Doxofylline SR+ Montelukast

(Fixed Dose Combination)

Asthma - Definition
Asthma is a Chronic inflammatory
disease characterized by Airway hyperesponsiveness to a variety of stimuli resulting in Bronchospasm which reverses

spontaneously - on treatment

Prevalence of Asthma

Asthma affects 300 million adults and children worldwide Estimated prevalence of asthma is increasing 50% per decade WHO: 15-20 million asthmatics in India Children: 12% and Adults 5%

Basic Cellular Mechanisms

FIRST EXPOSURE Sensitization process
SECOND EXPOSURE Early allergic reaction Late allergic reaction

1st exposure

Allergic Response
Allergen
SENSITIZA TION PHA SE

Body produces IgE antibodies

Enters the body

An tibodies + Allergens

Sensitization

Mast cell
Y
Y Y

Excess antibodies Bind to mast cells

Produce Inflammatory mediators (histamine) (not released)

Y
Y

Allergic Response
2 n d e x p o s u r e
IgE antibody
Allergen

Chemotactic Factors

Histamine

5-30 minutes after exposure

EARLY ALLERGIC RESPONSE (EAR)

Allergic Response
2 n d e x p o s u r e
C h e m o t a c t i c F a c t o r s
Migration & Activation

Basophils

EOSINOPHILS

Neutrophils

Secondary Mediators

ECP ; MBP

D a m a g e t o E p i t h e l i a l c e l l s ( t h i s e x p o s e s t h e p a r a s y m p a t h e t i c n e r v e s )

INFLAMMATION Bronchoconstriction Mucus production Ciliary activity V asodilation

LATE ALLERGIC RESPONSE (LAR)

REDNESS, SW ELLING

between 3-11 hours after exposure

Drugs
Relievers

Controllers

For treatment of

For long term control

bronchospasm and
to relieve acute attacks

of inflammation and
to prevent further attacks

What Are Relievers?

-

Rescue medications Quick relief of symptoms(within 2 min) Used during acute attacks Action lasts 4-6 hrs

Relievers

Short acting beta 2 agonists

Inhaled

salbutamol Inhaled levosalbutamol

What are Controllers?

-

Prevent future attacks Long term control of asthma Prevent airway remodeling

Controllers
Inhaled

Oral

Corticosteroids(ICS)

Leukotriene antagonists

Cromolyn sodium
Long acting inhaled

Theophylline - SR
Oral prednisolone

2-agonists (LABA)

Stepwise Approach to Asthma Therapy - Adults

Outcome: Asthma Control
Outcome: Best Possible Results

Controller:

Controller: Controller: Controller:

None Daily inhaled corticosteroid

Daily inhaled corticosteroid Daily long-acting inhaled 2-agonist

Daily inhaled corticosteroid Daily long acting inhaled 2-agonist plus (if needed)

When asthma is controlled, reduce therapy Monitor

-Theophylline-SR - Doxofylline -Anti-Leukotriene -Long-acting inhaled 2- agonist -Oral corticosteroid

Reliever:
STEP 1: Intermittent

Rapid-acting inhaled 2-agonist prn

STEP 2: Mild Persistent STEP 3: Moderate Persistent STEP 4: Severe Persistent STEP Down

Alternative controller and reliever medications may be considered

Doxofylline SR+ Montelukast

Compound: Doxofylline SR+ Montelukast

Indication: Bronchial Asthma

Formulation: Oral tablet preparation

Dose: Doxofylline SR 400 mg+ Montelukast 10 mg

MOA: Bronchodilator and leukotriene receptor antagonist

Doxofylline SR
Doxofylline SR is a sustained release formulation of the newer methylxanthine, Doxofylline, which needs to be given once daily

Mechanism of action
Inhibition of phosphodiesterase activity, leading to increase in the amount of cAMP in the cells.
Adenly cylase ATP Phosphodiesterase cAMP AMP

Protein Kinase Decrease intracellular calcium

Bronchodilation

Montelukast

Montelukast is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene (CysLT1) receptor

Physiology of Inflammation
Arachidonic Acid Metabolism
Chemical & Mechanical stimuli activates Phospholipase A

Harmful Stimulus

Cell Perturbation (agitation or disturbance)

Liberates Membrane Phospholipids
Release

ARACHIDONIC ACID (AA)

Lipoxygenase

Cyclo-oxygenase Endoperoxides PGG2 LEUKOTRIENES PROSTAGLANDINS PGE2 PGD2 PGF2a PROSTACYCLINS PGI2 THROMBOXANE TXA2 PGH2

Hydroperoxides

STOMACH, KIDNEYS

BLOOD VESSEL WALL

PLATELETS

LTD4 LTD4
Montelukast
Leukotriene Receptor (CysLT1)

LTD4

Montelukast is a selective leukotriene receptor antagonist that blocks LTD4, a substance correlated with the pathophysiology of allergic conditions which are associated with the inflammatory process

Airway cell (eosinophil, smooth muscle cell, etc.)

Inflammatory Effects of Leukotrienes in the Airways

Increased mucus secretion Decreased mucus transport Cationic proteins (Epithelial cell damage)

Airway Epithelium

Increased release of tachykinins Eosinophil recruitment

Blood vessel

CysLTs

Sensory C fibres
Smooth muscle

Oedema
Inflammatory Cells (e.g., Mast Cells, Eosinophils)

Contraction and proliferation

Adapted from Hay DW. Chest 1997;111:35S45S.

Pharmacokinetic Properties
Doxofylline Oral bioavailability: 62.6% Protein binding: 48% Tmax: 1.19 hrs 90% of drug metabolized in the liver Renal excretion: 4% Half life: 7-10 hrs Montelukast Oral bioavailability: 64% Tmax: 3-4 hrs Metabolized by the liver Renal excretion: < 0.2% Half life: 2.7-5.5 hrs

Low affinity of Doxofylline for Adenosine receptors

In vitro information studies have showed a much lower affinity of doxofylline for Adenosine receptors

Enprofylline

Bamifylline

Theophylline
Theophylline

Aminophylline

Doxofylline
0 0.5 1 1.5 2 2.5

Affinities for adenosine A1 receptors

Affinities of various methylxanthines for Adenosine A1 receptors

Curr Med Res Opin 2001; 16(4): 258-268

Enprofylline

Bamifylline

Theophylline

Decreased affinities towards adenosine A1 and A2 receptors reduces the unwanted extrapulmonary side effects Aminophylline (accounts for its better safety profile) The A1 and A2 antagonism is 10-20 times lower for doxofylline than theophylline 0 0.5 1 1.5 2 2.5
Affinities for adenosine A2 receptors Doxofylline

Affinities of various methylxanthines for Adenosine A2 receptors

Curr Med Res Opin 2001; 16(4): 258-268

Efficacy of Doxofylline

Study done on 346 patients with bronchial asthma for a duration of 12 weeks Drugs: Doxofylline 400 mg, Doxofylline 200 mg, Theophylline 250 mg and Placebo. There was a significant improvement in FEV1 with doxofylline and theophylline vs placebo There was a remarkable reduction in the asthma attack rate and albuterol use with doxofylline and theophylline Significantly more patients interrupted treatment because of adverse events with theophylline as compared to doxofylline

Med Sci Monit, 2002; 8(4): CR 297-304

Anti-inflammatory effects of Doxofylline

Bronchial biopsies were performed in 14 patients with chronic obstructive bronchitis to assess the presence or absence of neutrophilic infiltration, oedema, fibrosis and epithelial metaplasia before and after treatment for 3 months with Doxofylline 400 mg bid.

Results: 57% of patients showed absence of lesions in the doxofylline group. In the control group (placebo), absence of lesions was observed in 14% of patients.

Eur Rev Med Pharmacol Sci 2000; 4: 15-20

Safety of Doxofylline
In a series of 10 patients with COPD, no significant changes were noted in heart rate, compared with baseline values, during or after infusion of Doxofylline 400 mg IV or placebo as assessed by 24 hr Holter monitoring. Mean heart rate rose significantly during treatment with Aminophylline 240 mg IV.
Curr Med Res Opin 2001; 16(4): 258-268

Volume of gastric acid output and pepsin output was significantly less with doxofylline IV as compared to aminophylline IV Aliment Pharmacol Therap 1990; 4: 643-649 The number of arousals per hour during sleep was significantly increased in the theophylline group along with a reduction in the sleep efficiency. Doxofylline had no impact on the sleep arousals or the efficiency. Monaldi Arch Chest Dis 1995; 50:2; 98-103

Montelukast in asthma

There was a significant improvement in FEV1 and a significant reduction in beta agonist use (puffs/day) during 3 months randomized double blind treatment with montelukast 10 mg/day or placebo in 681 patients with asthma

Drugs 1998; 56(2): 251-256

Reduction of ICS use with Montelukast

In a 6 weeks study on 226 patients with stable asthma, clinically significant tapering of inhaled corticosteroid therapy was possible during treatment with montelukast 10 mg/day as compared to placebo.

Drugs 1998; 56(2): 251-256

Clinical benefits of Montelukast in SAR

A Multicenter, randomized, double-blind, placebo controlled study in which patients with SAR were randomly assigned to treatment with montelukast 10 mg (n=522) or placebo (n=171) once daily at bedtime for 2 weeks. Outcomes: Daytime nasal symptom score (mean score of congestion, rhinorrhea, pruritus and sneezing) Nighttime symptoms (mean score of difficulty in going to sleep, nighttime awakenings, nasal congestion on awakening) Result: Therapy with montelukast significantly improved the overall nasal symptom scores as compared with placebo.
Ann Allergy Asthma Immunol 2003;90:214-222

Tolerability of Montelukast

Tolerability data are available from 1955 adult patients who participated in placebo controlled clinical trials evaluating montelukast at a dose of 10 mg/kg. The most common adverse events were headache, cough, influenza and abdominal pain All adverse events were considered mild and self limiting and none required active treatment.

Drugs 1998; 56(2): 251-256

Rationale for combination

Doxofylline is an oral bronchodilator while montelukast is an oral anti-antileukotriene agent Both have separate mode of action and when combined will lead to an additive effect Asthmatic patients have bronchospasm and airway inflammation and this combination will be effective against both the aspects of asthma pathology The combination can be given once daily and hence there is compatibility in dosing

Indications

Prophylaxis and chronic treatment of asthma in adults 14 yrs of age and older

Dosage and Administration

The oral dose of the fixed dose combination will be Doxofylline SR 400 milligrams (mg) + Montelukast 10 mg to be taken once daily

Common adverse events

Dyspepsia, abdominal pain, rash, nasal congestion, dizziness, headache, cramps and palpitations. Occasionally vomiting and diarrhoea may occur.

Contraindications
Hypersensitivity to methylxanthines, montelukast and any other component of this product

USP of Doxofylline SR+ Montelukast

Combination of the safest xanthine bronchodilator with a safe oral anti-inflammatory agent Doxofylline has also shown to have some anti-inflammatory action Both the drugs have shown good efficacy and tolerability in patients with asthma. Once daily dosing Devoid of steroid side effects Drug of choice for patients not willing to take inhaled drugs For asthmatic patients not responding to high dose steroids Can help reduce the dose of inhaled steroids and also lessen the use of inhaled salbutamol. Effective for asthmatic patients with co-existing AR