in the nevirapine group had at least one such event). Store in a safe place below 30oC.
179
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BPL (BIO PRODUCTS LABORATORY)
SPDI
In the case of post-partum use, the product is intended for 5. PHARMACOLOGICAL PROPERTIES:
BPL maternal administration. It should not be given to the newborn 5.1 PHARMACODYNAMIC PROPERTIES
(BIO PRODUCTS LABORATORY ) infant. Pharmacotherapeutic group: immune sera and immunoglobulins:
P.O.BOX : 325015, RIYADH: 11371 The product is not intended for use in RhD positive Anti-D (Rh) immunoglobulin. ATC code: J06BB01.
individuals. Anti-D immunoglobulin contains specic antibodies (IgG)
SAUDI ARABIA
Patients should be observed for at least 20 minutes after against the RhD antigen of human erythrocytes.
TEL: 01-4724477, FAX:01-4765991 administration. 5.2 PHARMACOKINETIC PROPERTIES
If symptoms of allergic or anaphylactic type reactions occur, Measurable levels of antibodies are obtained approximately
D-GAM Human Anti-D Immunoglobulin immediate discontinuation of the administration is required. 8 hours after intramuscular injection. Peak serum levels are
True hypersensitivity reactions are rare but allergic type usually achieved 2 to 3 days later.
Solution for Injection
responses to Anti-D immunoglobulin may occur. Patients The half-life in the circulation of individuals with normal IgG
should be informed of the early signs of hypersensitivity levels is 3 to 4 weeks.
(Human Anti-D Immunoglobulin) reactions including hives, generalised urticaria, tightness of the IgG and IgG-complexes are broken down in cells of the
chest, wheezing, hypotension and anaphylaxis. The treatment reticuloendothelial system.
1. NAME OF PRODUCT: required depends on the nature and severity of the side effect. In
D-GAM, Human Anti-D Immunoglobulin 5.3 PRECLINICAL SAFETY DATA
case of shock, the current medical standards for shock treatment
should be observed. D-GAM is a preparation of human plasma proteins, so safety
2. QUALITATIVE AND QUANTITATIVE COMPOSITION: testing in animals is not particularly relevant to the safety of use
Human Anti-D Immunoglobulin Ph.Eur.* D-GAM contains a small quantity of IgA. Although anti-D in man. Acute toxicity studies in rat and mouse showed species
Each vial contains: 5 - 50 mg/L protein (250 and 500 iu vials) or immunoglobulin has been used successfully to treat selected IgA specic reactions, which bear no relevance to administration in
50 - 180 mg/L protein (1,500(N.R) and 2,500 iu vials) of which decient individuals, the attending physician must weigh the humans.
at least 95% is gammaglobulin (IgG). The product contains less benet against the potential risks of hypersensitivity reactions.
Repeated dose safety testing is impracticable due to the
than 0.02% w/w of IgA. For excipients see 6.1. Individuals decient in IgA have a potential for development of induction of and interference with antibodies to human protein.
The product is prepared from plasma from RhD-negative IgA antibodies and anaphylactic reactions after administration Clinical experience provides no sign of tumourigenic and
screened donors who have been immunised against RhD of blood components containing IgA. mutagenic effects.
antigen and contains specic antibodies against erythrocyte When medicinal products prepared from human blood or plasma
6. PHARMACEUTICAL PARTICULARS
RhD antigen. Donors are selected from the USA. are administered, infectious diseases due to transmission of
infective agents cannot be totally excluded. This also applies to 6.1 LIST OF EXCIPIENTS
*The product is presented in three different concentrations
but the highest concentration is lled in different volumes pathogens of hitherto unknown nature. The risk of transmission Sodium chloride
to achieve two dose presentations. The product is therefore of infective agents is however reduced by: Glycine
available in four nominal doses, namely 250 iu per vial, i) Selection of donors by a medical interview and screening Sodium acetate trihydrate
500 iu per vial (N.R), 1,500 iu per vial and 2,500 iu per vial. of individual donations and plasma pools for HBsAg and Sodium hydroxide
3. PHARMACEUTICAL FORM: antibodies to HIV and HCV.
6.2 INCOMPATIBILITIES
A solution for injection. ii) Testing of plasma pools for HCV genomic material.
This medicinal product must not be mixed with other medicinal
iii) Inactivation/removal procedures included in the production products.
4. CLINICAL PARTICULARS:
process that have been validated using model viruses. These
4.1 THERAPEUTIC INDICATIONS procedures are considered effective for HIV, HCV and HBV. 6.3 SHELF-LIFE
Prevention of RhD immunisation in RhD negative women: The specic virus inactivation process used is solvent/ Stored at 2 - 8C: 2 years.
i. Pregnancy/delivery of a RhD positive baby. detergent treatment. Stored at 25C: 1 week.
ii. Abortion/threatened abortion, ectopic pregnancy or The viral removal/inactivation procedures may be of limited
6.4 SPECIAL PRECAUTIONS FOR STORAGE
hydatidiform mole. value against non enveloped viruses such as hepatitis A virus
or parvovirus B19. D-GAM should be stored in the original container at 2C to
iii.After ante-partum haemorrhage (APH), amniocentesis,
8C. Storage for up to one week at ambient temperatures (25C)
chorionic biopsy or obstetric manipulative procedure e.g. In the interest of patients, it is recommended that, whenever in the original container is not detrimental. DO NOT FREEZE.
external version, or abdominal trauma, which may cause possible, every time that D-GAM is administered to them,
transplacental haemorrhage (TPH). The condition of date-expired, or incorrectly stored product
the name and batch number of the product is registered.
cannot be guaranteed. Such product may be unsafe, and should
Treatment of RhD negative patients after incompatible
4.5 INTERACTIONS WITH OTHER MEDICAMENTS not be used.
transfusions of RhD positive blood or other products
containing red blood cells (e.g. platelets). AND OTHER FORMS OF INTERACTIONS 6.5 NATURE AND CONTENTS OF CONTAINER
4.2 POSOLOGY AND METHOD OF ADMINISTRATION Active immunisation with live virus vaccines (e.g. measles, Neutral borosilicate glass vial (Type I Ph.Eur.) with overseal
mumps or rubella) should be postponed until 3 months after the consisting of a halobutyl rubber wad (Type I Ph.Eur.), clear
Posology
administration of Anti-D immunoglobulin, as the efcacy of the lacquered aluminium skirt and ip-off polypropylene cap.
a) Post-Natal Dosage
live virus vaccine may be impaired. If Anti-D immunoglobulin
The recommended dose is 500 iu. needs to be administered within 2-4 weeks of a live virus 6.6 INSTRUCTION FOR USE AND HANDLING AND
For postnatal use, the product should be administered as soon vaccination, then the efcacy of such a vaccination may be DISPOSAL
as possible within 72 hours of delivery. impaired. The product should be brought to room or body temperature
If a large fetomaternal haemorrhage is suspected, its extent before use.
After injection of immunoglobulin, the transitory rise of the
should be determined by a suitable method and additional various passively transferred antibodies in the patients blood The solution should be clear or slightly opalescent. Do not use
doses of anti-D should be administered as indicated. may result in misleading positive results in serological testing. solutions which are cloudy or have deposits.
b) Ante-Natal Prophylaxis Any unused product or waste material should be disposed of in
The results of blood typing and antibody testing, including the
500 iu given at both 28 and 34 weeks of gestation. accordance with local requirements.
Coombs or antiglobulin test, are signicantly affected by the
c) Following a Potentially Sensitising Event During Pregnancy administration of anti-D immunoglobulin.
D-GAM should be administered as soon as possible and no 4.6 PREGNANCY AND LACTATION DRIED FACTOR VIII FRACTION, 8Y
later than 72 hours after the event. This medicinal product is used in pregnancy. Power for reconstitution for injection
Up to 20 weeks gestation: recommended dose is 250 iu per
incident. 4.7 EFFECTS ON ABILITY TO DRIVE AND USE
MACHINES (Factor VIII with associated Von Willebrand
After 20 weeks gestation: recommended dose is 500 iu per
incident. A test for the size of the FMH should be performed No effects on ability to drive and use machines have been
observed.
Factor)
when anti-D is given after 20 weeks and additional doses of
anti-D should be administered as indicated. 1. NAME OF THE MEDICINAL PRODUCT:
4.8 UNDESIRABLE EFFECTS
d) Prevention of Immunisation in RhD Negative Patients Given DRIED FACTOR VIII FRACTION, 8Y.
Local pain and tenderness can be observed at the injection site;
Blood Components Containing RhD Positive Cells
this can be prevented by dividing larger doses over several 2. QUALITATIVE AND QUANTITATIVE COMPOSITION:
Recommended doses: 125 iu per ml of transfused RhD injection sites. DRIED FACTOR VIII FRACTION, 8Y is a concentrate
positive red cells;
Occasionally fever, malaise, headache, cutaneous reactions and of factor VIII with associated von Willebrand factor. When
250 iu per three adult doses of platelets. reconstituted the solution contains not less than 20.0 units factor
chills occur.
Method of administration VIII per ml and not less than 1.0 unit factor VIII per mg of
In rare cases: nausea, vomiting, hypotension, tachycardia and
For intramuscular use (preferably into the deltoid muscle). protein. This product is prepared from plasma from screened
allergic or anaphylactic type reactions, including dyspnoea
donors. Donors are selected from the USA.
D-GAM is for single injection only. and shock, are reported, even when the patient has shown no
In the case of haemorrhagic disorders, where intramuscular hypersensitivity to previous administration. 3. PHARMACEUTICAL FORM:
injections are contra-indicated, Anti-D immunoglobulin may For information on viral safety see Special warnings and special DRIED FACTOR VIII FRACTION, 8Y is presented as a
be administered subcutaneously. Careful manual pressure precautions for use. freeze-dried powder for reconstitution with 10ml (250iu vial)
with a compress should be applied to the site after injection. or 20ml (500iu vial) of Sterilised Water for Injections, Ph.Eur.
If large total doses (>5 ml) are required, it is advisable to 4.9 OVERDOSE
The reconstituted product is administered intravenously.
administer them in divided doses at different sites. No data are available on overdosage. Patients with incompatible
transfusion who receive a large dose of anti-D immunoglobulin 4. CLINICAL PARTICULARS:
4.3 CONTRAINDICATIONS
should be monitored clinically and by biological parameters, 4.1 THERAPEUTIC INDICATIONS:
Hypersensitivity to any of the components. because of the risk of haemolytic reaction. DRIED FACTOR VIII FRACTION, 8Y is used in the
4.4 SPECIAL WARNINGS AND SPECIAL PRECAUTIONS In other RhD negative individuals, overdosage should not lead treatment of Haemophilia A, for the prevention and control
FOR USE to more frequent or more severe undesirable effects than the of haemorrhage, and in the clinical management of von
Do not administer this product intravenously (risk of shock). normal dose. Willebrands Disease.
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SPDI
4.2 POSOLOGY AND ADMINISTRATION: 4.2.2 Method of Administration: 4.7 EFFECTS ON ABILITY TO DRIVE AND USE
4.2.1 Posology: Reconstitute as described in Instructions for Use/ MACHINES:
There is considerable variation in response between patients. Handling. None.
It is recommended that the following guidelines be adopted: The reconstituted solution should be administered within one 4.8 UNDESIRABLE EFFECTS:
The number of units needed and the duration of treatment hour of reconstitution.
Allergic or anaphylactic reactions are observed in rare cases.
depend on the condition being treated. After cleaning the stopper with a spirit swab the solution Increase in body temperature, and development of antibodies to
If the rise in the concentration of factor VIII in the plasma should be drawn from the vial into a plastic disposable syringe factor VIII are also observed in rare cases.
following administration of the concentrate is expressed in through the sterile lter needle provided which will remove
particulate matter. For intravenous injection attach a suitable Occasionally reported side effects include hypersensitivity
International Units (iu) per 100ml plasma and the total dose reactions, ushing, nausea, headache and lower back pain.
given in International Units of factor VIII per kg body weight needle or buttery to the syringe and inject the product at a
rate not exceeding 3ml per minute (note that increasing the Patients should be aware of the early signs of hypersensitivity
is calculated, the response is dened as follows: reactions including: hives, urticaria, tightness of the chest,
rate of administration may result in side effects).
Response = rise in plasma factor VIII (iu per 100ml) wheezing, hypotension and anaphylaxis and are advised to
Patients who are to receive the contents of more than one
dose (in iu per kg body weight) discontinue the use of the product.
vial may pool these contents into an appropriate size syringe
by drawing up the contents of each vial through a separate Patients with blood groups A, B or AB receiving large doses
The theoretical value of 2.4 for this ratio is rarely reached.
sterile lter needle. Sterile lter needles are intended to lter should be monitored for signs of intravascular haemolysis.
It is variable even in the same patient. A range of 1.6 - 2.2
is usual, but values outside this range may be found. A low the contents of a single bottle of DRIED FACTOR VIII 4.9 OVERDOSE:
value may indicate that the patients plasma contains an FRACTION, 8Y.
No specic side effects have been reported with overdosage
antibody to factor VIII and appropriate tests should be done. 4.3 CONTRA-INDICATIONS: of DRIED FACTOR VIII FRACTION, 8Y since the short
IMPORTANT There are no known contra-indications to the use of Dried half-life of factor VIII, about 12 hours, means the factor VIII:C
Factor VIII Fraction, 8Y for replacement therapy in activity in the patients plasma will rapidly decline.
The amount to be administered and the frequency of
application should always be oriented to the clinical classic haemophilia (Haemophilia A). Caution is advised in 5. PHARMACOLOGICAL PROPERTIES:
effectiveness in the individual case. patients with a known allergic reaction to constituents of the
preparation. 5.1 PHARMACODYNAMIC PROPERTIES:
The following table indicates the approximate levels of factor
4.4 SPECIAL WARNINGS AND SPECIAL PRECAUTIONS The factor VIII/von Willebrand factor complex consists of two
VIII required for haemostasis in various circumstances.
FOR USE: molecules (factor VIII and vWF) with different physiological
Condition Initial dose of Concentration of factor functions.
factor VIII describle in plasma If allergic or anaphylactic reactions occur the injection/infusion
should be stopped immediately. FVIII is responsible for the coagulation activity. As a cofactor
(iu per kg body immediately after
for factor IX it accelerates the conversion of factor X to
weight (iu per 100 ml) The current specic guidelines of shock therapy should be
activated factor X. Activated factor X converts prothrombin into
Minor spontaneous followed.
haemarthrosis and muscle 7-13 15-20
thrombin. Thrombin then converts brinogen into brin and a
Dried Factor VIII Fraction, 8Y contains blood group clot can be formed. The factor VIII activity is greatly reduced in
haematoma
antibodies derived from the starting plasma in amounts which patients with Haemophilia A and therefore substitution therapy
Severe haemarthrosis and are insignicant in the normal treatment of haemarthrosis and
muscle haematoma: 9-25 20-40 is necessary.
muscle haemorrhage. If high doses are necessary in patients
haematoma in potentially In the treatment of vWD, there is no general consensus on
with blood groups A, B or AB, the patient should be monitored
serious situations: the product characteristics essential for efficacy. In DRIED
haematuria
for signs of intravascular haemolysis.
FACTOR VIII FRACTION, 8Y concentrate, 1iu of vWF
Major surgery see below see below Patients congenitally decient in factor VIII may develop antigen is associated with approximately 0.8 iu Ristocetin
antibodies to factor VIII after treatment. This risk does not Cofactor (RCo) activity and approximately 0.4 iu factor
A dose of 1iu per kg body weight will give, on average, a rise appear to be signicantly increased by the use of Dried Factor VIII activity. The concentrate has collagen-binding activity
of about 2iu per 100ml plasma. If the desired concentration VIII Fraction, 8Y, but patients should be monitored as a and, although the multimer pattern obtained by SDS gel
or clinical response is not achieved another dose should be routine procedure. electrophoresis is not identical to that of normal plasma or
given the same day. If an abnormally low response persists, Failure to achieve the anticipated clinical response may indicate cryoprecipitate, multimers of high molecular weight are
test for specic antibody to factor VIII. The doses mentioned the development of factor VIII antibodies. Patients undergoing present.
are only rough guides since there is considerable variation in major surgery should be tested for factor VIII antibodies prior
response from patient to patient. to surgery. Presence of antibodies requires specialist advice and 5.2 PHARMACOKINETIC PROPERTIES:
It is usual to give the contents of the number of whole vials clinical management. The half disappearance time is approximately 12 hrs, i.e. that
nearest to the calculated dose. Doses may be repeated at Where possible, factor VIII assays should be performed before time taken for a 50% reduction in peak activity in the plasma.
intervals of approximately 8, 12 or 24 hours as needed to and after infusion, particularly in the rst course of treatment. When injected into a patient with vWD, vWF antigen and
maintain the desired concentration of factor VIII. Patients suffering from vWD may vary in their haemostatic RCo are recovered with high efciency in the circulation and
If factor VIII antibodies are identied, the guidance given response to DRIED FACTOR VIII FRACTION, 8Y disappear with a half-life of approximately 12-24 hours. Since
on dosage and administration does not apply and specialist administration. There have been cases reported in some injected vWF stimulates the release of factor VIII, synthesised
advice should be sought. patients, where it has not been possible to control bleeding by normally in vWD, plasma factor VIII levels may continue to
Posology in Children: administering DRIED FACTOR VIII FRACTION, 8Y. rise for many hours after the increment attributable to factor
Reconstituted DRIED FACTOR VIII FRACTION, 8Y should VIII in the concentrate.
In the case of children a dose of 1iu per kg will possibly give
a reduced rise, on average, of about 1.5iu per 100ml plasma. be used within one hour. 5.3 PRECLINICAL SAFETY DATA:
Posology in Major Surgery: Viral Safety: DRIED FACTOR VIII FRACTION, 8Y is a human plasma
Major surgery should be undertaken in a centre which All plasma used in the manufacture of DRIED FACTOR protein; therefore safety testing in animals is not particularly
has facilities for assaying factor VIII for ascertaining the VIII FRACTION, 8Y has been tested by validated procedures relevant to the safety of use in man.
patients response to treatment. The patients plasma should and found non-reactive for hepatitis B surface antigen and However, acute toxicity studies in rat and mouse showed that a
be tested for factor VIII antibodies. If antibody is not present, antibodies to HIV-1, HIV-2 and HCV. single intravenous injection of the product produced a maximum
a pre-operative dose of 35 to 50iu per kg is given to raise the The manufacture of DRIED FACTOR VIII FRACTION, 8Y non lethal dose of 1020 iu per kg in the rat and mouse. This
plasma factor VIII concentration to 80iu or more per 100ml includes a terminal heating step at 80C for 72 hours to reduce is approximately equivalent to 20 times the maximal dose in
plasma. During the rst few days after operation the plasma the risk of viral infection. man.
factor VIII Summary of Product Characteristics concentration When medicinal products prepared from human blood or plasma Repeated dose toxicity testing in animals is impracticable due
is monitored and the dose repeated 6-hourly or 8-hourly as are administered, infectious diseases due to the transmission of to interference with developing antibodies to heterologous
needed, so that the concentration does not fall below 30-50iu infective agents cannot be totally excluded. This applies also to protein.
per 100ml plasma. After the rst few days the frequency of pathogens of hitherto unknown origin. Since clinical experience provides no evidence of tumourigenic
the dose may be reduced. The course of treatment is usually To reduce the risk of transmission of infective agents, stringent and mutagenic effects of human plasma coagulation Factor
continued for ten days or longer. controls are applied to the selection of blood donors and VIII, experimental studies, particularly in heterologous species,
As indicated previously, if the factor VIII concentration donations. In addition, virus removal and/or inactivation are not considered imperative.
does not reach the expected level, or falls off with a reduced procedures are included in the production process. 6. PHARMACEUTICAL PARTICULARS:
half-disappearance time (less than 12 hours), the presence The current procedures applied in the manufacture of medicinal
of an antibody to factor VIII should be suspected and the 6.1 Excipients:
products derived from human blood or plasma are effective
appropriate laboratory tests done. The treatment of patients against enveloped viruses such as HIV, Total Protein 5-14 mg/ml
with antibodies to factor VIII is outside the scope of these Fibrinogen 2-12 mg/ml
hepatitis B and hepatitis C viruses. These procedures are of
notes. Sucrose 10-18 mg/ml
limited value against nonenveloped viruses such as hepatitis
Posology in von Willebrands Disease: Sodium 0.1-0.16 mmol/ml
A virus.
Chloride 0.1-0.14 mmol/ml
Larger doses might be necessary in a severe form of Appropriate vaccination for patients in receipt of medicinal Tris 0-0.02 mmol/ml
vWD, i.e. similar doses to major surgery in patients with products derived from human blood or plasma should be Citrate 0-0.02 mmol/ml
Haemophilia A. The amount of Dried Factor VIII Fraction, considered. Glycine 0-0.025 mmol/ml
8Y concentrate in vWD may be based upon the desired Heparin 0-2 iu/ml
increment in the patient`s circulating vWF used as if this 4.5 INTERACTION WITH OTHER MEDICAMENTS
AND OTHER FORMS OF INTERACTIONS: 6.2 INCOMPATIBILITIES:
increment was for factor VIII, e.g. an increment of 80%
in circulating vWF requires a dose of Dried Factor VIII DRIED FACTOR VIII FRACTION, 8Y should not be added Human plasma coagulation Factor VIII concentrate should not
Fraction, 8Y of 40iu/kg based on factor VIII content (given to other infusion uids, blood or pharmaceutical agents as their be mixed with other medicinal products as their effects on the
to the nearest number of whole vials). effects on the product have not been established. product are unknown.
The amount of vWF (as antigen, measured by ELISA) in 4.6 PREGNANCY AND LACTATION: Only NHS approved injection/infusion sets should be used
each vial is printed on the label for information (see 5.1 and Reproduction studies in animals have not been conducted with because treatment failure can occur as a consequence of human
5.2). Factor VIII and the product should be administered to a pregnant plasma coagulation Factor VIII adsorption to the internal
DO NOT EXCEED RECOMMENDED DOSE. woman or breast-feeding mother only if clearly needed. surfaces of some infusion equipment.
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SPDI
6.3 SHELF LIFE: 2.2 QUANTITATIVE COMPOSITION Patients should be monitored for the development of factor
Reconstituted (25C) 1 hour REPLENINE-VF has a potency of 250(N.R), 500 or 1000 IX inhibitors. If the expected factor IX activity plasma
Freeze-dried at 2C-8C(in the dark) 36 months IU(N.R) per vial against the current WHO standard. The levels are not attained, or if bleeding is not controlled
product has a specic activity of not less than 100 IU per mg with an appropriate dose, an assay should be performed to
Freeze-dried at 25C (in the dark) 2-3 months
of protein. determine if a factor IX inhibitor is present. If the inhibitor
6.4 SPECIAL PRECAUTIONS FOR STORAGE: is present at levels less than 10 Bethesda Units (BU) per
3. PHARMACEUTICAL FORM: ml, administration of additional REPLENINE-VF may
Sterilised Water for Injections, Ph.Eur. should be stored between
2C and 25C and must not be used beyond the expiry date REPLENINE-VF is a freeze-dried concentrate of factor IX neutralise the inhibitor. In patients with titres above 10 BU
printed on the label or if signs of particulate matter are visible. for reconstitution with Sterilised Water for Injections, Ph.Eur. or with high anamnestic response, the use of (activated)
After reconstitution with the supplied sterile water diluent the prothrombin complex concentrate (PCC) or recombinant
DRIED FACTOR VIII FRACTION, 8Y should be stored
product is administered intravenously. activated factor VII (rFVIIa) preparations has to be
between 2C and 8C in its carton in the dark, however, it
considered. These therapies should be directed by physicians
may be stored for short periods (up to 2-3 months) at ambient 4. CLINICAL PARTICULARS:
with experience in the care of patients with haemophilia.
temperature (25C). Where Dried Factor VIII Fraction, 8Y is 4.1 THERAPEUTIC INDICATIONS
for home use, a domestic refrigerator is suitable for storage. DO DO NOT EXCEED THE RECOMMENDED DOSE.
Treatment of bleeding and prophylaxis in patients with
NOT FREEZE. See also 4.4
haemophilia B (congenital factor IX deciency).
6.5 NATURE AND CONTENTS OF CONTAINER: 4.2.2. Method of Administration
4.2 POSOLOGY AND METHOD OF ADMINISTRATION
DRIED FACTOR VIII FRACTION, 8Y is supplied in Reconstitute the product as described in 6.6. The solution
4.2.1 Posology should be drawn from the vial into a plastic disposable
single dose vials of 250iu or 500iu nominal for reconstitution
Treatment should be under the supervision of a physician syringe (approved syringes are made by Becton Dickinson)
in 10ml (250iu vial) or 20ml (500iu vial) of Sterilised Water
experienced in the treatment of haemophilia. through the lter needle supplied with the product. For
for Injections, Ph.Eur., supplied with the product. Vials are
freeze-drying vials made of Type 1, Ph.Eur. glass with a The dosage and duration of the substitution therapy depend administration, a Number 23 buttery needle (Abbott
halobutyl rubber freeze-drying stopper. Product is stoppered on the severity of the factor IX deciency, on the location and venisystems) is approved for use with this product.
extent of the bleeding and on the patients clinical condition. Although the material is unlikely to cause side effects,
under vacuum. The vial stopper is oversealed with a snap-off
The number of units of factor IX administered is expressed in the dose, especially the rst dose, should be given slowly
polypropylene cap and lacquered skirt.
International Units (IU), which are related to the current WHO (approximately 3ml per minute). The solution must not be
6.6 INSTRUCTIONS FOR USE/HANDLING: standard for factor IX products. Factor IX activity in plasma stored and the slow intravenous injection of each dose should
Reconstitution: is expressed either as a percentage (relative to normal human be completed within one hour of reconstitution.
DRIED FACTOR VIII FRACTION, 8Y should only be plasma) or in International Units (relative to an international REPLENINE-VF should be administered when the rst
reconstituted with Sterilised Water for Injections, Ph.Eur. standard for factor IX in plasma). One International Unit (IU) sign of bleeding occurs and should be repeated as necessary
provided with the product. of factor IX activity is equivalent to that quantity of factor IX to stop bleeding. Each individual case must be assessed on
in one ml of normal human plasma. its merits.
The container of the Factor VIII concentrate and the Sterilised
Water for Injections, Ph.Eur. should be brought to between The calculation of the required dosage of factor IX is based 4.3. CONTRAINDICATIONS
20C and 30C prior to the removal of the ip-off closures. on the empirical nding that 1 International Unit (IU)
Hypersensitivity to the active substance or to any of the
Remove the caps from the concentrate and Sterilised Water for REPLENINE-VF per kg body weight raises the plasma
excipients.
Injections, Ph.Eur. and clean stoppers with a spirit swab. Either factor IX activity by 1.3% of normal activity. The required
dosage is determined using the following formula: The product should not be administered to patients showing
of the following methods of reconstitution can then be used:
signs of Disseminated Intravascular Coagulation (DIC),
a) Using a sterile disposable needle and syringe draw up the Required units = body weight (kg) x desired factor IX rise
or patients suffering from acute liver failure. Patients with
required volume of Sterilised Water for Injections, Ph.Eur. (%) (IU/dl) x 0.8
impaired liver function require monitoring for signs of DIC.
and transfer to the vial containing Factor VIII concentrate. The amount to be administered and the frequency of (See 4.4 Special Warnings and Special Precautions for Use).
On piercing the seal of the Factor VIII vial, the water will be administration should always be orientated to the clinical
drawn into the vial which is under vacuum. effectiveness in the individual case. Factor IX products rarely 4.4 SPECIALWARNINGS AND SPECIAL PRECAUTIONS
NB: THE FILTER NEEDLE PROVIDED MUST NOT BE require to be administered more than once daily. FOR USE
USED TO DRAW UP THE WATER FOR INJECTIONS. In the case of the following haemorrhagic events, the factor As with any intravenous protein product, allergic type
or IX activity should not fall below the given plasma activity hypersensitivity reactions are possible.
level (in IU/dl) in the corresponding period. The following REPLENINE-VF contains traces of human proteins other
b) Remove the cover guard from one end of a double ended
table can be used to guide dosing in bleeding episodes and than FIX. Patients should be informed of the early signs of
transfer needle and insert through the stopper into the vial of
surgery: hypersensitivity reactions including hives, generalised urticaria,
Sterilised Water for Injections, Ph.Eur.
Under certain circumstances larger amounts than those tightness of the chest, wheezing, hypotension and anaphylaxis.
Remove the other end of the needle guard, invert the water calculated may be required, If these symptoms occur, they should be advised to discontinue
vial over the product vial and insert the free end of the needle use of the product immediately and contact their physician. In
through the stopper into the vial of Factor VIII. On piercing the Degree of haemorrhage/ Factor IX level Frequency of dose
Type of surgical required (%) (hours)/Duration the case of shock current medical standards for shock-treatment
seal of the Factor VIII vial the water will be drawn into the vial should be
Procedure (IU/dl) of Therapy (days)
which is under vacuum. A small amount of water will remain
Haemorrhage Repeat every 24 hours observed.
in the water vial.
Early haemarthrosis, 20-40 At least 1 day, until When medicinal products prepared from human blood or plasma
If the water to be used for reconstitution is not drawn into the muscle bleed or oral the bleeding episode
are administered, infectious diseases due to the transmission of
vial containing Factor VIII this indicates loss of vacuum. If the bleed. as indicated by pain is
infective agents cannot be totally excluded. This also applies to
vial does not contain a vacuum or if the reconstituted Factor resolved or healing is
achieved. pathogens of hitherto unknown nature. The risk of transmission
VIII forms a gel or a clot, the vial must not be used.
More extensive 30-60 Repeat infusion every
of infective agents is however reduced by:
The container should be agitated to wet the product and the
haemarthrosis, muscle 24 hours for 3-4 days - Selection of donors by a medical interview and screening of
vacuum then released by either:
bleed or haematoma or more until pain and donations for the three major pathogenic viruses HIV, HCV,
a) Removing the syringe from the needle before removing the disability are resolved. HBV;
needle from the product vial. Life threatening bleeds 60-100 Repeat infusion every - Testing plasma pools for HCV genomic material;
or such as head surgery, 8 to 24 hours until - Removal/inactivation procedures included in the production
b) Disconnecting the two vials by rst removing the transfer throat bleed, severe threat is resolved.
process that have been validated using model viruses and are
abdominal bleed.
needle from the water vial and then removing the transfer considered effective for HIV, HCV, HAV, parvovirus B19
Surgery
needle from the product vial. and HBV.
Minor 30-60 Every 24 hours, at
Continue to agitate gently until dissolution is complete. A clear including tooth least 1 day, until It is recommended that patients are vaccinated against hepatitis
or slightly opalescent solution should be obtained within 15 extraction. healing is achieved. A and hepatitis B as a precaution.
minutes. If a gel or clot forms discard the vial. Major 80-100 Repeat infusion every After repeated treatment with human coagulation factor IX
Discard any unused Sterilised Water for Injections, Ph.Eur. 8-24 hours until products, patients should be monitored for the development of
Standard precautions for infusion of sterile solutions should adequate wound inhibitors that should be quantied in modied Bethesda Units
be observed. Discard any unused material or used materials by healing, then therapy using appropriate biological testing.
for at least another 7
normal safety practices. There have been reports in the literature showing a correlation
days to maintain a
FIX activity of 30% between the occurrence of a factor IX inhibitor and allergic
to 60% (IU/dl) reactions. Therefore, patients experiencing allergic reactions
REPLENINE-VF should be evaluated for the presence of an inhibitor. It should
especially in the case of the initial dose.
Concentrate for reconstitution for injection be noted that patients with factor IX inhibitors may be at an
Posology in Children increased risk of anaphylaxis with subsequent challenge with
In the case of children, a dose of 1 IU/kg will possibly give a factor IX. Because of the risk of allergic reactions with factor
reduced rise. There is insufcient data to recommend the use IX concentrates, the initial administration of factor IX should,
(High Purity Factor IX) according to the treating physicians judgement, be performed
of REPLENINE-VF in children less than 6 years old.
under medical observation where proper medical care for
During the course of treatment, appropriate determination of
1. NAME OF THE MEDICINAL PRODUCT: REPLENINE- allergic reactions could be provided.
factor IX levels is advised to guide the dose to be administered
VF and the frequency of repeated infusions. In the case of major The product should be used with caution in children less than 6
surgical interventions in particular, precise monitoring of years, who have limited exposure to factor IX products.
2. QUALITATIVE AND QUALITATIVE COMPOSITION
the replacement therapy by means of coagulation analysis Since the use of factor IX complex concentrates has historically
2.1 QUALITATIVE COMPOSITION (plasma factor IX activity) is indispensable. Individual been associated with the development of thromboembolic
REPLENINE-VF is a high purity factor IX. This product patients may vary in their response to factor IX, achieving complications, the risk being higher in low purity preparations,
is prepared from plasma from screened donors. Donors are different levels of in vivo recovery and demonstrating the use of factor IX containing products may be potentially
selected from the USA. different half-lives. hazardous in patients with signs of brinolysis and in patients
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SPDI
with disseminated intravascular coagulation (DIC). Because 5.3 PRECLINICAL SAFETY DATA The container should be agitated to wet the product and the
of the potential risk of thrombotic complications, clinical Human plasma coagulation factor IX (as contained in vacuum then released by either:
surveillance for early signs of thrombotic and consumptive REPLENINE-VF) is a normal constituent of the human a) Removing the syringe from the needle before removing the
coagulopathy should be initiated with appropriate biological plasma and acts like the endogenous factor IX. Single dose needle from the product vial.
testing when administering this product to patients with toxicity testing is of no relevance since higher doses result in or
liver disease, to patients post-operatively, to neonates, or to overloading.
patients at risk of thromboembolic phenomena or disseminated b) Disconnecting the two vials by rst removing the transfer
Repeated dose toxicity testing in animals is impracticable due to needle from the water vial and then removing the transfer
intravascular coagulation. In each of these situations, the
interference with developing antibodies to heterologous protein. needle from the product vial.
potential benet of treatment with REPLENINE-VF should
Since clinical experience provides no evidence for tumourgenic
be weighed against the risk of these complications. REPLENINE-VF dissolves rapidly and requires only
and mutagenic effects of human plasma coagulation factor IX,
very gentle agitation to ensure complete dissolution. A clear
4.5 INTERACTION WITH OTHER MEDICAMENTS experimental studies, particularly in heterologous species, are
or slightly opalescent solution should be obtained within 5
AND OTHER FORMS OF INTERACTION not considered necessary.
minutes. If a gel or clot forms discard the vial.
No interactions of REPLENINE-VF human plasma factor IX Single dose toxicity studies in rats and mice have established
Discard any unused Sterilised Water for Injections, Ph.Eur. and
with other medicinal products are known so far. greater than a 20 fold safety margin. Thrombogenicity testing
in rabbits and rats showed no evidence of thrombogenicity at unused product by approved means.
4.6 PREGNANCY AND LACTATION doses of 200-300 IU/kg body weight.
No animal reproduction and lactation studies have been
6. PHARMACEUTICAL PARTICULARS.
VIGAM LIQUID Injection
conducted with REPLENINE-VF. The safety of
REPLENINE-VF for use in human pregnancy has not been 6.1 LIST OF EXCIPIENTS
established. Particulars: REPLENINE-VF solution contains :
(Human normal Immunoglobulin)
Therefore, REPLENINE-VF should be administered to Factor IX, factor II, factor X, protein, glycine, lysine, sodium
pregnant and lactating women only if clearly needed and the 1. NAME OF THE MEDICINAL PRODUCT:
citrate, sodium phosphate, sodium chloride, polysorbate 80 and
benet outweighs the risk. VIGAM Liquid is a sterile liquid of 5 g% normal
tri-n-butyl phosphate.
immunoglobulin
4.7 EFFECTS ON ABILITY TO DRIVE AND USE 6.2 INCOMPATIBILITIES
MACHINES 2. QUALITATIVE AND QUANTITATIVE COMPOSITION:
REPLENINE-VF should not be mixed with other medicinal
There are no indications that human plasma factor IX may Human normal immunoglobulin for intravenous
products.
impair the ability to drive or to operate machinery. administration.
Only approved injection/infusion sets should be used with the
4.8 UNDESIRABLE EFFECTS 2.1 ACTIVE INGREDIENT
reconstituted product because treatment failure may occur as
If there are any side effects these should be controlled by a consequence of human factor IX adsorption to the internal This product is prepared from plasma from screened donors.
stopping the infusion, followed by specic treatment of the surface of some unapproved infusion equipment. Donors are selected from the USA.
particular side effect. 2.2 QUANTITATIVE COMPOSITION
6.3 SHELF LIFE
Hypersensitivity or allergic reactions (which may include VIGAM Liquid contains 7 g/100 ml of human protein of
When unopened, shelf-life is 36 months at 2C to 8C, up to
angioedema, burning and stinging at the infusion site, chills, which 5 g is human normal immunoglobulin.
3 months at normal ambient temperature (25C) within this
ushing, generalised urticaria, headache, hives, hypotension, period is not detrimental to the product. The expiry date is For excipients see List of excipients
lethargy, nausea, restlessness, tachycardia, tightness of the chest, printed on the label. VIGAM Liquid has an IgA content of less than 0.02% w/w of
tingling, vomiting, wheezing) have been observed infrequently the total protein and a sub-class distribution of IgG1:IgG2:IgG3:
in patients treated with factor IX containing products. In some When opened, store at 2C to 25C and use within one hour.
Warm to ambient (25C) before injection. IgG4 of approximately 64:29:6:1; this is similar to plasma.
cases, these reactions have progressed to severe anaphylaxis,
and they have occurred in close temporal association with Sterilised Water for Injections, Ph.Eur. should be stored between 2.3 PHARMACEUTICAL FORM:
development of factor IX inhibitors (see also 4.4). 2C and 25C. VIGAM Liquid is a sterile liquid for intravenous
THE TREATMENT REQUIRED DEPENDS ON THE 6.4 SPECIAL PRECAUTIONS FOR STORAGE administration which varies from colourless to pale amber or
NATURE AND SEVERITY OF THE REACTION. Store REPLENINE-VF in the dark in its carton at the pale green.
Nephrotic syndrome has been reported following attempted temperature specied on the packaging. 4. CLINICAL PARTICULARS:
immune tolerance induction in haemophilia B patients with DO NOT FREEZE. Do not use beyond the expiry date on the
4.1 THERAPEUTIC INDICATIONS
factor IX inhibitors and a history of allergic reaction. label. When the product is for home use a domestic refrigerator
is suitable for storage. Replacement therapy in:
Increase in body temperature is observed in rare cases.
Patients with haemophilia B may develop antibodies Primary immunodeciency syndromes such as: congenital
6.5 NATURE AND CONTENTS OF CONTAINER
(inhibitors) to factor IX. If such inhibitors occur, the condition agammaglobulinaemia and hypogammaglobulinaemia,
REPLENINE-VF is a freeze-dried plug of high purity factor common variable immunodeciency, severe combined
will manifest as an insufcient clinical response. In such cases, IX supplied in a single dose vial of either 250 IU (N.R.), 500 IU
it is recommended that a specialised haemophilia centre be immunodeciency; Wiskott Aldrich syndrome, Myeloma
or 1000 IU (N.R.) (nominal). The product is contained in glass or chronic lymphocytic leukaemia with severe secondary
contacted. There have been no reports of inhibitor development (type I Ph.Eur.) bottles stoppered with a halobutyl stopper. The
in patients treated with REPLENINE-VF. hypogammaglobulinaemia and recurrent infections. Children
bung is over-sealed with a snap-off polypropylene cap and a with congenital AIDS and recurrent infections.
There is a potential risk of thromboembolic episodes following clear lacquered aluminium skirt.
the administration of factor IX products, with a higher risk for Immunomodulation:
low purity preparations. The use of low purity factor IX products 6.6 INSTRUCTIONS FOR USE/HANDLING Idiopathic Thrombocytopenic Purpura (ITP), in children or
has been associated with instances of myocardial infarction, Reconstitute the product with the Sterilised Water for Injections, adults at high risk of bleeding spontaneously or prior to surgery
disseminated intravascular coagulation, venous thrombosis and Ph.Eur. supplied (2.5ml or 5ml for 250 IU, 5ml or 10ml for to correct the platelet count; Guillain Barr Syndrome and
pulmonary embolism. The use of high purity factor IX is rarely 500 IU and 10ml or 20ml for 1000 IU). Do not use the water Kawasaki disease.
associated with such side effects. if beyond the expiry date or if signs of particulate matter are Allogeneic bone marrow transplantation.
visible. Do not inject Sterilised Water for Injections, Ph.Eur. on
4.9 OVERDOSE its own. 4.2 POSOLOGY AND METHOD OF ADMINISTRATION
No symptoms of overdose with human factor IX have been Reconstitute REPLENINE-VF as follows: Posolgy:
reported. The dose and dosage regimen is dependent on the indication. In
The container of concentrate and the Sterilised Water for
5. PHARMACOLOGICAL PROPERTIES Injections, Ph. Eur. should be brought to between 20C and replacement therapy the dosage may need to be individualised
5.1. PHARMACODYNAMIC PROPERTIES 30C, prior to the removal of the ip-off closures. Remove the for each patient dependent on the pharmacokinetic and clinical
caps from the concentrate and Sterilised Water for Injections, response. The following dosage regimens are given as a
Properties: Pharmacotherapeutic group: Antihaemorrhagics:
Ph.Eur., and clean stoppers with a spirit swab. Either of the guideline.
blood coagulation factor IX.
following methods of reconstitution can then be used: Replacement therapy in primary immunodeciency
ATC code: B02BD04
a) Using a sterile disposable needle and syringe draw up the syndromes:
Factor IX is a single chain glycoprotein with a molecular mass required volume of Sterilised Water for Injections, Ph.Eur. The dosage regimen should achieve a trough level of IgG
of about 68,000. It is a vitamin K-dependent coagulation factor and transfer to the vial of the factor IX. On piercing the seal (measured before the next infusion) of at least 4 - 6 g/l. Three
and it is synthesised in the liver. of the factor IX vial, the water will be drawn into the vial to six months are required after the initiation of therapy for
Factor IX is activated by factor XIa in the intrinsic coagulation which is under vacuum. equilibration to occur. The recommended starting dose is 0.4
pathway and by the factor VII/tissue factor complex in the NB: THE FILTER NEEDLE PROVIDED MUST NOT BE - 0.8 g/kg followed by at least 0.2 g/kg every three weeks.
extrinsic pathway. Activated factor IX, in combination with USED TO DRAW UP THE WATER FOR INJECTIONS. The dose required to achieve a trough level of 6 g/l is of the
activated factor VIII, activates factor X. Activated factor X
or order of 0.2 - 0.8 g/kg/month.
converts prothrombin into thrombin.
b) Remove the cover guard from one end of a double ended The dosage interval when steady state has been reached varies
Thrombin then converts brinogen into brin and a clot is
transfer needle and insert through the stopper into the vial of from 2 - 4 weeks. Trough levels should be measured in order to
formed. Haemophilia B is a sexlinked hereditary disorder of
Sterilised Water for Injections, Ph.Eur. Remove the other end adjust the dose and dosage interval.
blood coagulation due to decreased levels of factor IX and results
of the needle guard, invert the water vial over the product Replacement therapy in myeloma or chronic lymphocytic
in profuse bleeding into joints, muscles or internal organs, either
vial and insert the free end of the needle through the stopper leukaemia with severe secondary hypogammaglobulinaemia
spontaneously or as a result of accidental or surgical trauma. By
into the vial of factor IX. On piercing the seal of the product and recurrent infections; replacement therapy in children with
replacement therapy the plasma level of factor IX is increased,
vial, the water will be drawn into the vial which is under
thereby enabling a temporary correction of the factor deciency AIDS and recurrent infections:
vacuum. A small amount of water will remain in the water
and correction of the bleeding tendencies. The recommended dose is 0.2 - 0.4 g/kg every 3 to 4 weeks.
vial. This method cannot be used to prepare the infusion at
5.2 PHARMACOKINETIC PROPERTIES reduced volume (see above). Idiopathic Thrombocytopenic Purpura (ITP):
Infusion of REPLENINE-VF into patients with haemophilia If the water to be used for reconstitution is not drawn into the For the treatment of an acute episode, 0.8 - 1 g/kg on day one,
B results in recoveries of greater than 70% of the plasma factor vial containing factor IX, this indicates loss of vacuum. If the which may be repeated once within 3 days, or 0.4 g/kg daily
IX activity. The plasma half-life of factor IX ranges from 16-30 vial does not contain a vacuum or if the reconstituted factor IX for two to ve days. The treatment can be repeated if relapse
hours, with an average of 24 hours. forms a gel or a clot, the vial must not be used. occurs.
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SPDI
Guillain Barr Syndrome: to human normal immunoglobulin, patients switched from immunoglobulins may cause a sudden fall in blood pressure
0.4 g/kg/day for 3 to 7 days. Experience in children is limited. an alternative IVIg product or when there has been a long and, in isolated cases, anaphylactic shock, even when the patient
interval since the previous infusion, should be monitored has shown no hypersensitivity to previous administration.
Kawasaki Disease:
during the rst infusion and for the rst hour after the rst Cases of reversible aseptic meningitis, isolated cases of
1.6 2 g/kg should be administered in divided doses over 2 infusion, in order to detect potential adverse signs. All other reversible haemolytic anaemia haemolysis and rare cases of
to 5 days or 2 g/kg as a single dose. Patients should receive patients should be observed for at least 20 minutes after
concomitant treatment with acetylsalicylic acid. regressive cutaneous reactions, often eczema-like, have been
administration. observed with human normal immunoglobulin.
Allogeneic Bone Marrow Transplantation: Cases of acute renal failure have been reported in patients Increase in creatininaemia and/or acute renal failure have been
Human normal immunoglobulin treatment is used as part of the receiving IVIg therapy. In most cases, risk factors have been observed.
conditioning regimen and after the transplant. For the treatment identied, such as pre-existing renal insufciency, diabetes
of infections and prophylaxis of graft versus host disease, Thrombotic events have been reported in the elderly, in patients
mellitus, hypovolaemia, overweight, concomitant nephrotoxic
dosage is individually tailored. The starting dose is normally with signs of cerebral or cardiac ischaemia, and in overweight
medicinal products or, aged over 65. In all patients, IVIg
0.5 g/kg/week, starting seven days before transplantation and administration requires: and severely hypovolaemic patients.
for up to 3 months after transplantation. In case of a persistent - adequate hydration prior to the initiation of the infusion of For information on viral safety see 4.4.
lack of antibody production, a dosage of 0.5 g/kg/month is IVIg; OVERDOSE
recommended until the antibody level returns to normal. - monitoring of urine output; Overdosage may lead to uid overload and hyperviscosity,
The dosage recommendations are summarised in the following - monitoring of serum creatinine levels; particularly in patients at risk, including elderly patients or
table: - avoidance of concomitant use of loop diuretics. patients with renal impairment.
Indication Dose Frequency of Injection In case of renal impairment, IVIg discontinuation should be
5. PHARMACOLOGICAL PROPERTIES
Replacement therapy Starting dose: considered. While these reports of renal dysfunction and acute
in primary 0.4-0.8g/kg renal failure have been associated with the use of many of the 5.1 PHARMACODYNAMIC PROPERTIES
immunodeciency Thereafter: Every 2-4 weeks to obtain lgG licensed IVIg products, those containing sucrose as a stabiliser Properties: VIGAM Liquid is in pharmacotherapeutic group:
0.2-0.8g/kg trough level of at least 4-6 g/L accounted for a disproportionate share of the total number. In Immune sera and immunoglobulins: immunoglobulins, normal
Replacement therapy 0.2-0.4 g/kg Every 3-4 weeks to obtain lgG patients at risk, the use of IVIg products that do not contain human, for intravascular administration, ATC code: J06BA02.
in secondary trough level of at least 4-6 g/L sucrose may be considered. In addition, the product should be VIGAM Liquid contains mainly immunoglobulin G (IgG),
immunodeciency administered at the minimum concentration and infusion-rate and has a broad spectrum of antibodies against various
Children with AIDS 0.2-0.4 g/kg Every 3-4 weeks practicable. infectious agents.
Immunomodulation:
In case of adverse reaction, either the rate of administration VIGAM Liquid contains the IgG antibodies present in the
Idiopathic 0.8-1 g/kg on day 1, possibly repeated
must be reduced or the infusion stopped. The treatment required normal population and is prepared from pooled plasma from
Thrombocytopenic or once within 3 days
0.4g/kg/d for 2-5 days depends on the nature and severity of the side effect. In case of not fewer than 1000 donors. VIGAM Liquid has a distribution
Guillain Barre 0.4 g/kg/d For 3-7 days
shock, the current medical standards for shock treatment should of immunoglobulin subclasses closely proportional to that in
syndrome be observed. native human plasma.
Kawasaki disease 1.6-2 g/kg in several doses for 2-5 days in When medicinal products prepared from human blood or plasma Adequate doses of this medicinal product may restore
association with acetylsalicylic are administered, infectious diseases due to transmission of abnormally low immunoglobulin G levels to the normal range.
or acid infective agents cannot be totally excluded. This also applies to The mechanism of action in indications other than replacement
2 g/kg in one dose in association pathogens of hitherto unknown nature. The risk of transmission therapy is not fully elucidated, but includes immunomodulatory
with acetylsalicylic acid of infective agents is however reduced by: effects.
Allogeneic bone - selection of donors by a medical interview and screening of
marrow 5.2 PHARMACOKINETIC PROPERTIES
donations and plasma pools for the three major pathogenic
transplantation: Human normal immunoglobulin is immediately and completely
- treatment of 0.5g/kg Every week from day-7 up to viruses, HIV, HCV and HBV
bioavailable in the recipients circulation after intravenous
infections and 3 months after transplantation - testing of plasma pools for HCV genomic material
administration. It is distributed relatively rapidly between the
prophylaxis of graft - removal/inactivation procedures included in the production plasma and extravascular uid, after approximately 3 - 5 days
versus host disease process that have been validated using model viruses and are an equilibrium is reached between intra and extravascular
- persistent lack of 0.5g/kg Every month until antibody considered effective for HIV, HCV and HBV.
antibody production levels return to normal compartments. Intravenous immunoglobulins have a half life
The viral removal/inactivation procedures may be of limited of about 23 - 25 days, although this can vary from patient to
Method of administration: value against non-enveloped viruses such as hepatitis A virus patient, particularly in primary immunodeciency.
or parvovirus B19.
VIGAM Liquid is administered intravenously preferably IgG and IgG complexes are broken down in cells of the reticulo-
using the recommended infusion In the interest of patients, it is recommended that, whenever endothelial system.
possible, every time that VIGAM Liquid is administered to
set, provided upon request (compatibility studies with the 5.3 PRECLINICAL SAFETY DATA
them, the name and batch number of the product is registered.
product have only been carried out on a Codan set with a 15 Human proteins include antibodies in heterologous species.
micron lter), at an initial rate of 0.01 - 0.02 ml/kg/minute for 4.5 INTERACTION WITH OTHER MEDICAMENTS Therefore, pre-clinical studies have not been carried out with
30 minutes. If well tolerated, the rate of administration may be AND OTHER FORMS OF INTERACTIONS VIGAM Liquid which contains immunoglobulins which are
gradually increased to 0.04 ml/kg/minute up to a maximum 4.5.1 Live attenuated vaccines normal constituents of human blood.
of 3 ml/minute, for the remainder of the infusion. Due to the
Immunoglobulin administration may impair for a period 6. PHARMACEUTICAL PARTICULARS:
absence of any anti-microbial preservatives, it is recommended
of at least 6 weeks and up to 3 months the efcacy of live
that administration should begin immediately after piercing the 6.1 LIST OF EXCIPIENTS
attenuated virus vaccines such as measles, rubella, mumps
cap. Human Albumin Solution 20% added at 2 g/100 ml (this
and varicella. After administration of this product, an
4.3 CONTRA-INDICATIONS interval of 3 months should elapse before vaccination with contains sodium n-octanoate as a stabiliser), sucrose, sodium
VIGAM Liquid is contra-indicated in patients with selective live attenuated virus vaccines. In the case of measles, this acetate and glycine are added to stabilise the immunoglobulin
IgA deciency who have developed antibodies to IgA. impairment may persist for up to a year. Therefore patients solution. The product pH 4.8 - 5.1 is achieved by adjustment
VIGAM Liquid may be contra-indicated in patients with receiving measles vaccine should have their antibody status with small quantities of hydrochloric acid and sodium
hypersensitivity to any of the product components. checked. hydroxide as required. This acidic pH has no detrimental effect
4.5.2 Interference with serological testing on the patient because of the substantial buffering capacity of
4.4 SPECIAL WARNINGS AND SPECIAL PRECAUTIONS the patients own blood.
FOR USE After infusion of immunoglobulin the transitory rise of the
various passively transferred antibodies in the patients 6.2 INCOMPATIBILITIES
Certain severe adverse drug reactions may be related to the blood may result in misleading positive results in serological
rate of infusion. The recommended infusion rate given under VIGAM Liquid should not be mixed with other medicinal
testing. products as their effects on the product have not been
4.2 Method of administration must be closely followed.
Patients must be closely monitored and carefully observed for Passive transmission of antibodies to erythrocyte antigens, established.
any symptoms throughout the infusion period. Certain adverse e.g. A, B, D may interfere with some serological tests
(reticulocyte count, haptoglobin and Coombs test). 6.3 SHELF LIFE
reactions may occur more frequently
24 months if stored unopened between 2C and 8C.
- in case of a high infusion rate; 4.6 PREGNANCY AND LACTATION
- in patients with hypo- or agammaglobulinaemia with or The safety of this medicinal product for use in human 6.4 SPECIAL PRECAUTIONS FOR STORAGE
without IgA deciency; pregnancy has not been established in controlled clinical trials VIGAM Liquid should be stored in the dark in its carton,
- in patients who receive human normal immunoglobulin and therefore should only be given with caution to pregnant between 2 and 8C. DO NOT FREEZE. A short period up to 3
for the rst time or, in rare cases, when the human normal women and breast-feeding mothers. Clinical experience with months at 25C is possible within the shelf-life period.
immunoglobulin product is switched or when there has been immunoglobulins suggests that no harmful effects on the course Do not use after the expiry date printed on the label. The
a long interval since the previous infusion. of pregnancy, or on the fetus, or the newborn, are to be expected. conditions of expired or incorrectly stored product cannot be
True hypersensitivity reactions are rare. They can occur in Immunoglobulins are excreted into the milk and may contribute guaranteed. Such product may be unsafe and should not be
the few cases of IgA deciency with anti-IgA antibodies. to the transfer of protective antibodies to the newborn. used.
Although rare, human normal immunoglobulins may cause 4.7 EFFECTS ON ABILITY TO DRIVE AND USE 6.5 NATURE AND CONTENTS OF CONTAINER
a sudden fall in blood pressure and, in isolated cases, MACHINES
anaphylactic shock, even when the patient has shown no VIGAM Liquid is a sterile colourless to pale amber or pale
No effects on the ability to drive or to use machines have been green liquid immunoglobulin G supplied as 2.5 g, 5 g and 10
hypersensitivity to previous administration.
observed. g doses. The product is contained in a clear glass bottle and
Potential complications can often be avoided by ensuring:
4.8 UNDESIRABLE EFFECTS stoppered with a rubber bung. The bung is oversealed with a
- that patients are not sensitive to human normal
immunoglobulin by rst injecting VIGAM Liquid slowly tamper-evident cap.
Adverse reactions such as chills, hypothermia, headache,
(0.01 ml/kg/min); fever, vomiting, allergic reactions including rash and urticaria, 6.6 INSTRUCTIONS FOR USE/HANDLING
- that patients are carefully monitored for any symptoms nausea, arthralgia, low blood pressure and moderate low back For product stored in a fridge the product container should be
throughout the infusion period. In particular, patients nave pain may occur occasionally. Although rare, human normal left out at room temperature to warm up before use.
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SPDI
VIGAM Liquid should be inspected visually for particulate - Pulmonary oedema At the rst clinical signs of either cardiovascular overload
matter and discoloration prior to administration. The solution - Haemorrhagic diathesis (headache, dyspnoea, jugular vein congestion), increased blood
should be clear or slightly opalescent. Products which are - Severe anaemia pressure, raised central venous pressure or pulmonary oedema,
cloudy or which have a deposit should not be used. - Renal and post-renal anuria the infusion should be stopped immediately. Additionally,
Use of VIGAM Liquid should begin immediately after - Dehydration (unless sufcient uid is infused diuresis or cardiac output should be increased according to the
piercing the cap. simultaneously) severity of the clinical situation.
VIGAM Liquid is for single use only; any used materials or 5. PHARMACOLOGICAL PROPERTIES
4.4 SPECIAL WARNINGS AND SPECIAL PRECAUTIONS
unused solution should be discarded by approved means. 5.1 PHARMACODYNAMIC PROPERTIES:
FOR USE:
If allergic or anaphylactic-type reactions occur, the infusion Pharmacotherapeutic group: Plasma substitutes and Perfusion
ZENALB 20 Solution for Injection should be stopped immediately and appropriate treatment solutions
instituted. ATC code: B05
(Human Albumin) In the case of shock, the current medical standards for shock Human albumin accounts quantitatively for more than half of
treatment are to be observed. the total protein in the plasma and represents about 10% of the
1. NAME OF THE MEDICINAL PRODUCT : The use of albumin for the therapy of shock should be consistent protein synthesis activity of the liver.
ZENALB 20, a Human Albumin 20% Solution. with current guidelines. Physicochemical data: ZENALB 20 has a corresponding
The colloid-osmotic effect of ZENALB 20 is approximately hyperoncotic effect.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
four times that of blood plasma. Therefore, when concentrated The most important physiological functions of albumin results
2.1 Active Ingredients: Human Albumin is prepared from albumin is administered care must be taken to ensure adequate from its contribution to oncotic pressure of the blood and
plasma from screened donors. Donors are selected from the hydration of the patient. Patients should be monitored carefully transport function.
USA. to guard against circulatory overload and hyperhydration, Albumin stabilises circulating blood volume and is a carrier for
2.2 Quantitative Composition: ZENALB 20 is a clear, respectively. hormones, enzymes, medicinal products and toxins.
yellow to green, sterilised solution. It is a low salt solution If the required volume of ZENALB 20 exceeds 200ml
containing 190-210g/L of plasma protein of which not less than appropriate additional electrolyte solutions should be 5.2 PHARMACOKINETIC PROPERTIES:
95% is albumin. The residual proteins are heat stable alpha- and administered to maintain normal uid balance. Alternatively Under normal conditions the total exchangeable albumin pool is
beta- globulins. ZENALB 20 is free from plasma proteins therapy may continue with ZENALB 4.5. 4-5g/kg bodyweight, of which 40-45% is present intravascularly
associated with the blood clotting mechanism and blood group and 55-60% in the extravascular space. Abnormal distribution
If comparatively large volumes are to be replaced, controls of
antibodies. may occur in conditions such as severe burns or septic shock
coagulation and haematocrit are necessary. Care must be taken
ZENALB 20 contains 50-120mmol/L sodium. The assayed to ensure adequate substitution of other blood constituents where capillary function is impaired.
sodium content is stated on the label of the bottle. For excipients (coagulation factors, electrolytes, platelets and erythrocytes). Increased capillary permeability will alter albumin kinetics.
see section 6.1. If the haematocrit falls below 30% packed red cells should be Under normal conditions the half-life of albumin is about 19
3. PHARMACEUTICAL FORM given to maintain the oxygen transport capacity of the blood. days. The balance between synthesis and breakdown is normally
ZENALB 20 is a low salt solution (hypotonic, but Hypervolaemia may occur if the dosage and rate of infusion achieved by feedback regulation. Elimination is predominantly
hyperoncotic) of albumin ready to be administered as an are too high. intracellular and due to lysosome proteases.
intravenous infusion only. At the rst clinical signs of cardiovascular overload (headache, In healthy people, less than 10% of infused albumin leaves the
dyspnoea, jugular vein congestion), or increased blood pressure, intravascular compartment during the rst 2 hours following
4. CLINICAL PARTICULARS
raised venous pressure and pulmonary oedema, the infusion is infusion. As a result the circulating volume will increase from 1
4.1 Therapeutic Indications: to be stopped immediately. Additionally, diuresis or cardiac to 3 hours after administration. There is considerable individual
ZENALB 20 is used for restoration and maintenance of output should be increased according to the severity of the variation in this effect on plasma volume. In some patients the
circulating blood volume where volume deciency has been clinical situation. plasma volume can remain increased for some hours. However,
demonstrated, use of a colloid such as albumin is appropriate, Special care should be taken when administering albumin in ill patients albumin can leak out of the vascular space in
and where electrolyte or uid load requires careful monitoring. in pathological states where capillary permeability may be substantial amounts at an unpredictable rate.
4.2 POSOLOGY AND METHOD OF ADMINISTRATION: increased. 5.3 Preclinical Safety Data:
ZENALB 20 is given by intravenous infusion. In general the When medicinal products prepared from human plasma are Human albumin is a normal constituent of plasma and acts like
dosage and the infusion-rate should be adjusted to the patients administered, infectious diseases due to the transmission of physiological albumin.
individual requirements. infective agents cannot be totally excluded. This applies to In animals, single dose toxicity testing is of little relevance
pathogens of hitherto unknown origin. and does not permit the estimation of toxic or lethal doses or
In anaphylactic reactions, treatment should follow the current
recommendations for shock therapy. The risk of transmission of infective agents is however reduced of a dose-effect relationship. Repeated dose toxicity testing
by: is impracticable due to the development of antibodies to
4.2.1 Posology:
- selection of donors by a medical interview and screening of heterologous protein in animal models.
The dose required depends on the size of the patient, the
donations for the three major pathogenic viruses HIV, HCV To date, human albumin has not been reported to be associated
severity of trauma or illness and on continuing uid and
and HBV. with embryo-fetal toxicity, oncogenic or mutagenic potential.
protein losses. Measures of circulating volume and not only
plasma albumin levels, should be used to determine the dose - testing of plasma pools for HCV genomic materials No signs of acute toxicity have been described in animal
required. - removal/inactivation procedures included in the production models.
If human albumin is to be administered, one or more of process that have been validated using model viruses and are
considered effective for HIV, HCV and HBV. 6. PHARMACEUTICAL PARTICULARS
the following variables should be measured frequently to
Two separate pasteurisation procedures are used in the 6.1 List of Excipients:
estimate changes in circulating blood volume, cardiac lling
pressure and circulatory performance: manufacture of ZENALB 20. Pasteurisation is effective Sodium range 50-120mmol/L
- arterial blood pressure and pulse rate against enveloped viruses such as HIV, HBV and HCV Potassium upper limit 10mmol/L
- central venous pressure viruses, and has also been shown to be effective against some Chloride upper limit 40mmol/L
non-enveloped viruses including hepatitis A virus. The viral Citrate upper limit 0.1mmol/L
- pulmonary artery occlusion pressure
inactivation procedures may be of limited value against some Sodium n-Octanoate range 20-40mmol/L
- urine output nonenveloped viruses such as parvovirus B19.
- electrolytes ZENALB 20 contains no preservative.
Paediatric Use: 4.5 INTERACTION WITH OTHER MEDICAMENTS In compliance with the European Pharmacopoeia ZENALB
AND OTHER FORMS OF INTERACTIONS: 20 has an aluminium content of not more than 200g/L, and is
In children the physiological plasma volume is age dependent.
This fact must be taken into account when determining dose None known. therefore suitable for premature infants and patients undergoing
volumes. dialysis.
4.6 PREGNANCY AND LACTATION:
4.2.2 Administration: 6.2 Incompatibilities:
No animal reproduction and lactation studies have been
Human albumin is ready for use and is for administration by conducted with ZENALB 20. The safety of ZENALB 20 Human albumin should not be mixed with other medicinal
intravenous infusion only. In patients with greatly reduced for use in human pregnancy has not been established.Therefore, products, whole blood and packed red cells. ZENALB 20 has
blood volume and/or shock, the infusion of ZENALB 20 ZENALB 20 should be administered to pregnant and lactating a hyperoncotic effect.
should not exceed 120ml/hour. As the clinical state of the women only if clearly indicated and the benet outweighs the 6.3 Shelf Life:
patient improves and circulating blood volume is returning risk. 50ml and 100ml size
to normal, the rate should be reduced to a recommended rate
4.7 EFFECTS ON ABILITY TO DRIVE AND USE Unopened 36 months
of 1-2ml/minute (60-120ml/hour). The infusion rate should
MACHINES: Opened 3 hours
be adjusted according to the individual circumstances and the
indication, but should normally not exceed 1-2ml/minute. No effects on the ability to drive and use machines have been
6.4 SPECIAL PRECAUTIONS FOR STORAGE:
observed.
If large volumes are administered, the product should be ZENALB 20 should be stored in its carton between 2C and
warmed to room or body temperature before use. 4.8 UNDESIRABLE EFFECTS: 25C protected from light, until required for use. DO NOT
4.3 CONTRA-INDICATIONS: Mild reactions such as ush, urticaria, fever and nausea occur FREEZE. STORE IN THE DARK.
rarely. The expiry date of the product is stated on the label.
Hypersensitivity to albumin preparations. Hypersensitivity to
any of the components. All conditions in which hypervolaemia These reactions normally disappear rapidly when the infusion
6.5 NATURE AND CONTENTS OF CONTAINER:
and its consequences (e.g. increased stroke volume, elevated rate is slowed down or the infusion is stopped. Very rarely,
reactions including shock may occur. In these cases, the The solution is contained in glass bottles stoppered with a
blood pressure) or haemodilution could represent a special risk
infusion should be stopped and appropriate treatment should rubber bung.
to the patient.
be initiated. The bung is over-sealed with a tamper evident cap.
Examples of such conditions are:
- Decompensated cardiac insufciency 4.9 OVERDOSE: 6.6 INSTRUCTIONS FOR USE AND HANDLING AND
- Hypertension Hypervolaemia may occur if the dosage and rate of infusion DISPOSAL:
- Oesophageal varices are too high. Do not use after the expiry date given on the label.
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Book_01.indd 185 6/4/2008 2:20:57 PM

SPDI
A polyethylene sling is provided with the bottle. For use, rst dehydro-aripiprazole, which has been shown to have afnities for Elderly
tear off the two side strips and the perforated disc, then insert D2 receptors similar to the parent drug and represents 40% of the In formal single-dose pharmacokinetic studies (with aripiprazole
the bottle into the sling. ZENALB 20 should be warmed to parent drug exposure in plasma. The mean elimination half-lives given in a single dose of 15 mg), aripiprazole clearance was
room temperature before infusion. are about 75 hours and 94 hours for aripiprazole and dehydro- 20% lower in elderly (65 years) subjects compared to younger
Usually the solution is clear or slightly opalescent. Do not use aripiprazole, respectively. Steady-state concentrations are attained adult subjects (18 to 64 years). There was no detectable age
solutions which are cloudy or have deposits. This may indicate within 14 days of dosing for both active moieties. Aripiprazole effect, however, in the population pharmacokinetic analysis in
that the protein is unstable or that the solution has become accumulation is predictable from single-dose pharmacokinetics. schizophrenia patients. Also, the pharmacokinetics of aripiprazole
infected. At steady state, the pharmacokinetics of aripiprazole are dose- after multiple doses in elderly patients appeared similar to that
proportional. Elimination of aripiprazole is mainly through observed in young, healthy subjects. No dosage adjustment
Once the infusion container has been penetrated, the contents
hepatic metabolism involving two P450 isozymes, CYP2D6 and is recommended for elderly patients (see Boxed WARNING,
should be used immediately. Any unused product should be
CYP3A4. WARNINGS: Increased Mortality in Elderly Patients with
disposed of in accordance with local requirements.
Absorption Dementia-Related Psychosis, and PRECAUTIONS: Geriatric
Tablet: Aripiprazole is well absorbed after administration of the Use).
BRISTOL-MYERS SQUIBB COMPANY tablet, with peak plasma concentrations occurring within 3 to 5 Gender
P.O.BOX: 19870, RIYADH: 11445 hours; the absolute oral bioavailability of the tablet formulation Cmax and AUC of aripiprazole and its active metabolite, dehydro-
is 87%. aripiprazole, are 30 to 40% higher in women than in men, and
SAUDI ARABIA
ABILIFY can be administered with or without food. Administration correspondingly, the apparent oral clearance of aripiprazole is
TEL: 01-4601534, FAX: 01-4601695 of a 15-mg ABILIFY tablet with a standard high-fat meal did not lower in women. These differences, however, are largely explained
signicantly affect the Cmax or AUC of aripiprazole or its active by differences in body weight (25%) between men and women. No
ABILIFY Tablet metabolite, dehydro-aripiprazole, but delayed Tmax by 3 hours for dosage adjustment is recommended based on gender.
aripiprazole and 12 hours for dehydro-aripiprazole.
ABILIFY Oral Solution(N.R) Race
Oral Solution: Aripiprazole is well absorbed when administered Although no specic pharmacokinetic study was conducted to
orally as the solution. At equivalent doses, the plasma concentrations investigate the effects of race on the disposition of aripiprazole,
(Aripiprazole) of aripiprazole from the solution were higher than that from the population pharmacokinetic evaluation revealed no evidence
tablet formulation. In a relative bioavailability study comparing of clinically signicant race-related differences in the
WARNING the pharmacokinetics of 30 mg aripiprazole as the oral solution to pharmacokinetics of aripiprazole. No dosage adjustment is
Increased Mortality in Elderly Patients with Dementia-Related 30 mg aripiprazole tablets in healthy subjects, the solution to tablet recommended based on race.
Psychosis ratios of geometric mean Cmax and AUC values were 122% and Smoking
114%, respectively (see DOSAGE AND ADMINISTRATION).
Elderly patients with dementia-related psychosis treated with Based on studies utilizing human liver enzymes in vitro,
The single-dose pharmacokinetics of aripiprazole were linear and
atypical antipsychotic drugs are at an increased risk of death aripiprazole is not a substrate for CYP1A2 and also does not
doseproportional between the doses of 5 to 30 mg.
compared to placebo. Analyses of seventeen placebocontrolled undergo direct glucuronidation. Smoking should, therefore, not
trials (modal duration of 10 weeks) in these patients revealed a Distribution have an effect on the pharmacokinetics of aripiprazole. Consistent
risk of death in the drug-treated patients of between 1.6 to 1.7 The steady-state volume of distribution of aripiprazole following with these in vitro results, population pharmacokinetic evaluation
times that seen in placebo-treated patients. intravenous administration is high (404 L or 4.9 L/kg), indicating did not reveal any signicant pharmacokinetic differences between
Over the course of a typical 10-week controlled trial, the rate extensive extravascular distribution. At therapeutic concentrations, smokers and nonsmokers. No dosage adjustment is recommended
of death in drug-treated patients was about 4.5%, compared to aripiprazole and its major metabolite are greater than 99% bound based on smoking status.
a rate of about 2.6% in the placebo group. Although the causes to serum proteins, primarily to albumin. In healthy human Drug-Drug Interactions
of death were varied, most of the deaths appeared to be either volunteers administered 0.5 to 30 mg/day aripiprazole for 14 days,
Potential for Other Drugs to Affect ABILIFY Aripiprazole
cardiovascular (e.g., heart failure, sudden death) or infectious there was dose-dependent D2 receptor occupancy indicating brain
is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6,
(e.g., pneumonia) in nature. ABILIFY (aripiprazole) penetration of aripiprazole in humans.
CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole
is not approved for the treatment of patients with dementia- Metabolism and Elimination also does not undergo direct glucuronidation. This suggests that
related psychosis. Aripiprazole is metabolized primarily by three biotransformation an interaction of aripiprazole with inhibitors or inducers of these
pathways: dehydrogenation, hydroxylation, and N-dealkylation. enzymes, or other factors, like smoking, is unlikely.
DESCRIPTION Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are Both CYP3A4 and CYP2D6 are responsible for aripiprazole
ABILIFY (aripiprazole) is a psychotropic drug that is available responsible for dehydrogenation and hydroxylation of aripiprazole, metabolism. Agents that induce CYP3A4 (e.g., carbamazepine)
as tablets and in solution for oral administration. Aripiprazole and N-dealkylation is catalyzed by CYP3A4. could cause an increase in aripiprazole clearance and lower blood
is7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4- Aripiprazole is the predominant drug moiety in the systemic
dihydrocarbostyril. The empirical formula is C23H27Cl2N3O2 levels. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6
circulation. At steady state, dehydroaripiprazole, the active (e.g., quinidine, uoxetine, or paroxetine) can inhibit aripiprazole
and its molecular weight is 448.38. The chemical structure is: metabolite, represents about 40% of aripiprazole AUC in plasma. elimination and cause increased blood levels.
Approximately 8% of Caucasians lack the capacity to metabolize Potential for ABILIFY to Affect Other Drugs
CYP2D6 substrates and are classied as poor metabolizers (PM),
Aripiprazole is unlikely to cause clinically important
whereas the rest are extensive metabolizers (EM). PMs have about
pharmacokinetic interactions with drugs metabolized by
an 80% increase in aripiprazole exposure and about a 30% decrease
cytochrome P450 enzymes. In in vivo studies, 10- to 30-mg/day
ABILIFY tablets are available in 2-mg(N.R), 5-mg (N.R), 10-mg, in exposure to the active metabolite compared to EMs, resulting in
doses of aripiprazole had no signicant effect on metabolism by
15-mg, 20-mg(N.R), and 30-mg(N.R) strengths. about a 60% higher exposure to the total active moieties from a
CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19
Inactive ingredients include cornstarch, hydroxypropyl cellulose, given dose of aripiprazole compared to EMs. Coadministration of
(omeprazole, warfarin), and CYP3A4 (dextromethorphan)
lactose monohydrate, magnesium stearate and microcrystalline ABILIFY with known inhibitors of CYP2D6, like quinidine in
substrates. Additionally, aripiprazole and dehydro-aripiprazole did
cellulose. Colorants include ferric oxide (yellow or red) and EMs, results in a 112% increase in aripiprazole plasma exposure,
not show potential for altering CYP1A2-mediated metabolism in
FD&C Blue and dosing adjustment is needed (see PRECAUTIONS: Drug-Drug vitro (see PRECAUTIONS: Drug-Drug Interactios).
No. 2 Aluminum Lake. Interactions). The mean elimination half-lives are about 75 hours
Aripiprazole had no clinically important interactions with the
and 146 hours for aripiprazole in EMs and PMs, respectively.
ABILIFY is also available as a 1 mg/mL oral solution(N.R). The following drugs:
inactive ingredients for this solution include disodium edetate, Aripiprazole does not inhibit or induce the CYP2D6 pathway.
Famotidine: Coadministration of aripiprazole (given in a single
fructose, glycerin, dl-lactic acid, methylparaben, propylene glycol, Following a single oral dose of [14C]-labeled aripiprazole, dose of 15 mg) with a 40-mg single dose of the H2 antagonist
propylparaben, sodium hydroxide, sucrose, and puried water. approximately 25% and 55% of the administered radioactivity famotidine, a potent gastric acid blocker, decreased the solubility
The oral solution is avored with natural orange cream and other was recovered in the urine and feces, respectively. Less than of aripiprazole and, hence, its rate of absorption, reducing by 37%
natural avors. 1% of unchanged aripiprazole was excreted in the urine and and 21% the Cmax of aripiprazole and dehydro-aripiprazole,
approximately 18% of the oral dose was recovered unchanged in respectively, and by 13% and 15%, respectively, the extent of
CLINICAL PHARMACOLOGY the feces. absorption (AUC).
Pharmacodynamics Special Populations No dosage adjustment of aripiprazole is required when
Aripiprazole exhibits high afnity for dopamine D2 and D3, In general, no dosage adjustment for ABILIFY (aripiprazole) administered concomitantly with famotidine.
serotonin 5-HT1A and 5-HT2A receptors (Ki values of 0.34, 0.8, is required on the basis of a patients age, gender, race, smoking Valproate: When valproate (500-1500 mg/day) and aripiprazole
1.7, and 3.4 nM, respectively), moderate afnity for dopamine D4, status, hepatic function, or renal function (see DOSAGE AND (30 mg/day) were coadministered at steady state, the Cmax and
serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 ADMINISTRATION: Dosage in Special Populations). The AUC of aripiprazole were decreased by 25%. No dosage adjustment
receptors (Ki values of 44, 15, 39, 57, and 61 nM, respectively), pharmacokinetics of aripiprazole in special populations are of aripiprazole is required when administered concomitantly with
and moderate afnity for the serotonin reuptake site (Ki=98 nM). described below. valproate.
Aripiprazole has no appreciable afnity for cholinergic muscarinic Hepatic Impairment Lithium: A pharmacokinetic interaction of aripiprazole with
receptors (IC50 >1000 nM). Aripiprazole functions as a partial
In a single-dose study (15 mg of aripiprazole) in subjects with lithium is unlikely because lithium is not bound to plasma proteins,
agonist at the dopamine D2 and the serotonin 5-HT1A receptors,
varying degrees of liver cirrhosis (Child-Pugh Classes A, B, is not metabolized, and is almost entirely excreted unchanged in
and as an antagonist at serotonin 5-HT2A receptor.
and C), the AUC of aripiprazole, compared to healthy subjects, urine.
The mechanism of action of aripiprazole, as with other drugs increased 31% in mild HI, increased 8% in moderate HI, and Coadministration of therapeutic doses of lithium (1200-1800
having efcacy in schizophrenia and bipolar disorder, is unknown. decreased 20% in severe HI. None of these differences would mg/day) for 21 days with aripiprazole (30 mg/day) did not result
However, it has been proposed that the efcacy of aripiprazole is require dose adjustment. in clinically signicant changes in the pharmacokinetics of
mediated through a combination of partial agonist activity at D2 Renal Impairment aripiprazole or its active metabolite, dehydro-aripiprazole (Cmax
and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. and AUC increased by less than 20%). No dosage adjustment of
In patients with severe renal impairment (creatinine clearance
Actions at receptors other than D2, 5-HT1A, and 5-HT2A may aripiprazole is required when administered concomitantly with
<30 mL/min), Cmax of aripiprazole (given in a single dose of
explain some of the other clinical effects of aripiprazole, e.g., lithium.
15 mg) and dehydro-aripiprazole increased by 36% and 53%,
the orthostatic hypotension observed with aripiprazole may be
respectively, but AUC was 15% lower for aripiprazole and Dextromethorphan: Aripiprazole at doses of 10 to 30 mg per day
explained by its antagonist activity at adrenergic alpha1 receptors.
7% higher for dehydro-aripiprazole. Renal excretion of both for 14 days had no effect on dextromethorphans O-dealkylation
Pharmacokinetics unchanged aripiprazole and dehydro-aripiprazole is less than 1% to its major metabolite, dextrorphan, a pathway known to be
ABILIFY activity is presumably primarily due to the parent of the dose. No dosage adjustment is required in subjects with dependent on CYP2D6 activity. Aripiprazole also had no effect
drug, aripiprazole, and to a lesser extent, to its major metabolite, renal impairment. on dextromethorphans N-demethylation to its metabolite 3-
186
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BRISTOL-MYERS SQUIBB COMPANY
SPDI
methyoxymorphan, a pathway known to be dependent on CYP3A4 trials in hospitalized patients who met the DSM-IV criteria for risk of death compared to placebo. ABILIFY is not approved
activity. No dosage adjustment of dextromethorphan is required Bipolar I Disorder with manic or mixed episodes (in one trial, for the treatment of patients with dementia-related psychosis
when administered concomitantly with aripiprazole. 21% of placebo and 42% of ABILIFY-treated patients had data (see Boxed WARNING).
Warfarin: Aripiprazole 10 mg per day for 14 days had no beyond two weeks). These trials included patients with or without Neuroleptic Malignant Syndrome (NMS)
effect on the pharmacokinetics of R- and S-warfarin or on the psychotic features and with orwithout a rapid-cycling course. A potentially fatal symptom complex sometimes referred to as
pharmacodynamic end point of International Normalized Ratio, The primary instrument used for assessing manic symptoms was Neuroleptic Malignant Syndrome (NMS) has been reported in
indicating the lack of a clinically relevant effect of aripiprazole the Young Mania Rating Scale (Y-MRS), an 11-item clinician- association with administration of antipsychotic drugs, including
on CYP2C9 and CYP2C19 metabolism or the binding of highly rated scale traditionally used to assess the degree of manic aripiprazole. Two possible cases of NMS occurred during
protein-bound warfarin. No dosage adjustment of warfarin is symptomatology (irritability, disruptive/aggressive behavior, aripiprazole treatment in the premarketing worldwide clinical
required when administered concomitantly with aripiprazole. sleep, elevated mood, speech, increased activity, sexual interest, database. Clinical manifestations of NMS are hyperpyrexia, muscle
Omeprazole: Aripiprazole 10 mg per day for 15 days had no effect language/thought disorder, thought content, appearance, and rigidity, altered mental status, and evidence of autonomic instability
on the pharmacokinetics of a single 20-mg dose of omeprazole, insight) in a range from 0 (no manic features) to 60 (maximum (irregular pulse or blood pressure, tachycardia, diaphoresis, and
a CYP2C19 substrate, in healthy subjects. No dosage adjustment score). A key secondary instrument included the Clinical Global cardiac dysrhythmia). Additional signs may include elevated
of omeprazole is required when administered concomitantly with Impression - Bipolar (CGI-BP) scale. creatine phosphokinase, myoglobinuria (rhabdomyolysis), and
aripiprazole. In the two positive, 3-week, placebo-controlled trials (n=268; acute renal failure.
n=248) which evaluated ABILIFY 15 or 30 mg/day, once daily The diagnostic evaluation of patients with this syndrome is
CLINICAL STUDIES (with a starting dose of 30 mg/day), ABILIFY was superior
Schizophrenia complicated. In arriving at a diagnosis, it is important to exclude
to placebo in the reduction of Y-MRS total score and CGI-BP cases where the clinical presentation includes both serious medical
The efcacy of ABILIFY in the treatment of schizophrenia was Severity of Illness score (mania). illness (e.g., pneumonia, systemic infection, etc.) and untreated or
evaluated in four short-term (4- and 6-week), placebo-controlled A trial was conducted in patients meeting DSM-IV criteria for inadequately treated extrapyramidal signs and symptoms (EPS).
trials of acutely relapsed inpatients who predominantly met DSM- Bipolar I Disorder with a recent manic or mixed episode who had Other important considerations in the differential diagnosis
III/IV criteria for schizophrenia. Three of the four trials were able to been stabilized on open-label ABILIFY and who had maintained include central anticholinergic toxicity, heat stroke, drug fever,
distinguish aripiprazole from placebo, but one study, the smallest, a clinical response for at least 6 weeks. The rst phase of this trial and primary central nervous system pathology.
did not. Three of these studies also included an active control was an open-label stabilization period in which inpatients and The management of NMS should include: 1) immediate
group consisting of either risperidone (one trial) or haloperidol outpatients were clinically stabilized and then maintained on discontinuation of antipsychotic drugs and other drugs not essential
(two trials), but they were not designed to allow for a comparison openlabel ABILIFY (15 or 30 mg/day, with a starting dose of 30 to concurrent therapy; 2) intensive symptomatic treatment and
of ABILIFY (aripiprazole) and the active comparators. mg/day) for at least 6 consecutive weeks. medical monitoring; and 3) treatment of any concomitant serious
In the three positive trials for ABILIFY, four primary measures One hundred sixty-one outpatients were then randomized in a medical problems for which specic treatments are available.
were used for assessing psychiatric signs and symptoms. The double-blind fashion, to either the same dose of ABILIFY they There is no general agreement about specic pharmacological
Positive and Negative Syndrome Scale (PANSS) is a multi- were on at the end of the stabilization and maintenance period or treatment regimens for uncomplicated NMS.
item inventory of general psychopathology used to evaluate the placebo and were then monitored for manic or depressive relapse. If a patient requires antipsychotic drug treatment after recovery
effects of drug treatment in schizophrenia. The PANSS positive During the randomization phase, ABILIFY was superior to from NMS, the potential reintroduction of drug therapy should be
subscale is a subset of items in the PANSS that rates seven placebo on time to the number of combined affective relapses carefully considered. The patient should be carefully monitored,
positive symptoms of schizophrenia (delusions, conceptual (manic plus depressive), the primary outcome measure for this
disorganization, hallucinatory behavior, excitement, grandiosity, since recurrences of NMS have been reported.
study. The majority of these relapses were due to manic rather than
suspiciousness/persecution, and hostility). The PANSS negative depressive symptoms. There is insufcient data to know whether Tardive Dyskinesia
subscale is a subset of items in the PANSS that rates seven negative ABILIFY is effective in delaying the time to occurrence of A syndrome of potentially irreversible, involuntary, dyskinetic
symptoms of schizophrenia (blunted affect, emotional withdrawal, depression in patients with Bipolar I Disorder. movements may develop in patients treated with antipsychotic
poor rapport, passive apathetic withdrawal, difculty in abstract An examination of population subgroups did not reveal any clear drugs. Although the prevalence of the syndrome appears to
thinking, lack of spontaneity/ow of conversation, stereotyped evidence of differential responsiveness on the basis of age and be highest among the elderly, especially elderly women, it is
thinking). The Clinical Global Impression (CGI) assessment gender; however, there were insufcient numbers of patients impossible to rely upon prevalence estimates to predict, at the
reects the impression of a skilled observer, fully familiar with in each of the ethnic groups to adequately assess inter-group inception of antipsychotic treatment, which patients are likely to
the manifestations of schizophrenia, about the overall clinical state differences. develop the syndrome.
of the patient. Whether antipsychotic drug products differ in their potential to
In a 4-week trial (n=414) comparing two xed doses of ABILIFY INDICATIONS AND USAGE
cause tardive dyskinesia is unknown.
(15 or 30 mg/day) and haloperidol (10 mg/day) to placebo, both Schizophrenia
The risk of developing tardive dyskinesia and the likelihood that
doses of ABILIFY were superior to placebo in the PANSS ABILIFY is indicated for the treatment of schizophrenia. The it will become irreversible are believed to increase as the duration
total score, PANSS positive subscale, and CGI-severity score. In efcacy of ABILIFY in the treatment of schizophrenia was of treatment and the total cumulative dose of antipsychotic drugs
addition, the 15-mg dose was superior to placebo in the PANSS established in short-term (4- and 6-week) controlled trials of administered to the patient increase. However, the syndrome can
negative subscale. schizophrenic inpatients (see CLINICAL PHARMACOLOGY: develop, although much less commonly, after relatively brief
In a 4-week trial (n=404) comparing two xed doses of ABILIFY Clinical Studies). treatment periods at low doses.
(20 or 30 mg/day) and risperidone (6 mg/day) to placebo, both The efcacy of ABILIFY in maintaining stability in patients There is no known treatment for established cases of tardive
doses of ABILIFY were superior to placebo in the PANSS total with schizophrenia who had been symptomatically stable on other dyskinesia, although the syndrome may remit, partially or
score, PANSS positive subscale, PANSS negative subscale, and antipsychotic medications for periods of 3 months or longer, were completely, if antipsychotic treatment is withdrawn. Antipsychotic
CGI-severity score. discontinued from those other medications, and were then treatment, itself, however, may suppress (or partially suppress) the
In a 6-week trial (n=420) comparing three xed doses of administered ABILIFY 15 mg/day and observed for relapse signs and symptoms of the syndrome and, thereby, may possibly
ABILIFY (10, 15, or 20 mg/day) to placebo, all three doses of during a period of up to 26 weeks was demonstrated in a placebo- mask the underlying process. The effect that symptomatic
ABILIFY were superior to placebo in the PANSS total score, controlled trial (see CLINICAL PHARMACOLOGY: Clinical suppression has upon the long-term course of the syndrome is
PANSS positive subscale, and the PANSS negative subscale. Studies). The physician who elects to use ABILIFY for extended unknown.
In a fourth study, a 4-week trial (n=103) comparing ABILIFY in periods should periodically re-evaluate the long-term usefulness Given these considerations, ABILIFY should be prescribed in a
a range of 5 to 30 mg/day or haloperidol 5 to 20 mg/day to placebo, of the drug for the individual patient (see DOSAGE AND manner that is most likely to minimize the occurrence of tardive
haloperidol was superior to placebo, in the Brief Psychiatric Rating ADMINISTRATION). dyskinesia. Chronic antipsychotic treatment should generally be
Scale (BPRS), a multi-item inventory of general psychopathology Bipolar Disorder reserved for patients who suffer from a chronic illness that (1)
traditionally used to evaluate the effects of drug treatment in ABILIFY is indicated for the treatment of acute manic and is known to respond to antipsychotic drugs, and (2) for whom
psychosis, and in a responder analysis based on the CGI-severity mixed episodes associated with Bipolar Disorder. alternative, equally effective, but potentially less harmful
score, the primary outcomes for that trial. ABILIFY was only treatments are not available or appropriate. In patients who do
The efcacy of ABILIFY was established in two placebo-
signicantly different compared to placebo in a responder analysis require chronic treatment, the smallest dose and the shortest
controlled trials (3-week) of inpatients with DSM-IV criteria for
based on the CGI-severity score. duration of treatment producing a satisfactory clinical response
Bipolar I Disorder who were experiencing an acute manic or
Thus, the efcacy of 15-mg, 20-mg, and 30-mg daily doses was mixed episode with or without psychotic features (see CLINICAL should be sought. The need for continued treatment should be
established in two studies for each dose, whereas the efcacy of the PHARMACOLOGY: Clinical Studies). reassessed periodically.
10-mg dose was established in one study. There was no evidence If signs and symptoms of tardive dyskinesia appear in a patient on
The efcacy of ABILIFY in maintaining efcacy in patients
in any study that the higher dose groups offered any advantage ABILIFY, drug discontinuation should be considered. However,
with Bipolar I Disorder with a recent manic or mixed episode who
over the lowest dose group. some patients may require treatment with ABILIFY despite the
had been stabilized and then maintained for at least 6 weeks, was
An examination of population subgroups did not reveal any clear demonstrated in a double-blind, placebo-controlled trial. Prior presence of the syndrome.
evidence of differential responsiveness on the basis of age, gender, to entering the double-blind, randomization phase of this trial, Cerebrovascular Adverse Events, Including Stroke, in Elderly
or race. patients were clinically stabilized and maintained their stability Patients with Dementia-Related Psychosis
A longer-term trial enrolled 310 inpatients or outpatients meeting for 6 consecutive weeks on ABILIFY. Following this 6-week In placebo-controlled clinical studies (two exible-dose and
DSM-IV criteria for schizophrenia who were, by history, maintenance phase, patients were randomized to either placebo one xed-dose study) of dementia-related psychosis, there
symptomatically stable on other antipsychotic medications for or ABILIFY (aripiprazole) and monitored for relapse (see was an increased incidence of cerebrovascular adverse events
periods of 3 months or longer. These patients were discontinued CLINICAL PHARMACOLOGY: Clinical Studies). Physicians (e.g., stroke, transient ischemic attack), including fatalities, in
from their antipsychotic medications and randomized to who elect to use ABILIFY for extended periods, that is, longer aripiprazole-treated patients (mean age: 84 years; range: 78-88
ABILIFY 15 mg or placebo for up to 26 weeks of observation than 6 weeks, should periodically re-evaluate the long-term years). In the xed-dose study, there was a statistically signicant
for relapse. Relapse during the double-blind phase was dened usefulness of the drug for the individual patient (see DOSAGE dose response relationship for cerebrovascular adverse events in
as CGI-Improvement score of 5 (minimally worse), scores 5 AND ADMINISTRATION). patients treated with aripiprazole. Aripiprazole is not approved for
(moderately severe) on the hostility or uncooperativeness items of the treatment of patients with dementia-related psychosis. (See
CONTRAINDICATIONS
the PANSS, or 20% increase in the PANSS total score. Patients also Boxed WARNING, WARNINGS: Increased Mortality
receiving ABILIFY 15 mg experienced a signicantly longer ABILIFY is contraindicated in patients with a known
in Elderly Patients with Dementia-Related Psychosis,
time to relapse over the subsequent 26 weeks compared to those hypersensitivity to the product.
and PRECAUTIONS: Use in Patients with Concomitant
receiving placebo. WARNINGS Illness: Safety Experience in Elderly Patients with Psychosis
Bipolar Disorder Increased Mortality in Elderly Patients with Dementia-Related Associated with Alzheimers Disease.)
The efcacy of ABILIFY in the treatment of acute manic Psychosis Elderly patients with dementia-related psychosis Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some
episodes was established in two 3-week, placebo-controlled treated with atypical antipsychotic drugs are at an increased cases extreme and associated with ketoacidosis or hyperosmolar
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SPDI
coma or death, has been reported in patients treated with atypical Body Temperature Regulation Potential for Other Drugs to Affect ABILIFY
antipsychotics. There have been few reports of hyperglycemia Disruption of the bodys ability to reduce core body temperature Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6,
in patients treated with ABILIFY. Although fewer patients have has been attributed to antipsychotic agents. Appropriate care is CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes.
been treated with ABILIFY, it is not known if this more limited advised when prescribing aripiprazole for patients who will be Aripiprazole also does not undergo direct glucuronidation. This
experience is the sole reason for the paucity of such reports. experiencing conditions which may contribute to an elevation suggests that an interaction of aripiprazole with inhibitors or
Assessment of the relationship between atypical antipsychotic use in core body temperature, e.g., exercising strenuously, exposure inducers of these enzymes, or other factors, like smoking, is
and glucose abnormalities is complicated by the possibility of an to extreme heat, receiving concomitant medication with unlikely.
increased background risk of diabetes mellitus in patients with anticholinergic activity, or being subject to dehydration. Both CYP3A4 and CYP2D6 are responsible for aripiprazole
schizophrenia and the increasing incidence of diabetes mellitus in
Dysphagia metabolism. Agents that induce CYP3A4 (e.g., carbamazepine)
the general population. Given these confounders, the relationship
Esophageal dysmotility and aspiration have been associated with could cause an increase in aripiprazole clearance and lower blood
between atypical antipsychotic use and hyperglycemia-
related adverse events is not completely understood. However, antipsychotic drug use. Aspiration pneumonia is a common cause levels. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6
epidemiological studies which did not include ABILIFY suggest of morbidity and mortality in elderly patients, in particular those (e.g., quinidine, uoxetine, or paroxetine) can inhibit aripiprazole
an increased risk of treatment-emergent hyperglycemia-related with advanced Alzheimers dementia. Aripiprazole and other elimination and cause increased blood levels.
adverse events in patients treated with the atypical antipsychotics antipsychotic drugs should be used cautiously in patients at risk Ketoconazole: Coadministration of ketoconazole (200 mg/day
included in these studies. Because ABILIFY was not marketed for aspiration pneumonia (see PRECAUTIONS: Use in Patients for 14 days) with a 15-mg single dose of aripiprazole increased
at the time these studies were performed, it is not known if with Concomitant Illness ). the AUC of aripiprazole and its active metabolite by 63% and
ABILIFY is associated with this increased risk. Precise risk Suicide 77%, respectively. The effect of a higher ketoconazole dose (400
estimates for hyperglycemia-related adverse events in patients The possibility of a suicide attempt is inherent in psychotic illnesses mg/day) has not been studied. When concomitant administration
treated with atypical antipsychotics are not available. and bipolar disorder, and close supervision of high-risk patients of ketoconazole with aripiprazole occurs, aripiprazole dose
Patients with an established diagnosis of diabetes mellitus should accompany drug therapy. Prescriptions for ABILIFY should be reduced to one-half of its normal dose. Other strong
who are started on atypical antipsychotics should be monitored should be written for the smallest quantity consistent with good inhibitors of CYP3A4 (itraconazole) would be expected to have
regularly for worsening of glucose control. Patients with risk patient management in order to reduce the risk of overdose. similar effects and need similar dose reductions; weaker inhibitors
factors for diabetes mellitus (e.g., obesity, family history of (erythromycin, grapefruit juice) have not been studied. When the
Use in Patients with Concomitant Illness Clinical experience with CYP3A4 inhibitor is withdrawn from the combination therapy,
diabetes) who are starting treatment with atypical antipsychotics
ABILIFY in patients with certain concomitant systemic illnesses aripiprazole dose should then be increased.
should undergo fasting blood glucose testing at the beginning of
(see CLINICAL PHARMACOLOGY: Special Populations: Renal
treatment and periodically during treatment. Any patient treated Quinidine: Coadministration of a 10-mg single dose of
Impairment and Hepatic Impairment) is limited.
with atypical antipsychotics should be monitored for symptoms aripiprazole with quinidine (166 mg/day for 13 days), a potent
of hyperglycemia including polydipsia, polyuria, polyphagia, and ABILIFY has not been evaluated or used to any appreciable inhibitor of CYP2D6, increased the AUC of aripiprazole by
weakness. Patients who develop symptoms of hyperglycemia extent in patients with a recent history of myocardial infarction 112% but decreased the AUC of its active metabolite, dehydro-
during treatment with atypical antipsychotics should undergo or unstable heart disease. Patients with these diagnoses were aripiprazole, by 35%. Aripiprazole dose should be reduced to
fasting blood glucose testing. In some cases, hyperglycemia excluded from premarketing clinical studies. one-half of its normal dose when concomitant administration of
has resolved when the atypical antipsychotic was discontinued; Safety Experience in Elderly Patients with Psychosis Associated quinidine with aripiprazole occurs.
however, some patients required continuation of anti-diabetic with Alzheimers Disease: In three, 10-week, placebo-controlled Other signicant inhibitors of CYP2D6, such as uoxetine
treatment despite discontinuation of the suspect drug. studies of aripiprazole in elderly patients with psychosis associated or paroxetine, would be expected to have similar effects and,
with Alzheimers disease (n=938; mean age: 82.4 years; range: 56- therefore, should be accompanied by similar dose reductions.
PRECAUTIONS
99 years), the treatmentemergent adverse events that were reported When the CYP2D6 inhibitor is withdrawn from the combination
General at an incidence of 3% and aripiprazole incidence at least twice therapy, aripiprazole dose should then be increased.
Orthostatic Hypotension that for placebo were asthenia (placebo 3%, aripiprazole 8%),
Carbamazepine: Coadministration of carbamazepine (200 mg
Aripiprazole may be associated with orthostatic hypotension, somnolence (placebo 3%, aripiprazole 9%), urinary incontinence
BID), a potent CYP3A4 inducer, with aripiprazole (30 mg QD)
perhaps due to its _1-adrenergic receptor antagonism. The incidence (placebo 1%, aripiprazole 5%), excessive salivation (placebo 0%,
resulted in an approximate 70% decrease in Cmax and AUC
of orthostatic hypotension-associated events from ve short-term, aripiprazole 4%), and lightheadedness (placebo 1%, aripiprazole values of both aripiprazole and its active metabolite, dehydro-
placebo-controlled trials in schizophrenia (n=926) on ABILIFY 4%). aripiprazole. When carbamazepine is added to aripiprazole therapy,
(aripiprazole) included: orthostatic hypotension (placebo 1%, The safety and efcacy of ABILIFY in the treatment of patients aripiprazole dose should be doubled. Additional dose increases
aripiprazole 1.9%), orthostatic lightheadedness (placebo 1%, with psychosis associated with dementia have not been established. should be based on clinical evaluation. When carbamazepine is
aripiprazole 0.9%), and syncope (placebo 1%, aripiprazole 0.6%).
If the prescriber elects to treat such patients with ABILIFY, withdrawn from the combination therapy, aripiprazole dose should
The incidence of orthostatic hypotensionassociated events from then be reduced.
vigilance should be exercised, particularly for the emergence
short-term, placebo-controlled trials in bipolar mania (n=597)
of difculty swallowing or excessive somnolence, which could No clinically signicant effect of famotidine, valproate, or lithium
on ABILIFY included: orthostatic hypotension (placebo 0%,
predispose to accidental injury or aspiration. (See also Boxed was seen on the pharmacokinetics of aripiprazole (see CLINICAL
aripiprazole 0.7%), orthostatic lightheadedness (placebo 0.5%,
WARNING and WARNINGS: Increased Mortality in Elderly PHARMACOLOGY: Drug-Drug Interactions).
aripiprazole 0.5%), and syncope (placebo 0.9%, aripiprazole
Patients with Dementia-Related Psychosis and Cerebrovascular Potential for ABILIFY to Affect Other Drugs
0.5%).
Adverse Events, Including Stroke, in Elderly Patients with
The incidence of a signicant orthostatic change in blood pressure Aripiprazole is unlikely to cause clinically important
Dementia-Related Psychosis.)
(dened as a decrease of at least 30 mmHg in systolic blood pharmacokinetic interactions with drugs metabolized by
pressure when changing from a supine to standing position) INFORMATION FOR PATIENTS cytochrome P450 enzymes. In in vivo studies, 10- to 30-mg/day
for aripiprazole was not statistically different from placebo (in Physicians are advised to discuss the following issues with patients doses of aripiprazole had no signicant effect on metabolism by
schizophrenia: 14% among aripiprazoletreated patients and 12% for whom they prescribe ABILIFY: CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19
among placebo-treated patients and in bipolar mania: 3% among (omeprazole, warfarin), and CYP3A4 (dextromethorphan)
Interference with Cognitive and Motor Performance Because
aripiprazole-treated patients and 2% among placebo-treated substrates. Additionally, aripiprazole and dehydro-aripiprazole
aripiprazole may have the potential to impair judgment, thinking,
patients). did not show potential for altering CYP1A2-mediated metabolism
or motor skills, patients should be cautioned about operating
Aripiprazole should be used with caution in patients with known in vitro (see CLINICAL PHARMACOLOGY: Drug-Drug
hazardous machinery, including automobiles, until they are
cardiovascular disease (history of myocardial infarction or Interactions).
reasonably certain that aripiprazole therapy does not affect them
ischemic heart disease, heart failure or conduction abnormalities), adversely. Alcohol: There was no signicant difference between aripiprazole
cerebrovascular disease, or conditions which would predispose coadministered with ethanol and placebo coadministered with
Pregnancy
patients to hypotension (dehydration, hypovolemia, and treatment ethanol on performance of gross motor skills or stimulus response
Patients should be advised to notify their physician if they become
with antihypertensive medications). in healthy subjects. As with most psychoactive medications,
pregnant or intend to become pregnant during therapy with
Seizure patients should be advised to avoid alcohol while taking
ABILIFY. ABILIFY.
Seizures occurred in 0.1% (1/926) of aripiprazole-treated patients Nursing
with schizophrenia in short-term, placebo-controlled trials. In Carcinogenesis, Mutagenesis, Impairment of Fertility
Patients should be advised not to breast-feed an infant if they are Carcinogenesis
short-term, placebo-controlled clinical trials of patients with
taking ABILIFY. Lifetime carcinogenicity studies were conducted in ICR mice
bipolar mania, 0.3% (2/597) of aripiprazole-treated patients and
0.2% (1/436) of placebo-treated patients experienced seizures. Concomitant Medication and in Sprague-Dawley (SD) and F344 rats. Aripiprazole was
As with other antipsychotic drugs, aripiprazole should be used Patients should be advised to inform their physicians if they are administered for 2 years in the diet at doses of 1, 3, 10, and 30
cautiously in patients with a history of seizures or with conditions taking, or plan to take, any prescription or over-the-counter drugs, mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats
that lower the seizure threshold, e.g., Alzheimers dementia. since there is a potential for interactions. (0.2 to 5 and 0.3 to 3 times the maximum recommended human
Conditions that lower the seizure threshold may be more prevalent Alcohol dose [MRHD] based on mg/m2, respectively). In addition, SD rats
in a population of 65 years or older. were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to
Patients should be advised to avoid alcohol while taking
Potential for Cognitive and Motor Impairment 19 times the MRHD based on mg/m2). Aripiprazole did not induce
ABILIFY.
tumors in male mice or rats. In female mice, the incidences of
In short-term, placebo-controlled trials of schizophrenia, Heat Exposure and Dehydration pituitary gland adenomas and mammary gland adenocarcinomas
somnolence was reported in 11% of patients on ABILIFY
Patients should be advised regarding appropriate care in avoiding and adenoacanthomas were increased at dietary doses of 3 to 30
compared to 8% of patients on placebo; somnolence led to
overheating and dehydration. mg/kg/day (0.1 to 0.9 times human exposure at MRHD based
discontinuation in 0.1% (1/926) of patients with schizophrenia
Sugar Content on AUC and 0.5 to 5 times the MRHD based on mg/m2). In
on ABILIFY in short-term, placebo-controlled trials. In short-
female rats, the incidence of mammary gland broadenomas was
term, placebo-controlled trials of bipolar mania, somnolence was Patients should be advised that each mL of ABILIFY
reported in 14% of patients on ABILIFY compared to 7% of increased at a dietary dose of 10 mg/kg/day (0.1 times human
(aripiprazole) oral solution contains 400 mg of sucrose and 200
patients on placebo, but did not lead to discontinuation of any exposure at MRHD based on AUC and 3 times the MRHD based
mg of fructose.
patients with bipolar mania. Despite the relatively modest increased on mg/m2); and the incidences of adrenocortical carcinomas and
incidence of somnolence compared to placebo, ABILIFY, like DRUG-DRUG INTERACTIONS combined adrenocortical adenomas/carcinomas were increased at
other antipsychotics, may have the potential to impair judgment, Given the primary CNS effects of aripiprazole, caution should be an oral dose of 60 mg/kg/day (14 times human exposure at MRHD
thinking, or motor skills. Patients should be cautioned about used when ABILIFY is taken in combination with other centrally based on AUC and 19 times the MRHD based on mg/m2).
operating hazardous machinery, including automobiles, until they acting drugs and alcohol. Due to its 1-adrenergic receptor Proliferative changes in the pituitary and mammary gland of
are reasonably certain that therapy with ABILIFY does not antagonism, aripiprazole has the potential to enhance the effect of rodents have been observed following chronic administration
affect them adversely. certain antihypertensive agents. of other antipsychotic agents and are considered prolactin-
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SPDI
mediated. Serum prolactin was not measured in the aripiprazole Pediatric Use in the incidence of discontinuation due to adverse events between
carcinogenicity studies. However, increases in serum prolactin Safety and effectiveness in pediatric and adolescent patients have aripiprazole-treated (11%) and placebo-treated (9%) patients. The
levels were observed in female mice in a 13-week dietary study not been established. types of adverse events that led to discontinuation were similar
at the doses associated with mammary gland and pituitary tumors. between the aripiprazole and placebo-treated patients.
Geriatric Use
Serum prolactin was not increased in female rats in 4- and 13- Commonly Observed Adverse Events in Short-Term, Placebo-
Of the 7951 patients treated with aripiprazole in premarketing
week dietary studies at the dose associated with mammary gland Controlled Trials of Patients with Bipolar Mania
clinical trials, 991 (12%) were 65 years old and 789 (10%)
tumors. The relevance for human risk of the ndings of prolactin- Commonly observed adverse events associated with the use of
were 75 years old. The majority (88%) of the 991 patients were
mediated endocrine tumors in rodents is unknown. aripiprazole in patients with bipolar mania (incidence of 5% or
diagnosedwith dementia of the Alzheimers type.
Mutagenesis greater and aripiprazole incidence at least twice that for placebo)
Placebo-controlled studies of aripiprazole in schizophrenia are shown in Table 1. There were no adverse events in the short-
The mutagenic potential of aripiprazole was tested in the in vitro or bipolar mania did not include sufcient numbers of
bacterial reverse-mutation assay, the in vitro bacterial DNA term trials of schizophrenia that met these criteria.
subjects aged 65 and over to determine whether they respond
repair assay, the in vitro forward gene mutation assay in mouse differently from younger subjects. There was no effect of age Table 1: Commonly Observed Adverse Events in Short-Term,
lymphoma cells, the in vitro chromosomal aberration assay in on the pharmacokinetics of a single 15-mg dose of aripiprazole. Placebo-Controlled Trials of Patients with Bipolar Mania
Chinese hamster lung (CHL) cells, the in vivo micronucleus Aripiprazole clearance was decreased by 20% in elderly subjects Percentage of Patients Reporting Event
assay in mice, and the unscheduled DNA synthesis assay in rats. (65 years) compared to younger adult subjects (18 to 64 years), Aripiprazole Placebo
Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in but there was no detectable effect of age in the population Adverse Event (n=597) (n=436)
the in vitro chromosomal aberration assay in CHL cells with and pharmacokinetic analysis in schizophrenia patients.
without metabolic activation. The metabolite, 2,3-DCPP, produced Accidental Injury 6 3
Studies of elderly patients with psychosis associated with
increases in numerical aberrations in the in vitro assay in CHL Constipation 13 6
Alzheimers disease have suggested that there may be a different
cells in the absence of metabolic activation. A positive response Akathisia 15 4
tolerability prole in this population compared to younger patients
was obtained in the in vivo micronucleus assay in mice, however,
with schizophrenia (see Boxed WARNING; WARNINGS: Adverse Events Occurring at an Incidence of 2% or More
the response was shown to be due to a mechanism not considered Increased Mortality in Elderly Patients with Dementia-Related Among Aripiprazole-Treated Patients and Greater than
relevant to humans. Psychosis; Cerebrovascular Adverse Events, Including Stroke, Placebo in Short-Term, Placebo-Controlled Trials
Impairment of Fertility in Elderly Patients with Dementia-Related Psychosis; and Table 2 enumerates the pooled incidence, rounded to the nearest
Female rats were treated with oral doses of 2, 6, and 20 mg/kg/ PRECAUTIONS: Use in Patients with Concomitant Illness). percent, of treatment-emergent adverse events that occurred during
day (0.6, 2, and 6 times the maximum recommended human dose The safety and efcacy of ABILIFY (aripiprazole) in the acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks
[MRHD] on a mg/m2 basis) of aripiprazole from 2 weeks prior to treatment of patients with psychosis associated with Alzheimers in bipolar mania), including only those events that occurred in 2%
mating through day 7 of gestation. Estrus cycle irregularities and disease has not been established. If the prescriber elects to treat or more of patients treated with aripiprazole (doses 2 mg/day)
increased corpora lutea were seen at all doses, but no impairment such patients with ABILIFY, vigilance should be exercised. and for which the incidence in patients treated with aripiprazole
of fertility was seen. Increased pre-implantation loss was seen at 6 was greater than the incidence in patients treated with placebo in
ADVERSE REACTIONS
and 20 mg/kg, and decreased fetal weight was seen at 20 mg/kg. the combined dataset.
Aripiprazole has been evaluated for safety in 7951 patients who
Male rats were treated with oral doses of 20, 40, and 60 mg/kg/day participated in multiple-dose, premarketing trials in schizophrenia, Table 2: Treatment-Emergent Adverse Events in Short-
(6, 13, and 19 times the MRHD on a mg/m2 basis) of aripiprazole bipolar mania, and dementia of the Alzheimers type, and who had Term, Placebo-Controlled Trials
from 9 weeks prior to mating through mating. Disturbances in approximately 5235 patient-years of exposure. A total of 2280 Percentage of Patients Reporting Eventa
spermatogenesis were seen at 60 mg/kg, and prostate atrophy was aripiprazole-treated patients were treated for at least 180 days and Body System Aripiprazole Placebo
seen at 40 and 60 mg/kg, but no impairment of fertility was seen. 1558 aripiprazole-treated patients had at least 1 year of exposure. Adverse Event (n=1523) (n=849)
Pregnancy The conditions and duration of treatment with aripiprazole Body as a Whole
Pregnancy Category C included (in overlapping categories) double-blind, comparative
Headache 31 26
In animal studies, aripiprazole demonstrated developmental and noncomparative open-label studies, inpatient and outpatient
studies, xed- and exible-dose studies, and short- and longer- Asthenia 8 7
toxicity, including possible teratogenic effects in rats and rabbits.
term exposure. Accidental Injury 5 4
Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/
Adverse events during exposure were obtained by collecting Peripheral Edema 2 1
day (1, 3, and 10 times the maximum recommended human dose
[MRHD] on a mg/m2 basis) of aripiprazole during the period of volunteered adverse events, as well as results of physical Cardiovascular System
examinations, vital signs, weights, laboratory analyses, and ECG. Hypertension 2 1
organogenesis. Gestation was slightly prolonged at 30 mg/kg.
Treatment caused a slight delay in fetal development, as evidenced Adverse Digestive System
by decreased fetal weight (30 mg/kg), undescended testes (30 experiences were recorded by clinical investigators using Nausea 16 12
mg/kg), and delayed skeletal ossication (10 and 30 mg/kg). terminology of their own choosing. In the tables and tabulations Dyspepsia 15 13
There were no adverse effects on embryofetal or pup survival. that follow, modied COSTART dictionary terminology has been Vomiting 11 6
Delivered offspring had decreased bodyweights (10 and 30 mg/ used initially to classify reported adverse events into a smaller Constipation 11 7
kg), and increased incidences of hepatodiaphragmatic nodules and number of standardized event categories, in order to provide a
Musculoskeletal System
diaphragmatic hernia at 30 mg/kg (the other dose groups were not meaningful estimate of the proportion of individuals experiencing
adverse events. Myalgia 4 3
examined for these ndings). (A low incidence of diaphragmatic
The stated frequencies of adverse events represent the proportion Nervous System
hernia was also seen in the fetuses exposed to 30 mg/kg.)
Postnatally, delayed vaginal opening was seen at 10 and 30 mg/ of individuals who experienced at least once, a treatment-emergent Agitation 25 24
kg and impaired reproductive performance (decreased fertility adverse event of the type listed. An event was considered treatment Anxiety 20 17
rate, corpora lutea, implants, and live fetuses, and increased emergent if it occurred for the rst time or worsened while Insomnia 20 15
post-implantation loss, likely mediated through effects on female receiving therapy following baseline evaluation. There was no Somnolence 12 8
offspring) was seen at 30 mg/kg. Some maternal toxicity was seen attempt to use investigator causality assessments; i.e., all reported Akathisia 12 5
at 30 mg/kg, however, there was no evidence to suggest that these events are included.
Lightheadedness 11 8
developmental effects were secondary to maternal toxicity. The prescriber should be aware that the gures in the tables and Extrapyramidal Syndrome 6 4
Pregnant rabbits were treated with oral doses of 10, 30, and 100 tabulations cannot be used to predict the incidence of side effects in
Tremor 4 3
mg/kg/day (2, 3, and 11 times human exposure at MRHD based the course of usual medical practice where patient characteristics
Increased Salivation 3 1
on AUC and 6, 19, and 65 times the MRHD based on mg/m2) and other factors differ from those that prevailed in the clinical
of aripiprazole during the period of organogenesis. Decreased Respiratory System
trials. Similarly, the cited frequencies cannot be compared with
maternal food consumption and increased abortions were seen gures obtained from other clinical investigations involving Pharyngitis 4 3
at 100 mg/kg. Treatment caused increased fetal mortality (100 different treatment, uses, and investigators. The cited gures, Rhinitis 4 3
mg/kg), decreased fetal weight (30 and 100 mg/kg), increased however, do provide the prescribing physician with some basis for Coughing 3 2
incidence of skeletal abnormality (fused sternebrae at 30 and 100 estimating the relative contribution of drug and nondrug factors to Special Senses
mg/kg) and minor skeletal variations (100 mg/kg). the adverse event incidence in the population studied. Blurred Vision 3 1
In a study in which rats were treated with oral doses of 3, 10, Adverse Findings Observed in Short-Term, Placebo-Controlled a Events reported by at least 2% of patients treated with
and 30 mg/kg/day (1, 3, and 10 times the MRHD on a mg/m2 Trials of Patients with Schizophrenia aripiprazole, except the following events, which had an
basis) of aripiprazole perinatally and postnatally (from day 17 of The following ndings are based on a pool of ve placebo- incidence equal to or less than placebo: abdominal pain, back
gestation through day 21 postpartum), slight maternal toxicity and controlled trials (four 4-week and one 6-week) in which aripiprazole pain, dental pain, diarrhea, dry mouth, anorexia, psychosis,
slightly prolonged gestation were seen at 30 mg/kg. An increase in was administered in doses ranging from 2 to 30 mg/day. hypertonia, upper respiratory tract infection, rash, vaginitisf,
stillbirths, and decreases in pup weight (persisting into adulthood) Adverse Events Associated with Discontinuation of Treatment dysmenorrheaf.
and survival, were seen at this dose. in Short-Term, Placebo-ControlledTrials f Percentage based on gender total.
There are no adequate and well-controlled studies in pregnant Overall, there was no difference in the incidence of discontinuation An examination of population subgroups did not reveal any clear
women. It is not known whether aripiprazole can cause fetal harm due to adverse events between aripiprazole-treated (7%) and evidence of differential adverse event incidence on the basis of
when administered to a pregnant woman or can affect reproductive placebo-treated (9%) patients. The types of adverse events that age, gender, or race.
capacity. Aripiprazole should be used during pregnancy only if the led to discontinuation were similar between the aripiprazole- and Dose-Related Adverse Events
potential benet outweighs the potential risk to the fetus. placebo-treated patients.
Schizophrenia
Labor and Delivery Adverse Findings Observed in Short-Term, Placebo-Controlled
Trials of Patients with Bipolar Mania Dose response relationships for the incidence of treatment-
The effect of aripiprazole on labor and delivery in humans is
emergent adverse events were evaluated from four trials in patients
unknown. The following ndings are based on a pool of 3-week, placebo- with schizophrenia comparing various xed doses (2, 10, 15, 20,
Nursing Mothers controlled, bipolar mania trials in which aripiprazole was and 30 mg/day) of aripiprazole to placebo. This analysis, stratied
Aripiprazole was excreted in milk of rats during lactation. It is administered at doses of 15 or 30 mg/day. by study, indicated that the only adverse event to have a possible
not known whether aripiprazole or its metabolites are excreted in Adverse Events Associated with Discontinuation of Treatment dose response relationship, and then most prominent only with 30
human milk. It is recommended that women receiving aripiprazole in Short-Term, Placebo-Controlled Trials mg, was somnolence (placebo, 7.7%; 15 mg, 8.7%; 20 mg, 7.5%;
should not breast-feed. Overall, in patients with bipolar mania, there was no difference 30 mg, 15.3%).
189
Book_01.indd 189 6/4/2008 2:21:00 PM

SPDI
Extrapyramidal Symptoms Additional Findings Observed in Clinical Trials paresthesia, impotence, extremity tremor, hypesthesia, vertigo,
In the short-term, placebo-controlled trials of schizophrenia, the Adverse Events in Long-Term, Double-Blind, Placebo-Controlled stupor, bradykinesia, apathy, panic attack, decreased libido,
incidence of reported EPS for aripiprazole-treated patients was Trials hypersomnia, dyskinesia, manic depressive reaction, ataxia,
6% vs. 6% for placebo. In the short-term, placebo-controlled visual hallucination, cerebrovascular accident, hypokinesia,
The adverse events reported in a 26-week, double-blind trial
trials in bipolar mania, the incidence of reported EPS-related depersonalization, impaired memory, delirium, dysarthria, tardive
comparing ABILIFY (aripiprazole) and placebo in patients with
events excluding events related to akathisia for aripiprazole- schizophrenia were generally consistent with those reported in the dyskinesia, amnesia, hyperactivity, increased libido, myoclonus,
treated patients was 17% vs. 12% for placebo. In the short- shortterm, placebo-controlled trials, except for a higher incidence restless leg, neuropathy, dysphoria, hyperkinesia, cerebral
term, placebo-controlled trials in bipolar mania, the incidence of tremor [9% (13/153) for ABILIFY vs. ischemia, increased reexes, akinesia, decreased consciousness,
of akathisia-related events for aripiprazole-treated patients was hyperesthesia, slowed thinking; Rare blunted affect, euphoria,
1% (2/153) for placebo]. In this study, the majority of the incoordination, oculogyric crisis, obsessive thought, hypotonia,
15% vs. 4% for placebo. Objectively collected data from those cases of tremor were of mild intensity (9/13 mild and 4/13
trials was collected on the Simpson Angus Rating Scale (for EPS), buccoglossal syndrome, decreased reexes, derealization,
moderate), occurred early in therapy (9/13 49 days), and were intracranial hemorrhage.
the Barnes Akathisia Scale (for akathisia) and the Assessments of limited duration (9/13 10 days). Tremor infrequently led to
of Involuntary Movement Scales (for dyskinesias). In the discontinuation (<1%) of ABILIFY. In addition, in a long-term Respiratory System: Frequent sinusitis, dyspnea, pneumonia,
schizophrenia trials, the objectively collected data did not show a (52-week), active-controlled study, the incidence of tremor for asthma; Infrequent epistaxis, hiccup, laryngitis, aspiration
difference between aripiprazole and placebo, with the exception of ABILIFY was 4% (34/859). pneumonia; Rare pulmonary edema, increased sputum,
the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, -0.05). In pulmonary embolism, hypoxia, respiratory failure, apnea, dry
A similar adverse event prole was observed in a long-term study nasal passages, hemoptysis.
the bipolar mania trials, the Simpson Angus Rating Scale and the in bipolar disorder.
Barnes Akathisia Scale showed a signicant difference between Skin and Appendages: Frequent skin ulcer, sweating, dry skin;
Other Adverse Events Observed During the Premarketing Infrequent pruritus, vesiculobullous rash, acne, eczema, skin
aripiprazole and placebo (aripiprazole, 0.61; placebo, 0.03 and
Evaluation of Aripiprazole discoloration, alopecia, seborrhea, psoriasis; Rare maculopapular
aripiprazole, 0.25; placebo, -0.06). Changes in the Assessments
of Involuntary Movement Scales were similar for the aripiprazole Following is a list of modied COSTART terms that reect rash, exfoliative dermatitis, urticaria.
and placebo groups. treatment-emergent adverse events as dened in the introduction to Special Senses: Frequent conjunctivitis; Infrequent ear pain,
the ADVERSE REACTIONS section reported by patients treated dry eye, eye pain, tinnitus, cataract, otitis media, altered taste,
Similarly, in a long-term (26-week), placebo-controlled trial of with aripiprazole at multiple doses 2 mg/day during any phase
schizophrenia, objectively collected data on the Simpson Angus blepharitis, eye hemorrhage, deafness; Rare diplopia, frequent
of a trial within the database of 7951 patients. All reported events
Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), are included except those already listed in Table 2, or other parts blinking, ptosis, otitis externa, amblyopia, photophobia.
and the Assessments of Involuntary Movement Scales (for of the ADVERSE REACTIONS section, those considered in the Urogenital System: Frequent urinary incontinence; Infrequent
dyskinesias) did not show a difference betweenaripiprazole and WARNINGS or PRECAUTIONS, those event terms which were so urinary frequency, leukorrhea, urinary retention, cystitis,
placebo. general as to be uninformative, events reported with an incidence hematuria, dysuria, amenorrhea, vaginal hemorrhage, abnormal
Laboratory Test Abnormalities of 0.05% and which did not have a substantial probability of ejaculation, kidney failure, vaginal moniliasis, urinary urgency,
A between group comparison for 3- to 6-week, placebo-controlled being acutely life-threatening, events that are otherwise common gynecomastia, kidney calculus, albuminuria, breast pain, urinary
trials revealed no medically important differences between the as background events, and events considered unlikely to be drug burning; Rare nocturia, polyuria, menorrhagia, anorgasmy,
aripiprazole and placebo groups in the proportions of patients related. It is important to emphasize that, although the events glycosuria, cervicitis, uterus hemorrhage, female lactation,
reported occurred during treatment with aripiprazole, they were urolithiasis, priapism.
experiencing potentially clinically signicant changes in routine
serum chemistry, hematology, or urinalysis parameters. Similarly, not necessarily caused by it. Other Events Observed During the Postmarketing Evaluation
there were no aripiprazole/placebo differences in the incidence of Events are further categorized by body system and listed in order of Aripiprazole
discontinuations for changes in serum chemistry, hematology, or of decreasing frequency according to the following denitions: Voluntary reports of adverse events in patients taking aripiprazole
urinalysis. frequent adverse events are those occurring in at least 1/100 that have been received since market introduction and not listed
patients (only those not already listed in the tabulated results from above that may have no causal relationship with the drug include
In a long-term (26-week), placebo-controlled trial there were no placebo-controlled trials appear in this listing); infrequent adverse
medically important differences between the aripiprazole and rare occurrences of allergic reaction (e.g., anaphylactic reaction,
events are those occurring in 1/100 to 1/1000 patients; rare events angioedema, laryngospasm, pruritis, or urticaria).
placebo patients in the mean change from baseline in prolactin,
are those occurring in fewer than 1/1000 patients.
fasting glucose, triglyceride, HDL, LDL, and total cholesterol DRUG ABUSE AND DEPENDENCE
measurements. Body as a Whole: Frequent u syndrome, fever, chest pain,
rigidity (including neck and extremity), neck pain, pelvic pain; Controlled Substance
Weight Gain ABILIFY (aripiprazole) is not a controlled substance.
Infrequent face edema, suicide attempt, malaise, migraine, chills,
In 4- to 6-week trials in schizophrenia, there was a slight difference photosensitivity, tightness (including abdomen, back, extremity, Abuse and Dependence
in mean weight gain between aripiprazole and placebo patients head, jaw, neck, and tongue), jaw pain, bloating, enlarged Aripiprazole has not been systematically studied in humans for
(+0.7 kg vs. -0.05 kg, respectively), and also a difference in the abdomen, chest tightness, throat pain; Rare moniliasis, head its potential for abuse, tolerance, or physical dependence. In
proportion of patients meeting a weight gain criterion of >7% heaviness, throat tightness, Mendelsons syndrome, heat stroke. physical dependence studies in monkeys, withdrawal symptoms
of body weight [aripiprazole (8%) compared to placebo (3%)]. Cardiovascular System: Frequent tachycardia (including were observed upon abrupt cessation of dosing. While the clinical
In 3-week trials in mania, the mean weight gain for aripiprazole ventricular and supraventricular), hypotension, bradycardia; trials did not reveal any tendency for any drug-seeking behavior,
and placebo patients was 0.0 kg vs. -0.2 kg, respectively. The Infrequent palpitation, hemorrhage, heart failure, myocardial these observations were not systematic and it is not possible to
proportion of patients meeting a weight gain criterion of 7% of infarction, cardiac arrest, atrial brillation, AV block, prolonged predict on the basis of this limited experience the extent to which
body weight was aripiprazole (3%) compared to placebo (2%). QT interval, extrasystoles, myocardial ischemia, deep vein a CNS-active drug will be misused, diverted, and/or abused once
Table 3 provides the weight change results from a long-term (26- thrombosis, angina pectoris, pallor, cardiopulmonary arrest, marketed. Consequently, patients should be evaluated carefully
week), placebo-controlled study of aripiprazole, both mean change phlebitis; Rare bundle branch block, atrial utter, vasovagal for a history of drug abuse, and such patients should be observed
from baseline and proportions of patients meeting a weight gain reaction, cardiomegaly, thrombophlebitis, cardiopulmonary closely for signs of ABILIFY misuse or abuse (e.g., development
criterion of 7% of body weight relative to baseline, categorized failure. of tolerance, increases in dose, drug-seeking behavior).
by BMI at baseline: Digestive System: Frequent nausea and vomiting; Infrequent OVERDOSAGE
Table 3: Weight Change Results Categorized by BMI at increased appetite, dysphagia, gastroenteritis, atulence, MedDRA terminology has been used to classify the adverse
Baseline: tooth caries, gastritis, gingivitis, gastrointestinal hemorrhage, events.
hemorrhoids, gastroesophageal reux, periodontal abscess,
Placebo-Controlled Study in Schizophrenia, Safety Sample Human Experience
fecal incontinence, rectal hemorrhage, stomatitis, colitis, tongue
BMI <23 BMI 23-27 BMI >27 edema, cholecystitis, mouth ulcer, oral moniliasis, eructation, A total of 76 cases of deliberate or accidental overdosage with
Placebo Aripip- Placebo Aripip- Placebo Aripip- fecal impaction, cholelithiasis; Rare esophagitis, hematemesis, aripiprazole have been reported worldwide. These include
razole razole razole intestinal obstruction, gum hemorrhage, hepatitis, peptic ulcer, overdoses with aripiprazole alone and in combination with other
glossitis, melena, duodenal ulcer, cheilitis, hepatomegaly, substances.
Mean change
pancreatitis. No fatality was reported from these cases. Of the 44 cases with
from
Endocrine System: Infrequent hypothyroidism; Rare goiter, known outcome, 33 recovered without sequelae and one recovered
baseline (kg) -0.5 -0.5 -0.6 -1.3 -1.5 -2.1 with sequelae (mydriasis and feeling abnormal). The largest
hyperthyroidism.
% with >7% known acute ingestion with a known outcome involved 1080 mg
Hemic/Lymphatic System: Frequent ecchymosis, anemia;
increase BW 3.7% 6.8% 4.2% 5.1% 4.1% 5.7% of aripiprazole (36 times the maximum recommended daily dose)
Infrequent hypochromic anemia, leukocytosis, leukopenia
in a patient who fully recovered. Included in the 76 cases are 10
(including neutropenia), lymphadenopathy, eosinophilia,
Table 4 provides the weight change results from a long-term (52- cases of deliberate or accidental overdosage in children (age 12
macrocytic anemia;
week) study of aripiprazole, both mean change from baseline and and younger) involving aripiprazole ingestions up to 195 mg with
proportions of patients meeting a weight gain criterion of 7% of Rare thrombocythemia, thrombocytopenia, petechiae. no fatalities.
body weight relative to baseline, categorized by BMI at baseline: Metabolic and Nutritional Disorders: Frequent weight Common adverse events (reported in at least 5% of all overdose
Table 4: Weight Change Results Categorized by BMI at loss, creatine phosphokinase increased, dehydration; Infrequent cases) reported with aripiprazole overdosage (alone or in
Baseline: edema, hyperglycemia, hypercholesteremia, hypokalemia, combination with other substances) include vomiting, somnolence,
diabetes mellitus, hypoglycemia, hyperlipemia, SGPT increased, and tremor. Other clinically important signs and symptoms
Active-Controlled Study in Schizophrenia, Safety Sample thirst, BUN increased, hyponatremia, SGOT increased, creatinine observed in one or more patients with aripiprazole overdoses (alone
BMI <23 BMI 23-27 BMI >27 increased, cyanosis, alkaline phosphatase increased, bilirubinemia, or with other substances) include acidosis, aggression, aspartate
Mean change from iron deciency anemia, hyperkalemia, hyperuricemia, obesity; aminotransferase increased, atrial brillation, bradycardia, coma,
Rare lactic dehydrogenase increased, hypernatremia, gout, confusional state, convulsion, blood creatine phosphokinase
baseline (kg) 2.6 1 .4 -1.2
hypoglycemic reaction. increased, depressed level of consciousness, hypertension,
% with >7% increase BW 30% 19% 8%
Musculoskeletal System: Frequent muscle cramp; Infrequent hypokalemia, hypotension, lethargy, loss of consciousness,
ECG Changes arthralgia, myasthenia, arthrosis, bone pain, arthritis, muscle QRS complex prolonged, QT prolonged, pneumonia aspiration,
weakness, spasm, bursitis, myopathy; Rare rheumatoid arthritis, respiratory arrest, status epilepticus, and tachycardia.
Between group comparisons for a pooled analysis of placebo-
controlled trials in patients with schizophrenia or bipolar mania, rhabdomyolysis, tendonitis, tenosynovitis. Management of Overdosage
revealed no signicant differences between aripiprazole and Nervous System: Frequent depression, nervousness, No specic information is available on the treatment of overdose
placebo in the proportion of patients experiencing potentially schizophrenic reaction, hallucination, hostility, confusion, with aripiprazole. An electrocardiogram should be obtained in
important changes in ECG parameters. Aripiprazole was associated paranoid reaction, suicidal thought, abnormal gait, manic reaction, case of overdosage and, if QTc interval prolongation is present,
with a median increase in heart rate of 5 beats per minute compared delusions, abnormal dream; Infrequent emotional lability, twitch, cardiac monitoring should be instituted. Otherwise, management
to a 1 beat per minute increase among placebo patients. cogwheel rigidity, impaired concentration, dystonia, vasodilation, of overdose should concentrate on supportive therapy, maintaining
190
Book_01.indd 190 6/4/2008 2:21:00 PM

SPDI
an adequate airway, oxygenation and ventilation, and management for maintenance of the initial response and for prevention of DESCRIPTION
of symptoms. Close medical supervision and monitoring should new manic episodes, there are no systematically obtained data to CAPOZIDE (captopril and hydrochlorothiazide tablets, USP)
continue until the patient recovers. support the use of aripiprazole in such longer-term treatment (i.e., for oral administration combines two antihypertensive agents:
Charcoal: In the event of an overdose of ABILIFY, an early beyond 6 weeks). CAPOZIDE (captopril) and hydrochlorothiazide. Captopril,
charcoal administration may be useful in partially preventing the Oral Solution the rst of a new class of antihypertensive agents, is a specic
absorption of aripiprazole. Administration of 50 g of activated The oral solution can be given on a mg-per-mg basis in place of competitive inhibitor of angiotensin I-converting enzyme (ACE),
charcoal, one hour after a single 15-mg oral dose of aripiprazole, the 5-, 10-, 15-, or 20-mg tablet strengths. Solution doses can be the enzyme responsible for the conversion of angiotensin I to an-
decreased the mean AUC and Cmax of aripiprazole by 50%. giotensin II. Hydrochlorothiazide is a benzothiadiazide (thiazide)
substituted for the tablet doses on a mg-per-mg basis up to 25 mg
Hemodialysis: Although there is no information on the effect diuretic-antihypertensive. CAPOZIDE tablets are available in
of the tablet. Patients receiving 30-mg tablets should receive four combinations of captopril with hydrochlorothiazide: 25 mg
of hemodialysis in treating an overdose with aripiprazole,
25 mg of the solution (see CLINICAL PHARMACOLOGY: with 15 mg(N.R), 25 mg with 25 mg(N.R), 50 mg with 15 mg
hemodialysis is unlikely to be useful in overdose management
Pharmacokinetics). (N.R), and 50 mg with 25 mg. Inactive ingredients: microcrystal-
since aripiprazole is highly bound to plasma proteins.
DOSAGE AND ADMINISTRATION ANIMAL TOXICOLOGY line cellulose, colorant (FD& C Yellow No. 6), lactose, magne-
Aripiprazole produced retinal degeneration in albino rats in a 26- sium stearate, pregelatinized starch, and stearic acid. Captopril is
Schizophrenia
designated chemically as 1-[(2S)-3-mercapto-2-methylpropionyl]-
Usual Dose week chronic toxicity study at a dose of 60 mg/kg and in a 2-year
L-proline; hydrochlorothiazide is 6-Chloro-3,4-dihydro-2H-1,2,4-
carcinogenicity study at doses of 40 and 60 mg/kg. The 40- and
The recommended starting and target dose for ABILIFY benzothiadiazine-7-sulfonamide 1,1-dioxide.
(aripiprazole) is 10 or 15 mg/day administered on a once-a- 60- mg/kg doses are 13 and 19 times the maximum recommended
human dose (MRHD) based on mg/m2 and 7 to 14 times human Captopril is a white to off-white crystalline powder that may have
day schedule without regard to meals. ABILIFY has been a slight sulfurous odor; it is soluble in water (approx. 160 mg/mL),
systematically evaluated and shown to be effective in a dose range exposure at MRHD based on AUC. Evaluation of the retinas of
albino mice and of monkeys did not reveal evidence of retinal methanol, and ethanol and sparingly soluble in chloroform and
of 10 to 30 mg/day, when administered as the tablet formulation, ethyl acetate. Hydrochlorothiazide is a white crystalline powder
however, doses higher than 10 or 15 mg/day, the lowest doses in degeneration. Additional studies to further evaluate the mechanism
have not been performed. The relevance of this nding to human slightly soluble in water but freely soluble in sodium hydroxide
these trials, were not more effective than 10 or 15 mg/day. Dosage solution.
increases should not be made before 2 weeks, the time needed to risk is unknown.
achieve steady state. HOW SUPPLIED CLINICAL PHARMACOLOGY
Dosage in Special Populations ABILIFY (aripiprazole) Tablets are available in the following Captopril-Mechanism of Action
Dosage adjustments are not routinely indicated on the basis of strengths and packages. The mechanism of action of captopril has not yet been fully
age, gender, race, or renal or hepatic impairment status (see elucidated. Its benecial effects in hypertension and heart
The 2-mg ABILIFY tablets(N.R) are green, modied rectangular
CLINICAL PHARMACOLOGY: Special Populations). failure appear to result primarily from suppression of the renin-
tablets, debossed on one side
Dosage adjustment for patients taking aripiprazole concomitantly angiotensin-aldosterone system. However, there is no consistent
with A-006 and 2. correlation between renin levels and response to the drug. Renin, an
with potential CYP3A4 inhibitors: When concomitant
administration of ketoconazole with aripiprazole occurs, Bottles of 30 NDC 59148-006-13 enzyme synthesized by the kidneys, is released into the circulation
aripiprazole dose should be reduced to one-half of the usual dose. Blister of 100 NDC 59148-006-35 where it acts on a plasma globulin substrate to produce angiotensin
When the CYP3A4 inhibitor is withdrawn from the combination The 5-mg ABILIFY tablets(N.R) are blue, modied rectangular I, a relatively inactive decapeptide. Angiotensin I is then converted
therapy, aripiprazole dose should then be increased. tablets, debossed on one side by angiotensin converting enzyme (ACE) to angiotensin II, a
Dosage adjustment for patients taking aripiprazole concomitantly potent endogenous vasoconstrictor substance. Angiotensin II also
with A-007 and 5. stimulates aldosterone secretion from the adrenal cortex, thereby
with potential CYP2D6 inhibitors: When concomitant
administration of potential CYP2D6 inhibitors such as quinidine, Bottles of 30 NDC 59148-007-13 contributing to sodium and uid retention.
uoxetine, or paroxetine with aripiprazole occurs, aripiprazole Blister of 100 NDC 59148-007-35 Captopril prevents the conversion of angiotensin I to angiotensin
dose should be reduced at least to one-half of its normal dose. The 10-mg ABILIFY tablets are pink, modied rectangular II by inhibition of A.E. a peptidyldipeptide carboxy hydrolase.
When the CYP2D6 inhibitor is withdrawn from the combination tablets, debossed on one side This inhibition has been demonstrated in both healthy human
therapy, aripiprazole dose should then be increased. with A-008 and 10. subjects and in animals by showing that the elevation of blood
Dosage adjustment for patients taking potential CYP3A4 inducers: pressure caused by exogenously administered angiotensin I was
Bottles of 30 NDC 59148-008-13 attenuated or abolished by captopril. In animal studies, captopril
When a potential CYP3A4 inducer such as carbamazepine is added
to aripiprazole therapy, the aripiprazole dose should be doubled Blister of 100 (N.R) NDC 59148-008-35 did not alter the pressor responses to a number of other agents,
(to 20 or 30 mg). Additional dose increases should be based on The 15-mg ABILIFY tablets are yellow, round tablets, debossed including angiotensin II and norepinephrine, indicating specicity
clinical evaluation. When carbamazepine is withdrawn from the on one side with A-009 of action.
combination therapy, the aripiprazole dose should be reduced to and 15. ACE is identical to bradykininase, and captopril may also interfere
10 to 15 mg. with the degradation of the vasodepressor peptide, bradykinin.
Bottles of 30 NDC 59148-009-13
Maintenance Therapy Increased concentrations of bradykinin or prostaglandin E2 may
Blister of 100 (N.R) NDC 59148-009-35
While there is no body of evidence available to answer the also have a role in the therapeutic effect of captopril.
The 20-mg (N.R)ABILIFY tablets(N.R) are white, round tablets, Inhibition of ACE results in decreased plasma angiotensin II and
question of how long a patient treated with aripiprazole should
debossed on one side with A-010 increased plasma renin activity (PRA), the latter resulting from
remain on it, systematic evaluation of patients with schizophrenia
who had been symptomatically stable on other antipsychotic and 20. loss of negative feedback on renin release caused by reduction in
medications for periods of 3 months or longer, were discontinued Bottles of 30 NDC 59148-010-13 angiotensin II. The reduction of angiotensin II leads to decreased
from those medications, and were then administered ABILIFY Blister of 100 NDC 59148-010-35 aldosterone secretion, and as a result, small increases in serum
15 mg/day and observed for relapse during a period of up to 26 potassium may occur along with sodium and uid loss.
The 30-mg(N.R) ABILIFY tablets are pink, round tablets,
weeks, demonstrated a benet of such maintenance treatment (see The antihypertensive effects persist for a longer period of time than
CLINICAL PHARMACOLOGY: Clinical Studies). Patients debossed on one side with A-011
does demonstrable inhibition of circulating A.E. It is not known
should be periodically reassessed to determine the need for and 30. whether the ACE present in vascular endothelium is inhibited
maintenance treatment. Bottles of 30 NDC 59148-011-13 longer than the ACE in circulating blood.
Switching from Other Antipsychotics Blister of 100 NDC 59148-011-35 Pharmacokinetics
There are no systematically collected data to specically address ABILIFY (aripiprazole) Oral Solution (1 mg/mL)(N.R) is After oral administration of therapeutic doses of captopril, rapid
switching patients with schizophrenia from other antipsychotics supplied in child-resistant bottles along with a calibrated absorption occurs with peak blood levels at about one hour. The
to ABILIFY or concerning concomitant administration with other
oral dosing cup. ABILIFY oral solution is available as follows: presence of food in the gastrointestinal tract reduces absorption
antipsychotics. While immediate discontinuation of the previous by about 30 to 40 percent; captopril therefore should be given one
antipsychotic treatment may be acceptable for some patients 150-mL bottle NDC 59148-013-15
hour before meals. Based on carbon-14 labeling, average minimal
with schizophrenia, more gradual discontinuation may be most STORAGE
absorption is approximately 75 percent. In a 24-hour period, over
appropriate for others. In all cases, the period of overlapping Tablets 95 percent of the absorbed dose is eliminated in the urine; 40 to 50
antipsychotic administration should be minimized. percent is unchanged drug; most of the remainder is the disulde
Store at 25 C (77 F); excursions permitted between 15 C to 30
Bipolar Disorder C (59 F to 86 F) [see USP dimer of captopril and captopril-cysteine disulde.
Usual Dose Controlled Room Temperature]. Approximately 25 to 30 percent of the circulating drug is bound
In clinical trials, the starting dose was 30 mg given once a day. A Oral Solution to plasma proteins. The apparent elimination half-life for total
dose of 30 mg/day was found to be effective when administered radioactivity in blood is probably less than three hours. An
Store at 25 C (77 F); excursions permitted between 15 C to
as the tablet formulation. Approximately 15% of patients had their accurate determination of half-life of unchanged captopril is not, at
dose decreased to 15 mg based on assessment of tolerability. The 30 C (59 F to 86 F) [see USP Controlled Room Temperature].
present, possible, but it is probably less than two hours. In patients
safety of doses above 30 mg/day has not been evaluated in clinical Opened bottles of ABILIFY oral solution can be used for up to
with renal impairment, however, retention of captopril occurs (see
trials. 6 months after opening, but not beyond the expiration date on the DOSAGE AND ADMINISTRATION).
bottle. The bottle and its contents should be discarded after the
Dosage in Special Populations Pharmacodynamics
expiration date.
See Dosage in Special Populations under DOSAGE AND Administration of captopril results in a reduction of peripheral
ADMINISTRATION: Schizophrenia. arterial resistance in hypertensive patients with either no change,
Maintenance Therapy
CAPOZIDE or an increase, in cardiac output. There is an increase in renal
While there is no body of evidence available to answer the question blood ow following administration of captopril and glomerular
of how long a patient treated with aripiprazole should remain on (Captopril and Hydrochlorothiazide tablets, ltration rate is usually unchanged. In patients with heart failure,
it, patients with Bipolar I Disorder who had been symptomatically signicantly decreased peripheral (systemic vascular) resistance
stable on ABILIFY Tablets (15 mg/day or 30 mg/day with a
USP) and blood pressure (afterload), reduced pulmonary capillary
starting dose of 30 mg/day) for at least 6 consecutive weeks and wedge pressure (preload) and pulmonary vascular resistance,
CAPOZIDE 25/15 (N.R) increased cardiac output, and increased exercise tolerance time
then randomized to ABILIFY Tablets (15 mg/day or 30 mg/day) or
placebo and monitored for relapse, demonstrated a benet of such CAPOZIDE 25/25 (N.R) (ETT) have been demonstrated.
maintenance treatment (see CLINICAL PHARMACOLOGY: CAPOZIDE 50/15 (N.R) Reductions of blood pressure are usually maximal 60 to 90
Clinical Studies). While it is generally agreed that pharmacological CAPOZIDE 50/25 minutes after oral administration of an individual dose of
treatment beyond an acute response in mania is desirable, both (Captopril and Hydrochlorothiazide tablets, USP) captopril. The duration of effect is dose related and is extended in
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Book_01.indd 191 6/4/2008 2:21:01 PM

SPDI
the presence of a thiazide-type diuretic. The full effect of a given distinct orange mottling; they are biconvex rounded squares with Nervous/Psychiatric: ataxia, confusion, depression, nervousness,
dose may not be attained for 6-8 weeks (see DOSAGE AND quadrisect bars. somnolence.
ADMINISTRATION). 25 mg captopril combined with 25 mg hydrochlorothiazide Respiratory: bronchospasm, eosinophilic pneumonitis, rhinitis.
The blood pressure lowering effects of captopril and thiazide-type in bottles of 100(N.R) (NDC 0003-0349-50). Tablets are peach- Special Senses: blurred vision.
diuretics are additive. In contrast, captopril and beta-blockers have colored and may show slight mottling; they are biconvex rounded
Urogenital: impotence. As with other ACE inhibitors, a syndrome
a less than additive effect. Blood pressure is lowered to about the squares with quadrisect bars.
has been reported which may include: fever, myalgia, arthralgia,
same extent in both standing and supine positions. Orthostatic 50 mg captopril combined with 15 mg hydrochlorothiazide in interstitial nephritis, vasculitis, rash or other dermatologic
effects and tachycardia are infrequent but may occur in volume- bottles of 100 (N.R)(NDC 0003-0384-50). Tablets are white with manifestations, eosinophilia and an elevated E.R.
depleted patients. Abrupt withdrawal of captopril has not been distinct orange mottling; they are biconvex ovals with a bisect
associated with a rapid increase in blood pressure. Studies in rats Fetal/Neonatal Morbidity and Mortality See WARNINGS:
bar.
and cats indicate that captopril does not cross the blood-brain CAPTOPRIL, Fetal/Neonatal Morbidity and Mortality.
50 mg captopril combined with 25 mg hydrochlorothiazide in
barrier to any signicant extent. Hydrochlorothiazide
bottles of 100 (N.R)(NDC 0003-0390-50)& 28 Tablets are peach-
Hydrochlorothiazide colored and may show slight mottling; they are biconvex ovals Gastrointestinal System: anorexia, gastric irritation, nausea,
Thiazides affect the renal tubular mechanism of electrolyte with a bisect bar. vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic
reabsorption. At maximal therapeutic dosage all thiazides are cholestatic jaundice), pancreatitis, and sialadenitis.
approximately equal in their diuretic potency. Thiazides increase STORAGE Central Nervous System: dizziness, vertigo, paresthesias,
excretion of sodium and chloride in approximately equivalent Keep bottles tightly closed (protect from moisture); do not store headache, and xanthopsia.
amounts. Natriuresis causes a secondary loss of potassium and above 86 F. Hematologic: leukopenia, agranulocytosis, thrombocytopenia,
bicarbonate. The mechanism of the antihypertensive effect of aplastic anemia, and hemolytic anemia.
SIDE EFFECTS
thiazides is unknown. Thiazides do not affect normal blood
Captopril Cardiovascular: orthostatic hypotension.
pressure. The mean plasma half-life of hydrochlorothiazide in
fasted individuals has been reported to be approximately 2.5 Reported incidences are based on clinical trials involving Hypersensitivity: purpura, photosensitivity, rash, urticaria,
hours. Onset of diuresis occurs in two hours and the peak effect at approximately 7000 patients. necrotizing angiitis (vasculitis; cutaneous vasculitis), fever,
about four hours. Its action persists for approximately six to twelve respiratory distress including pneumonitis, and anaphylactic
Renal: About one of 100 patients developed proteinuria (see
hours. Hydrochlorothiazide is eliminated rapidly by the kidney. reactions.
WARNINGS).
Other: hyperglycemia, glycosuria, hyperuricemia, muscle spasm,
INDICATIONS Each of the following has been reported in approximately 1 to 2 of
weakness, restlessness, and transient blurred vision. Whenever
CAPOZIDE (captopril and hydrochlorothiazide tablets, USP) is 1000 patients and are of uncertain relationship to drug use: renal
adverse reactions are moderate or severe, thiazide dosage should
indicated for the treatment of hypertension. The blood pressure insufciency, renal failure, nephrotic syndrome, polyuria, oliguria,
be reduced or therapy withdrawn.
lowering effects of captopril and thiazides are approximately and urinary frequency.
Altered Laboratory Findings
additive. Hematologic: Neutropenia/agranulocytosis has occurred
(see WARNINGS). Cases of anemia, thrombocytopenia, and Serum Electrolytes: Hyperkalemia: small increases in serum
This xed combination drug may be used as initial therapy
pancytopenia have been reported. potassium, especially in patients with renal impairment (see
or substituted for previously titrated doses of the individual
Dermatologic: Rash, often with pruritus, and sometimes with PRECAUTIONS: Captopril).
components. When captopril and hydrochlorothiazide are given
together it may not be necessary to administer captopril in divided fever, arthralgia, and eosinophilia, occurred in about 4 to 7 Hyponatremia: particularly in patients receiving a low sodium
doses to attain blood pressure control at trough (before the next (depending on renal status and dose) of 100 patients, usually diet or concomitant diuretics.
dose). Also, with such a combination, a daily dose of 15 mg of during the rst four weeks of therapy. It is usually maculopapular, BUN/Serum Creatinine: Transient elevations of BUN or serum
hydrochlorothiazide may be adequate. and rarely urticarial. The rash is usually mild and disappears creatinine especially in volume or salt depleted patients or those
Treatment may, therefore, be initiated with CAPOZIDE 25 mg/ within a few days of dosage reduction, short-term treatment with with renovascular hypertension may occur. Rapid reduction of
15 mg once daily. Subsequent titration should be with additional an antihistaminic agent, and/or discontinuing therapy; remission longstanding or markedly elevated blood pressure can result
doses of the components (captopril, hydrochlorothiazide) as single may occur even if captopril is continued. Pruritus, without rash, in decreases in the glomerular ltration rate and in turn, lead to
agents or as CAPOZIDE 50 mg/15 mg, 25 mg/25 mg, or 50 mg/ occurs in about 2 of 100 patients. Between 7 and 10 percent of increases in BUN or serum creatinine.
25 mg (see DOSAGE AND ADMINISTRATION). patients with skin rash have shown eosinophilia and/or positive Hematologic: A positive ANA has been reported.
ANA titers. A reversible associated pemphigoid-like lesion, and
In using CAPOZIDE, consideration should be given to the risk Liver Function Tests: Elevations of liver transaminases, alkaline
photosensitivity, have also been reported. Flushing or pallor has
of neutropenia/agranulocytosis (see WARNINGS). phosphatase, and serum bilirubin have occurred.
been reported in 2 to 5 of 1000 patients.
CAPOZIDE may be used for patients with normal renal DRUG INTERACTIONS
Cardiovascular: Hypotension may occur; see WARNINGS and
function, in whom the risk is relatively low. In patients with
Captopril
impaired renal function, particularly those with collagen vascular DRUG INTERACTIONS for discussion of hypotension with
disease, CAPOZIDE should be reserved for hypertensives who captopril therapy. Tachycardia, chest pain, and palpitations have Hypotension Patients on Diuretic Therapy: Patients on
have either developed unacceptable side effects on other drugs, or each been observed in approximately 1 of 100 patients. Angina diuretics and especially those in whom diuretic therapy was
have failed to respond satisfactorily to other drug combinations. pectoris, myocardial infarction, Raynauds syndrome, and recently instituted, as well as those on severe dietary salt restriction
ACE inhibitors (for which adequate data are available) cause a congestive heart failure have each occurred in 2 to 3 of 1000 or dialysis, may occasionally experience a precipitous reduction
higher rate of angioedema in black than in non-black patients (see patients. of blood pressure usually within the rst hour after receiving the
WARNINGS: Angioedema). initial dose of captopril.
Dysgeusia: Approximately 2 to 4 (depending on renal status
and dose) of 100 patients developed a diminution or loss of taste The possibility of hypotensive effects with captopril can be
perception. Taste impairment is reversible and usually self-limited minimized by either discontinuing the diuretic or increasing the
DOSAGE MUST BE INDIVIDUALIZED ACCORDING TO salt intake approximately one week prior to initiation of treatment
PATIENTS RESPONSE. CAPOZIDE may be substituted for the (2 to 3 months) even with continued drug administration. Weight
loss may be associated with the loss of taste. with captopril or initiating therapy with small doses (6.25 or
previously titrated individual components. 12.5 mg). Alternatively, provide medical supervision for at least
Alternatively, therapy may be instituted with a single tablet Angioedema: Angioedema involving the extremities, face, lips,
one hour after the initial dose. If hypotension occurs, the patient
of CAPOZIDE 25 mg/15 mg taken once daily. For patients mucous membranes, tongue, glottis or larynx has been reported
should be placed in a supine position and if necessary, receive an
insufciently responsive to the initial dose, additional captopril or in approximately one in 1000 patients. Angioedema involving
intravenous infusion of normal saline. This transient hypotensive
hydrochlorothiazide may be added as individual components or the upper airways has caused fatal airway obstruction. (See
response is not a contraindication to further doses which can be
by using CAPOZIDE 50 mg/15 mg, 25 mg/25 mg or 50 mg/25 WARNINGS: CAPTOPRIL: Angioedema and PATIENT
given without difculty once the blood pressure has increased
mg, or divided doses may be used. Because the full effect of a INFORMATION)
after volume expansion.
given dose may not be attained for 6-8 weeks, dosage adjustments Cough: Cough has been reported in 0.5-2% of patients treated with
Agents Having Vasodilator Activity: Data on the effect of
should generally be made at 6 week intervals, unless the clinical captopril in clinical trials (see PRECAUTIONS: GENERAL,
concomitant use of other vasodilators in patients receiving
situation demands more rapid adjustment. In general, daily doses Captopril, Cough).
captopril for heart failure are not available; therefore, nitroglycerin
of captopril should not exceed 150 mg and of hydrochlorothiazide The following have been reported in about 0.5 to 2 percent of or other nitrates (as used for management of angina) or other drugs
should not exceed 50 mg. CAPOZIDE should be taken one hour patients but did not appear at increased frequency compared to having vasodilator activity should, if possible, be discontinued
before meals. placebo or other treatments used in controlled trials: gastric before starting captopril. If resumed during captopril therapy, such
Dosage Adjustment in Renal Impairment Because captopril irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, agents should be administered cautiously, and perhaps at lower
and hydrochlorothiazide are excreted primarily by the kidneys, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, dosage.
excretion rates are reduced in patients with impaired renal function. malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia,
Agents Causing Renin Release: Captoprils effect will be
These patients will take longer to reach steady-state captopril levels paresthesias. Other clinical adverse effects reported since the drug
augmented by antihypertensive agents that cause renin release.
and will reach higher steady-state levels for a given daily dose was marketed are listed below by body system. In this setting, an
For example, diuretics (e.g., thiazides) may actIvate the renin-
than patients with normal renal function. Therefore, these patients incidence or causal relationship cannot be accurately determined.
angiotensin-aldosterone system.
may respond to smaller or less frequent doses of CAPOZIDE. Body as a whole: anaphylactoid reactions (see WARNINGS:
After the desired therapeutic effect has been achieved, the dose Agents Affecting Sympathetic Activity: The sympathetic nervous
CAPTOPRIL: Anaphylactoid and possibly related REACTIONS
intervals should be increased or the total daily dose reduced until system may be especially important in supporting blood pressure
and PRECAUTIONS: Hemodialysis).
the minimal effective dose is achieved. When concomitant diuretic in patients receiving captopril alone or with diuretics. Therefore,
General: asthenia, gynecomastia. agents affecting sympathetic activity (e.g., ganglionic blocking
therapy is required in patients with severe renal impairment, a
loop diuretic (e.g., furosemide), rather than a thiazide diuretic is Cardiovascular: cardiac arrest, cerebrovascular accident/insuf- agents or adrenergic neuron blocking agents) should be used
preferred for use with captopril; therefore, for patients with severe ciency, rhythm disturbances, orthostatic hypotension, syncope. with caution. Beta-adrenergic blocking drugs add some further
renal dysfunction the captopril-hydrochlorothiazide combination Dermatologic: bullous pemphigus, erythema multiforme antihypertensive effect to captopril, but the overall response is less
tablet is not usually recommended. (See WARNINGS: (including Stevens-Johnson syndrome), exfoliative dermatitis. than additive.
CAPTOPRIL: Anaphylactoid reactions during membrane Gastrointestinal: pancreatitis, glossitis, dyspepsia. Agents Increasing Serum Potassium: Since captopril decreases
exposure and PRECAUTIONS: Hemodialysis.) Hematologic: anemia, including aplastic and hemolytic. aldosterone production, elevation of serum potassium may occur.
Potassium-sparing diuretics such as spironolactone, triamterene,
HOW SUPPLIED Hepatobiliary: jaundice, hepatitis, including rare cases of or amiloride, or potassium supplements, should be given only for
CAPOZIDE (captopril and hydrochlorothiazide tablets, USP) necrosis, cholestasis. documented hypokalemia, and then with caution, since they may
25 mg captopril combined with 15 mg hydrochlorothiazide in Metabolic: symptomatic hyponatremia. lead to a signicant increase of serum potassium. Salt substitutes
bottles of 100(N.R) (NDC 0003-0338-50). Tablets are white with Musculoskeletal: myalgia, myasthenia. containing potassium should also be used with caution.
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Inhibitors Of Endogenous Prostaglandin Synthesis: It has been WARNINGS Proteinuria
reported that indomethacin may reduce the antihypertensive effect Captopril Total urinary proteins greater than 1 g per day were seen in about
of captopril, especially in cases of low renin hypertension. Other 0.7 percent of patients receiving captopril. About 90 percent of
Anaphylactoid and Possibly Related REACTIONS
nonsteroidal anti-inammatory agents (e.g., aspirin) may also affected patients had evidence of prior renal disease or received
have this effect. Presumably because angiotensin-converting enzyme inhibitors
relatively high doses of captopril (in excess of 150 mg/day),
affect the metabolism of eicosanoids and polypeptides, including
Lithium: Increased serum lithium levels and symptoms of lithium or both. The nephrotic syndrome occurred in about one-fth
endogenous bradykinin, patients receiving ACE inhibitors
toxicity have been reported in patients receiving concomitant of proteinuric patients. In most cases, proteinuria subsided or
(including CAPOZIDE) may be subject to a variety of adverse
lithium and ACE inhibitor therapy. These drugs should be cleared within six months whether or not captopril was continued.
reactions, some of them serious.
coadministered with caution and frequent monitoring of serum Parameters of renal function, such as BUN and creatinine, were
lithium levels is recommended. If a diuretic is also used, it may Angioedema: Angioedema involving the extremities, face, lips, seldom altered in the patients with proteinuria.
increase the risk of lithium toxicity (see mucous membranes, tongue, glottis or larynx has been seen
Hypotension
in patients treated with ACE inhibitors, including captopril.
DRUG INTERACTIONS If angioedema involves the tongue, glottis or larynx, airway Excessive hypotension was rarely seen in hypertensive patients but
, Hydrochlorothiazide, Lithium below). obstruction may occur and be fatal. Emergency therapy, including is a possible consequence of captopril use in salt/volume depleted
but not necessarily limited to, subcutaneous administration of a persons (such as those treated vigorously with diuretics), patients
Hydrochlorothiazide with heart failure or those patients undergoing renal dialysis. (See
1: 1000 solution of epinephrine should be promptly instituted.
When administered concurrently the following drugs may interact DRUG INTERACTIONS)
Swelling conned to the face, mucous membranes of the mouth,
with thiazide diuretics: Fetal/Neonatal Morbidity and Mortality
lips and extremities has usually resolved with discontinuation of
Alcohol, barbiturates, or narcotics potentiation of orthostatic treatment; some cases required medical therapy. (See PATIENT ACE inhibitors can cause fetal and neonatal morbidity and death
hypotension may occur. INFORMATION and ADVERSE REACTIONS: Captopril) when administered to pregnant women. Several dozen cases have
Amphotericin B, corticosteroids, or corticotropin (ACTH) Anaphylactoid reactions during desensitization: Two patients been reported in the world literature. When pregnancy is detected,
may intensify electrolyte imbalance, particularly hypokalemia. undergoing desensitizing treatment with hymenoptera venom while ACE inhibitors should be discontinued as soon as possible.
Monitor potassium levels; use potassium replacements if receiving ACE inhibitors sustained life-threatening anaphylactoid The use of ACE inhibitors during the second and third trimesters
necessary. reactions. In the same patients, these reactions were avoided when of pregnancy has been associated with fetal and neonatal injury,
Anticoagulants (oral) dosage adjustments of anticoagulant ACE inhibitors were temporarily withheld, but they reappeared including hypotension, neonatal skull hypoplasia, anuria, reversible
medication may be necessary since hydrochlorothiazide may upon inadvertent rechallenge. or irreversible renal failure, and death. Oligohydramnios has also
decrease their effects. Anaphylactoid reactions during membrane exposure: been reported, presumably resulting from decreased fetal renal
Antigout medications dosage adjustments of antigout Anaphylactoid reactions have been reported in patients dialyzed function; oligohydramnios in this setting has been associated with
medication may be necessary since hydrochlorothiazide may raise with high-ux membranes and treated concomitantly with an fetal limb contractures, craniofacial deformation, and hypoplastic
the level of blood uric acid. ACE inhibitor. Anaphylactoid reactions have also been reported lung development. Prematurity, intrauterine growth retardation,
Other antihypertensive medications (e.g., ganglionic or in patients undergoing low-density lipoprotein apheresis with and patent ductus arteriosus have also been reported, although it is
peripheral adrenergic blocking agents) dosage adjustments dextran sulfate absorption. not clear whether these occurrences were due to the ACE-inhibitor
may be necessary since hydrochlorothiazide may potentiate their exposure.
Neutropenia/Agranulocytosis
effects. These adverse effects do not appear to have resulted from
Neutropenia (< 1000/mm3) with myeloid hypoplasia has resulted
Antidiabetic drugs (oral agents and insulin) since thiazides intrauterine ACE-inhibitor exposure that has been limited to the
from use of captopril. About half of the neutropenic patients
may elevate blood glucose levels, dosage adjustments of rst trimester. Mothers whose embryos and fetuses are exposed
developed systemic or oral cavity infections or other features
antidiabetic agents may be necessary. to ACE inhibitors only during the rst trimester should be so
of the syndrome of agranulocytosis. The risk of neutropenia is
informed. Nonetheless, when patients become pregnant, physicians
Calcium salts increased serum calcium levels due to decreased dependent on the clinical status of the patient:
should make every effort to discontinue the use of captopril as
excretion may occur. If calcium must be prescribed monitor serum In clinical trials in patients with hypertension who have normal soon as possible.
calcium levels and adjust calcium dosage accordingly. renal function (serum creatinine less than 1.6 mg/dL and no
Rarely (probably less often than once in every thousand
Cardiac glycosides enhanced possibility of digitalis toxicity collagen vascular disease), neutropenia has been seen in one
pregnancies), no alternative to ACE inhibitors will be found. In
associated with hypokalemia. Monitor potassium levels (see patient out of over 8,600 exposed.
these rare cases, the mothers should be apprised of the potential
DRUG INTERACTIONS In patients with some degree of renal failure (serum creatinine hazards to their fetuses, and serial ultrasound examinations should
at least 1.6 mg/dL) but no collagen vascular disease, the risk of be performed to assess the intraamniotic environment.
, Captopril above). neutropenia in clinical trials was about 1 per 500, a frequency
Cholestyramine and colestipol resins Absorption of If oligohydramnios is observed, captopril should be discontinued
over 15 times that for uncomplicated hypertension. Daily doses of
hydrochlorothiazide is impaired in the presence of anionic unless it is considered life-saving for the mother. Contraction
captopril were relatively high in these patients, particularly in view
exchange resins. Single doses of either cholestyramine or colestipol stress testing (CST), a nonstress test (NST), or biophysical
of their diminished renal function. In foreign marketing experience
resins bind the hydrochlorothiazide and reduce its absorption from proling (BPP) may be appropriate, depending upon the week of
in patients with renal failure, use of allopurinol concomitantly with
the gastrointestinal tract by up to 85 and 43 percent, respectively. pregnancy. Patients and physicians should be aware, however, that
captopril has been associated with neutropenia but this association
oligohydramnios may not appear until after the fetus has sustained
Diazoxide enhanced hyperglycemic, hyperuricemic, and has not appeared in U. S. reports.
irreversible injury.
antihypertensive effects. Be cognizant of possible interaction; In patients with collagen vascular diseases (e.g., systemic lupus
monitor blood glucose and serum uric acid levels. Infants with histories of in utero exposure to ACE inhibitors should
erythematosus, scleroderma) and impaired renal function, be closely observed for hypotension, oliguria, and hyperkalemia.
Lithium diuretic agents reduce the renal clearance of lithium neutropenia occurred in 3.7 percent of patients in clinical trials. If oliguria occurs, attention should be directed toward support
and increase the risk of lithium toxicity. These drugs should be While none of the over 750 patients in formal clinical trials of of blood pressure and renal perfusion. Exchange transfusion or
coadministered with caution and frequent monitoring of serum heart failure developed neutropenia, it has occurred during the dialysis may be required as a means of reversing hypotension
lithium levels is recommended (see subsequent clinical experience. About half of the reported cases and/or substituting for disordered renal function. While captopril
DRUG INTERACTIONS had serum creatinine 1.6 mg/dL and more than 75 percent were may be removed from the adult circulation by hemodialysis, there
in patients also receiving procainamide. In heart failure, it appears is inadequate data concerning the effectiveness of hemodialysis
, Captopril, Lithium above).
that the same risk factors for neutropenia are present. for removing it from the circulation of neonates or children.
MAO inhibitors dosage adjustments of one or both agents may Peritoneal dialysis is not effective for removing captopril; there
The neutropenia has usually been detected within three months
be necessary since hypotensive effects are enhanced. is no information concerning exchange transfusion for removing
after captopril was started. Bone marrow examinations in patients
Nondepolarizing muscle relaxants, preanesthetics and with neutropenia consistently showed myeloid hypoplasia, captopril from the general circulation.
anesthetics used in surgery (e.g., tubocurarine chloride frequently accompanied by erythroid hypoplasia and decreased When captopril was given to rabbits at doses about 0.8 to 70
and gallamine triethiodide) effects of these agents may be numbers of megakaryocytes (e.g., hypoplastic bone marrow and times (on a mg/kg basis) the maximum recommended human
potentiated; dosage adjustments may be required. Monitor and pancytopenia); anemia and thrombocytopenia were sometimes dose, low incidences of craniofacial malformations were seen. No
correct any uid and electrolyte imbalances prior to surgery if seen. In general, neutrophils returned to normal in about two teratogenic effects of captopril were seen in studies of pregnant
feasible. weeks after captopril was discontinued, and serious infections rats and hamsters. On a mg/kg basis, the doses used were up to
Nonsteroidal anti-inammatory agents in some patients, were limited to clinically complex patients. About 13 percent of 150 times (in hamsters) and 625 times (in rats) the maximum
the administration of a nonsteroidal anti-inammatory agent can the cases of neutropenia have ended fatally, but almost all fatalities recommended human dose.
reduce the diuretic, natriuretic, and antihypertensive effect of were in patients with serious illness, having collagen vascular Hepatic Failure
loop, potassium-sparing or thiazide diuretics. Therefore, when disease, renal failure, heart failure or immunosuppressant therapy,
hydrochlorothiazide and nonsteroidal anti-inammatory agents Rarely, ACE Inhibitors have been associated with a syndrome
or a combination of these complicating factors.
that starts with cholestatic jaundice and progresses to fulminant
are used concomitantly, the patient should be observed closely to Evaluation of the hypertensive or heart failure patient should hepatic necrosis and (sometimes) death. The mechanism of this
determine if the desired effect of the diuretic is obtained. always include assessment of renal function. syndrome is not understood. Patients receiving ACE inhibitors
Methenamine possible decreased effectiveness due to If captopril is used in patients with impaired renal function, white who develop jaundice or marked elevations of hepatic enzymes
alkalinization of the urine. blood cell and differential counts should be evaluated prior to should discontinue the ACE inhibitor and receive appropriate
Pressor amines (e.g., norepinephrine) decreased arterial starting treatment and at approximately two-week intervals for medical follow-up.
responsiveness, but not sufcient to preclude effectiveness of the about three months, then periodically.
pressor agent for therapeutic use. Use caution in patients taking both HYDROCHLOROTHIAZIDE
In patients with collagen vascular disease or who are exposed to
medications who undergo surgery. Administer preanesthetic and Thiazides should be used with caution in severe renal disease. In
other drugs known to affect the white cells or immune response,
anesthetic agents in reduced dosage, and if possible, discontinue patients with renal disease, thiazides may precipitate azotemia.
particularly when there is impaired renal function, captopril
hydrochlorothiazide therapy one week prior to surgery. Cumulative effects of the drug may develop in patients with
should be used only after an assessment of benet and risk, and
Probenecid or sulnpyrazone increased dosage of these impaired renal function. Thiazides should be used with caution
then with caution.
agents may be necessary since hydrochlorothiazide may have in patients with impaired hepatic function or progressive liver
All patients treated with captopril should be told to report any disease, since minor alterations of uid and electrolyte balance
hyperuricemic effects. signs of infection (e.g., sore throat, fever). If infection is suspected, may precipitate hepatic coma. Sensitivity reactions may occur in
Drug/Laboratory Test Interactions white cell counts should be performed without delay. patients with or without a history of allergy or bronchial asthma.
Captopril: Captopril may cause a false-positive urine test for Since discontinuation of captopril and other drugs has generally led The possibility of exacerbation or activation of systemic lupus
acetone. to prompt return of the white count to normal, upon conrmation erythematosus has been reported. In general, lithium should
Hydrochlorothiazide: Hydrochlorothiazide may cause diagnostic of neutropenia (neutrophil count < 1000/mm3) the physician not be given with diuretics (see DRUG INTERACTIONS,
interference of the bentiromide test should withdraw captopril and closely follow the patients course Hydrochlorothiazide).
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PRECAUTIONS Thiazides have been shown to increase the urinary excretion of In the two-year rat study, irreversible and progressive variations in
GENERAL magnesium; this may result in hypomagnesemia. the caliber of retinal vessels (focal sacculations and constrictions)
Laboratory Tests occurred at all dose levels (7 to 200 times MRHD) in a dose-
Captopril
related fashion. The effect was rst observed in the 88th week of
Impaired Renal Function Some patients with renal disease, Serum electrolyte levels should be regularly monitored (see
dosing, with a progressively increased incidence thereafter, even
particularly those with severe renal artery stenosis, have WARNINGS after cessation of dosing.
developed increases in BUN and serum creatinine after reduction
CAPTOPRIL and HYDROCHLOROTHIAZIDE; GENERAL, PREGNANCY
of blood pressure with captopril. Captopril dosage reduction
Hydrochlorothiazide). Pregnancy Categories C (rst trimester) and D (second and
and/or discontinuation of diuretic may be required. For some
of these patients, it may not be possible to normalize blood Carcinogenesis, Mutagenesis, Impairment of Fertility third trimesters) See WARNINGS
pressure and maintain adequate renal perfusion (see CLINICAL Carcinogenicity and fertility studies have not been conducted CAPTOPRIL, Fetal/Neonatal Morbidity and Mortality.
PHARMACOLOGY, DOSAGE AND ADMINISTRATION, with CAPOZIDE, however, in animals they have been Nonteratogenic Effects Hydrochlorothiazide
ADVERSE REACTIONS: Altered Laboratory Findings). conducted with the individual components as noted below. Thiazides cross the placental barrier and appear in cord blood. The
Hyperkalemia Elevations in serum potassium have been Mutagenicity studies indicate that captopril in a 2:1 combination use of thiazides in pregnant women requires that the anticipated
observed in some patients treated with ACE inhibitors, including with hydrochlorothiazide was not mutagenic or clastogenic, with benet be weighed against possible hazards to the fetus. These
captopril. When treated with ACE inhibitors, patients at risk or without metabolic activation, in the following in vitro assays: hazards include fetal or neonatal jaundice, thrombocytopenia, and
for the development of hyperkalemia include those with: renal 1) Ames reverse-mutation in Salmonella; 2) forward mutation possibly other adverse reactions which have occurred in the adult.
insufciency; diabetes mellitus; and those using concomitant study in Saccharomyces pombe; 3) mitotic gene conversion test
potassium-sparing diuretics, potassium supplements or potassium- in Saccharomyces cerevisiae; and 4) sister-chromatid-exchange NURSING MOTHERS
containing salt substitutes; or other drugs associated with increases study in human lymphocytes. Both captopril and hydrochlorothiazide are excreted in human
in serum potassium. (See PATIENT INFORMATION and DRUG In a cytogenetics study using human lymphocytes, there were milk. Because of the potential for serious adverse reactions in
INTERACTIONS, Captopril; ADVERSE REACTIONS: Altered no increases in chromosomal abnormalities without metabolic nursing infants from both drugs, a decision should be made
Laboratory Findings) activation, nor with metabolic activation at 28 hours post- whether to discontinue nursing or to discontinue therapy taking
Cough: Presumably due to the inhibition of the degradation of treatment. into account the importance of CAPOZIDE (captopril
endogenous bradykinin, persistent nonproductive cough has and hydrochlorothiazide tablets, USP) to the mother. (See
A statistically signicant increase was found at 22 hours with
PEDIATRIC USE below)
been reported with all ACE inhibitors, always resolving after metabolic activation at the three concentrations tested (captopril/
discontinuation of therapy. ACE inhibitor-induced cough should hydrochlorothiazide in a 2:1 combination at 5, 25, 50 g/ml total PEDIATRIC USE
be considered in the differential diagnosis of cough. weight); however, there was no dose response, and the difference is Safety and effectiveness in pediatric patients have not been
Surgery/Anesthesia In patients undergoing major surgery or probably attributable to the unusual absence of any abnormalities established. There is limited experience reported in the literature
during anesthesia with agents that produce hypotension, captopril in the negative-control cultures in this test. with the use of captopril in the pediatric population; dosage, on
will block angiotensin II formation secondary to compensatory In an oral micronucleus study in mice, the captopril/ a weight basis, was generally reported to be comparable to or
renin release. If hypotension occurs and is considered to be due to hydrochlorothiazide combination (2:1 mixture at 2500 mg/kg total less than that used in adults. Infants, especially newborns, may
this mechanism, it can be corrected by volume expansion. weight) was not genotoxic. be more susceptible to the adverse hemodynamic effects of
Hemodialysis Captopril: Two-year studies with doses of 50 to 1350 mg/kg/ captopril. Excessive, prolonged and unpredictable decreases in
Recent clinical observations have shown an association day in mice and rats failed to show any evidence of carcinogenic blood pressure and associated complications, including oliguria
of hypersensitivity-like (anaphylactoid) reactions during potential. Studies in rats have revealed no impairment of fertility. and seizures, have been reported. CAPOZIDE (captopril and
hemodialysis with high-ux dialysis membranes (e.g., AN69) in hydrochlorothiazide tablets, USP) should be used in pediatric
Hydrochlorothiazide: Two-year feeding studies in mice and
patients receiving ACE inhibitors as medication. In these patients, patients only if other measures for controlling blood pressure have
rats conducted under the auspices of the National Toxicology
not been effective.
consideration should be given to using a different type of dialysis Program (NTP) uncovered no evidence of a carcinogenic
membrane or a different class of medication. (See potential of hydrochlorothiazide in female mice (at doses of up to OVERDOSE
WARNINGS approximately 600 mg/kg/day) or in male and female rats (at doses Captopril
CAPTOPRIL: Anaphylactoid reactions during membrane of up to approximately 100 mg/kg/day). The NTP, however, found
Correction of hypotension would be of primary concern.
exposure) equivocal evidence for hepatocarcinogenicity in male mice.
Volume expansion with an intravenous infusion of normal saline
Hydrochlorothiazide Hydrochlorothiazide was not genotoxic in in vitro assays is the treatment of choice for restoration of blood pressure.
using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 While captopril may be removed from the adult circulation by
Periodic determination of serum electrolytes to detect possible of Salmonella typhimurium (Ames assay) and in the Chinese
electrolyte imbalance should be performed at appropriate hemodialysis, there is inadequate data concerning the effectiveness
Hamster Ovary (CHO) test for chromosomal aberrations, or in of hemodialysis for removing it from the circulation of neonates
intervals. in vivo assays using mouse germinal cell chromosomes, Chinese or children. Peritoneal dialysis is not effective for removing
All patients receiving thiazide therapy should be observed hamster bone marrow chromosomes, and the Drosophila sex linked captopril; there is no information concerning exchange transfusion
for clinical signs of uid or electrolyte imbalance, namely: recessive lethal trait gene. Positive test results were obtained only for removing captopril from the general circulation.
hyponatremia, hypochloremic alkalosis, and hypokalemia. in the in vitro CHO Sister Chromatid Exchange (clastogenicity)
Serum and urine electrolyte determinations are particularly Hydrochlorothiazide
and in the Mouse Lymphoma Cell (mutagenicity) assays, using
important when the patient is vomiting excessively or receiving concentrations of hydrochlorothiazide from 43 to 1300 g/mL, and In addition to the expected diuresis, overdosage of thiazides may
parenteral uids. Warning signs or symptoms of uid and in the Aspergillus nidulans non-disjunction assay at an unspecied produce varying degrees of lethargy which may progress to coma
electrolyte imbalance may include: dryness of mouth, thirst, concentration. within a few hours, with minimal depression of respiration and
weakness, lethargy, drowsiness, restlessness, muscle pains or cardiovascular function and without evidence of serum electrolyte
Hydrochlorothiazide had no adverse effects on the fertility of mice changes or dehydration. The mechanism of thiazideinduced
cramps, muscular fatigue, hypotension, oliguria, tachycardia, and and rats of either sex in studies wherein these species were exposed,
gastrointestinal disturbances such as nausea and vomiting. CNS depression is unknown. Gastrointestinal irritation and
via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior hypermotility may occur. Transitory increase in BUN has been
Hypokalemia may develop, especially with brisk diuresis, or to conception and throughout gestation. reported, and serum electrolyte changes may occur, especially in
when severe cirrhosis is present. Interference with adequate oral
ANIMAL TOXICOLOGY patients with impaired renal function. In addition to gastric lavage
electrolyte intake will also contribute to hypokalemia. Hypokalemia
and supportive therapy for stupor or coma, symptomatic treatment
can sensitize or exaggerate the response of the heart to the toxic Captopril
of gastrointestinal effects may be needed. The degree to which
effects of digitalis (e.g., increased ventricular irritability). Because Chronic oral toxicity studies were conducted in rats (2 years), hydrochlorothiazide is removed by hemodialysis has not been
captopril reduces the production of aldosterone, concomitant dogs (47 weeks; 1 year), mice (2 years), and monkeys (1 year). clearly established. Measures as required to maintain hydration,
therapy with captopril reduces the diuretic-induced hypokalemia. Signicant drug-related toxicity included effects on hematopoiesis, electrolyte balance, respiration, and cardiovascular and renal
Fewer patients may require potassium supplements and/or foods renal toxicity, erosion/ulceration of the stomach, and variation of function should be instituted.
with a high potassium content (see DRUG INTERACTIONS, retinal blood vessels.
Agents Increasing Serum Potassium). Reductions in hemoglobin and/or hematocrit values were seen in CONTRAINDICATIONS
Any chloride decit is generally mild and usually does not require mice, rats, and monkeys at doses 50 to 150 times the maximum Captopril
specic treatment except under extraordinary circumstances (as recommended human dose (MRHD). Anemia, leukopenia, This product is contraindicated in patients who are hypersensitive
in liver disease or renal disease). Dilutional hyponatremia may thrombocytopenia, and bone marrow suppression occurred in dogs to captopril or any other angiotensin-converting enzyme inhibitor
occur in edematous patients in hot weather; appropriate therapy is at doses 8 to 30 times MRHD. The reductions in hemoglobin and (e.g., a patient who has experienced angioedema during therapy
water restriction, rather than administration of salt except in rare hematocrit values in rats and mice were only signicant at 1 year with any other ACE inhibitor).
instances when the hyponatremia is life-threatening. In actual salt and returned to normal with continued dosing by the end of the Hydrochlorothiazide
depletion, appropriate replacement is the therapy of choice. study. Marked anemia was seen at all dose levels (8 to 30 times Hydrochlorothiazide is contraindicated in anuria. It is also
Hyperuricemia may occur or frank gout may be precipitated MRHD) in dogs, whereas moderate to marked leukopenia was contraindicated in patients who have previously demonstrated
in certain patients receiving thiazide therapy. Latent diabetes noted only at 15 and 30 times MRHD and thrombocytopenia at 30 hypersensitivity to hydrochlorothiazide or other sulfonamide-
mellitus may become manifest during thiazide administration. The times MRHD. The anemia could be reversed upon discontinuation derived drugs.
antihypertensive effect of thiazide diuretics may be enhanced in of dosing. Bone marrow suppression occurred to a varying degree,
the postsympathectomy patient. being associated only with dogs that died or were sacriced in a PATIENT INFORMATION
If progressive renal impairment becomes evident, as indicated by a moribund condition in the 1 year study. However, in the 47-week Patients should be advised to immediately report to their physician
rising nonprotein nitrogen or blood urea nitrogen (BUN), a careful study at a dose 30 times MRHD, bone marrow suppression was any signs or symptoms suggesting angioedema (e.g., swelling
reappraisal of therapy is necessary with consideration given to found to be reversible upon continued drug administration. of face, eyes, lips, tongue, larynx and extremities; difculty in
withholding or discontinuing diuretic therapy. Thiazides may Captopril caused hyperplasia of the juxtaglomerular apparatus of swallowing or breathing; hoarseness) and to discontinue therapy.
decrease serum PBI levels without signs of thyroid disturbance. the kidneys at doses 7 to 200 times the MRHD in rats and mice, (See WARNINGS: CAPTOPRIL: Angioedema)
Calcium excretion is decreased by thiazides. Pathological changes at 20 to 60 times MRHD in monkeys, and at 30 times the MRHD Patients should be told to report promptly any indication of
in the parathyroid gland with hypercalcemia and hypophosphatemia in dogs. infection (e.g., sore throat, fever), which may be a sign of
have been observed in a few patients on prolonged thiazide Gastric erosions/ulcerations were increased in incidence at 20 and neutropenia, or of progressive edema which might be related to
therapy. The common complications of hyperparathyroidism such 200 times MRHD in male rats and at 30 and 65 times MRHD proteinuria and nephrotic syndrome.
as renal lithiasis, bone resorption, and peptic ulceration have not in dogs and monkeys, respectively. Rabbits developed gastric and All patients should be cautioned that excessive perspiration
been seen. Thiazides should be discontinued before carrying out intestinal ulcers when given oral doses approximately 30 times and dehydration may lead to an excessive fall in blood pressure
tests for parathyroid function. MRHD for only ve to seven days. because of reduction in uid volume. Other causes of volume
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SPDI
depletion such as vomiting or diarrhea may also lead to a fall in obtained within 1.5 hours after dosing. Urinary recovery accounted Aerobic gram-positive Aerobic gram-negative
blood pressure; patients should be advised to consult with the for approximately 60% of the administered dose. (See Table.) microorganisms: microorganisms:
physician. Dosage Mean Plasma Cefprozil 8-hour Urinary Staphylococcus aureus Haemophilus inuenzae
Patients should be advised not to use potassium-sparing diuretics, (mg) Concentrations (g /mL)* Excretion (%) (including -lactamase- (including -lactamase-
potassium supplements or potassium-containing salt substitutes producing strains) producing strains)
Peak
without consulting their physician. (See PRECAUTIONS: NOTE: Cefprozil is inactive Moraxella (Branhamella)
GENERAL, DRUG INTERACTIONS, Captopril; and appx.1.5 h 4h 8h
against methicillin-resistant catarrhalis (including -
ADVERSE REACTIONS: Captopril) 250 mg 6.1 1.7 0.2 60% staphylococci. lactamase-producing strains)
Patients should be warned against interruption or discontinuation 500 mg 10.5 3.2 0.4 62% Streptococcus pneumoniae
of medication unless instructed by the physician. Heart failure 1000 mg 18.3 8.4 1.0 54% Streptococcus pyogenes
patients on captopril therapy should be cautioned against rapid The following in vitro data are available; however, their clinical
increases in physical activity. Patients should be informed that *Data represent mean values of 12 healthy volunteers. signicance is unknown. Cefprozil exhibits in vitro minimum
CAPOZIDE (captopril and hydrochlorothiazide tablets, USP) During the rst 4-hour period after drug administration, the inhibitory concentrations (MICs) of 8 g/mL or less against most
should be taken one hour before meals (see DOSAGE AND average urine concentrations following 250 mg, 500 mg, and 1 (90%) strains of the following microorganisms; however, the
ADMINISTRATION). g doses were approximately 700 g/mL, 1000 g/mL, and 2900 safety and effectiveness of cefprozil in treating clinical infections
Pregnancy: Female patients of childbearing age should be told g/mL, respectively. due to these microorganisms have not been established in adequate
about the consequences of second-and third-trimester exposure Administration of CEFZIL tablet or suspension formulation with and well-controlled clinical trials.
to ACE inhibitors, and they should also be told that these food did not affect the extent of absorption (AUC) or the peak Aerobic gram-positive microorganisms:
consequences do not appear to have resulted from intrauterine plasma concentration (Cmax) of cefprozil. However, there was an Enterococcus durans Staphylococcus warneri
ACE-inhibitor exposure that has been limited to the rst trimester. increase of 0.25 to 0.75 hours in the time to maximum plasma Enterococcus faecalis Streptococcus agalactiae
These patients should be asked to report pregnancies to their concentration of cefprozil (Tmax). Listeria monocytogenes Streptococci (Groups C, D, F, and G)
physicians as soon as possible. The bioavailability of the capsule formulation of cefprozil was not Staphylococcus epidermidis viridans group Streptococci
affected when administered 5 minutes following an antacid. Staphylococcus saprophyticus
NOTE: Cefprozil is inactive against Enterococcus faecium.
CEFZIL Tablets 250 mg and 500 mg Plasma protein binding is approximately 36% and is independent
of concentration in the range of 2 g/mL to 20 g/mL. Aerobic gram-negative microorganisms:
CEFZIL for Oral Suspension There was no evidence of accumulation of cefprozil in the plasma Citrobacter diversus Proteus mirabilis
125 mg/5 mL and 250 mg/5 mL in individuals with normal renal function following multiple oral Escherichia coli Salmonella spp.
doses of up to 1000 mg every 8 hours for 10 days. Klebsiella pneumoniae Shigella spp.
In patients with reduced renal function, the plasma half-life may Neisseria gonorrhoeae Vibrio spp.
(including -lactamase-
be prolonged up to 5.2 hours depending on the degree of the renal
producing strains)
dysfunction. In patients with complete absence of renal function,
(CEFPROZIL) the plasma half-life of cefprozil has been shown to be as long as 5.9 NOTE: Cefprozil is inactive against most strains of Acinetobacter,
hours. The half-life is shortened during hemodialysis. Excretion Enterobacter, Morganella morganii, Proteus vulgaris, Providencia,
To reduce the development of drug-resistant bacteria and maintain pathways in patients with markedly impaired renal function have Pseudomonas, and Serratia.
the effectiveness of CEFZIL (cefprozil) and other antibacterial not been determined. (See PRECAUTIONS and DOSAGE AND Anaerobic microorganisms:
drugs, CEFZIL should be used only to treat or prevent infections ADMINISTRATION.) Prevotella (Bacteroides) Fusobacterium spp.
that are proven or strongly suspected to be caused by bacteria. melaninogenicus
In patients with impaired hepatic function, the half-life increases
DESCRIPTION to approximately 2 hours. The magnitude of the changes does not Clostridium difcile Peptostreptococcus spp.
warrant a dosage adjustment for patients with impaired hepatic Clostridium perfringens Propionibacterium acnes
CEFZIL is a semi-synthetic broad-spectrum cephalosporin
antibiotic. function. NOTE: Most strains of the Bacteroides fragilis group are resistant
Healthy geriatric volunteers (65 years old) who received a single to cefprozil.
Cefprozil is a cis and trans isomeric mixture (90% cis). The
chemical name for the monohydrate is (6R, 7R)-7-[(R)-2-ami- 1-g dose of cefprozil had 35%-60% higher AUC and 40% lower Susceptibility Tests
no-2-(p-hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5-thia-1- renal clearance values compared with healthy adult volunteers 20- Dilution Techniques: Quantitative methods are used to determine
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate, and 40 years of age. The average AUC in young and elderly female antimicrobial minimal inhibitory concentrations (MICs). These
subjects was approximately 15-20% higher than in young and MICs provide estimates of the susceptibility of bacteria to
the structural formula is:
elderly male subjects. The magnitude of these age- and gender- antimicrobial compounds. The MICs should be determined using
related changes in the pharmacokinetics of cefprozil is not a standardized procedure. Standardized procedures are based on a
sufcient to necessitate dosage adjustments. dilution method1,2 (broth or agar) or equivalent with standardized
Adequate data on CSF levels of cefprozil are not available. inoculum concentrations and standardized concentrations of
cefprozil powder. The MIC values should be interpreted according
Comparable pharmacokinetic parameters of cefprozil are observed
to the following criteria:
between pediatric patients (6 months12 years) and adults
following oral administration of selected matched doses. The MIC (g/mL) Interpretation
Cefprozil is a white to yellowish powder with a molecular formula maximum concentrations are achieved at 12 hours after dosing. 8 Susceptible (S)
for the monohydrate of C18H19N3O5SH2O and a molecular The plasma elimination half-life is approximately 1.5 hours. 16 Intermediate (I)
weight of 407.45. In general, the observed plasma concentrations of cefprozil in 32 Resistant (R)
CEFZIL tablets and CEFZIL for oral suspension are intended pediatric patients at the 7.5, 15, and 30 mg/kg doses are similar to A report of Susceptible indicates that the pathogen is likely to
for oral administration. those observed within the same time frame in normal adult subjects be inhibited if the antimicrobial compound in the blood reaches
at the 250, 500 and 1000 mg doses, respectively. The comparative the concentrations usually achievable. A report of Intermediate
CEFZIL tablets contain cefprozil equivalent to 250 mg or 500
plasma concentrations of cefprozil in pediatric patients and adult indicates that the result should be considered equivocal, and, if
mg of anhydrous cefprozil.
subjects at the equivalent dose level are presented in the table the microorganism is not fully susceptible to alternative, clinically
In addition, each tablet contains the following inactive ingredients: feasible drugs, the test should be repeated. This category implies
below.
cellulose, hypromellose, magnesium stearate, methylcellulose, possible clinical applicability in body sites where the drug is
Mean (SD) Plasma Cefprozil
simethicone, sodium starch glycolate, polyethylene glycol, physiologically concentrated or in situations where high dosage of
polysorbate 80, sorbic acid, and titanium dioxide. The 250 mg Concentrations (mg/mL) drug can be used. This category also provides a buffer zone which
tablets also contain FD&C Yellow No. 6. Population Dose 1h 2h 4h 6h T prevents small uncontrolled technical factors from causing major
1/2 (h) discrepancies in interpretation. A report of Resistant indicates
CEFZIL for oral suspension contains cefprozil equivalent
children 7.5 mg/kg 4.70 3.99 0.91 0.23 a 0.94 that the pathogen is not likely to be inhibited if the antimicrobial
to 125 mg or 250 mg anhydrous cefprozil per 5 mL constituted
compound in the blood reaches the concentrations usually
suspension. In addition, the oral suspension contains the following (n = 18) (1.57) (1.24) (0.30) (0.13) (0.32)
achievable; other therapy should be selected.
inactive ingredients: aspartame, cellulose, citric acid, colloidal adults 250 mg 4.82 4.92 1.70b 0.53 1.28
silicone dioxide, FD&C Red No. 3, avors (natural and articial), Standardized susceptibility test procedures require the use of
(n = 12) (2.13) (1.13) (0.53) (0.17) (0.34) laboratory control microorganisms to control the technical aspects
glycine, polysorbate 80, simethicone, sodium benzoate, sodium
children 15 mg/kg 10.86 8.47 2.75 0.61c 1.24 of the laboratory procedures. Standard cefprozil powder should
carboxymethylcellulose, sodium chloride, and sucrose.
(n = 19) (2.55) (2.03) (1.07) (0.27) (0.43) provide the following MIC values:
CLINICAL PHARMACOLOGY adults 500 mg 8.39 9.42 3.18d 1.00d 1.29 Microorganism MIC (g/mL)
The pharmacokinetic data were derived from the capsule (n = 12) (1.95) (0.98) (0.76) (0.24) (0.14) Enterococcus faecalis ATCC 29212 416
formulation; however, bioequivalence has been demonstrated children 30 mg/kg 6.69 17.61 8.66 -- 2.06 Escherichia coli ATCC 25922 146
for the oral solution, capsule, tablet, and suspension formulations Haemophilus inuenzae ATCC 49766 146
(n = 10) (4.26) (6.39) (2.70) (0.21)
under fasting conditions. Staphylococcus aureus ATCC 29213 0.251
adults 1000 mg 11.99 16.95 8.36 2.79 1.27 Streptococcus pneumoniae ATCC 49619 0.251
Following oral administration of cefprozil to fasting subjects,
approximately 95% of the dose was absorbed. The average plasma (n = 12) (4.67) (4.07) (4.13) (1.77) (0.12) Diffusion Techniques: Quantitative methods that require
half-life in normal subjects was 1.3 hours, a n = 11; bn = 5; cn = 9; dn = 11. measurement of zone diameters also provide reproducible
while the steady-state volume of distribution was estimated to be estimates of the susceptibility of bacteria to antimicrobial
Microbiology compounds. One such standardized procedure3 requires the use of
0.23 L/kg. The
Cefprozil has in vitro activity against a broad range of gram- standardized inoculum concentrations. This procedure uses paper
total body clearance and renal clearance rates were approximately positive and gram-negative bacteria. The bactericidal action of disks impregnated with 30 g cefprozil to test the susceptibility of
3 mL/min/kg and 2.3 mL/min/kg, respectively. cefprozil results from inhibition of cell-wall synthesis. microorganisms to cefprozil.
Average peak plasma concentrations after administration of 250 Cefprozil has been shown to be active against most strains of the Reports from the laboratory providing results of the standard
mg, 500 mg, or 1 g doses of cefprozil to fasting subjects were following microorganisms both in vitro and in clinical infections single-disk susceptibility test with a 30 g cefprozil disk should be
approximately 6.1, 10.5, and 18.3 g/mL, respectively, and were as described in the INDICATIONS AND USAGE section. interpreted according to the following criteria:
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SPDI
Zone diameter (mm) Interpretation REQUIRE TREATMENT WITH EPINEPHRINE AND Impairment of fertility was not observed in male or female
18 Susceptible (S) OTHER EMERGENCY MEASURES, INCLUDING rats given oral doses of cefprozil up to 18.5 times the highest
1517 Intermediate (I) OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS recommended human dose based upon mg/m2.
14 Resistant (R) ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR Pregnancy: Teratogenic Effects. Pregnancy Category B
Interpretation should be as stated above for results using dilution AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY
Reproduction studies have been performed in rabbits, mice, and
techniques. INDICATED.
rats using oral doses of cefprozil of 0.8, 8.5, and 18.5 times the
Interpretation involves correlation of the diameter obtained in the Pseudomembranous colitis has been reported with nearly all maximum daily human dose (1000 mg) based upon mg/m2,
disk test with the MIC for cefprozil. antibacterial agents, including cefprozil, and may range in severity and have revealed no harm to the fetus. There are, however, no
from mild to life threatening. adequate and well-controlled studies in pregnant women. Because
As with standardized dilution techniques, diffusion methods
require the use of laboratory control microorganisms that are used Therefore, it is important to consider this diagnosis in patients animal reproduction studies are not always predictive of human
to control the technical aspects of the laboratory procedures. For who present with diarrhea subsequent to the administration of response, this drug should be used during pregnancy only if clearly
the diffusion technique, the 30 g cefprozil disk should provide the antibacterial agents. needed.
following zone diameters in these laboratory test quality control Treatment with antibacterial agents alters the normal ora of the Labor and Delivery
strains. colon and may permit overgrowth of clostridia. Studies indicate Cefprozil has not been studied for use during labor and delivery.
Microorganism Zone diameter (mm) that a toxin produced by Clostridium difcile is one primary cause Treatment should only be given if clearly needed.
of antibiotic-associated colitis.
Escherichia coli ATCC 25922 2127 Nursing Mothers
Haemophilus inuenzae ATCC 49766 2027 After the diagnosis of pseudomembranous colitis has been
established, appropriate therapeutic measures should be initiated. Small amounts of cefprozil (< 0.3% of dose) have been detected
Staphylococcus aureus ATCC 25923 2733 in human milk following administration of a single 1 gram dose to
Streptococcus pneumoniae ATCC 49619 2532 Mild cases of pseudomembranous colitis usually respond to drug
discontinuation alone. In moderate to severe cases, consideration lactating women. The average levels over 24 hours ranged from
INDICATIONS AND USAGE 0.25 to 3.3 g/mL. Caution should be exercised when CEFZIL
should be given to management with uids and electrolytes,
CEFZIL (cefprozil) is indicated for the treatment of patients with is administered to a nursing woman, since the effect of cefprozil
protein supplementation, and treatment with an antibacterial drug
mild to moderate infections caused by susceptible strains of the on nursing infants is unknown.
clinically effective against Clostridium difcile colitis.
designated microorganisms in the conditions listed below: Pediatric Use: (See INDICATIONS AND USAGE and
PRECAUTIONS DOSAGE AND ADMINISTRATION.)
UPPER RESPIRATORY TRACT General The safety and effectiveness of cefprozil in the treatment of otitis
Pharyngitis/tonsillitis caused by Streptococcus pyogenes. Prescribing CEFZIL in the absence of proven or strongly media have been established in the age groups 6 months to 12 years.
NOTE: The usual drug of choice in the treatment and prevention suspected bacterial infection or a prophylactic indication is Use of CEFZIL (cefprozil) for the treatment of otitis media is
of streptococcal infections, including the prophylaxis of rheumatic unlikely to provide benet to the patient and increases the risk of supported by evidence from adequate and well-controlled studies
fever, is penicillin given by the the development of drug-resistant bacteria. of cefprozil in pediatric patients. (See CLINICAL STUDIES.)
intramuscular route. Cefprozil is generally effective in the In patients with known or suspected renal impairment (see The safety and effectiveness of cefprozil in the treatment of
eradication of Streptococcus pyogenes from the nasopharynx; DOSAGE AND ADMINISTRATION), careful clinical pharyngitis/ tonsillitis or uncomplicated skin and skin structure
however, substantial data establishing the efcacy of cefprozil in observation and appropriate laboratory studies should be done infections have been established in the age groups 2 to 12 years.
the subsequent prevention of rheumatic fever are not available at prior to and during therapy. The total daily dose of CEFZIL Use of CEFZIL for the treatment of these infections is supported
present. should be reduced in these patients because high and/or prolonged by evidence from adequate and well-controlled studies of cefprozil
Otitis Media caused by Streptococcus pneumoniae, Haemophilus plasma antibiotic concentrations can occur in such individuals in pediatric patients.
inuenzae (including -lactamase-producing strains), and from usual doses. Cephalosporins, including CEFZIL, should The safety and effectiveness of cefprozil in the treatment of acute
Moraxella (Branhamella) catarrhalis (including -lactamase- be given with caution to patients receiving concurrent treatment sinusitis have been established in the age groups 6 months to
producing strains). (See CLINICAL STUDIES.) with potent diuretics since these agents are suspected of adversely 12 years. Use of CEFZIL in these age groups is supported by
NOTE: In the treatment of otitis media due to -lactamase affecting renal function. evidence from adequate and well-controlled studies of cefprozil
producing organisms, cefprozil had bacteriologic eradication Prolonged use of CEFZIL may result in the overgrowth of in adults.
rates somewhat lower than those observed with a product nonsusceptible organisms. Safety and effectiveness in pediatric patients below the age of 6
containing a specic -lactamase inhibitor. In considering the use Careful observation of the patient is essential. If superinfection months have not been established for the treatment of otitis media
of cefprozil, lower overall eradication rates should be balanced occurs during therapy, appropriate measures should be taken. or acute sinusitis or below the age of 2 years for the treatment
against the susceptibility patterns of the common microbes in a Cefprozil should be prescribed with caution in individuals with a of pharyngitis/tonsillitis or uncomplicated skin and skin structure
given geographic area and the increased potential for toxicity with history of gastrointestinal disease particularly colitis. infections. However, accumulation of other cephalosporin
products containing -lactamase inhibitors. antibiotics in newborn infants (resulting from prolonged drug half-
Positive direct Coombs tests have been reported during treatment
Acute Sinusitis caused by Streptococcus pneumoniae, with cephalosporin life in this age group) has been reported.
Haemophilus inuenzae (including -lactamase-producing Geriatric Use
strains), and Moraxella (Branhamella) catarrhalis (including - antibiotics.
lactamase-producing strains). Information for Patients Of the more than 4500 adults treated with CEFZIL in clinical
studies, 14% were 65 years and older, while 5% were 75 years and
Phenylketonurics: CEFZIL (cefprozil) for oral suspension
LOWER RESPIRATORY TRACT older. When geriatric patients received the usual recommended
contains phenylalanine 28 mg per 5 mL (1 teaspoonful) constituted
Secondary Bacterial Infection of Acute Bronchitis and Acute suspension for both the 125 mg/5 mL and 250 mg/5 mL dosage adult doses, their clinical efcacy and safety were comparable
Bacterial Exacerbation of Chronic Bronchitis caused by forms. to clinical efcacy and safety in nongeriatric adult patients.
Streptococcus pneumoniae, Haemophilus inuenzae (including Other reported clinical experience has not identied differences
Patients should be counseled that antibacterial drugs including in responses between elderly and younger patients, but greater
-lactamase-producing strains), and Moraxella (Branhamella)
CEFZIL should only be used to treat bacterial infections. sensitivity of some older individuals to the effects of CEFZIL
catarrhalis (including -lactamase-producing strains).
They do not treat viral infections (e.g., the common cold). When cannot be excluded (see CLINICAL PHARMACOLOGY).
SKIN AND SKIN STRUCTURE CEFZIL is prescribed to treat a bacterial infection, patients
should be told that although it is common to feel better early in CEFZIL is known to be substantially excreted by the kidney,
Uncomplicated Skin and Skin-Structure Infections caused by and the risk of toxic reactions to this drug may be greater in
Staphylococcus aureus (including penicillinase-producing strains) the course of therapy, the medication should be taken exactly
as directed. Skipping doses or not completing the full course patients with impaired renal function. Because elderly patients
and Streptococcus pyogenes. are more likely to have decreased renal function, care should
of therapy may (1) decrease the effectiveness of the immediate
Abscesses usually require surgical drainage. be taken in dose selection and it may be useful to monitor renal
treatment and (2) increase the likelihood that bacteria will
To reduce the development of drug-resistant bacteria and maintain develop resistance and will not be treatable by CEFZIL or other function. See DOSAGE AND ADMINISTRATION for dosing
the effectiveness of CEFZIL and other antibacterial drugs, antibacterial drugs in the future. recommendations for patients with impaired renal function.
CEFZIL should be used only to treat or prevent infections
Drug Interactions ADVERSE REACTIONS
that are proven or strongly suspected to be caused by susceptible
bacteria. Nephrotoxicity has been reported following concomitant The adverse reactions to cefprozil are similar to those observed
administration of aminoglycoside antibiotics and cephalosporin with other orally administered cephalosporins. Cefprozil was
When culture and susceptibility information are available, they
antibiotics. Concomitant administration of probenecid doubled the usually well tolerated in controlled clinical trials.
should be considered in selecting or modifying antibacterial
AUC for cefprozil. Approximately 2% of patients discontinued cefprozil therapy due
therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of The bioavailability of the capsule formulation of cefprozil was not to adverse events.
therapy. affected when administered 5 minutes following an antacid. The most common adverse effects observed in patients treated
Drug/Laboratory Test Interactions with cefprozil are:
CONTRAINDICATIONS
Cephalosporin antibiotics may produce a false positive reaction Gastrointestinal: Diarrhea (2.9%), nausea (3.5%), vomiting
CEFZIL (cefprozil) is contraindicated in patients with known for glucose in the urine with copper reduction tests (Benedicts or (1%), and abdominal pain (1%).
allergy to the cephalosporin class of antibiotics. Fehlings solution or with Clinitest tablets), but not with enzyme- Hepatobiliary: Elevat ions of AST (SGOT) (2%), ALT (SGPT)
WARNINGS based tests for glycosuria (e.g., Clinistix). A false negative (2%), alkaline phosphatase (0.2%), and bilirubin values (<0.1%).
BEFORE THERAPY WITH CEFZIL IS INSTITUTED, reaction may occur in the ferricyanide test for blood glucose. The As with some penicillins and some other cephalosporin antibiotics,
CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE presence of cefprozil in the blood does not interfere with the assay cholestatic jaundice has been reported rarely.
WHETHER THE PATIENT HAS HAD PREVIOUS of plasma or urine creatinine by the alkaline picrate method.
Hypersensitivity: Rash (0.9%), urticaria (0.1%). Such reactions
HYPERSENSITIVITY REACTIONS TO CEFZIL, Carcinogenesis, Mutagenesis, and Impairment of Fertility
have been reported
CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. Long term in vivo studies have not been performed to evaluate the
more frequently in children than in adults. Signs and symptoms
IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN- carcinogenic potential of cefprozil.
usually occur a few daysafter initiation of therapy and subside
SENSITIVE PATIENTS, CAUTION SHOULD BE Cefprozil was not found to be mutagenic in either the Ames within a few days after cessation of therapy.
EXERCISED BECAUSE CROSS-SENSITIVITY AMONG Salmonella or E. coli WP2 urvA reversion assays or the Chinese
CNS: Dizziness (1%). Hyperactivity, headache, nervousness,
-LACTAM ANTIBIOTICS HAS BEEN CLEARLY hamster ovary cell HGPRT forward gene mutation assay and it did
insomnia, confusion,and somnolence have been reported rarely
DOCUMENTED AND MAY OCCUR IN UP TO 10% not induce chromosomal abnormalities in Chinese hamster ovary
(<1%). All were reversible.
OF PATIENTS WITH A HISTORY OF PENICILLIN cells or unscheduled DNA synthesis in rat hepatocytes in vitro.
ALLERGY. IF AN ALLERGIC REACTION TO CEFZIL Chromosomal aberrations were not observed in bone marrow cells Hematopoietic: Decreased leukocyte count (0.2%), eosinophilia
OCCURS, DISCONTINUE THE DRUG. SERIOUS from rats dosed orally with over 30 times the highest recommended (2.3%).
ACUTE HYPERSENSITIVITY REACTIONS MAY human dose based upon mg/m2. Renal: Elevated BUN (0.1%), serum creatinine (0.1%).
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Other: Diaper rash and superinfection (1.5%), genital pruritus and HOW SUPPLIED 10-16 days post-therapy follow-up, the following presumptive
vaginitis (1.6%). CEFZIL (cefprozil) Tablets bacterial eradication /clinical cure outcomes (i.e. clinical success)
The following adverse events, regardless of established causal were obtained:
Each light orange lm-coated tablet, imprinted with 7720 on one
relationship to CEFZIL,have been rarely reported during side and 250 on the other, contains the equivalent of 250 mg European Acute Otitis Media Study
postmarketing surveillance: anaphylaxis, angioedema, colitis anhydrous cefprozil. Cefprozil vs -lactamase inhibitor-containing
(including pseudomembranous colitis), erythema multiforme, control drug
Bottles of 100 Tablets (N.R) &10 Tablets NDC 0087-7720-60
fever, serum-sickness like reactions, Stevens-Johnson syndrome, EFFICACY:
and thrombocytopenia. Each white lm-coated tablet, imprinted with 7721 on one
side and 500 on the other, contains the equivalent of 500 mg Pathogen % of Cases Outcome
Cephalosporin class paragraph with Pathogen
anhydrous cefprozil.
In addition to the adverse reactions listed above which have been (n=47)
Bottles of 50 Tablets (N.R) NDC 0087-7721-50(N.R)
observed in patients treated with cefprozil, the following adverse
reactions and altered laboratory tests have been reported for Bottles of 100 Tablets (N.R)&10 Tablets NDC 0087-7721-60 S. pneumoniae 51.0% cefprozil equivalent
cephalosporin-class antibiotics: Store at controlled room temperature, 59 to 86 F (15 to 30 C). to control
Aplastic anemia, hemolytic anemia, hemorrhage, renal CEFZIL (cefprozil) For Oral Suspension H. inuenzae 29.8% cefprozil equivalent
dysfunction, toxic epidermal necrolysis, toxic nephropathy, Each 5 mL of constituted suspension contains the equivalent of to control
prolonged prothrombin time, positive Coombs test, elevated 125 mg anhydrous cefprozil. M. catarrhalis 6.4% cefprozil equivalent
LDH, pancytopenia, neutropenia, agranulocytosis. 50 mL Bottle NDC 0087-7718-40 to control
Several cephalosporins have been implicated in triggering seizures, 75 mL Bottle(N.R) NDC 0087-7718-62 S. pyogenes 12.8% cefprozil equivalent
particularly in patients with renal impairment, when the dosage 100 mL Bottle(N.R) NDC 0087-7718-64
to control
was not reduced. (See DOSAGE AND ADMINISTRATION and Each 5 mL of constituted suspension contains the equivalent of
OVERDOSAGE.) If seizures associated with drug therapy occur, Overall 100.0% cefprozil equivalent
250 mg anhydrous
the drug should be discontinued. Anticonvulsant therapy can be to control
cefprozil.
given if clinically indicated.
50 mL Bottle NDC 0087-7719-40 SAFETY:
OVERDOSAGE 75 mL Bottle(N.R) NDC 0087-7719-62 The incidence of adverse events in the cefprozil arm was
Single 5000 mg/kg oral doses of cefprozil caused no mortality 100 mL Bottle(N.R) NDC 0087-7719-64 comparable to the incidence of adverse events in the control arm
or signs of toxicity in adult, weanling, or neonatal rats, or adult All powder formulations for oral suspension contain cefprozil in a (agent that contained a specic -lactamase inhibitor).
mice. A single oral dose of 3000 mg/kg caused diarrhea and loss of bubble-gum avored mixture. REFERENCES
appetite in cynomolgus monkeys, but no mortality.
Reconstitution Directions for Oral Suspension 1. National Committee for Clinical Laboratory Standards. Methods
Cefprozil is eliminated primarily by the kidneys. In case of for Dilution
Prepare the suspension at the time of dispensing; for ease in
severe overdosage, especially in patients with compromised renal
preparation, add water in two portions and shake well after each Antimicrobial Susceptibility Tests for Bacteria that Grow
function, hemodialysis will aid in the removal of cefprozil from
aliquot. Aerobically-Third Edition.
the body.
Total Amount of Water Required for Reconstitution Approved Standard NCCLS Document M7-A3, Vol. 13, No.
DOSAGE AND ADMINISTRATION 25, NCCLS, Villanova, PA, December 1993.
Bottle Final Concentration Final Concentration
CEFZIL (cefprozil) is administered orally. Size 125 mg/5 mL 250 mg/5 mL 2. National Committee for Clinical Laboratory Standards.
Dosage Duration 50 mL 36 mL 36 mL Methods for Antimicrobial Susceptibility Testing of Anaerobic
Population/Infection (mg) (days) 75 mL 54 mL 54 mL Bacteria -Third Edition. Approved Standard NCCLS Document
100 mL 72 mL 72 mL M11-A3, Vol. 13, No. 26, NCCLS, Villanova, PA, December
ADULTS (13 years and older)
1993.
UPPER RESPIRATORY TRACT After mixing, store in a refrigerator and discard unused portion
after 14 days. 3. National Committee for Clinical Laboratory Standards.
Pharyngitis /Tonsillitis 500 q24h 10a Performance Standards for Antimicrobial Disk Susceptibility
Acute Sinusitis 250 q12h or 10 Store at 59 to 77 F (15 to 25 C) prior to constitution. Tests-Fifth Edition. Approved Standard NCCLS Document M2-
(For moderate to severe infections 500 q12h U.S. Patent No. 4,520,022 A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.
the higher dose should be used) CLINICAL STUDIES E2-B0001-12-03 7718DIM-14
LOWER RESPIRATORY TRACT Study One:
Secondary Bacterial Infection 500 q12h 10 In a controlled clinical study of acute otitis media performed MAXIPIME Injection
of Acute Bronchitis and Acute in the United States where signicant rates of -lactamase- For intravenous or intramuscular Use
Bacterial Exacerbation of Chronic producing organisms were found, cefprozil was compared to an
Bronchitis oral antimicrobial agent that contained a specic -lactamase
SKIN AND SKIN STRUCTURE
inhibitor. In this study, using very strict evaluability criteria and (Cefepime hydrochloride, USP)
microbiologic and clinical response criteria at the 10-16 days post-
Uncomplicated Skin and 250 q12h or 10 therapy follow-up, the following presumptive bacterial eradication To reduce the development of drug-resistant bacteria and maintain
Skin Structure Infections 500 q24h or /clinical cure outcomes (i.e. clinical success) and safety results the effectiveness of MAXIPIME and other antibacterial drugs,
` 500 q12h were obtained: MAXIPIME should be used only to treat or prevent infections
CHILDREN (2 years - 12 years) U.S. Acute Otitis Media Study that are proven or strongly suspected to be caused by bacteria.
UPPER RESPIRATORY TRACTb Cefprozil vs -lactamase inhibitor-containing control drug DESCRIPTION
Pharyngitis /Tonsillitis 7.5 mg/kg 10a EFFICACY: MAXIPIME (cefepime hydrochloride, USP) is a semi-synthetic,
q12h Pathogen % of Cases with Pathogen Outcome broad spectrum, cephalosporin antibiotic for parenteral administra-
SKIN AND SKIN STRUCTUREb tion. The chemical name is 1-[[(6R,7R)-7-[2-(2-amino-4-thiazo-
(n = 155)
Uncomplicated Skin and 20 mg/kg 10 lyl)-glyoxylamido]- 2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]
S. pneumoniae 48.4% cefprozil success rate 5% oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride, 72-(Z)-
Skin Structure Infections q24h better than control (O-methyloxime), monohydrochloride, monohydrate,
INFANTS & CHILDREN H. inuenzae 35.5% cefprozil success rate which corresponds to the following structural formula:
(6 months - 12 years) 17% less than control
UPPER RESPIRATORY TRACTb M. catarrhalis 13.5% cefprozil success rate
Otitis Media 15 mg/kg 10 12% less than control
(See INDICATIONS AND USAGE q12h S. pyogenes 2.6% cefprozil equivalent to
and CLINICAL STUDIES) control
Acute Sinusitis 7.5 mg/kg 10 Overall 100.0% cefprozil success rate
(For moderate to severe infections, q12h or 5%
the higher dose should be used) 15 mg/kg less than control Cefepime hydrochloride is a white to pale yellow powder.
a In the treatment of infections due to Streptococcus pyogenes, SAFETY: Cefepime hydrochloride contains the equivalent of not less than
CEFZIL should be administered for at least 10 days. 825 g and not more than 911 g of cefepime (C19H24N6O5S2)
The incidences of adverse events, primarily diarrhea and rash*,
per mg, calculated on an anhydrous basis. It is highly soluble in
Clinitest and Clinistix are registered trademarks of Bayer were clinically and statistically signicantly higher in the control
water.
HealthCare LLC. b Not to exceed recommended adult doses. arm versus the cefprozil arm.
MAXIPIME for Injection is supplied for intramuscular
Renal Impairment Age Group Cefprozil Control
or intravenous administration in strengths equivalent to 500
Cefprozil may be administered to patients with impaired renal 6 months-2 years 21% 41% mg(N.R), 1 g, and 2 g of cefepime. (See DOSAGE AND
function. The following dosage schedule should be used. 3-12 years 10% 19% ADMINISTRATION.) MAXIPIME is a sterile, dry mixture of
CreatinineClearance Dosage Dosing Interval * The majority of these involved the diaper area in young cefepime hydrochloride and L-arginine. It contains the equivalent
(mL/min) (mg) children. of not less than 90.0 percent and not more than 115.0 percent of the
30120 standard standard labeled amount of cefepime (C19H24N6O5S2). The L-arginine, at
Study Two:
029*0 50% of standard standard an approximate concentration of 725 mg/g of cefepime, is added
In a controlled clinical study of acute otitis media performed in to control the pH of the constituted solution at 4.06.0. Freshly
* Cefprozil is in part removed by hemodialysis; therefore, Europe, cefprozil was compared to an oral antimicrobial agent that constituted solutions of MAXIPIME will range in color from
cefprozil should be administered after the completion of contained a specic -lactamase inhibitor. colorless to amber.
hemodialysis. As expected in a European population, this study population had a
Hepatic Impairment lower incidence of - lactamase-producing organisms than usually CLINICAL PHARMACOLOGY
No dosage adjustment is necessary for patients with impaired seen in U.S. trials. In this study, using very strict evaluability PHARMACOKINETICS
hepatic function. criteria and microbiologic and clinical response criteria at the The average plasma concentrations of cefepime observed in
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healthy adult male volunteers (n=9) at various times following Data suggest that cefepime does cross the inamed blood-brain Aerobic Gram-Negative Microorganisms:
single 30-minute infusions (IV) of cefepime 500 mg, 1 g, and 2 g barrier. The clinical relevance of these data is uncertain at this Acinetobacter calcoaceticus subsp. lwof
are summarized in Table 1. Elimination of cefepime is principally time. Citrobacter diversus
via renal excretion with an average (SD) half-life of 2.0 Metabolism and Excretion Citrobacter freundii
(0.3) hours and total body clearance of 120.0 (8.0) mL/min in Cefepime is metabolized to N-methylpyrrolidine (NMP) which
healthy volunteers. Cefepime pharmacokinetics are linear over Enterobacter agglomerans
is rapidly converted to the N-oxide (NMPN- oxide). Urinary
the range 250 mg to 2 g. There is no evidence of accumulation in Haemophilus inuenzae (including beta-lactamase producing
recovery of unchanged cefepime accounts for approximately 85%
healthy adult male volunteers (n=7) receiving clinically relevant strains)
of the administered dose. Less than 1% of the administered dose is
doses for a period of 9 days. recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% Hafnia alvei
Absorption as an epimer of cefepime. Because renal excretion is a signicant Klebsiella oxytoca
The average plasma concentrations of cefepime and its derived pathway of elimination, patients with renal dysfunction and Moraxella catarrhalis (including beta-lactamase producing
pharmacokinetic parameters after intravenous administration are patients undergoing hemodialysis require dosage adjustment. (See strains)
portrayed in Table 1. DOSAGE AND ADMINISTRATION.) Morganella morganii
TABLE 1 Special Populations Proteus vulgaris
Average Plasma Concentrations in g/mL of Cefepime and Pediatric patients: Cefepime pharmacokinetics have been
Derived Pharmacokinetic Parameters (SD), Intravenous Providencia rettgeri
evaluated in pediatric patients from 2 months to 11 years of age
Administration Providencia stuartii
following single and multiple doses on q8h (n=29) and q12h
MAXIPIME (n=13) schedules.Following a single IV dose, total body clearance Serratia marcescens
Parameter 500 mg IV 1 g IV 2 g IV and the steady-state volume of distribution averaged 3.3 (1.0) NOTE: Cefepime is inactive against many strains of
0.5 h 38.2 78.7 163.1 mL/min/kg and 0.3 (0.1) L/kg, respectively. The urinary recovery Stenotrophomonas (formerly Xanthomonas maltophilia and
of unchanged cefepime was 60.4 (30.4)% of the administered Pseudomonas maltophilia).
1.0 h 21.6 44.5 85.8
dose, and the average renal clearance was 2.0 (1.1) mL/min/kg. Anaerobic Microorganisms:
2.0 h 11.6 24.3 44.8 There were no signicant effects of age or gender (25 male vs NOTE: Cefepime is inactive against most strains of Clostridium
4.0 h 5.0 10.5 19.2 17 female) on total body clearance or volume of distribution, difcile.
8.0 h 1.4 2.4 3.9 corrected for body weight. No accumulation was seen when
Susceptibility Tests
12.0 h 0.2 0.6 1.1 cefepime was given at 50 mg/kg q12h (n=13), while Cmax, AUC,
and t1/2 were increased about 15% at steady state after 50 mg/kg Dilution Techniques: Quantitative methods are used to determine
Cmax, g/Ml 39.1(3.5) 81.7(5.1) 163.9(25.3) antimicrobial minimum inhibitory concentrations (MICs). These
q8h. The exposure to cefepime following a 50 mg/kg IV dose in a
AUC, hg/mL 70.8(6.7) 148.5(15.1) 284.8(30.6) pediatric patient is comparable to that in an adult treated with a 2 g MICs provide estimates of the susceptibility of bacteria to
Number of IV dose. The absolute bioavailability of cefepime after an IM dose antimicrobial compounds.
subjects (male) 9 9 9 of 50 mg/kg was 82.3 (15)% in eight patients. The MICs should be determined using a standardized procedure.
Geriatric patients: Cefepime pharmacokinetics have been Standardized procedures are based on a dilution method1 (broth or
Following intramuscular (IM) administration, cefepime is investigated in elderly (65 years of age and older) men (n=12) and agar) or equivalent with standardized inoculum concentrations and
completely absorbed. The average plasma concentrations of women (n=12) whose mean (SD) creatinine clearance was 74.0 standardized concentrations of cefepime powder. The MIC values
cefepime at various times following a single IM injection are (15.0) mL/min. should be interpreted according to the following criteria:
summarized in Table 2. The pharmacokinetics of cefepime are TABLE 4
linear over the range of 500 mg to 2 g IM and do not vary with There appeared to be a decrease in cefepime total body clearance
respect to treatment duration. as a function of creatinine clearance. MIC(g/mL)
TABLE 2 Therefore, dosage administration of cefepime in the elderly should Microorganism Susceptible intermediate(I) Resistant(R)
Average Plasma Concentrations in g/mL of Cefepime be adjusted as appropriate if the patients creatinine clearance is 60 Microorganism
and Derived Pharmacokinetic Parameters (SD), mL/min or less. (See DOSAGE AND ADMINISTRATION.) other than
Intramuscular Administration Renal insufciency: Cefepime pharmacokinetics have been Haemophilus
MAXIPIME investigated in patients with various degrees of renal insufciency spp. and
(n=30). The average half-life in patients requiring hemodialysis S.pneumoniae 8 16 32
Parameter 500 mg IV 1 g IV 2 g IV
was 13.5 (2.7) hours and in patients requiring continuous Haemophilus spp 2 _ _
0.5 h 8.2 14.8 36.1 peritoneal dialysis was 19.0 (2.0) hours. Cefepime total body Streptococcus
1.0 h 12.5 25.9 49.9 clearance decreased proportionally with creatinine clearance in pneumoniae 0.5 1 2
2.0 h 12.0 26.3 51.3 patients with abnormal renal function, which serves as the basis
4.0 h 6.9 16.0 31.5 for dosage adjustment recommendations in this group of patients. *NOTE: Isolates from these species should be tested for
(See DOSAGE AND ADMINISTRATION.) susceptibility using specialized dilution testing methods.1 Also,
8.0 h 1.9 4.5 8.7
Hepatic insufciency: The pharmacokinetics of cefepime were strains of Haemophilus spp. with MICs greater than 2 g/mL
12.0 h 0.7 1.4 2.3 should be considered equivocal and should be further evaluated.
unaltered in patients with impaired hepatic function who received
Cmax, g/Ml 13.9(3.4) 29.6(4.4) 57.5(9.5) a single 1 g dose (n=11). A report of Susceptible indicates that the pathogen is likely to
AUC, hg/mL 60.(8.0) 137.0(11.0) 262.0(23.0) Microbiology be inhibited if the antimicrobial compound in the blood reaches
Number of Cefepime is a bactericidal agent that acts by inhibition of the concentrations usually achievable. A report of Intermediate
subjects (male) 6 6 12 bacterial cell wall synthesis. Cefepime has a broad spectrum of indicates that the result should be considered equivocal, and, if
in vitro activity that encompasses a wide range of gram-positive the microorganism is not fully susceptible to alternative, clinically
Distribution feasible drugs, the test should be repeated. This category implies
and gram-negative bacteria. Cefepime has a low afnity for
The average steady-state volume of distribution of cefepime is 18.0 chromosomally-encoded beta-lactamases. Cefepime is highly possible clinical applicability in body sites where the drug is
(2.0) L. The serum protein binding of cefepime is approximately resistant to hydrolysis by most beta-lactamases and exhibits rapid physiologically concentrated or in situations where high dosage
20% and is independent of its concentration in serum. penetration into gram-negative bacterial cells. Within bacterial of drug can be used. This category also provides a buffer zone that
Cefepime is excreted in human milk. A nursing infant consuming cells, the molecular targets of cefepime are the penicillin binding prevents small uncontrolled technical factors from causing major
approximately 1000 mL of human milk per day would receive proteins (PBP). discrepancies in interpretation. A report of Resistant indicates
approximately 0.5 mg of cefepime per day. (See PRECAUTIONS: that the pathogen is not likely to be inhibited if the antimicrobial
Cefepime has been shown to be active against most strains of the compound in the blood reaches the concentrations usually
Nursing Mothers.) following microorganisms, both in vitro and in clinical infections achievable; other therapy should be selected.
Concentrations of cefepime achieved in specic tissues and body as described in the INDICATIONS AND USAGE section.
uids are listed in Table 3. Standardized susceptibility test procedures require the use of
Aerobic Gram-Negative Microorganisms: laboratory control microorganisms to control the technical aspects
TABLE 3 Enterobacter of the laboratory procedures. Laboratory control microorganisms
Average Concentrations of Cefepime in Specic
Escherichia coli are specic strains of microbiological assay organisms with
Body Fluids (g/mL) or Tissues
Klebsiella pneumoniae intrinsic biological properties relating to resistance mechanisms
Average
Average Proteus mirabilis and their genetic expression within bacteria; the specic strains
time of are not clinically signicant in their current microbiological status.
concentration Pseudomonas aeruginosa
Sample Standard cefepime powder should provide the following MIC
Aerobic Gram-Positive Microorganisms:
post dose values (Table 5) when tested against the designated quality control
Tissue or Fluid Dose/ (h) Staphylococcus aureus (methicillin-susceptible strains only) strains:
# of
Route Streptococcus pneumoniae Table 5
Patients
Streptococcus pyogenes (Lanceelds Group A streptococci)
Blister Fluid 2 g IV 6 1.5 81.4 g/mL Microorganism ATCC MIC (g/mL)
Viridans group streptococci
Bronchial 2 g IV 20 4.8 24.1 g/g Escherichia coli 25922 0.0160.12
The following in vitro data are available, but their clinical
Mucosa Staphylococcus aureus 29213 14
signicance is unknown. Cefepime has been shown to have in
Sputum 2 g IV 5 4.0 7.4 g/mL vitro activity against most strains of the following microorganisms; Pseudomonas aeruginosa 27853 14
Urine 500 mgIV 8 0-4 292.0 g/mL however, the safety and effectiveness of cefepime in treating Haemophilus inuenza e 49247 0.52
1g IV 12 0-4 926.0 g /mL clinical infections due to these microorganisms have not been Streptococcus pneumoniae 49619 0.060.25
established in adequate and well-controlled trials.
2g IV 12 0-4 3120.0 g /mL Diffusion Techniques: Quantitative methods that require
Aerobic Gram-Positive Microorganisms:
Bile 2g IV 26 9.4 17.8 g/mL measurement of zone diameters also provide reproducible
Staphylococcus epidermidis (methicillin-susceptible strains only) estimates of the susceptibility of bacteria to antimicrobial
Peritoneal Fluid 2g IV 19 4.4 18.3 g/mL
Staphylococcus saprophyticus compounds. One such standardized procedure2 requires the use of
Appendix 2g IV 31 5.7 5.2 g/g
Streptococcus agalactiae (Lanceelds Group B streptococci) standardized inoculum concentrations. This procedure uses paper
Gallbladder 2g IV 38 8.9 11.9 g/g
NOTE: Most strains of enterococci, eg, Enterococcus faecalis, disks impregnated with 30 g of cefepime to test the susceptibility
Prostate 2g IV 5 1.0 31.5 g/g and methicillin-resistant staphylococci are resistant to cefepime. of microorganisms to cefepime.
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Interpretation is identical to that stated above for results using These studies comprised 317 evaluable patients. cephalosporin class of antibiotics, penicillins or other beta-lactam
dilution techniques. Table 8 describes the characteristics of the evaluable patient antibiotics.
Reports from the laboratory providing results of the standard population. WARNINGS
single-disk susceptibility test with a 30-g cefepime disk should TABLE 8 BEFORE THERAPY WITH MAXIPIME (CEFEPIME
be interpreted according to the following criteria:
Demographics of Evaluable Patients (First Episodes Only) HYDROCHLORIDE) FOR INJECTION IS INSTITUTED,
TABLE 6 Cefepime Ceftazidime CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE
Zone diameter 164 153 WHETHER THE PATIENT HAS HAD PREVIOUS
(mm) Total IMMEDIATE HYPERSENSITIVITY REACTIONS TO
Microorganism susceptible(s) Intermediate(i) Resistant(R ) 56.0 (range, 18-82) 55.0 (range16-84) CEFEPIME, CEPHALOSPORINS, PENICILLINS, OR
Male 86 (52%) 85 (56%) OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO
Microorganisms PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD
other than Female 78 (48%) 68 (44%) BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY
Haemophilus spp.* Leukemia 65 (40%) 52 (34%) AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN
and S. pneumoniae* 18 15-17 14 Other hematologic CLEARLY DOCUMENTED AND MAY OCCUR IN
malignancies 43 (26%) 36 (24%) UP TO 10% OF PATIENTS WITH A HISTORY OF
Haemophilus spp.* 26 --- ----
PENICILLIN ALLERGY. IF AN ALLERGIC REACTION
Solid tumor 54 (33%) 56 (37%)
*NOTE: Isolates from these species should be tested for TO MAXIPIME OCCURS, DISCONTINUE THE DRUG.
susceptibility using specialized diffusion testing methods2 . Median ANC nadir SERIOUS ACUTE HYPERSENSITIVITY REACTIONS
Isolates of Haemophilus spp. with zones smaller than 26 mm (cells/L) 20.0 (range, 0-500) 20.0 (range, 0-500) MAY REQUIRE TREATMENT WITH EPINEPHRINE
should be considered equivocal and should be further evaluated. Median duration of AND OTHER EMERGENCY MEASURES INCLUDING
Isolates of S. pneumoniae should be tested against a 1-g oxacillin neutropenia (days) 6.0 (range, 0-39) 6.0 (range, 0-32) OXYGEN, CORTICOSTEROIDS, INTRAVENOUS FLUIDS,
disk; isolates with oxacillin zone sizes larger than or equal to 20 Indwelling venous INTRAVENOUS ANTIHISTAMINES, PRESSOR AMINES,
mm may be considered susceptible to cefepime. catheter 97 (59%) 86 (56%) AND AIRWAY MANAGEMENT, AS CLINICALLY
As with standardized dilution techniques, diffusion methods INDICATED.
Prophylactic antibiotics 62 (38%) 64 (42%)
require the use of laboratory control microorganisms to control In patients with impaired renal function (creatinine clearance
Bone marrow graft 9 ( 5%) 7 ( 5%) 60 mL/min), the dose of MAXIPIME should be adjusted to
the technical aspects of the laboratory procedures. Laboratory
control microorganisms are specic strains of microbiological SBP <90 mm Hg at compensate for the slower rate of renal elimination. Because
assay organisms with intrinsic biological properties relating entry 7 ( 4%) 2 ( 1%) high and prolonged serum antibiotic concentrations can occur
to resistance mechanisms and their genetic expression within from usual dosages in patients with renal insufciency or other
bacteria; the specic strains are not clinically signicant in their ANC = absolute neutrophil count; SBP = systolic blood pressure.
conditions that may compromise renal function, the maintenance
current microbiological status. For the diffusion technique, the 30- Table 9 describes the clinical response rates observed. For all dosage should be reduced when cefepime is administered to such
g cefepime disk should provide the following zone diameters in outcome measures, cefepime was therapeutically equivalent to patients. Continued dosage should be determined by degree of
these laboratory test quality control strains (Table 7): ceftazidime. renal impairment, severity of infection, and susceptibility of
TABLE 7 TABLE 9 the causative organisms. (See specic recommendations for
Zone Size Pooled Response Rates for Empiric Therapy of Febrile dosing adjustment in DOSAGE AND ADMINISTRATION.)
Neutropenic Patients During postmarketing surveillance, serious adverse events have
Microorganism ATCC Range (mm)
% Response been reported including life-threatening or fatal occurrences of
Escherichia coli 25922 2935 the following: encephalopathy (disturbance of consciousness
Staphylococcus aureus 25923 2329 Cefepime Ceftazidime
including confusion, hallucinations, stupor and coma), myoclonus,
Pseudomonas aeruginosa 27853 2430 OutcomMeasures (n=164) (n=153) and seizures (see ADVERSE REACTIONS: Postmarketing
Haemophilus inuenzae 49247 2531 Primary episode resolved with Experience). Most cases occurred in patients with renal impairment
no treatment modication, no new who received doses of cefepime that exceeded the recommended
INDICATIONS AND USAGE febrile episodes or infection, and dosage schedules. However, some cases of encephalopathy
MAXIPIME is indicated in the treatment of the following oral antibiotics allowed for 51 55 occurred in patients receiving a dosage adjustment for their renal
infections caused by susceptible strains of the designated completion of treatment function. In the majority of cases, symptoms of neurotoxicity were
microorganisms (see also PRECAUTIONS: Pediatric Use and Primary episode resolved with no reversible and resolved after discontinuation of cefepime and/or
DOSAGE AND ADMINISTRATION): treatment modication, no new after hemodialysis.
Pneumonia (moderate to severe) caused by Streptococcus febrile episodes or 34 39 Pseudomembranous colitis has been reported with nearly all
pneumoniae, including cases associated with concurrent infection, and no post-treatment antibacterial agents, including MAXIPIME, and may range in
bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or oral antibiotics severity from mild to life-threatening. Therefore, it is important
Enterobacter species. Survival, any treatment to consider this diagnosis in patients who present with diarrhea
Empiric Therapy for Febrile Neutropenic Patients. Cefepime modication allowed 93 97 subsequent to the administration of antibacterial agents.
as monotherapy is indicated for empiric treatment of febrile Primary episode resolved Treatment with antibacterial agents alters the normal ora of the
neutropenic patients. In patients at high risk for severe infection with no treatment modication and 62 67 colon and may permit overgrowth of clostridia. Studies indicate
(including patients with a history of recent bone marrow oral antibiotics allowed for that a toxin produced by Clostridium difcile is a primary cause of
transplantation, with hypotension at presentation, with an completion of treatment antibiotic- associated colitis.
underlying hematologic malignancy, or with severe or prolonged Primary episode resolved with After the diagnosis of pseudomembranous colitis has been
neutropenia), antimicrobial no treatment modication and established, therapeutic measures should be initiated. Mild
monotherapy may not be appropriate. Insufcient data exist to no post-treatment oral cases of pseudomembranous colitis usually respond to drug
support the efcacy of cefepime monotherapy in such patients. antibiotics 46 51 discontinuation alone. In moderate- to-severe cases, consideration
(See CLINICAL STUDIES.) should be given to management with uids and electrolytes,
Insufcient data exist to support the efcacy of cefepime
Uncomplicated and Complicated Urinary Tract Infections protein supplementation, and treatment with an antibacterial drug
monotherapy in patients at high risk for severe infection (including
(including pyelonephritis) caused by Escherichia coli or clinically effective against Clostridium difcile colitis.
patients with a history of recent bone marrow transplantation, with
Klebsiella pneumoniae, when the infection is severe, or caused hypotension at presentation, with an underlying hematologic PRECAUTIONS
by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, malignancy, or with severe or prolonged neutropenia). No data are General
when the infection is mild to moderate, including casesassociated available in patients with septic shock.
with concurrent bacteremia with these microorganisms. Prescribing MAXIPIME in the absence of proven or strongly
Complicated Intra-abdominal Infections suspected bacterial infection or a prophylactic indication is
Uncomplicated Skin and Skin Structure Infections caused by
Patients hospitalized with complicated intra-abdominal infections unlikely to provide benet to the patient and increases the risk of
Staphylococcus aureus (methicillinsusceptible strains only) or
participated in a randomized, doubleblind, multicenter trial the development of drug-resistant bacteria.
Streptococcus pyogenes.
comparing the combination of cefepime (2 g q12h) plus intravenous As with other antimicrobials, prolonged use of MAXIPIME
Complicated Intra-abdominal Infections (used in combination metronidazole (500 mg q6h) versus imipenem/cilastatin (500 mg may result in overgrowth of nonsusceptible microorganisms.
with metronidazole) caused by Escherichia coli, viridans group q6h) for a maximum duration of 14 days of therapy. Repeated evaluation of the patients condition is essential. Should
streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae,
The study was designed to demonstrate equivalence of the two superinfection occur during therapy, appropriate measures should
Enterobacter species, or Bacteroides fragilis. (See CLINICAL
therapies. The primary analyses were conducted on the protocol- be taken.
STUDIES.)
valid population, which consisted of those with a surgically Many cephalosporins, including cefepime, have been associated
To reduce the development of drug-resistant bacteria and maintain conrmed complicated infection, at least one pathogen isolated with a fall in prothrombin activity.
the effectiveness of MAXIPIME and other antibacterial drugs, pretreatment, at least 5 days of treatment, and a 4- to
MAXIPIME should be used only to treat or prevent infections Those at risk include patients with renal or hepatic impairment,
6-week follow-up assessment for cured patients. Subjects in the or poor nutritional state, as well as patients receiving a protracted
that are proven or strongly suspected to be caused by susceptible
imipenem/cilastatin arm had higher APACHE II scores at baseline. course of antimicrobial therapy. Prothrombin time should
bacteria. When culture and susceptibility information are available,
The treatment groups were otherwise generally comparable with be monitored in patients at risk, and exogenous vitamin K
they should be considered in selecting or modifying antibacterial
regard to their pretreatment characteristics. The overall clinical administered as indicated.
therapy. In the absence of such data, local epidemiology and
cure rate among the protocol-valid patients was 81% (51 cured/63
susceptibility patterns may contribute to the empiric Positive direct Coombs tests have been reported during treatment
evaluable patients) in the cefepime plus metronidazole group
selection of therapy. with MAXIPIME. In hematologic studies or in transfusion cross-
and 66% (62/94) in the imipenem/cilastatin group. The observed
matching procedures when antiglobulin tests are performed on the
CLINICAL STUDIES differences in efcacy may have been due to a greater proportion
minor side or in Coombs testing of newborns whose mothers have
Febrile Neutropenic Patients of patients with high APACHE II scores in the imipenem/cilastatin received cephalosporin antibiotics before parturition, it should be
The safety and efcacy of empiric cefepime monotherapy of group. recognized that a positive Coombs test may be due to the drug.
febrile neutropenic patients have been assessed in two multicenter, CONTRAINDICATIONS MAXIPIME (cefepime hydrochloride) should be prescribed
randomized trials, comparing cefepime monotherapy (at a dose of MAXIPIME is contraindicated in patients who have shown with caution in individuals with a history of gastrointestinal
2 g IV q8h) to ceftazidime monotherapy (at a dose of 2 g IV q8h). immediate hypersensitivity reactions to cefepime or the disease, particularly colitis.
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Arginine has been shown to alter glucose metabolism and elevate Geriatric Use As with some other drugs in this class, encephalopathy (disturbance
serum potassium transiently when administered at 33 times the Of the more than 6400 adults treated with MAXIPIME in clinical of consciousness including confusion, hallucinations, stupor, and
amount provided by the maximum recommended human dose of studies, 35% were 65 years or older while 16% were 75 years or coma), myoclonus, and seizures have been reported. Although
MAXIPIME. The effect of lower doses is not presently known. older. When geriatric patients received the usual recommended most cases occurred in patients with renal impairment who
Information for Patients adult dose, clinical efcacy and safety were comparable to clinical received doses of cefepime that exceeded recommended dosage
efcacy and safety in nongeriatric adult patients. schedules, some cases of encephalopathy occurred in patients
Patients should be counseled that antibacterial drugs including
receiving a dosage adjustment for their renal function. (See also
MAXIPIME should only be used to treat bacterial infections. Serious adverse events have occurred in geriatric patients
with renal insufciency given unadjusted doses of cefepime, WARNINGS.) If seizures associated with drug therapy occur, the
They do not treat viral infections (eg, the common cold). When
drug should be discontinued. Anticonvulsant therapy can be given
MAXIPIME is prescribed to treat a bacterial infection, patients including life-threatening or fatal occurrences of the following:
encephalopathy, myoclonus, and seizures. (See WARNINGS and if clinically indicated. Precautions should be taken to adjust daily
should be told that although it is common to feel better early in
ADVERSE REACTIONS.) dosage in patients with renal insufciency or other conditions that
the course of therapy, the medication should be taken exactly
may compromise renal function to reduce antibiotic concentrations
as directed. Skipping doses or not completing the full course This drug is known to be substantially excreted by the kidney,
that can lead or contribute to these and other serious adverse
of therapy may (1) decrease the effectiveness of the immediate and the risk of toxic reactions to this drug may be greater in
events, including renal failure.
treatment and (2) increase the likelihood that bacteria will develop patients with impaired renal function. Because elderly patients
resistance and will not be treatable by MAXIPIME or other are more likely to have decreased renal function, care should be As with other cephalosporins, anaphylaxis including anaphylactic
antibacterial drugs in the future. taken in dose selection, and renal function should be monitored. shock, transient leukopenia, neutropenia, agranulocytosis, and
(See CLINICAL PHARMACOLOGY: Special Populations, thrombocytopenia have been reported.
Drug Interactions
WARNINGS; and DOSAGE AND ADMINISTRATION.) Cephalosporin-class Adverse Reactions
Renal function should be monitored carefully if high doses of
aminoglycosides are to be administered with MAXIPIME because ADVERSE REACTIONS In addition to the adverse reactions listed above that have been
of the increased potential of nephrotoxicity and ototoxicity of Clinical Trials observed in patients treated with cefepime, the following adverse
aminoglycoside antibiotics. Nephrotoxicity has been reported reactions and altered laboratory tests have been reported for
In clinical trials using multiple doses of cefepime, 4137 patients
following concomitant administration of other cephalosporins cephalosporin-class antibiotics:
were treated with the recommended dosages of cefepime (500 mg
with potent diuretics such as furosemide. to 2 g IV q12h). There were no deaths or permanent disabilities Stevens-Johnson syndrome, erythema multiforme, toxic epidermal
Drug/Laboratory Test Interactions thought related to drug toxicity. Sixty-four (1.5%) patients necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia,
discontinued medication due to adverse events thought by the hemolytic anemia, hemorrhage, hepatic dysfunction including
The administration of cefepime may result in a false-positive
investigators to be possibly, probably, or almost certainly related cholestasis,and pancytopenia.
reaction for glucose in the urine when using Clinitest tablets.
It is recommended that glucose tests based on enzymatic glucose to drug toxicity. Thirtythree (51%) of these 64 patients who OVERDOSAGE
oxidase reactions (such as Clinistix) be used. discontinued therapy did so because of rash. The percentage of
Patients who receive an overdose should be carefully observed and
Carcinogenesis, Mutagenesis, and Impairment of Fertility cefepime-treated patients who discontinued study drug because
given supportive treatment. In the presence of renal insufciency,
of drug-related adverse events was very similar at daily doses of
No long-term animal carcinogenicity studies have been conducted hemodialysis, not peritoneal dialysis, is recommended to aid in
500 mg, 1 g, and 2 g q12h (0.8%, 1.1%, and 2.0%, respectively).
with cefepime. A battery of in vivo and in vitro genetic toxicity the removal of cefepime from the body. Accidental overdosing has
However, the incidence of discontinuation due to rash increased
tests, including the Ames Salmonella reverse mutation assay, occurred when large doses were given to patients with impaired
with the higher recommended doses. The following adverse events
CHO/HGPRT,mammalian cell forward gene mutation assay, renal function. Symptoms of overdose include encephalopathy
were thought to be probably related to cefepime during evaluation
chromosomal aberration and sister chromatid exchange assays (disturbance of consciousness including confusion, hallucinations,
of the drug in clinical trials conducted in North America (n=3125
in human lymphocytes, CHO broblast clastogenesis assay, and stupor, and coma), myoclonus, seizures, and neuromuscular
cefepime-treated patients).
cytogenetic and micronucleus assays in mice were conducted. excitability. (See WARNINGS, ADVERSE REACTIONS, and
TABLE 10 DOSAGE AND ADMINISTRATION.)
The overall conclusion of these tests indicated no denitive
Adverse Clinical Reactions
evidence of genotoxic potential. No untoward effects on fertility DOSAGE AND ADMINISTRATION
Cefepime Multiple-Dose Dosing Regimens
or reproduction have been observed in rats, mice, and rabbits
Clinical TrialsNorth America The recommended adult and pediatric dosages and routes of
when cefepime is administered subcutaneously at 1 to 4 times
INCIDENCE EQUAL TO Local reactions (3.0%), administration are outlined in the following table. MAXIPIME
the recommended maximum human dose calculated on a mg/m2
should be administered intravenously over approximately 30
basis. OR GREATER THAN 1% including phlebitis (1.3%)
minutes.
Usage in PregnancyTeratogenic effectsPregnancy pain and/or inammation
Category B Table 12
(0.6%)*; rash (1.1%)
Recommended Dosage Schedule for MAXIPIME
Cefepime was not teratogenic or embryocidal when administered INCIDENCE LESS THAN 1% Colitis (including in Patients with CrCL >60 mL/min
during the period of organogenesis to rats at doses up to 1000 BUT GREATER THAN 0.1% pseudomembranous colitis),
mg/kg/day (4 times the recommended maximum human dose Duration
calculated on a mg/m2 basis) or to mice at doses up to 1200 mg/ diarrhea, fever, headache, Site and Type of Infection Dose Frequency (days)
kg (2 times the recommended maximum human dose calculated nausea, oral moniliasis, Adults
on a mg/m2 basis) or to rabbits at a dose level of 100 mg/kg pruritus, urticaria, vaginitis, Moderate to Severe Pneumo-
(approximately equal to the recommended maximum human dose vomiting nia due to S. pneumoniae*, P.
calculated on a mg/m2 basis). aeruginosa, K. pneumoniae, or
*Local reactions, irrespective of relationship to cefepime in those 1-2 g IV q12h 10
There are, however, no adequate and well-controlled studies of Enterobacter species
patients who received intravenous infusion (n=3048).
cefepime use in pregnant women. Empiric therapy for febrile
At the higher dose of 2 g q8h, the incidence of probably-related neutropenic patients (See IN-
Because animal reproduction studies are not always predictive of
adverse events was higher among the 795 patients who received DICATIONS AND USAGE
human response, this drug should be used during pregnancy only
this dose of cefepime. They consisted of rash (4%), diarrhea and CLINICAL STUDIES.) 2 g IV q8h 7**
if clearly needed.
(3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and
Nursing Mothers Mild to Moderate Uncompli-
headache (1%).
cated or Complicated Urinary
Cefepime is excreted in human breast milk in very low The following adverse laboratory changes, irrespective of Tract Infections, including
concentrations (0.5 g/mL). Caution should be exercised when relationship to therapy with cefepime, were seen during clinical pyelonephritis,due to E. coli, K. 0.5-1 g
cefepime is administered to a nursing woman. trials conducted in North America. pneumoniae, or P. mirabilis* IV/IM*** q12h 7-10
Labor and Delivery TABLE 11 Severe Uncomplicated or Com-
Cefepime has not been studied for use during labor and delivery. Adverse Laboratory Change plicated Urinary Tract Infections,
Treatment should only be given if clearly indicated. Cefepime Multiple-Dose Dosing Regimens including pyelonephritis, due to
Pediatric Use Clinical TrialsNorth America E. coli or K. pneumoniae* 2 g IV q12h 10
The safety and effectiveness of cefepime in the treatment of INCIDENCE EQUAL TO Positive Coombs test (without Moderate to Severe Uncom-
uncomplicated and complicated urinary tract infections (including OR GREATER THAN 1% hemolysis) (16.2%); decreased plicated Skin and Skin Struc-
pyelonephritis), uncomplicated skin and skin structure infections, phosphorus (2.8%); increased ture Infections due to S. aureus
2 g IV q12h 10
ALT/SGPT (2.8%), AST/SGOT or S. pyogenes
pneumonia, and as empiric therapy for febrile neutropenic patients
(2.4%), eosinophils (1.7%); Complicated Intra-abdominal
have been established in the age groups 2 months up to 16 years.
abnormal PTT (1.6%), PT (1.4%) Infections (used in combina-
Use of MAXIPIME in these age groups is supported by evidence
from adequate and well controlled studies of cefepime in adults INCIDENCE LESS THAN Increased alkaline phosphatase, tion with metronidazole) caused
with additional pharmacokinetic and safety data from pediatric 1% BUT GREATER THAN BUN, calcium, creatinine, by E. coli, viridans group
trials (see CLINICAL PHARMACOLOGY). 0.1%, phosphorus, potassium total streptococci,P. aeruginosa,
bilirubin; decreased calcium*, K. pneumoniae, Enterobac-
Safety and effectiveness in pediatric patients below the age of 2 hematocrit, neutrophils, platelets, ter species,or B. fragilis. (See
months have not been established. WBC CLINICAL STUDIES.) 2 g IV q12h 7-10
There are insufcient clinical data to support the use of Pediatric Patients (2 months up to 16 years)
*Hypocalcemia was more common among elderly patients.
MAXIPIME in pediatric patients under 2 months of age or
Clinical consequences from changes in either calcium or The maximum dose for pediatric patients should not exceed the
for the treatment of serious infections in the pediatric population
phosphorus were not reported. recommended adult dose. The usual recommend-ed dosage in
where the suspected or proven pathogen is Haemophilus inuenzae
A similar safety prole was seen in clinical trials of pediatric pediatric patients up to 40 kg in weight for uncomplicated and
type b. complicated urinary tract infections (including pyelonephritis),
patients (see PRECAUTIONS: Pediatric Use).
IN THOSE PATIENTS IN WHOM MENINGEAL SEEDING uncomplicated skin and skin structure infections, and pneumonia
FROM A DISTANT INFECTION SITE OR IN WHOM Postmarketing Experience is 50 mg/kg/dose, administered q12h (50 mg/kg/dose, q8h for
MENINGITIS IS SUSPECTED OR DOCUMENTED, AN In addition to the events reported during North American clinical febrile neutropenic patients), for durations as given above.
ALTERNATE AGENT WITH DEMONSTRATED CLINICAL trials with cefepime, the following adverse experiences have been
EFFICACY IN THIS SETTING SHOULD BE USED. reported during worldwide postmarketing experience. * including cases associated with concurrent bacteremia.
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SPDI
** or until resolution of neutropenia. In patients whose fever Preparation of MAXIPIME solutions is summarized in (3646 F) withthe following diluents: Sterile Water for Injection,
resolves but who remain neutropenic for more than 7 days, Table 14. 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile
the need for continued antimicrobial therapy should be re- TABLE 14 Bacteriostatic Water for Injection with Parabens or Benzyl Alco-
evaluated frequently. Preparation of Solutions of MAXIPIME hol, or 0.5% or 1% Lidocaine Hydrochloride
*** IM route of administration is indicated only for mild to Single-Dose ials Amount of Approximate Approximate NOTE: PARENTERAL DRUGS SHOULD BE INSPECTED
moderate, uncomplicated or complicated UTIs due to E. coli for Intravenous/ Siluent to Available Cefepime VISUALLY FOR PARTICULATE MATTER BEFORE
when the IM route is considered to be a more appropriate Intramuscular beadded Volume Concentration ADMINISTRATION.
route of drug administration. Administration (mL) (mL) (mg/mL) As with other cephalosporins, the color of MAXIPIME powder,
Impaired Hepatic Function No adjustment is necessary for cefepime vial as well as its solutions, tends to darken depending on storage
patients with impaired hepatic function. content conditions; however, when stored as recommended, the product
Impaired Renal Function In patients with impaired renal 500 mg(IV) 5.0 5.6 100 potency is not adversely affected.
function (creatinine clearance 60 mL/min), the dose of 500 mg (IM) 1.3 1.8 280 HOW SUPPLIED
MAXIPIME should be adjusted to compensate for the slower 1 g (IV) 10.0 11.3 100 MAXIPIME (cefepime hydrochloride, USP) for Injection is
rate of renal elimination. The recommended initial dose of 1 g (IM) 2.4 3.6 280 supplied as follows:
MAXIPIME should be the same as in patients with normal 2 g (IV) 10.0 12.5 160 500 mg*(N.R) 15 mL vial (tray of 10) NDC 51479-053-10
renal function except in patients undergoing hemodialysis. The 1 g* (N.R) Piggyback bottle 100 mL NDC 51479-054-10
Piggyback
recommended doses of MAXIPIME in patients with renal
(100 mL) (tray of 10)
insufciency are presented in Table 13.
1 g bottle 50 50 20 1 g* ADD-Vantage vial NDC 51479-054-20
When only serum creatinine is available, the following formula
1 g bottle 100 100 10 (tray of 10)
(Cockcroft and Gault equation)3 may be used to estimate creatinine
clearance. The serum creatinine should represent a steady state of 2 g bottle 50 50 40 1 g* 15 mL vial (tray of 10) NDC 51479-054-30
renal function: 2 g bottle 100 100 20 2 g* (N.R) Piggyback bottle 100 mL NDC 51479-055-20
Males:Creatinine ADD-Vantage (tray of 10)
Weight (kg) x (140age) 2 g* ADD-Vantage vial NDC 51479-055-10
Clearance (mL/min) = 1 g vial 50 50 20
72 x serum creatinine (mg/dL) (tray of 10)
1 g vial 100 100 10
Females: 0.85 x above value 2 g vial 50 50 40 2 g* 20 mL vial (tray of 10) NDC 51479-055-30
TABLE 13 2 g vial 100 100 20 *Based on cefepime activity
Recommended Dosing Schedule for MAXIPIME in Adult
Compatibility and Stability: STORAGE
Patients (Normal Renal Function, Renal Insufciency, and
Hemodialysis) Intravenous: MAXIPIME is compatible at concentrations MAXIPIME IN THE DRY STATE SHOULD BE STORED
between 1 and 40 mg/mL with the following IV infusion uids: BETWEEN 225 C (3677 F) AND PROTECTED FROM
Creatinine 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, LIGHT.
Clearance Recommended Maintenance Schedule M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium
(mL/min) (1) National Committee for Clinical Laboratory Standards.
Chloride Injection, Lactated Ringers and 5% Dextrose Injection, Methods for Dilution Antimicrobial
>60 500 mg q12h 1 g q12h 2 g q12h 2 g q8h Normosol-RTM, and Normosol-MTM in 5% Dextrose Injection.
Susceptibility Tests for Bacteria that Grow Aerobically-Third
Normal These solutions may be stored up to 24 hours at controlled room
Edition. Approved Standard NCCLS
Recommended temperature 2025 C (6877 F) or 7 days in a refrigerator
dosing schedule 28 C (3646 F). MAXIPIME in ADD-Vantage vials is Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA,
stable at concentrations of 1040 mg/mL in 5% Dextrose Injection December 1993.
3060 500 mg q24h 1 g q24h 2 g q24h 2 g q12h
1129 500 mg q24h 500 mg q24h 1 g q24h 2 g q24h or 0.9% Sodium Chloride Injection for 24 hours at controlled room (2) National Committee for Clinical Laboratory Standards.
temperature 2025 C or 7 days in a refrigerator 28 C. Performance Standards for Antimicrobial Disk
<11 250 mg q24h 250 mg q24h 500 mg q24h 1 g q24h
MAXIPIME admixture compatibility information is summarized Susceptibility Tests-Fifth Edition. Approved Standard
CAPD 500 mg q48h 1 g q48h 2 g q48h 2 g q48h
in Table 15. NCCLS Document M2-A5, Vol. 13, No. 24,
Hemodi- 1 g on day 1, then 500 mg q24h thereafter 1 g q24h Table 15
alysis* Cefepime Admixture Stability
* On hemodialysis days, cefepime should be administered TAXOL Injection
Stability time for
following hemodialysis. Whenever possible, cefepime should be
Admixture IV RT/L Refrigeration
administered at the same time each day. MAXIPIME and Concen- (2025
Infusion (28 C)
Concentration tration Solutions C) (Paclitaxel)
In patients undergoing continuous ambulatory peritoneal dialysis,
40 mg/mL Amikacin NS or D5W 24 hours 7 days
MAXIPIME may be administered at normally recommended 6mg/mL
doses at a dosage interval of every 48 hours (see Table 13). WARNING
40 mg/mL Ampicillin D5W 8 hours 8 hours
In patients undergoing hemodialysis, approximately 68% of 1 mg/mL TAXOL (paclitaxel) Injection should be administered
the total amount of cefepime present in the body at the start of 40 mg/mL Ampicillin D5W 2 hours 8 hours under the supervision of a physician experienced in the use of
10 mg/mL cancer chemotherapeutic agents. Appropriate management of
dialysis will be removed during a 3-hour dialysis period. The
40 mg/mL Ampicillin NS 24 hours 48 hours complications is possible only when adequate diagnostic and
dosage of MAXIPIME for hemodialysis patients is 1 g on Day 1 1 mg/mL
treatment facilities are readily available.
followed by 500 mg q24h for the treatment of all infections except 40 mg/mL Ampicillin NS 8 hours 48 hours
febrile neutropenia, which is 1 g q24h. MAXIPIME should be 1 mg/mL Anaphylaxis and severe hypersensitivity reactions characterized
administered at the same time each day following the completion 4 mg/mL Ampicillin NS 8 hours 8 hours by dyspnea and hypotension requiring treatment, angioedema,
40 mg/mL andgeneralized urticaria have occurred in 2%-4% of patients
of hemodialysis on hemodialysis days (see Table 13).
4-40mg/mL Clindamycin NS or 24 hours 7days receiving TAXOL in clinical trials. Fatal reactions have
Data in pediatric patients with impaired renal function are Phosphate D5W
occurred in patients despite premedication. All patients should
not available; however, since cefepime pharmacokinetics 0.25-6 mg/mL
be pretreated with corticosteroids, diphenhydramine, and H2
are similar in adults and pediatric patients (see CLINICAL 4 mg/mL Heparin NS or 24 hours 7 days
10-50 D5W antagonists. (See DOSAGE AND ADMINISTRATION.)
PHARMACOLOGY), changes in the dosing regimen proportional
units/mL Patients who experience severe hypersensitivity reactions to
to those in adults (see Tables 12 and 13) are recommended for TAXOL should not be rechallenged with the drug.
4 mg/mL Potassium NS or 24 hours 7 days
pediatric patients. Chloride D5W TAXOL therapy should not be given to patients with solid
Administration: 10-40 mEg/L
tumors who have baseline neutrophil counts of less than 1,500
For Intravenous Infusion, constitute the 1 g or 2 g piggyback (100 4 mg/mL Theophylline D5W 24 hours 7 days cells/mm3 and should not be given to patients with AIDS-
0.8 mg/mL
mL) bottle with 50 or 100 mL of a compatible IV uid listed in the related Kaposis sarcoma if the baseline neutrophil count is
1-4 mg/mL na AMINOSYN 11 8 hours 3 days
Compatibility and Stability subsection. Alternatively, constitute 4025% with less than 1000 cells/mm3. In order to monitor the occurrence of
the 500 mg, 1 g, or 2 g vial, and add an appropriate quantity of the electrolytes bone marrow suppression, primarily neutropenia, which may be
resulting solution to an IV container with one of the compatible and xalcium severe and result in infection, it is recommended that frequent
IV uids. THE RESULTING SOLUTION SHOULD BE 0.125-0.25 na inpersol with 24 hours 7 days peripheral blood cell counts be performed on all patients
ADMINISTERED OVERAPPROXIMATELY 30 MINUTES. mg/mL 4.25% dextrose receiving TAXOL.
Intermittent IV infusion with a Y-type administration set can be NS = 0.9% Sodium Chloride Injection.
DESCRIPTION
accomplished with compatible solutions. However, during infusion D5W = 5% Dextrose Injection.
of a solution containing cefepime, it is desirable to discontinue the na = not applicable. TAXOL (paclitaxel) Injection is a clear colorless to slightly
other solution. RT/L = Ambient room temperature and light. yellow viscous solution. It is supplied as a nonaqueous solution
intended for dilution with a suitable parenteral uid prior to
ADD-VANTAGE vials are to be constituted only with 50 or 100 Solutions of MAXIPIME, like those of most beta-lactam
intravenous infusion. TAXOL is available in 30 mg (5 mL), 100
mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection antibiotics, should not be added to solutions of ampicillin at a
mg (16.7 mL), and 300 mg (50 mL) multidose vials(N.R). Each
in Abbott ADD-VANTAGE exible diluent containers. (See concentration greater than 40 mg/mL, and should not be added to mL of sterile nonpyrogenic solution contains 6 mgpaclitaxel, 527
ADD-VANTAGE Vial Instructions for Use.) metronidazole, vancomycin, gentamicin, tobramycin, netilmicin mg of puried CREMOPHOR EL* (polyoxyethylated castor
Intramuscular Administration: For IM administration, sulfate or aminophylline because of potential interaction. oil) and 49.7% (v/v) dehydrated alcohol, USP.
MAXIPIME (cefepime hydrochloride) should be constituted However, if concurrent therapy with MAXIPIME is indicated, Paclitaxel is a natural product with antitumor activity. TAXOL
with one of the following diluents: Sterile Water for Injection, 0.9% each of these antibiotics can be administered separately. is obtained via a semi-synthetic process from Taxus baccata. The
Sodium Chloride, 5% Dextrose Injection, 0.5% or 1.0% Lidocaine Intramuscular: MAXIPIME (cefepime hydrochloride) consti- chemical name for paclitaxel is 5, 20-Epoxy-1,2,4,7,10,13-
Hydrochloride, or Sterile Bacteriostatic Water for Injection with tuted as directed is stable for 24 hours at controlled room tempera- hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester
Parabens or Benzyl Alcohol (refer to Table 14). ture 2025 C (6877 F) or for 7 days in a refrigerator 28 C with (2R,3S)-N-benzoyl-3-phenylisoserine.
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Paclitaxel has the following structural formula: The disposition and toxicity of paclitaxel 3-hour infusion were
evaluated in 35 patients with varying degrees of hepatic function.
Relative to patients with normal bilirubin, plasma paclitaxel
exposure in patients with abnormal serum bilirubin 2 times upper
limit of normal (ULN) administered 175 mg/m2 was increased,
but with no apparent increase in the frequency or severity of
toxicity. In ve patients with serum total bilirubin >2 times ULN,
there was a statistically nonsignicant higher incidence of severe
myelosuppression, even at a reduced dose (110 mg/m2), but no
Paclitaxel is a white to off-white crystalline powder with the observed increase in plasma exposure. (See PRECAUTIONS:
empirical formula C47H51NO14 and a molecular weight of 853.9. Hepatic and DOSAGE AND ADMINISTRATION.) The effect
It is highly lipophilic, insoluble in water, and melts at around of renal dysfunction on the disposition of paclitaxel has not been
216-217C. investigated.
CLINICAL PHARMACOLOGY Possible interactions of paclitaxel with concomitantly administered
medications have not been formally investigated.
Paclitaxel is a novel antimicrotubule agent that promotes the
assembly of microtubules from tubulin dimers and stabilizes CLINICAL STUDIES
microtubules by preventing depolymerization. This stability Ovarian Carcinoma:
results in the inhibition of the normal dynamic reorganization of First-Line Data- The safety and efcacy of TAXOL followed
the microtubule network that is essential for vital interphase and by cisplatin in patients with advanced ovarian cancer and no
mitotic cellular functions. In addition, paclitaxel induces abnormal prior chemotherapy were evaluate in two Phase 3 multicenter,
arrays or bundles of microtubules throughout the cell cycle and randomized, controlled trials. In an Intergroup study led by the
multiple asters of microtubules during mitosis. European Organization for Research and Treatment of Cancer
Following intravenous administration of TAXOL, paclitaxel involving the Scandinavian Group NOCOVA, the National
plasma concentrations declined in a biphasic manner. The Cancer Institute of Canada, and the Scottish Group, 680 patients
initial rapid decline represents distribution to the peripheral with Stage IIB-C, III, or IV disease (optimally or non-optimally The adverse event prole for patients receiving TAXOL
compartment and elimination of the drug. The later phase is due, debulked) received either TAXOL 175 mg/m2 infused over 3 (paclitaxel) Injection in combination with cisplatin in these studies
in part, to a relatively slow efux of paclitaxel from the peripheral hours followed by cisplatin 75 mg/m2 (Tc) or cyclophosphamide was qualitatively consistent with that seen for the pooled analysis
compartment. 750 mg/m2 followed by cisplatin 75 mg/m2 (Cc) for a median of of data from 812 patients treated with single-agent TAXOL in
Pharmacokinetic parameters of paclitaxel following 3- and 24- six courses. Although the protocol allowed further therapy, only 10 clinical studies. These adverse events and adverse events from
hour infusions of TAXOL at dose levels of 135 and 175 mg/m2 15% received both drugs for nine or more courses. In a study the Phase 3 rst-line ovarian carcinoma studies are described in
were determined in a Phase 3 randomized study in ovarian cancer conducted by the Gynecological Oncology Group (GOG), 410 the ADVERSE REACTIONS section in tabular (Tables 10 and 11)
patients and are summarized in the following table: patients with Stage III or IV disease (>1 cm residual disease and narrative form.
Table 1: Summary of Pharmacokinetic Parameters - Mean after staging laparotomy or distant metastases) received either Second-Line Data- Data from ve Phase 1 & 2 clinical studies
Values TAXOL 135 mg/m2 infused over 24 hours followed by cisplatin (189 patients),a multicenter randomized Phase 3 study (407
75 mg/m2 or cyclophosphamide 750 mg/m2 followed by cisplatin patients), as well as an interim analysis of data from more than
Dose Infusion N Cmax AUC (0-) T-HALF CLT
(mg/m2) Duration (patients) (ng/mL) (ngh/mL)
75 mg/m2 for six courses. 300 patients enrolled in a treatment referral center program were
(h) (L/h/m2)
(h) In both studies, patients treated with TAXOL in combination used in support of the use of TAXOL in patients who have failed
135 24 2 195 6300 52.7 21.7 with cisplatin had signicantly higher response rate, longer time initial or subsequent chemotherapy for metastatic carcinoma of the
175 24 4 365 7993 15.7 23.8 to progression, and longer survival time compared with standard ovary. Two of the Phase 2 studies (92 patients) utilized an initial
135 3 7 2170 7952 13.1 17.7 therapy. These differences were also signicant for the subset dose of 135 to 170 mg/m2 in most patients (>90%) administered
175 3 5 3650 15007 20.2 12.2 over 24 hours by continuous infusion. Response rates in these two
of patients in the Intergroup study with non-optimally debulked
Cmax = Maximum plasma concentration disease, although the study was not fully powered for subset studies were 22% (95% Cl: 11% to 37%) and 30% (95% Cl: 18%
AUC (0-) = Area under the plasma concentration-time analyses (Tables 2A and 2B). Kaplan-Meier survival curves for to 46%) with a total of 6 complete and 18 partial responses in
curve from time 0 to innity each study are shown in Figures 1 and 2. 92 patients. The median duration of overall response in these two
CLT = Total body clearance studies measured from the rst day of treatment was 7.2 months
Table 2A: Efcacy in the Phase 3 First-Line
It appeared that with the 24-hour infusion of TAXOL, a 30% Ovarian Carcinoma Studies (range: 3.5-15.8 months) and 7.5 months (range: 5.3-17.4 months),
increase in dose (135 mg/m2 versus 175 mg/m2) increased the Intergroup GOG-111 respectively. The median survival was 8.1 months (range: 0.2-36.7
Cmax by 87%, whereas the AUC (0-) remained proportional. (non-optimally debulked subset) months) and 15.9 months (range: 1.8-34.5+ month).
However, with a 3-hour infusion, for a 30% increase in dose, T175/3a C750a T135/24a C750a The Phase 3 study had a bifactorial design and compared the
the Cmax and AUC (0-) were increased by 68% and 89%, c75 c75 c75 c75 efcacy and safety of TAXOL, administered at two different
respectively. The mean apparent volume of distribution at steady (n=218) (n=227) (n=196) (n=214) doses (135 or 175 mg/m2) and schedules (3- or 24-hour infusion).
state, with the 24-hour infusion of TAXOL, ranged from 227 to The overall response rate for the 407 patients was 16.2% (95%
Clinical Responseb (n=153) (n=153) (n=113) (n=127)
688 L/m2, indicating extensive extravascular distribution and/or Cl: 12.8% to 20.2%), with 6 complete and 60 partial responses.
- rate (percent) 58 43 62 48
tissue binding of paclitaxel. Duration of response, measured from the rst day of treatment was
- p-valuec 0.016 0.04
The pharmacokinetics of paclitaxel were also evaluated in adult 8.3 months (range: 3.2-21.6 months). Median time to progression
Time to Progression was 3.7 months (range: 0.1+ - 25.1+ months). Median survival
cancer patients who received single doses of 15-135 mg/m2
- median (months) 13.2 9.9 16.6 13.0 was 11.5 months (range: 0.2-26.3+ months).
given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour
- p-valuec 0.0060 0.0008
infusions (n=36), and 200-275 mg/m2 given by 24-hour infusions Response rates, median survival, and median time to progression
- hazard ratio (HR)c 0.76 0.70
(n=54) in Phase 1 & 2 studies. Values for CLT and volume of for the 4 arms are given in the following table.
distribution were consistent with the ndings in the Phase 3 study. - 95% Clc 0.62-0.92 0.56-0.86
Table 3: Efcacy in the Phase 3 Second-Line Ovarian
The pharmacokinetics of TAXOL in patients with AIDS-related Survival
Carcinoma Study
Kaposis sarcoma have not been studied. - median (months) 29.5 21.9 35.5 24.2
- p-valuec 0.0057 0.0002 175/3 175/24 135/3 135/24
In vitro studies of binding to human serum proteins, using
- hazard ratioc 0.73 0.64 (n=96) (n=106) (n=99) (n=106)
paclitaxel concentrations ranging from 0.1 to 50 g/mL, indicate
that between 89%-98% of drug is bound; the presence of - 95% Clc 0.58-0.91 0.50-0.81 Response
cimetidine, ranitidine, dexamethasone, or diphenhydramine did a TAXOL dose in mg/m2/infusion duration in hours; - rate (percent) 14.6 21.7 15.2 13.2
not affect protein binding of paclitaxel. cyclophosphamide and cisplatin doses in mg/m2. - 95% Condence (8.5-23.6) (14.5-31.0) (9.0-24.1) (7.7-21.5)
After intravenous administration of 15-275 mg/m2 doses of b Among patients with measurable disease only. Interval
TAXOL (paclitaxel) Injection as 1-, 6-, or 24-hour infusions, c Unstratied for the Intergroup Study, Stratied for Study GOG- Time to
mean values for cumulative urinary recovery of unchanged drug 111. Progression
ranged from 1.3% to 12.6% of the dose, indicating extensive non- Table 2B: Efcacy in the Phase 3 First-Line - median (months) 4.4 4.2 3.4 2.8
renal clearance. In ve patients administered a 225 or 250 mg/m2 Ovarian Carcinoma Intergroup Study - 95% Condence (3.0-5.6) (3.5-5.1) (2.8-4.2) (1.9-4.0)
dose of radiolabeled TAXOL as a 3-hour infusion, a mean of 71% Interval
T175/3a C750 a
of the radioactivity was excreted in the feces in 120 hours, and 14%
c75 c75 Survival
was recovered in the urine. Total recovery of radioactivity ranged
from 56% to 101% of the dose. Paclitaxel represented a mean (n=342) (n=338) - median (months) 11.5 11.8 13.1 10.7
of 5% of the administered radioactivity recovered in the feces, Clinical Responseb (n=162) (n=161) -95%Condence (8.4-14.4) (8.9-14.6) (9.1-14.6) (8.1-13.6)
while metabolites, primarily 6-hydroxypaclitaxel, accounted for - rate (percent) 59 45 Interval
the balance. In vitro studies with human liver microsomes and - p-valuec 0.014
Analyses were performed as planned by the bifactorial study
tissue slices showed that paclitaxel was metabolized primarily Time to Progression
design described in the protocol, by comparing the two doses (135
to 6-hydroxypaclitaxel by the cytochrome P450 isozyme - median (months) 15.3 11.5 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and
CYP2C8; and to two minor metabolites, 3-p-hydroxypaclitaxel - p-valuec 0.0005 the two schedules irrespective of dose. Patients receiving the 175
and 6, 3-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the - hazard ratioc 0.74 mg/m2 dose had a response rate similar to that for those receiving
metabolism of paclitaxel to 6-hydroxypaclitaxel was inhibited - 95% Clc 0.60-0.89 the 135 mg/m2 dose:
by a number of agents (ketoconazole, verapamil, diazepam, Survival
quinidine, dexamethasone, cyclosporin, teniposide, etoposide, 18% vs. 14% (p=0.28). No difference in response rate was detected
- median (months) 35.6 25.9
and vincristine), but the concentrations used exceeded those found when comparing the 3-hour with the 24-hour infusion: 15% vs.
- p-valuec 0.0016
in vivo following normal therapeutic doses. Testosterone, 17- 17% (p=0.50).
- hazard ratioc 0.73
ethinyl estradiol, retinoic acid, and quercetin, a specic inhibitor - 95% Clc 0.60-0.89 Patients receiving the 175 mg/m2 dose of TAXOL had a
of CYP2C8, also inhibited the formation of 6-hydroxypaclitaxel longer time to progression than those receiving the 135 mg/m2
in vitro. The pharmacokinetics of paclitaxel may also be altered a TAXOL dose in mg/m2/infusion duration in hours; dose: median 4.2 vs. 3.1 months (p=0.03). The median time to
in vivo as a result of interactions with compounds that are cyclophosphamide and cisplatin doses in mg/m2. progression for patients receiving the 3-hour vs. the 24-hour
substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. b Among patients with measurable disease only. infusion was 4.0 months vs. 3.7 months, respectively. Median
(See PRECAUTIONS: Drug Interactions.) c Unstratied. survival was 11.6 months in patients receiving the 175 mg/m2
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SPDI
dose of TAXOL and 11.0 months in patients receiving the Subset analyses- Subsets dened by variables of known prognostic
135 mg/m2 dose (p=0.92). Median survival was 11.7 months for importance in adjuvant breast carcinoma were examined, including
patients receiving the 3-hour infusion of TAXOL and 11.2 number of positive lymph nodes, tumor size, hormone receptor
months for patients receiving the 24-hour infusion (p=0.91). These status, and menopausal status. Such analyses must be interpreted
statistical analyses should be viewed with caution because of the with care, as the most secure nding is the overall study result. In
multiple comparisons made. general, a reduction in hazard similar to the overall reduction was
TAXOL remained active in patients who had developed seen with TAXOL for both disease-free and overall survival in
resistance to platinum- containing therapy (dened as tumor all of the larger subsets with one exception; patients with receptor-
progression while on, or tumor relapse within 6 months from positive tumors had a smaller reduction in hazard (HR = 0.92) for
completion of, a platinum-containing regimen) with response disease-free survival with TAXOL than other groups. Results of
rates of 14% in the Phase 3 study and 31% in the Phase 1 & 2 subset analyses are shown in Table 4.
clinical studies. Table 4: Subset AnalysesAdjuvant Breast Carcinoma Study
The adverse event prole in this Phase 3 study was consistent Disease-Free Survival Overall Survival
with that seen for the pooled analysis of data from 812 patients The adverse event prole for the patients who received TAXOL
Patient No. of No. of Hazard No. of Hazard subsequent to AC was consistent with that seen in the pooled
treated in 10 clinical studies. These adverse events and adverse
Subset Ratio Ratio analysis of data from 812 patients (Table 10) treated with single-
events from the Phase 3 second-line ovarian carcinoma study are
Patients Recur- (95% Cl) Deaths (95% Cl) agent TAXOL in 10 clinical studies. These adverse events are
described in the ADVERSE REACTIONS section in tabular
rences described in the ADVERSE REACTIONS section in tabular
(Tables 10 and 12) and narrative form.
No. of Positive Nodes (Tables 10 and 13) and narrative form.
The results of this randomized study support the use of TAXOL 1-3 1449 221 0.72 107 0.76
at doses of 135 to 175 mg/m2, administered by a 3-hour After Failure of Initial Chemotherapy- Data from 83 patients
(0.55-0.94) (0.52-1.12) accrued in three Phase 2 open label studies and from 471
intravenous infusion. The same doses administered by 24-hour
infusion were more toxic. However, the study had insufcient 4-9 1310 274 0.78 148 0.66 patients enrolled in a Phase 3 randomized study were available
power to determine whether a particular dose and schedule (0.61-0.99) (0.47-0.91) to support the use of TAXOL in patients with metastatic breast
produced superior efcacy. 10+ 360 129 0.93 87 0.90 carcinoma.
Breast Carcinoma: (0.66-1.31) (0.59-1.36) Phase 2 open label studies- Two studies were conducted in
Adjuvant Therapy- A Phase 3 intergroup study (Cancer and Tumor Size (cm) 53 patients previously treated with a maximum of one prior
Leukemia Group B [CALGB], Eastern Cooperative Oncology 2 1096 153 0.79 67 0.73 chemotherapeutic regimen.
Group [ECOG], North Central Cancer Treatment Group (0.57-1.08) (0.45-1.18) TAXOL was administered in these two trials as a 24-hour
[NCCTG], and Southwest Oncology Group [SWOG]) randomized > 2 and 5 1611 358 0.79 201 0.74 infusion at initial doses of 250 mg/m2 (with G-CSF support) or
3170 patients with node-positive breast carcinoma to adjuvant (0.64-0.97) (0.56-0.98) 200 mg/m2. The response rates were 57% (95% CI: 37% to 75%)
therapy with TAXOL (paclitaxel) Injection or to no further >5 397 111 0.75 72 0.73 and 52% (95% CI: 32% to 72%), respectively.
chemotherapy following four courses of doxorubicin and (0.51-1.08) (0.46-1.16) The third Phase 2 study was conducted in extensively pretreated
cyclophosphamide (AC). This multicenter trial was conducted in patients who had failed anthracycline therapy and who had
Menopausal Status
women with histologically positive lymph nodes following either received a minimum of two chemotherapy regimens for the
a mastectomy or segmental mastectomy and nodal dissections. Pre 1929 374 0.83 187 0.72
treatment of metastatic disease. The dose of TAXOL was 200
The 3 x 2 factorial study was designed to assess the efcacy (0.67-1.01) (0.54-0.97)
mg/m2 as a 24-hour infusion with G-CSF support. Nine of 30
and safety of three different dose levels of doxorubicin (A) and Post 1183 250 0.73 155 0.77
patients achieved a partial response, for a response rate of 30%
to evaluate the effect of the addition of TAXOL administered (0.57-0.93) (0.56-1.06) (95% CI: 15% to 50%).
following the completion of AC therapy. After stratication for Receptor Status
the number of positive lymph nodes (1-3, 4-9, or 10+), patients Phase 3 randomized study- This multicenter trial was conducted
Positivea 2066 293 0.92 126 0.83 in patients previously treated with one or two regimens of
were randomized to receive cyclophosphamide at a dose of 600
mg/m2 and doxorubicin at doses of either 60 mg/m2 (on day 1), (0.73-1.16) (0.59-1.18) chemotherapy.
75 mg/m2 (in two divided doses on days 1 and 2), or 90 mg/m2 Negative/ Patients were randomized to receive TAXOL at a dose of either
(in two divided doses on days 1 and 2 with prophylactic G-CSF Unknownb 1055 331 0.68 216 0.71 175 mg/m2 or 135 mg/m2 given as a 3-hour infusion. In the 471
support and ciprooxacin) every 3 weeks for four courses and (0.55-0.85) (0.54-0.93) patients enrolled, 60% had symptomatic disease with impaired
either TAXOL 175 mg/m2 as a 3-hour infusion every 3 weeks a Positive for either estrogen or progesterone receptors. performance status at study entry, and 73% had visceral metastases.
for four additional courses or no additional chemotherapy. Patients b Negative or missing for both estrogen and progesterone These patients had failed prior chemotherapy either in the adjuvant
whose tumors were positive were to receive subsequent tamoxifen receptors (both missing: n=15). setting (30%), the metastatic setting (39%), or both (31%). Sixty-
treatment (20 mg daily for 5 years); patients who received seven percent of the patients had been previously exposed to
segmental mastectomies prior to study were to receive breast These retrospective subgroup analyses suggest that the benecial anthracyclines and 23% of them had disease considered resistant
irradiation after recovery from treatment-related toxicities. effect of TAXOL (paclitaxel) Injection is clearly established in to this class of agents.
At the time of the current analysis, median follow-up was 30.1 the receptornegative subgroup, but the benet in receptor-positive
The overall response rate for the 454 evaluable patients was 26%
months. patients is not yet clear. With respect to menopausal status, the
(95% CI: 22% to 30%), with 17 complete and 99 partial responses.
benet of TAXOL is consistent (see Table 4 and Figures 5-8).
Of the 2066 patients who were hormone receptor positive, 93% The median duration of response, measured from the rst day of
received tamoxifen. The primary analyses of disease-free survival treatment, was 8.1 months (range: 3.4-18.1+ months). Overall for
and overall survival used multivariate Cox models, which the 471 patients, the median time to progression was 3.5 months
included TAXOL administration, doxorubicin dose, number of (range: 0.03- 17.1 months). Median survival was 11.7 months
positive lymph nodes, tumor size, menopausal status, and estrogen (range: 0-18.9 months).
receptor status as factors. Based on the model for disease-free Response rates, median survival and median time to progression
survival, patients receiving AC followed by TAXOL had a 22% for the 2 arms are given in the following table.
reduction in the risk of disease recurrence compared to patients
Table 5: Efcacy in Breast Cancer after Failure of Initial
randomized to AC alone (Hazard Ratio [HR] = 0.78, 95% CI
Chemotherapy or Within 6 Months of Adjuvant
0.67-0.91, p=0.0022). They also had a 26% reduction in the risk
Chemotherapy
of death (HR = 0.74, 95% CI 0.60-0.92, p=0.0065). For disease-
free survival and overall survival, p values were not adjusted for 175/3 135/3
interim analyses. Kaplan-Meier curves are shown in Figures 3 and (n=235) (n=236)
4. Increasing the dose of doxorubicin higher than 60 mg/m2 had no Response
effect on either disease-free survival or overall survival.
- rate (percent) 28 22
- p-value 0.135
Time to Progression
-p-value 0.027
Survival
- p-value 0.321
The adverse event prole of the patients who received single-agent

TAXOL (paclitaxel) Injection in the Phase 3 study was consistent
with that seen for the pooled analysis of data from 812 patients
treated in 10 clinical studies. These adverse events and adverse
events from the Phase 3 breast carcinoma study are described in
the ADVERSE REACTIONS section in tabular (Tables 10 and 14)
and narrative form.
Non-Small Cell Lung Carcinoma (NSCLC)- In a Phase 3 open
label randomized study conducted by the ECOG, 599 patients
were randomized to either TAXOL (T) 135 mg/m2 as a 24-hour
infusion in combination with cisplatin (c) 75 mg/m2, TAXOL
(T) 250 mg/m2 as a 24-hour infusion in combination with cisplatin
(c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2 on
day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and
3 (control).
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SPDI
Response rates, median time to progression, median survival, the amended ACTG criteria and by seeking evidence of clinical Bone marrow suppression (primarily neutropenia) is dosedependent
and oneyear survival rates are given in the following table. The benet in patients in six domains of symptoms and/or conditions and is the dose-limiting toxicity. Neutrophil nadirs occurred
reported p-values have not been adjusted for multiple comparisons. that are commonly related to AIDS-related Kaposis sarcoma. at a median of 11 days. TAXOL should not be administered
There were statistically signicant differences favoring each of Cutaneous Tumor Response (Amended ACTG Criteria)- The to patients with baseline neutrophil counts of less than 1500
the TAXOL plus cisplatin arms for response rate and time to objective response rate was 59% (95% CI: 46% to 72%)(35 of cells/mm3 (<1000 cells/mm3 for patients with KS). Frequent
tumor progression. There was no statistically signicant difference 59 patients) in patients with prior systemic therapy. Cutaneous monitoring of blood counts should be instituted during TAXOL
in survival between either TAXOL plus cisplatin arm and the responses were primarily dened as attening of more than 50% treatment. Patients should not be re-treated with subsequent cycles
cisplatin plus etoposide arm. of previously raised lesions. of TAXOL until neutrophils recover to a level >1500 cells/mm3
Table 6: Efcacy Parameters in the Phase 3 First-Line (>1000 cells/mm3 for patients with KS) and platelets recover to a
Table 8: Overall Best Response (Amended ACTG Criteria)
NSCLC Study level >100,000 cells/mm3.
Percent of Patients
T135/24 T250/24 VP100a Severe conduction abnormalities have been documented in < 1%
Prior Systemic Therapy of patients during TAXOL therapy and in some cases requiring
c75 c75 c75
(n=59) pacemaker placement. If patients develop signicant conduction
(n=198) (n=201) (n=200) abnormalities during TAXOL infusion, appropriate therapy
Complete response 3
Response should be administered and continuous cardiac monitoring should
Partial response 56
- rate (percent) 25 23 12 be performed during subsequent therapy with TAXOL.
Stable disease 29
- p-valueb 0.001 <0.001 Pregnancy: TAXOL can cause fetal harm when administered
Progression 8 to a pregnant woman. Administration of paclitaxel during the
Time to Progression
Early death/toxicity 3 period of organogenesis to rabbits at doses of 3.0 mg/kg/day
- median (months) 4.3 4.9 2.7
(about 0.2 the daily maximum recommended human dose on a
- p-valueb 0.05 0.004 The median time to response was 8.1 weeks and the median
mg/m2 basis) caused embryoand fetotoxicity, as indicated by
duration of response measured from the rst day of treatment was
Survival intrauterine mortality, increased resorptions, and increased fetal
10.4 months (95% CI: 7.0 to 11.0 months) for the patients who
- median (months) 9.3 10.0 7.4 deaths. Maternal toxicity was also observed at this dose. No
had previously received systemic therapy. The median time to
- p-valueb 0.12 0.08 teratogenic effects were observed at 1.0 mg/kg/day (about 1/15
progression was 6.2 months (95% CI: 4.6 to 8.7 months).
the daily maximum recommended human dose on a mg/m2 basis);
One-Year Survival Additional Clinical Benet - Most data on patient benet teratogenic potential could not be assessed at higher doses due to
- percent of patients 36 40 32 were assessed retrospectively (plans for such analyses were not extensive fetal mortality.
a Etoposide (VP) 100 mg/m2 was administered I.V. on days 1, included in the study protocols). Nonetheless, clinical descriptions
There are no adequate and well-controlled studies in pregnant
2 and 3. and photographs indicated clear benet in some patients,
women. If TAXOL (paclitaxel) Injection is used during
including instances of improved pulmonary function in patients
b Compared to cisplatin/etoposide. pregnancy, or if the patient becomes pregnant while receiving this
with pulmonary involvement, improved ambulation, resolution of
drug, the patient should be apprised of the potential hazard to the
In the ECOG study, the Functional Assessment of Cancer Therapy- ulcers, and decreased analgesic requirements in patients with KS
fetus. Women of childbearing potential should be advised to avoid
Lung (FACT-L) questionnaire had seven subscales that measured involving the feet and resolution of facial lesions and edema in
becoming pregnant.
subjective assessment of treatment. Of the seven, the Lung Cancer patients with KS involving the face, extremities, and genitalia.
Specic Symptoms subscale favored the TAXOL 135 mg/m2/24 Safety- The adverse event prole of TAXOL administered to PRECAUTIONS
hour plus cisplatin arm compared to the cisplatin/etoposide arm. patients with advanced HIV disease and poor-risk AIDS-related Contact of the undiluted concentrate with plasticized polyvinyl
For all other factors, there was no difference in the treatment Kaposis sarcoma was generally similar to that seen in the pooled chloride (PVC) equipment or devices used to prepare solutions for
groups. analysis of data from 812 patients with solid tumors. These adverse infusion is not recommended.
The adverse event prole for patients who received TAXOL in events and adverse events from the Phase 2 second-line Kaposis In order to minimize patient exposure to the plasticizer DEHP
combination with cisplatin in this study was generally consistent sarcoma studies are described in the ADVERSE REACTIONS [di- (2-ethylhexyl) hthalate], which may be leached from PVC
with that seen for the pooled analysis of data from 812 patients section in tabular (Tables 10 and 16) and narrative form. In infusion bags or sets, diluted TAXOL solutions should
treated with single-agent TAXOL in 10 clinical studies. These this immunosuppressed patient population, however, a lower preferably be stored in bottles (glass, polypropylene) or plastic
adverse events and adverse events from the Phase 3 rst-line dose intensity of TAXOL and supportive therapy including bags (polypropylene, polyolen) and administered through
NSCLC study are described in the ADVERSE REACTIONS hematopoietic growth factors in patients with severe neutropenia polyethylene-lined administration sets.
section in tabular (Tables 10 and 15) and narrative form. are recommended.
TAXOL should be administered through an in-line lter with a
AIDS-Related Kaposis Sarcoma- Data from two Phase 2 open Patients with AIDS-related Kaposis sarcoma may have more microporous membrane not greater than 0.22 microns. Use of lter
label studies support the use of TAXOL as second-line therapy severe hematologic toxicities than patients with solid tumors. devices such as IVEX-2 lters which incorporate short inlet and
in patients with AIDS-related Kaposis sarcoma. Fifty-nine of INDICATIONS outlet PVC-coated tubing has not resulted in signicant leaching
the 85 patients enrolled in these studies had previously received of DEHP.
systemic therapy, including interferon alpha (32%), DaunoXome TAXOL is indicated as rst-line and subsequent therapy for
the treatment of advanced carcinoma of the ovary. As rst-line Drug Interactions: In a Phase I trial using escalating doses of
(31%), DOXIL (2%), and doxorubicin containing chemotherapy TAXOL (110-200 mg/m2) and cisplatin (50 or 75 mg/m2) given
(42%), with 64% having received prior anthracyclines. therapy, TAXOL is indicated in combination with cisplatin.
as sequential infusions, myelosuppression was more profound
Eighty-ve percent of the pretreated patients had progressed on, or TAXOL is indicated for the adjuvant treatment of node- when TAXOL was given after cisplatin than with the alternate
could not tolerate, prior systemic therapy. positive breast cancer administered sequentially to standard sequence (ie, TAXOL before cisplatin). Pharmacokinetic data
doxorubicin-containing combination chemotherapy. In the clinical from these patients demonstrated a decrease in paclitaxel clearance
In Study CA139-174 patients received TAXOL at 135 mg/m2
trial, there was an overall favorable effect on disease-free and of approximately 33% when TAXOL was administered
as a 3-hour infusion every 3 weeks (intended dose intensity 45
overall survival in the total population of patients with receptor- following cisplatin.
mg/m2/week). If no doselimiting toxicity was observed, patients
positive and receptor-negative tumors, but the benet has been
were to receive 155 mg/m2 and 175 mg/m2 in subsequent courses. The metabolism of TAXOL is catalyzed by cytochrome P450
specically demonstrated by available data (median follow-up
Hematopoietic growth factors were not to be used initially. In isoenzymes CYP2C8 and CYP3A4. In the absence of formal
30 months) only in the patients with estrogen and progesterone
Study CA139-281 patients received TAXOL at 100 mg/m2 as clinical drug interaction studies, caution should be exercised when
receptor-negative tumors. (See CLINICAL STUDIES: Breast
a 3-hour infusion every 2 weeks (intended dose intensity 50 mg/ administering TAXOL concomitantly with known substrates
Carcinoma.) TAXOL is indicated for the treatment of breast
m2/week). In this study patients could be receiving hematopoietic or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and
cancer after failure of combination chemotherapy for metastatic
growth factors before the start of TAXOL therapy, or this CYP3A4. (See CLINICAL PHARMACOLOGY.) Potential
disease or relapse within 6 months of adjuvant chemotherapy.
support was to be initiated as indicated; the dose of TAXOL interactions between TAXOL, a substrate of CYP3A4, and
Prior therapy should have included an anthracycline unless
was not increased. The dose intensity of TAXOL used in this protease inhibitors (ritonavir, saquinavir, indinavir, and nelnavir),
clinically contraindicated.
patient population was lower than the dose intensity recommended which are substrates and/or inhibitors of CYP3A4, have not been
for other solid tumors. All patients had widespread and poor-risk TAXOL, in combination with cisplatin, is indicated for the rst- evaluated in clinical trials.
disease. Applying the ACTG staging criteria to patients with prior line treatment of non-small cell lung cancer in patients who are
Reports in the literature suggest that plasma levels of doxorubicin
systemic therapy, 93% were poor risk for extent of disease (T1), not candidates for potentially curative surgery and/or radiation
(and its active metabolite doxorubicinol) may be increased when
88% had a CD4 count <200 cells/mm3 (I1), and 97% had poor risk therapy.
paclitaxel and doxorubicin are used in combination.
considering their systemic illness (S1). TAXOL is indicated for the second-line treatment of AIDS
Hematology: TAXOL therapy should not be administered
All patients in Study CA139-174 had a Karnofsky performance related Kaposis sarcoma.
to patients with baseline neutrophil counts of less than 1,500
status of 80 or 90 at baseline; in Study CA139-281, there were CONTRAINDICATIONS cells/mm3. In order to monitor the occurrence of myelotoxicity,
26 (46%) patients with a Karnofsky performance status of 70 or it is recommended that frequent peripheral blood cell counts be
TAXOL is contraindicated in patients who have a history of
worse at baseline. performed on all patients receiving TAXOL.
hypersensitivity reactions to TAXOL or other drugs formulated
Table 7: Extent of Disease at Study Entry in CREMOPHOR EL (polyoxyethylated castor oil). Patients should not be re-treated with subsequent cycles of
Percent of Patients TAXOL should not be used in patients with solid tumors who TAXOL until neutrophils recover to a level >1500 cells/mm3
Prior Systemic Therapy have baseline neutrophil counts of < 1500 cells/mm3 or in patients and platelets recover to a level >100,000 cells/mm3. In the case
with AIDS-related Kaposis sarcoma with baseline neutrophil of severe neutropenia (<500 cells/mm3 for seven days or more)
(n=59)
counts of <1000 cells/mm3. during a course of TAXOL therapy, a 20% reduction in dose for
Visceral _ edema oral cutaneous 42 subsequent courses of therapy is recommended.
Edema or lymph nodes oral cutaneous 41 WARNINGS For patients with advanced HIV disease and poor-risk AIDS-
Oral cutaneous 10 Anaphylaxis and severe hypersensitivity reactions characterized related Kaposis sarcoma, TAXOL, at the recommended dose
Cutaneous only 7 by dyspnea and hypotension requiring treatment, angioedema, and for this disease, can be initiated and repeated if the neutrophil
generalized urticaria have occurred in 2%-4% of patients receiving count is at least 1000 cells/mm3.
Although the planned dose intensity in the two studies was slightly TAXOL in clinical trials. Fatal reactions have occurred in Hypersensitivity Reactions: Patients with a history of severe
different (45 mg/m2/week in Study CA139-174 and 50 mg/m2/ patients despite premedication. hypersensitivity reactions to products containing Cremophor
week in Study CA139-281), delivered dose intensity was 38-39 All patients should be pretreated with corticosteroids, EL (eg, cyclosporin for injection concentrate and teniposide for
mg/m2/week in both studies, with a similar range (20-24 to 51- diphenhydramine, and H2 antagonists. (See DOSAGE AND injection concentrate) should not be treated with TAXOL. In
61). ADMINISTRATION.) Patients who experience severe order to avoid the occurrence of severe hypersensitivity reactions,
Efcacy- The efcacy of TAXOL (paclitaxel) Injection was hypersensitivity reactions to TAXOL should not be rechallenged all patients treated with TAXOL should be premedicated with
evaluated by assessing cutaneous tumor response according to with the drug. corticosteroids (such as dexamethasone), diphenhydramine
204
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SPDI
and H2 antagonists (such as cimetidine or ranitidine). Minor Geriatric Use: Of 2228 patients who received TAXOL in Information for Patients: (See Patient Information Leaet.)
symptoms such as ushing, skin reactions, dyspnea, hypotension, eight clinical studies evaluating its safety and effectiveness in
ADVERSE REACTIONS
or tachycardia do not require interruption of therapy. However, the treatment of advanced ovarian cancer, breast carcinoma,
severe reactions, such as hypotension requiring treatment, or NSCLC, and 1570 patients who were randomized to receive Pooled Analysis of Adverse Event Experiences from Single-
dyspnea requiring bronchodilators, angioedema, or generalized TAXOL in the adjuvant breast cancer study, 649 patients (17%) Agent Studies:
urticaria require immediate discontinuation of TAXOL and were 65 years or older and 49 patients (1%) were 75 years or older. Data in the following table are based on the experience of 812
aggressive symptomatic therapy. Patients who have developed In most studies, severe myelosuppression was more frequent in patients (493 with ovarian carcinoma and 319 with breast
severe hypersensitivity reactions should not be rechallenged with elderly patients; in some studies, severe neuropathy was more carcinoma) enrolled in 10 studies who received single-agent
TAXOL. common in elderly patients. In two clinical studies in NSCLC, the TAXOL.
Cardiovascular: Hypotension, bradycardia, and hypertension elderly patients treated with TAXOL had a higher incidence of Two hundred and seventy-ve patients were treated in eight Phase
have been observed during administration of TAXOL, but cardiovascular events. Estimates of efcacy appeared similar in 2 studies with TAXOL doses ranging from 135 to 300 mg/m2
generally do not require treatment. Occasionally TAXOL elderly patients and in younger patients; however, comparative administered over 24 hours (in four of these studies, G-CSF was
infusions must be interrupted or discontinued because of initial or efcacy cannot be determined with condence due to the small administered as hematopoietic support). Three hundred and one
recurrent hypertension. Frequent vital sign monitoring, particularly number of elderly patients studied. In a study of rst-line treatment patients were treated in the randomized Phase 3 ovarian carcinoma
during the rst hour of TAXOL infusion, is recommended. of ovarian cancer, elderly patients had a lower median survival study which compared two doses (135 or 175 mg/m2) and two
than younger patients, but no other efcacy parameters favored schedules (3 or 24 hours) of TAXOL. Two hundred and thirty-
Continuous cardiac monitoring is not required except for patients six patients with breast carcinoma received TAXOL (135 or 175
the younger group. Table 9 presents the incidences of Grade IV
with serious conduction abnormalities. (See WARNINGS.) mg/m2) TAXOL-2 is a registered trademark of the Millipore
neutropenia and severe neuropathy in clinical studies according
Nervous System: Although the occurrence of peripheral Corporation. administered over 3 hours in a controlled study.
to age.
neuropathy is frequent, the development of severe symptomatology
Table 9: Selected Adverse Events in Geriatric Patients Table 10: Summarya of Adverse Events in Patients With Solid
is unusual and requires a dose reduction of 20% for all subsequent
courses of TAXOL. Receiving TAXOL in Clinical Studies Tumors Receiving Single-Agent TAXOL (paclitaxel)
Patients [n/total (%)] Injection
TAXOL contains dehydrated alcohol USP, 396 mg/mL;
consideration should be given to possible CNS and other effects Neutropenia Peripheral Neuropathy Percent of Patients
of alcohol. (See PRECAUTIONS: Pediatric Use.) (Grade IV) Grades III/IV) (n=812)
Hepatic: There is limited evidence that the myelotoxicity of INDICATION Age (yrs) Age (yrs) Bone Marrow
TAXOL may be exacerbated in patients with serum total bilirubin (Study/Regimen) 65 <65 65 <65 - Neutropenia < 2,000/mm3 90
>2 times ULN (see CLINICAL PHARMACOLOGY). Extreme OVARIAN < 500/mm3 52
caution should be exercised when administering TAXOL to such Cancer
patients, with dose reduction as recommended in DOSAGE AND - Leukopenia < 4,000/mm3 90
(Intergroup < 1,000/mm3 17
ADMINISTRATION, Table 17.
First-Line/
Injection Site Reaction: Injection site reactions, including - Thrombocytopenia < 100,000/mm3 20
T175/3 c75a) 34/83 (41) 78/252 (31) 24/84 46/255
reactions secondary to extravasation, were usually mild and < 50,000/mm3 7
consisted of erythema, tenderness, skin discoloration, or swelling (29)*b (18)b
- Anemia < 11 g/dL 78
at the injection site. These reactions have been observed more (GOG-111
< 8 g/dL 16
frequently with the 24-hour infusion than with the 3-hour infusion. First-Line/
- Infections 30
Recurrence of skin reactions at a site of previous extravasation T135/24 c75a) 48/61 (79) 106/129 (82) 3/62 (5) 2/134 (1)
following administration of TAXOL at a different site, ie, - Bleeding 14
(Phase 3
recall, has been reported rarely. - Red Cell Transfusions 25
Second-Line/
Rare reports of more severe events such as phlebitis, cellulitis, - Platelet Transfusions 2
T175/3c) 5/19 (26) 21/76 (28) 1/19 (5) 0/76 (0)
induration, skin exfoliation, necrosis, and brosis have been
(Phase 3 Hypersensitivity Reactionb
received as part of the continuing surveillance of TAXOL
safety. In some cases the onset of the injection site reaction either Second-Line/ - All 41
occurred during a prolonged infusion or was delayed by a week T175/24c) 21/25 (84) 57/79 (72) 0/25 (0) 2/80 (3) - Severe 2
to ten days. (Phase 3 Cardiovascular
A specic treatment for extravasation reactions is unknown at this Second-Line/ - Vital Sign Changesc
time. T135/3c) 4/16 (25) 10/81 (12) 0/17 (0) 0/81 (0) - Bradycardia (n=537) 3
Given the possibility of extravasation, it is advisable to closely (Phase 3 - Hypotension (n=532) 12
monitor the infusion site for possible inltration during drug Second-Line/
administration. - Signicant Cardiovascular Events
T135/24c) 17/22 (77) 53/83 (64) 0/22 (0) 0/83 (0)
Carcinogenesis, Mutagenesis, Impairment of Fertility: The Abnormal ECG
(Phase 3
carcinogenic potential of TAXOL has not been studied. - All Pts 23
Second-Line
Paclitaxel has been shown to be clastogenic in vitro (chromosome - Pts with normal baseline (n=559) 14
Pooled) 47/82 (57)* 141/319 (44) 1/83 (1) 2/320 (1)
aberrations in human lymphocytes) and in vivo (micronucleus test
Adjuvant Peripheral Neuropathy
in mice).
BREAST - Any symptoms 60
Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT
gene mutation assay. Cancer - Severe symptoms 3
Administration of paclitaxel prior to and during mating produced (Intergroup/ Myalgia/Arthralgia
impairment of fertility in male and female rats at doses equal AC followed - Any symptoms 60
to or greater than 1 mg/kg/day (about 0.04 the daily maximum by Td) 56/102 (55) 734/1468 5/102 (5)e 46/1468 - Severe symptoms 8
recommended human dose on a mg/m2 basis). At this dose, (50) (3)e
paclitaxel caused reduced fertility and reproductive indices, and BREAST Cancer After Gastrointestinal
increased embryo- and fetotoxicity. - Nausea and vomiting 52
Failure of Initial Therapy
(See WARNINGS.) (Phase 3/T175/3c) 7/24 (29) 56/200 (28) 3/25 (12) 12/204 (6) - Diarrhea 38
Pregnancy: Pregnancy Category D. (See WARNINGS.) (Phase 3/T135/3c) 7/20 (35) 37/207 (18) 0/20 (0) 6/209 (3) - Mucositis 31
Nursing Mothers: It is not known whether the drug is excreted Non-Small Cell LUNG Cancer Alopecia 87
inhuman milk. Following intravenous administration of carbon- (ECOG/T 58/71 (82) 86/124 (69) 9/71 (13)f 16/124 (13)f
14 labeled TAXOL (paclitaxel) Injection to rats on days 9 to Hepatic (Pts with normal baseline and on study data)
135/24 c75a) - Bilirubin elevations (N=765) 7
10 postpartum, concentrations of radioactivity in milk were
higher than in plasma and declined in parallel with the plasma (Phase 3/T 37/89 (42)* 56/267 (21) 11/91 (12)* 11/271 (4)
- Alkaline phosphatase elevations (N=575) 22
concentrations. Because many drugs are excreted in human milk 175/3 c80a)
- AST (SGOT) elevations (N=591) 19
and because of the potential for serious adverse reactions in
* p<0.05 Injection Site Reaction 13
nursing infants, it is recommended that nursing be discontinued
when receiving TAXOL therapy. a TAXOL dose in mg/m2/infusion duration in hours; cisplatin a Based on worst course analysis.
doses in mg/m2.
Pediatric Use: The safety and effectiveness of TAXOL in b All patients received premedication.
b Peripheral neuropathy was included within the neurotoxicity
pediatric patients have not been established. c During the rst 3 hours of infusion.
category in the Intergroup First-Line Ovarian Cancer study
There have been reports of central nervous system (CNS) toxicity (see Table 11). Severe events are dened as at least Grade III toxicity
(rarely associated with death) in a clinical trial in pediatric patients c TAXOL dose in mg/m2/infusion duration in hours.
in which TAXOL was infused intravenously over 3 hours at None of the observed toxicities were clearly inuenced by age.
d TAXOL (T) following four courses of doxorubicin and
doses ranging from 350 mg/m2 to 420 mg/m2. The toxicity is most Disease-Specic Adverse Event Experiences First-Line Ovary
cyclophosphamide (AC) at a dose of 175 mg/m2/3 hours
likely attributable to the high dose of the ethanol component of in Combination:
every
the TAXOL vehicle given over a short infusion time. The use For the 1084 patients who were evaluable for safety in the Phase
3 weeks for four courses.
of concomitant antihistamines may intensify this effect. Although 3 rst-line ovary combination therapy studies, Table 11 shows
e Peripheral neuropathy reported as neurosensory toxicity in the
a direct effect of the paclitaxel itself cannot be discounted, the the incidence of important adverse events. For both studies, the
Intergroup Adjuvant Breast Cancer study (see Table 13).
high doses used in this study (over twice the recommended adult analysis of safety was based on all courses of therapy (six courses
dosage) must be considered in assessing the safety of TAXOL f Peripheral neuropathy reported as neurosensory toxicity in the for the GOG-111 study and up to nine courses for the Intergroup
for use in this population. ECOG NSCLC study (see Table 15).
study).
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SPDI
Table 11: Frequencya of Important Adverse Events in the Myelosuppression was dose and schedule related, with the Percent of Patients
Phase 3 First-Line Ovarian Carcinoma Studies schedule effect being more prominent. The development of severe
175/3b 135/3b
Percent of Patients hypersensitivity reactions (HSRs) was rare; 1% of the patients
(n=229) (n=229)
and 0.2% of the courses overall. There was no apparent dose or
Intergroup GOG-111 schedule effect seen for the HSRs. Peripheral neuropathy was Hypersensitivity
T175/3b C750c T135/24b C750c clearly dose-related, but schedule did not appear to affect the Reactionc
c75c c75c c75c c75c incidence. - All 36 31
(n=339) (n=336) (n=196) (n=213) Adjuvant Breast: For the Phase 3 adjuvant breast carcinoma - Severe 0 <1
Bone Marrow study, the following table shows the incidence of important severe Peripheral Neuropathy
- Neutropenia adverse events for the 3121 patients (total population) who were - Any symptoms 70 46
< 2000/mm3 91 d 95 d 96 92 evaluable for safety as well as for a group of 325 patients (early - Severe symptoms 7 3
< 500/mm3 33 d 43 d 81 d 58 d population) who, per the study protocol, were monitored more Mucositis
- Thrombocytopenia intensively than other patients. - Any symptoms 23 17
< 100,000/mm3e 21 d 33 d 26 30 Table 13: Frequencya of Important Severeb Adverse Events - Severe symptoms 3 <1
< 50,000/mm3 3d 7d 10 9 in the Phase 3 Adjuvant Breast Carcinoma Study a Based on worst course analysis.
- Anemia Percent of Patients b TAXOL dose in mg/m2/infusion duration in hours.
< 11 g/dLf 96 97 88 86 Early Population Total Population c All patients received premedication.
< 8 g/dL 3d 8d 1 9 Acc ACc Severe events are dened as at least Grade III toxicity.
Acc ACc
- Infections 25 27 21 15
followed followed
- Febrile Neutropenia 4 7 15 d 4d Myelosuppression and peripheral neuropathy were dose related.
by Td by Td There was one severe hypersensitivity reaction (HSR) observed at
Hypersensitivity
(n=166) (n=159) (n=1551) (n=1570) the dose of 135 mg/m2.
Reaction
- All 11 d 6d 8 d,g 1 d,g Bone Marrowe First-Line NSCLC in Combination: In the study conducted
- Severe 1 1 3d,g --- d,g - Neutropenia by the Eastern Cooperative Oncology Group (ECOG), patients
Neurotoxicityh < 500/mm3 79 76 48 50 were randomized to either TAXOL (paclitaxel) Injection (T)
- Any symptoms 87 d 52 d 25 20 - Thrombocytopenia 135 mg/m2 as a 24-hour infusion in combination with cisplatin
- Severe symptoms 21 d 2d 3d --- d < 50,000/mm3 27 25 11 11 (c) 75 mg/m2, TAXOL (T) 250 mg/m2 as a 24-hour infusion in
Nausea and Vomiting - Anemia combination with cisplatin (c) 75 mg/m2 with G-CSF support, or
- Any symptoms 88 93 65 69 < 8 g/dL 17 21 8 8 cisplatin (c) 75 mg/m2 on day 1, followed by etoposide(VP) 100
- Infections 6 14 5 6 mg/m2 on days 1, 2 and 3 (control).
- Severe symptoms 18 2 10 11
Myalgia/Arthralgia - Fever without Infection 3 <1 1 The following table shows the incidence of important adverse
Hypersensitivity events.
- Any symptoms 60 d 27 d 9d 2d
- Severe symptoms 6 d 1 d 1 --- Reaction f 1 4 1 2 Table 15: Frequencya of Important Adverse Events in the
Cardiovascular Events 1 2 1 2 Phase 3 Study for First-Line NSCLC
Diarrhea
- Any symptoms 37 d 29 d 16 d 8d Neuromotor Toxicity 1 1 <1 1 Percent of Patients
- Severe symptoms 2 3 4 1 Neurosensory Toxicity 3 <1 3 T135/24b T250/24c VP100d
Asthenia Myalgia/Arthralgia 2 <1 2 c75 c75 c75
- Any symptoms NC NC 17 d 10 d Nausea/Vomiting 13 18 8 9 (n=195) (n=197) (n=196)
- Severe symptoms NC NC 1 1 Mucositis 13 4 6 5 Bone Marrow
a Based on worst course analysis.
Alopecia - Neutropenia < 2,000/mm3 89 86 84
b Severe events are dened as at least Grade III toxicity.
- Any symptoms 96 d 89 d 55 d 37 d < 500/mm3 74e 65 55
c Patients received 600 mg/m2 cyclophosphamide and
- Severe symptoms 51 d 21 d 6 8 - Thrombocytopenia < normal 48 68 62
a Based on worst course analysis. doxorubicin (AC) at doses of either 60 mg/m2, 75 mg/m2, or 90
< 50,000/mm3 6 2 16
b TAXOL (T) dose in mg/m2/infusion duration in hours. mg/m2 (with prophylactic G-CSF support and ciprooxacin),
every 3 weeks for four courses. - Anemia < normal 94 96 95
c Cyclophosphamide (C) or cisplatin (c) dose in mg/m2. d TAXOL (T) following four courses of AC at a dose of 175 < 8 g/dL 22 19 28
d p<0.05 by Fisher exact test. mg/m2/3 hours every 3 weeks for four courses. - Infections 38 31 35
e <130,000/mm3 in the Intergroup study. e The incidence of febrile neutropenia was not reported in this Hypersensitivity Reactionf
f <12 g/dL in the Intergroup study. study. - All 16 27 13
g All patients received premedication. f All patients were to receive premedication.
- Severe 1 4e 1
h In the GOG-111 study, neurotoxicity was collected as peripheral The incidence of an adverse event for the total population likely Arthralgia/Myalgia
neuropathy and in the Intergroup study, neurotoxicity was represents an underestimation of the actual incidence given that - Any symptoms 21e 42e 9
collected as either neuromotor or neurosensory symptoms. safety data were collected differently based on enrollment cohort. - Severe symptoms 3 11 1
Severe events are dened as at least Grade III toxicity. However, since safety data were collected consistently across Nausea/Vomiting
NC Not Collected. regimens, the safety of the sequential addition of TAXOL
- Any symptoms 85 87 81
following AC therapy may be compared with AC therapy alone.
Second-Line Ovary: For the 403 patients who received single- Compared to patients who received AC alone, patients who - Severe symptoms 27 29 22
agent TAXOL (paclitaxel) Injection in the Phase 3 second-line received AC followed by TAXOL experienced more Grade III/IV Mucositis
ovarian carcinoma study, the following table shows the incidence neurosensory toxicity, more Grade III/IV myalgia/arthralgia, more - Any symptoms 18 28 16
of important adverse events. Grade III/IV neurologic pain (5% vs 1%), more Grade III/IV u - Severe symptoms 1 4 2
Table 12: Frequencya of Important Adverse Events like symptoms (5% vs 3%), and more Grade III/IV hyperglycemia Neuromotor Toxicity
in the Phase 3 Second-Line Ovarian Carcinoma Study (3% vs 1%). During the additional four courses of treatment with
- Any symptoms 37 47 44
TAXOL, two deaths (0.1%) were attributed to treatment. During
Percent of Patients - Severe symptoms 6 12 7
TAXOL treatment, Grade IV neutropenia was reported for 15%
175/3b 175/24b 135/3b 135/24b of patients, Grade II/III neurosensory toxicity for 15%, Grade II/ Neurosensory Toxicity
(n=95) (n=105) (n=98) (n=105) III myalgias for 23%, and alopecia for 46%. - Any symptoms 48 61 25
Bone Marrow The incidences of severe hematologic toxicities, infections, - Severe symptoms 13 28e 8
- Neutropenia < 2,000/mm3 78 98 78 98 mucositis, and cardiovascular events increased with higher doses Cardiovascular Events
< 500/mm3 27 75 14 67 of doxorubicin. - Any symptoms 33 39 24
- Thrombo- Breast Cancer After Failure of Initial Chemotherapy: For the - Severe symptoms 13 12 8
458 patients who received single-agent TAXOL in the Phase 3
cytopenia < 100,000/mm3 4 18 8 6 a Based on worst course analysis.
breast carcinoma study, the following table shows the incidence
< 50,000/mm3 1 7 2 1 of important adverse events by treatment arm (each arm was
b TAXOL (T) dose in mg/m2/infusion duration in hours;
- Anemia < 11 g/dL 84 90 68 88 administered by a 3-hour infusion). cisplatin (c) dose in mg/m2.
< 8 g/dL 11 12 6 10 c TAXOL dose in mg/m2/infusion duration in hours with G-
Table 14: Frequencya of Important Adverse Events in
- Infections 26 29 20 18 the Phase 3 Study of Breast Cancer After Failure of CSF support; cisplatin dose in mg/m2.
Hypersensitivity Reactionc Initial Chemotherapy or Within 6 Months of Adjuvant d Etoposide (VP) dose in mg/m2 was administered I.V. on days
- All 41 45 38 45 Chemotherapy 1, 2 and 3; cisplatin dose in mg/m2.

Percent of Patients e p<0.05.
- Severe 2 0 2 1
175/3b 135/3b f All patients received premedication.
Peripheral Neuropathy
- Any symptoms 63 60 55 42 (n=229) (n=229) Severe events are dened as at least Grade III toxicity.
- Severe symptoms 1 2 0 0 Bone Marrow
Toxicity was generally more severe in the high-dose TAXOL
Mucositis - Neutropenia < 2,000/mm3 90 81
(paclitaxel) Injection treatment arm (T250/c75) than in the low-dose
< 500/mm3 28 19
- Any symptoms 17 35 21 25 3 TAXOL arm (T135/c75). Compared to the cisplatin/etoposide
- Thrombocytopenia < 100,000/mm 11 7
- Severe symptoms 0 3 0 2 3 arm, patients in the low-dose TAXOL arm experienced more
< 50,000/mm 3 2
a Based on worst course analysis. arthralgia/myalgia of any grade and more severe neutropenia. The
- Anemia < 11 g/Dl 55 47
b TAXOL dose in mg/m2/infusion duration in hours. incidence of febrile neutropenia was not reported in this study.
< 8 g/dL 4 2
c All patients received premedication. Kaposis Sarcoma: The following table shows the frequency of
- Infections 23 15
important adverse events in the 85 patients with KS treated with
Severe events are dened as at least Grade III toxicity. - Febrile Neutropenia 2 2
two different single-agent TAXOL regimens.
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SPDI
Table 16: Frequencya of Important Adverse Events in the a lower dose intensity and supportive care. (See CLINICAL tachycardia (2%) and hypertension (1%). The frequency of
AIDS-Related Kaposis Sarcoma Studies STUDIES: AIDSRelated Kaposis Sarcoma.) Toxicities that hypersensitivity reactions remained relatively stable during the
Percent of Patients were observed only in or were noted to have occurred with greater entire treatment period.
Study Study severity in the population with Kaposis sarcoma and that occurred Rare reports of chills and reports of back pain in association
CA139-174 CA139-281 with a difference that was clinically signicant in this population with hypersensitivity reactions have been received as part of the
TAXOL are described. continuing surveillance of TAXOL safety.
TAXOL
135/3b q 3 wk 100/3b q 2 wk Hematologic: Bone marrow suppression was the major dose- Cardiovascular: Hypotension, during the rst 3 hours of
(n=29) (n=56) limiting toxicity of TAXOL. Neutropenia, the most important infusion, occurred in 12% of all patients and 3% of all courses
Bone Marrow hematologic toxicity, was dose and schedule dependent and was administered.
- Neutropenia < 2,000/mm3

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Saudi Food and Drug Authority, 2008

King Fahd National Library Cataloging-in-Publication Data

All rights reserved. No part of this publication may be printed, stored in a

Saudi food and Drug Authority

Prof. Mohammed AL-Kanhal Prof. Saleh Bawazir

Part A Page No.

Brand Name Index

Generic Name Index

Product Identification Guide

Guide to Controlled Substance Category

Guide to use-in-pregnancy ratings :

Use in pregnancy rating system weighs the degree to which available

Brand Name Index

Generic Name Index

Product Identification Guide

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