Drug Interaction Report PDF

7/4/2019 Drug Interaction Report - Drugs.
com
Drug Interaction Report

Drug interactions for the following 61 drug(s):
My Interactions List: (Unsaved)
amoxicillin
tranexamic acid
glimepiride
loperamide
ibuprofen
guaifenesin
methylprednisolone
omeprazole
kaolin / pectin
The interactions information for this drug may not be up-to-date. More...
aminophylline
acyclovir
hydrocortisone
gentamicin
diclofenac
ciprofloxacin
attapulgite
amlodipine
cefixime
https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,2378-… 1/111
7/4/2019 Drug Interaction Report - Drugs.com
lansoprazole
dimenhydrinate
hyoscyamine
metoclopramide
acetylcysteine
nifedipine
captopril
sodium bicarbonate
glycerin / phenol
metformin
ketoconazole
metronidazole
nystatin
folic acid
allopurinol
doxycycline
ketoconazole
clindamycin
chloramphenicol
Cotrim (sulfamethoxazole / trimethoprim)
albuterol
mefenamic acid
Aceta (acetaminophen)
Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
ranitidine
Zinc (zinc sulfate)
isosorbide dinitrate
chloramphenicol
acyclovir
miconazole
permethrin
Vitamin C (ascorbic acid)
Vitamin B12 (cyanocobalamin)
Vitamin B1 (thiamine)
Vitamin B6 (pyridoxine)
Vitamin K (phytonadione)
calcium lactate
ferrous fumarate / folic acid
simvastatin
dexamethasone
chlorpheniramine
loratadine
cetirizine
Interactions between your drugs
Major
captopril  allopurinol
Applies to: captopril, allopurinol
MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE)

inhibitors has been associated with a risk of severe hypersensitivity reactions, neutropenia,
agranulocytosis, and serious infections. The mechanism of interaction is unknown, but impaired renal
function may be a predisposing factor. Case reports, albeit rare, have mostly involved captopril. Fever,
myalgia, arthralgia, exfoliative dermatitis, and Stevens-Johnson syndrome (including one fatality) have
been reported, with the latter occurring 3 to 5 weeks after initiation of allopurinol. In an isolated case
involving enalapril, a man who had been receiving enalapril without incident developed generalized
pruritus, urticaria, severe chest pain, severe nausea, peripheral cyanosis, hypotension, sinus
tachycardia, and mild bronchospasm approximately 20 minutes after the first dose of allopurinol 100
mg prescribed for acute gout. Serial electrocardiograms and cardiac enzyme studies revealed
evidence of acute myocardial infarction. Following recovery, the patient continued to take enalapril
uneventfully without allopurinol. No pharmacokinetic interactions have been reported between
allopurinol and ACE inhibitors. In a study of 12 healthy volunteers, allopurinol had no significant
effect on the bioavailability of captopril.
MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor,

particularly in the elderly and patients with renal impairment. Periodic monitoring of white blood cell
counts is recommended. Patients should be advised to promptly discontinue these medications and
seek medical attention if they develop dyspnea; throat constriction; swelling of the face, lips, or
tongue; urticaria; rash; fever; arthralgia; or myalgia. Patients should also contact their physician if they
notice signs of infection or experience fever, chills, sore throat, lethargy, body aches, or other flu-like
symptoms.
References
1. Pennell DJ, Nunan TO, O'Doherty MJ, Croft DN "Fatal Stevens-Johnson syndrome in a patient on captopril and allopurinol." Lancet 1 (1984): 463
2. EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports. Available from: URL:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landingpage.jsp&mid."
3. Ahmad S "Allopurinol and enalapril: drug induced anaphylactic coronary spasm and acute myocardial infarction." Chest 108 (1995): 586
View all 6 references
Major
captopril  trimethoprim
Applies to: captopril, Cotrim (sulfamethoxazole / trimethoprim)
MONITOR CLOSELY: The use of trimethoprim in combination with other potassium-sparing drugs or
potassium salts may increase the risk of hyperkalemia. Trimethoprim inhibits sodium reabsorption
and potassium excretion by blocking sodium channels in the renal distal tubules. Studies of patients
treated with standard and high dosages of trimethoprim-sulfamethoxazole compared to similar
controls treated with other antibiotics indicate that reversible increases in serum potassium are fairly
common with trimethoprim use. Although generally asymptomatic, severe hyperkalemia including
metabolic acidosis, paralysis, nonoliguric renal failure, and ventricular arrhythmia have been reported.
Risk factors for developing hyperkalemia include use of high dosages of trimethoprim (e.g., for the
treatment of MRSA skin infections or Pneumocystis jiroveci pneumonia (PCP) in AIDS patients); renal
impairment or age-related decline in renal function; aldosterone or adrenal insufficiency; concomitant
use of drugs that increase the risk of hyperkalemia (e.g., ACE inhibitors, angiotensin II receptor
blockers, aldosterone antagonists; potassium-sparing diuretics); diets with potassium-rich foods (e.g.,
tomatoes, raisins, figs, baked potatoes, bananas, papayas, pears, cantaloupe, mangoes); and use of
potassium salt substitutes.
MANAGEMENT: Serum potassium and sodium levels as well as renal function should be closely
monitored during coadministration of trimethoprim with other potassium-sparing drugs or
potassium salts, particularly in patients receiving high-dose or long-term trimethoprim treatment and
in patients with renal impairment, diabetes, old age, severe or worsening heart failure, or dehydration.
A dosage reduction of trimethoprim is recommended in renal dysfunction (50% reduction for CrCl
between 15 and 30 mL/min). Patients should be given dietary counseling to avoid excessive intake of
potassium-rich foods and salt substitutes, and advised to seek medical attention if they experience
signs and symptoms of hyperkalemia such as nausea, vomiting, weakness, listlessness, tingling of the
extremities, paralysis, confusion, weak pulse, and a slow or irregular heartbeat. Trimethoprim should
be discontinued if hyperkalemia occurs.
References
1. Canaday DH, Johnson JR "Hyperkalemia in elderly patients receiving standard doses of trimethoprim-sulfamethoxazole." Ann Intern Med 120
(1994): 438
2. Alappan R, Perazella MA, Buller GK "Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole." Ann Intern Med 124
(1996): 316-20
3. Witt JM, Koo JM, Danielson BD "Effect of standard-dose trimethoprim/sulfamethoxazole on the serum potassium concentration in elderly men."
Ann Pharmacother 30 (1996): 347-50
Major ciprofloxacin  methylPREDNISolone

Applies to: ciprofloxacin, methylprednisolone
MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of

tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is
unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although
cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been
reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can
occur during or up to several months after completion of fluoroquinolone therapy.
MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with

corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years;
recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the
fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if
they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only
be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if
the benefits outweigh the risks.
References
1. Khaliq Y, Zhanel GG "Fluoroquinolone-Associated Tendinopathy: A Critical Review of the Literature." Clin Infect Dis 36 (2003): 1404-1410
2. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH "Increased risk of achilles tendon rupture with quinolone
antibacterial use, especially in elderly patients taking oral corticosteroids." Arch Intern Med 163 (2003): 1801-7
3. "Product Information. Cipro (ciprofloxacin)." Bayer, West Haven, CT.
Major ciprofloxacin  glimepiride

Applies to: ciprofloxacin, glimepiride
MONITOR CLOSELY: Quinolone antibiotics may interfere with the therapeutic effects of insulin and
other antidiabetic agents. The use of quinolones has been associated with disturbances in blood
glucose homeostasis possibly stemming from effects on pancreatic beta cell ATP-sensitive potassium
channels that regulate insulin secretion. Both hyperglycemia and hypoglycemia have been reported,
usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent or
insulin. Although hyperglycemia is significantly more common and infection itself may be an
underlying risk factor, hypoglycemia may cause greater morbidity and mortality. An internal safety
review conducted by the U.S. Food and Drug Administration (FDA) identified at least 67 reports of
severe hypoglycemia associated with quinolone use resulting in coma, death, or permanent and
disabling injuries, primarily in elderly and diabetic patients with renal impairment and/or complicated
infections. This is in addition to the numerous cases that have been reported for gatifloxacin, which
led to its withdrawal from the U.S. market in 2008. Of the five quinolones that the FDA reviewed,
levofloxacin had the most cases (44), followed by ciprofloxacin (12), moxifloxacin (9), ofloxacin (2),
and gemifloxacin (0). Other quinolones such as nalidixic acid and norfloxacin, as well as some others
that have never been marketed or are no longer marketed such as clinafloxacin and temafloxacin,
have also been associated with dysglycemia, thus it is generally believed to be a class effect, albeit
with varying risks amongst the individual agents. Available data also seem to indicate different time
frames for the development of hypo- and hyperglycemia, with the former generally occurring within
1 to 3 days following quinolone initiation and the latter within 4 to 10 days later. Pharmacokinetically,
ciprofloxacin is also a known inhibitor of CYP450 1A2 and 3A4 and may inhibit the hepatic
metabolism of glyburide. Hypoglycemia in association with elevated serum glyburide level occurred
in a patient after one week of ciprofloxacin therapy.
MANAGEMENT: Blood glucose should be closely monitored whenever quinolones are prescribed to
diabetic patients, especially if they are elderly, have renal impairment, or are severely ill. Due to the
risk of profound and potentially life-threatening hypoglycemia, particular caution is advised during
concomitant use of insulin and insulin secretagogues (e.g., sulfonylureas, meglitinides). Patients
should also be apprised of the increased risk of hypoglycemia and be alert to potential signs and
symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger,
weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients should initiate
appropriate remedial therapy immediately, discontinue the quinolone, and contact their physician.
Alternative antibiotics may need to be considered.
References
2. Park-Wyllie LY, Juurlink DN, Kopp A, et al. "Outpatient gatifloxacin therapy and dysglycemia in older adults." N Engl J Med 354 (2006): 1352-61
3. Saraya A, Yokokura M, Gonoi T, Seino S "Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K(+) channels." Eur J
Pharmacol 497 (2004): 111-7
Major
ciprofloxacin  aminophylline
Applies to: ciprofloxacin, aminophylline
GENERALLY AVOID: Coadministration with ciprofloxacin may significantly increase the serum
concentrations of theophylline and the associated risk of toxicity. The mechanism is ciprofloxacin
inhibition of theophylline metabolism via CYP450 1A2. Case reports and pharmacokinetic studies
indicate that ciprofloxacin 500 mg to 750 mg twice daily can reduce the clearance of theophylline by
approximately 20% to 65%, resulting in toxic theophylline levels and/or clinical toxicity in some
patients. Up to fourfold increases in theophylline serum levels have been reported, with onset of
clinical toxicity as early as two to three days and typically within a week of initiating ciprofloxacin.
However, the interaction is subject to a high degree of interpatient variability and does not
consistently produce clinically significant pharmacokinetic changes. Serious and severe reactions have
included cardiac arrest, seizure, status epilepticus, respiratory failure, and even death. Seizures may
also occur in the absence of toxic theophylline levels due to additive inhibitory effect of ciprofloxacin
and theophylline on gamma-aminobutyric acid (GABA) receptor sites. Because elderly patients and
patients with chronic obstructive pulmonary disease, congestive heart failure, or cirrhosis generally
have lower theophylline clearance rates, they may be particularly vulnerable to theophylline toxicity.
Theophylline does not appear to alter the pharmacokinetics of ciprofloxacin and other quinolones.
MANAGEMENT: The use of theophylline or its salts in combination with ciprofloxacin should generally
be avoided. If coadministration is required, theophylline dosage may need to be reduced.
Pharmacologic response and serum levels should be closely monitored following initiation,
discontinuation or change of dosage of ciprofloxacin, and the theophylline dosage adjusted
accordingly. Patients should be advised to contact their physician if they experience signs and
symptoms suggestive of theophylline toxicity such as nausea, vomiting, diarrhea, anorexia, headache,
tremor, irritability, confusion, insomnia, seizure, palpitation, and arrhythmia. Other quinolones
including gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin have been reported to cause minor
or no changes in theophylline levels at normally recommended dosages and may be safer
alternatives in theophylline-treated patients.
References
1. Wijnands WJ, Vree TB "Interaction between the fluoroquinolones and the bronchodilator theophylline." J Antimicrob Chemother 22 (1988): 109-14
2. Davis RL, Quenzer RW, Kelly HW, Powell JR "Effect of the addition of ciprofloxacin on theophylline pharmacokinetics in subjects inhibited by
cimetidine." Ann Pharmacother 26 (1992): 11-3
3. Bem JL, Mann RD "Danger of interaction between ciprofloxacin and theophylline." Br Med J (Clin Res Ed) 296 (1988): 1131
Major
ciprofloxacin  dexamethasone
Applies to: ciprofloxacin, dexamethasone
MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of

tendinitis and tendon rupture associated with fluoroquinolone treatment. The mechanism is
unknown. Tendinitis and tendon rupture have most frequently involved the Achilles tendon, although
cases involving the rotator cuff (the shoulder), the hand, the biceps, and the thumb have also been
reported. Some have required surgical repair or resulted in prolonged disability. Tendon rupture can
occur during or up to several months after completion of fluoroquinolone therapy.
MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with

corticosteroids, particularly in patients with other concomitant risk factors (e.g., age over 60 years;
recipient of kidney, heart, and/or lung transplant). Patients should be advised to stop taking the
fluoroquinolone, avoid exercise and use of the affected area, and promptly contact their physician if
they experience pain, swelling, or inflammation of a tendon. In general, fluoroquinolones should only
be used to treat conditions that are proven or strongly suspected to be caused by bacteria and only if
the benefits outweigh the risks.
References
1. Khaliq Y, Zhanel GG "Fluoroquinolone-Associated Tendinopathy: A Critical Review of the Literature." Clin Infect Dis 36 (2003): 1404-1410
2. van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Stricker BH "Increased risk of achilles tendon rupture with quinolone
antibacterial use, especially in elderly patients taking oral corticosteroids." Arch Intern Med 163 (2003): 1801-7
Major raNITIdine  loperamide

Applies to: ranitidine, loperamide
MONITOR CLOSELY: Coadministration with drugs that enhance the gastrointestinal absorption or
inhibit the metabolism of loperamide (e.g., potent CYP450 3A4 or 2C8 inhibitors) may increase the
plasma concentrations and adverse effects of loperamide. When a single 16 mg dose of loperamide
was administered to 12 healthy volunteers with a single 600 mg dose of ritonavir, a potent CYP450
3A4 inhibitor, median loperamide systemic exposure (AUC) increased by 223% compared to
administration with placebo. Likewise, administration of a single 4 mg dose of loperamide to 12
healthy volunteers on day 3 of treatment with the potent CYP450 2C8 inhibitor gemfibrozil (600 mg
twice day for 5 days) increased loperamide peak plasma concentration (Cmax) and AUC by 1.6- and
2.2-fold, respectively, and prolonged its elimination half-life from 11.9 to 16.7 hours. The same study
also found that gemfibrozil had substantial additive effects with itraconazole, a strong CYP450 3A4
and P-glycoprotein inhibitor, on the pharmacokinetics of loperamide. Whereas itraconazole (100 mg
twice daily for 5 days) alone increased the Cmax and AUC of loperamide by 2.9- and 3.8-fold,
respectively, gemfibrozil combined with itraconazole increased loperamide Cmax and AUC by 4.2-
and 12.6-fold, respectively. The elimination half-life of loperamide was 18.7 hours during
coadministration of itraconazole, compared to 36.9 hours during coadministration of gemfibrozil plus
itraconazole. High levels of loperamide, including through abuse or misuse, has been associated with
serious and potentially fatal cardiac adverse events such as syncope, cardiac arrest, and arrhythmia
related to prolongation of the QT interval. According to the FDA, the agency received reports of 48
cases of serious heart problems associated with use of loperamide from when it was first approved in
1976 through 2015. Thirty-one of these cases resulted in hospitalizations, and 10 patients died. The
serious heart problems occurred mostly in patients who were using loperamide dosages that were
much higher than recommended in an attempt to achieve euphoria, prevent opioid withdrawal, or
treat diarrhea. In the most severe cases, individuals self-treated with dosages ranging from 70 to
1600 mg/day, or 4 to 100 times the recommended dosage. In other cases, patients were taking the
recommended dosage, but with concomitant interacting drugs that caused an increase in loperamide
levels. There have been additional cases of serious heart problems associated with loperamide use
reported in the medical literature.
MANAGEMENT: Caution is recommended if loperamide is used with drugs that enhance its
gastrointestinal absorption or inhibit its metabolism. Particular caution is advised when drugs that
inhibit CYP450 3A4 (e.g., azole antifungal agents, clarithromycin, cobicistat, conivaptan, delavirdine,
erythromycin, idelalisib, nefazodone, protease inhibitors, telithromycin) and CYP450 2C8 (e.g.,
gemfibrozil, clopidogrel) are used together with loperamide, or when one or more of these drugs are
combined with inhibitors of P-glycoprotein transport (e.g., amiodarone, cyclosporine, diltiazem,
dronedarone, quinidine, verapamil), since they may act synergistically to increase loperamide
concentrations. Patients should be counseled to not exceed the recommended dosage and frequency
or duration of use of loperamide, and to seek prompt medical attention if they experience symptoms
that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting,
palpitation, irregular heart rhythm, shortness of breath, or syncope. If loperamide-induced
cardiotoxicity is suspected, promptly discontinue loperamide and initiate therapy to manage and
prevent cardiac arrhythmias and adverse outcomes. Electrical pacing or cardioversion may be
necessary if torsade de pointes persists despite pharmacotherapy. In many of the reported cases of
loperamide-induced cardiotoxicity, standard antiarrhythmic drugs were ineffective, and electrical
pacing or cardioversion was necessary.
References
1. Tayrouz Y, Ganssmann B, Ding R, et al. "Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement."
Clin Pharmacol Ther 70 (2001): 405-14
2. Eggleston W, Clark KH, Marraffa JM "Loperamide abuse associated with cardiac dysrhythmia and death." Ann Emerg Med 69 (2017): 83-6
3. "Product Information. Imodium (loperamide)." Janssen Pharmaceutica, Titusville, NJ.
Major ketoconazole  methylPREDNISolone

Applies to: ketoconazole, methylprednisolone
ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the
plasma concentrations of methylprednisolone. Various CYP450 3A4 inhibitors including
clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, mibefradil, nefazodone, and
troleandomycin have been shown to increase methylprednisolone systemic exposure (AUC) by
approximately 100% to 300%, with increased adrenal suppression as evidenced by reduced plasma
cortisol levels.
MANAGEMENT: The possibility of increased corticosteroid effects should be considered when

methylprednisolone is used with potent CYP450 3A4 inhibitors. Coadministration is not
recommended unless the potential benefit to the patient outweighs the risk. If concomitant use is
necessary, a 50% reduction in methylprednisolone dosage has been recommended by some
investigators. Patients should be monitored for signs and symptoms of hypercorticism such as acne,
striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity,
increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle
wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and
menstrual disorders. Other systemic glucocorticoid effects may include adrenal suppression,
immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in
children and adolescents. Following extensive use with a potent CYP450 3A4 inhibitor, a progressive
dosage reduction may be required over a longer period if methylprednisolone is to be withdrawn
from therapy, as there may be a significant risk of adrenal suppression. Signs and symptoms of
adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting,
fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as
inability to respond to stress (e.g., illness, infection, surgery, trauma).
References
1. Varis T, Backman JT, Kivisto KT, Neuvonen PJ "Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-
suppressant effect of oral methylprednisolone." Clin Pharmacol Ther 67 (2000): 215-21
2. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ "Plasma concentrations and effects of oral methylprednisolone are considerably increased by
itraconazole." Clin Pharmacol Ther 64 (1998): 363-8
3. Agencia Española de Medicamentos y Productos Sanitarios Healthcare "Centro de información online de medicamentos de la AEMPS - CIMA.
Available from: URL: https://cima.aemps.es/cima/publico/home.html." ([2018]):
Major ketoconazole  loperamide

Applies to: ketoconazole, loperamide
MONITOR CLOSELY: Coadministration with drugs that enhance the gastrointestinal absorption or
inhibit the metabolism of loperamide (e.g., potent CYP450 3A4 or 2C8 inhibitors) may increase the
plasma concentrations and adverse effects of loperamide. When a single 16 mg dose of loperamide
was administered to 12 healthy volunteers with a single 600 mg dose of ritonavir, a potent CYP450
3A4 inhibitor, median loperamide systemic exposure (AUC) increased by 223% compared to
administration with placebo. Likewise, administration of a single 4 mg dose of loperamide to 12
healthy volunteers on day 3 of treatment with the potent CYP450 2C8 inhibitor gemfibrozil (600 mg
twice day for 5 days) increased loperamide peak plasma concentration (Cmax) and AUC by 1.6- and
2.2-fold, respectively, and prolonged its elimination half-life from 11.9 to 16.7 hours. The same study
also found that gemfibrozil had substantial additive effects with itraconazole, a strong CYP450 3A4
and P-glycoprotein inhibitor, on the pharmacokinetics of loperamide. Whereas itraconazole (100 mg
twice daily for 5 days) alone increased the Cmax and AUC of loperamide by 2.9- and 3.8-fold,
respectively, gemfibrozil combined with itraconazole increased loperamide Cmax and AUC by 4.2-
and 12.6-fold, respectively. The elimination half-life of loperamide was 18.7 hours during
coadministration of itraconazole, compared to 36.9 hours during coadministration of gemfibrozil plus
itraconazole. High levels of loperamide, including through abuse or misuse, has been associated with
serious and potentially fatal cardiac adverse events such as syncope, cardiac arrest, and arrhythmia
related to prolongation of the QT interval. According to the FDA, the agency received reports of 48
cases of serious heart problems associated with use of loperamide from when it was first approved in
1976 through 2015. Thirty-one of these cases resulted in hospitalizations, and 10 patients died. The
serious heart problems occurred mostly in patients who were using loperamide dosages that were
much higher than recommended in an attempt to achieve euphoria, prevent opioid withdrawal, or
treat diarrhea. In the most severe cases, individuals self-treated with dosages ranging from 70 to
1600 mg/day, or 4 to 100 times the recommended dosage. In other cases, patients were taking the
recommended dosage, but with concomitant interacting drugs that caused an increase in loperamide
levels. There have been additional cases of serious heart problems associated with loperamide use
reported in the medical literature.
MANAGEMENT: Caution is recommended if loperamide is used with drugs that enhance its
gastrointestinal absorption or inhibit its metabolism. Particular caution is advised when drugs that
inhibit CYP450 3A4 (e.g., azole antifungal agents, clarithromycin, cobicistat, conivaptan, delavirdine,
erythromycin, idelalisib, nefazodone, protease inhibitors, telithromycin) and CYP450 2C8 (e.g.,
gemfibrozil, clopidogrel) are used together with loperamide, or when one or more of these drugs are
combined with inhibitors of P-glycoprotein transport (e.g., amiodarone, cyclosporine, diltiazem,
dronedarone, quinidine, verapamil), since they may act synergistically to increase loperamide
concentrations. Patients should be counseled to not exceed the recommended dosage and frequency
or duration of use of loperamide, and to seek prompt medical attention if they experience symptoms
palpitation, irregular heart rhythm, shortness of breath, or syncope. If loperamide-induced
cardiotoxicity is suspected, promptly discontinue loperamide and initiate therapy to manage and
prevent cardiac arrhythmias and adverse outcomes. Electrical pacing or cardioversion may be
necessary if torsade de pointes persists despite pharmacotherapy. In many of the reported cases of
loperamide-induced cardiotoxicity, standard antiarrhythmic drugs were ineffective, and electrical
pacing or cardioversion was necessary.
References
1. Tayrouz Y, Ganssmann B, Ding R, et al. "Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement."
Clin Pharmacol Ther 70 (2001): 405-14
3. "Product Information. Imodium (loperamide)." Janssen Pharmaceutica, Titusville, NJ.
Major
ketoconazole  simvastatin
Applies to: ketoconazole, simvastatin
CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly

increase the plasma concentrations of lovastatin and simvastatin as well as their pharmacologically
active metabolites, all of which are primarily metabolized by the isoenzyme. The interaction has been
https://www.drugs.com/interactions-check.php?drug_list=187-0,2224-0,1176-0,1482-0,1310-0,1200-0,1607-0,1750-0,1410-0,161-0,100-0,237… 10/111
reported with potent CYP450 3A4 inhibitors such as azole antifungal agents, macrolide antibiotics,
HIV protease inhibitors, and nefazodone. Clinically, high levels of HMG-CoA reductase inhibitory
activity in plasma may be associated with an increased risk of musculoskeletal toxicity. Myopathy
manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase
exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has
also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria
and may result in death.
MANAGEMENT: Due to the potential for severe interaction, concomitant use of lovastatin or
simvastatin with potent CYP450 3A4 inhibitors is considered contraindicated. Red yeast rice, which
contains lovastatin, should also be avoided during treatment with a potent CYP450 3A4 inhibitor.
Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are probably safer alternatives, since they are
not metabolized by CYP450 3A4. All patients treated with HMG-CoA reductase inhibitors should be
advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if
accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly
elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.
References
1. Neuvonen PJ, Kantola T, Kivisto KT "Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole." Clin
Pharmacol Ther 63 (1998): 332-41
2. Akram K, Rao S, Parker M "A lesson for everyone in drug-drug interactions." Int J Cardiol 118 (2007): e19-20
3. Horn M "Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals." Arch Dermatol 132 (1996):
1254
Major miconazole  glimepiride

Applies to: miconazole, glimepiride
MONITOR CLOSELY: Coadministration with inhibitors of CYP450 2C9 including certain azole
antifungal agents such as fluconazole, miconazole, and voriconazole may increase the plasma
concentrations of sulfonylureas, many of which have been found to be substrates of the isoenzyme.
Pharmacokinetic data are available for single-dose administration of chlorpropamide (250 mg),
tolbutamide (500 mg), glipizide (2.5 mg), glyburide (5 mg), and glimepiride (0.5 mg) in combination
with fluconazole. In healthy study subjects, fluconazole 100 mg daily for 7 days increased the single-
dose systemic exposures (AUCs) of various sulfonylureas by an average of nearly 30%
(chlorpropamide, tolbutamide) to almost 50% (glipizide, glyburide). Mean changes in blood glucose
levels were not statistically significant in these studies, although approximately 48% of patients
treated with fluconazole experienced symptoms consistent with hypoglycemia compared to 40% of
patients treated with placebo. One in four of the fluconazole-treated patients in the glyburide study
also required oral glucose. A higher dosage of fluconazole (400 mg for one day, followed by 200 mg
daily for 3 days) increased single-dose glimepiride AUC by 138% and prolonged its half-life from 2.0
to 3.3 hours in healthy volunteers. In another study, low-dose fluconazole (50 mg/day) given to treat
vulvovaginal candidiasis in 14 postmenopausal diabetic women receiving gliclazide or glyburide
therapy demonstrated no effect on blood glucose control; pharmacokinetic data were not included.
Based on available data, fluconazole use does not appear to be associated with a significant risk of
severe hypoglycemia at dosages <200 mg/day in sulfonylurea-treated patients. However, higher
dosages may cause greater inhibition of sulfonylurea clearance and increased hypoglycemic effects,
particularly in the elderly and patients with renal or hepatic impairment. There have been case reports
of profound hypoglycemia, including coma and death, during treatment of sulfonylureas with
fluconazole, oral miconazole, as well as voriconazole. Concomitant use of sulfonylureas with
fluconazole has also been associated with increased risk of serum transaminase elevations.
MANAGEMENT: Caution is advised when sulfonylureas are used concomitantly with azole antifungal
agents that inhibit CYP450 2C9. Blood glucose should be closely monitored, and the sulfonylurea
dosage adjusted as necessary. Patients should also be apprised of the increased risk of hypoglycemia
and be alert to potential signs and symptoms such as headache, dizziness, drowsiness, nervousness,
confusion, tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia
occurs, patients should initiate appropriate remedial therapy immediately, discontinue the azole
antifungal agent, and contact their physician.
References
1. Tirkkonen T, Heikkila P, Huupponen R, Laine K "Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients
treated with the sulphonylureas glibenclamide, glimepiride or glipizide." J Intern Med 268 (2010): 359-66
2. Lazar JD, Wilner KD "Drug interactions with fluconazole." Rev Infect Dis 12 Suppl 3 (1990): s327-33
3. "Product Information. Amaryl (glimepiride)." Hoechst Marion-Roussel Inc, Kansas City, MO.
Major amLODIPine  simvastatin

Applies to: amlodipine, simvastatin
ADJUST DOSE: Coadministration with amlodipine may significantly increase the plasma
concentrations of simvastatin and its active metabolite, simvastatin acid, and potentiate the risk of
statin-induced myopathy. The proposed mechanism is amlodipine inhibition of simvastatin
metabolism via intestinal and hepatic CYP450 3A4. When a single 80 mg dose of simvastatin was
administered on day 10 of amlodipine given at a dosage of 10 mg once daily, simvastatin peak
plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 1.5- and 1.8-
fold, respectively, while simvastatin acid Cmax and AUC increased by an average of 1.6-fold each.
High levels of statin or HMG-CoA reductase inhibitory activity in plasma is associated with an
increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness
associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has
been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by
acute renal failure secondary to myoglobinuria and may result in death.
MANAGEMENT: Simvastatin dosage should not exceed 20 mg daily when used in combination with
amlodipine. The benefits of this combination should be carefully weighed against the potentially
increased risk of myopathy including rhabdomyolysis. Fluvastatin, pravastatin, and rosuvastatin are
probably safer alternatives in patients receiving amlodipine, since they are not metabolized by
CYP450 3A4. All patients receiving statin therapy should be advised to promptly report any
unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise
and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in
the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.
References
1. "Product Information. Zocor (simvastatin)." Merck & Co, Inc, West Point, PA.
Moderate captopril  methylPREDNISolone

Applies to: captopril, methylprednisolone
MONITOR: Corticosteroids may antagonize the effects of antihypertensive medications by inducing
sodium and fluid retention. These effects may be more common with the natural corticosteroids
(cortisone, hydrocortisone) because they have greater mineralocorticoid activity. Conversely, some
calcium channel blockers such as diltiazem and verapamil may increase corticosteroid plasma levels
and effects by inhibiting their clearance via CYP450 3A4 metabolism.
MANAGEMENT: Patients on prolonged (i.e., longer than about a week) or high-dose corticosteroid
therapy should have blood pressure, electrolyte levels, and body weight monitored regularly, and be
observed for the development of edema and congestive heart failure. The dosages of
antihypertensive medications may require adjustment.
References
1. "Multum Information Services, Inc. Expert Review Panel"
2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
Moderate captopril  dexamethasone

Applies to: captopril, dexamethasone
References
Moderate captopril  ibuprofen

Applies to: captopril, ibuprofen
MONITOR: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive
effects of ACE inhibitors. The proposed mechanism is NSAID-induced inhibition of renal
prostaglandin synthesis, which results in unopposed pressor activity producing hypertension. In
addition, NSAIDs can cause fluid retention, which also affects blood pressure. Some NSAIDs may also
alter the pharmacokinetics of certain ACE inhibitors. For example, oxaprozin has been shown to
reduce the systemic exposure (AUC) of enalapril and its active metabolite, enalaprilat.
MONITOR: Concomitant use of NSAIDs and ACE inhibitors may cause deterioration in renal function,
particularly in patients who are elderly or volume-depleted (including those on diuretic therapy) or
have compromised renal function. Acute renal failure may occur, although effects are usually
reversible. Chronic use of NSAIDs alone may be associated with renal toxicities, including elevations
in serum creatinine and BUN, tubular necrosis, glomerulitis, renal papillary necrosis, acute interstitial
nephritis, nephrotic syndrome, and renal failure. Additionally, in patients with prerenal conditions
whose renal perfusion may be dependent on the function of prostaglandins, NSAIDs may precipitate
overt renal decompensation via a dose-related inhibition of prostaglandin synthesis. ACE inhibitors
can further worsen renal function by blocking the effect of angiotensin II-mediated efferent arteriolar
vasoconstriction, thereby decreasing glomerular filtration.
MANAGEMENT: Patients receiving ACE inhibitors who require prolonged (greater than 1 week)
concomitant therapy with an NSAID should have blood pressure monitored more closely following
initiation, discontinuation, or change of dosage of the NSAID. Renal function should also be
evaluated periodically during prolonged coadministration. The interaction is not expected to occur
with low doses (e.g., low-dose aspirin) or intermittent short-term administration of NSAIDs.
References
1. Townend JN, Doran J, Lote CJ, Davies MK "Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and
interactions with captopril." Br Heart J 73 (1995): 434-41
2. Silberbauer K, Stanek B, Templ H "Acute hypotensive effect of captopril in man modified by prostaglandin synthesis inhibition." Br J Clin Pharmacol
14 (1982): s87-93
3. Ahmad S "Indomethacin-enalapril interaction: an alert." South Med J 84 (1991): 411-2
Moderate captopril  glimepiride

Applies to: captopril, glimepiride
MONITOR: The hypoglycemic effect of insulin secretagogues (e.g., sulfonylureas, meglitinides) may
be potentiated by certain drugs, including ACE inhibitors, amylin analogs, anabolic steroids, fibrates,
monoamine oxidase inhibitors (MAOIs, including linezolid), nonsteroidal anti-inflammatory drugs
(NSAIDs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide,
propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia
by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion
(salicylates, NSAIDs, disopyramide, quinine, quinidine, MAOIs, ginseng); increasing peripheral glucose
utilization (SSRIs, insulin-like growth factor); inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like
growth factor); slowing the rate of gastric emptying (amylin analogs); and/or suppressing
postprandial glucagon secretion (amylin analogs). Or, they may increase plasma concentration of
insulin secretagogues by displacing them from plasma protein binding sites and/or inhibiting their
metabolism (fibrates, NSAIDs, salicylates, sulfonamides). Clinical hypoglycemia has been reported
during use of some of these agents alone or with insulin and/or sulfonylureas. Use of SSRIs has also
been associated with loss of awareness of hypoglycemia in isolated cases.
MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these

drugs are coadministered with insulin secretagogues, particularly in patients with advanced age
and/or renal impairment. The oral antidiabetic dosage(s) may require adjustment if an interaction is
suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache,
dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and
to contact their doctor if it occurs. Patients should be observed for loss of glycemic control when
these drugs are withdrawn.
References
1. Christensen LK, Hansen JM, Kristensen M "Sulphaphenazole-induced hypoglycemic attacks in tolbutamide-treated diabetics." Lancet 2 (1963):
1298-301
2. Turtle JR, Burgess JA "Hypoglycemic action of fenfluramine in diabetes mellitus." Diabetes 22 (1973): 858-67
3. Sievenpiper JL, Arnason JT, Leiter LA, Vuksan V "Variable effects of American ginseng: a batch of American ginseng (Panax quinquefolius L.) with a
depressed ginsenoside profile does not affect postprandial glycemia." Eur J Clin Nutr 57 (2003): 243-8
Moderate captopril  isosorbide dinitrate

Applies to: captopril, isosorbide dinitrate
MONITOR: Angiotensin converting enzyme (ACE) inhibitors may enhance the vasodilatory and
hypotensive effects of nitroglycerin. Data have also shown that captopril can prevent nitrate
tolerance. ACE inhibitors can decrease systemic vascular resistance and cardiac work, further
enhancing the effectiveness of nitroglycerin.
MANAGEMENT: In general, this combination is used to clinical advantage; however, some

manufacturers recommend that nitrates and other vasodilators should be discontinued before
starting ACE inhibitors or resumed at a reduced dose. Blood pressure monitoring is advisable.
References
1. Katz RJ, Levy WS, Buff L, Wasserman AG "Prevention of nitrate tolerance with angiotension converting enzyme inhibitors." Circulation 83 (1991):
1271-7
Moderate captopril  diclofenac

Applies to: captopril, diclofenac
References
14 (1982): s87-93
Moderate captopril  mefenamic acid

Applies to: captopril, mefenamic acid
References
14 (1982): s87-93
Moderate captopril  metFORMIN

Applies to: captopril, metformin
MONITOR: Limited data suggest that ACE inhibitors may potentiate the hypoglycemic effects of oral
antidiabetic drugs, including metformin. The mechanism is unknown. Symptomatic and sometimes
severe hypoglycemia has occurred.
MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if ACE

inhibitors are coadministered with metformin, particularly in patients with advanced age and/or renal
impairment. Dosage adjustments may be required if an interaction is suspected. Patients should be
apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea,
hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it
occurs. Patients should be observed for loss of glycemic control when ACE inhibitors are withdrawn.
References
1. "Product Information. Altace (ramipril)." Hoechst Marion-Roussel Inc, Kansas City, MO.
Moderate ciprofloxacin  loperamide

Applies to: ciprofloxacin, loperamide
MONITOR: The use of higher than recommended dosages of loperamide (e.g., through abuse or
misuse) has been associated with serious and potentially fatal cardiac adverse events, including
syncope, cardiac arrest, and arrhythmia related to prolongation of the QT interval. Under such
circumstances, coadministration with other agents that can prolong the QT interval may result in
additive effects and increased risk of ventricular arrhythmias such as torsade de pointes and sudden
death. According to the FDA, the agency received reports of 48 cases of serious heart problems
associated with use of loperamide from when it was first approved in 1976 through 2015. Thirty-one
of these cases resulted in hospitalizations, and 10 patients died. The serious heart problems occurred
mostly in patients who were using loperamide dosages that were much higher than recommended in
an attempt to achieve euphoria, prevent opioid withdrawal, or treat diarrhea. In the most severe
cases, individuals self-treated with dosages ranging from 70 to 1600 mg/day, or 4 to 100 times the
recommended dosage. In other cases, patients were taking the recommended dosage, but with
concomitant interacting drugs that caused an increase in loperamide levels. There have been
additional cases of serious heart problems associated with loperamide use reported in the medical
literature. In general, the risk of an individual agent or a combination of agents causing ventricular
arrhythmia in association with QT prolongation is largely unpredictable but may be increased by
certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte
disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT
prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).
MANAGEMENT: Caution is recommended if loperamide is used in combination with other drugs that
can prolong the QT interval. Patients should be counseled to not exceed the recommended dosage
and frequency or duration of use of loperamide, and to seek prompt medical attention if they
experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness,
lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. If
loperamide-induced cardiotoxicity is suspected, promptly discontinue loperamide and initiate therapy
to manage and prevent cardiac arrhythmias and adverse outcomes. Electrical pacing or cardioversion
may be necessary if torsade de pointes persists despite pharmacotherapy. In many of the reported
cases of loperamide-induced cardiotoxicity, standard antiarrhythmic drugs were ineffective, and
electrical pacing or cardioversion was necessary.
References
2. US Food and Drug Administration "FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium),
including from abuse and misuse. Available from: URL: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM505108.pdf." ([2016, Jun 7]):
Moderate
ciprofloxacin  amLODIPine
Applies to: ciprofloxacin, amlodipine
MONITOR: Coadministration with CYP450 3A4 inhibitors may increase the plasma concentrations of
amlodipine, which is a substrate of the isoenzyme. In 8 elderly hypertensive patients, administration
of a single 5 mg dose of amlodipine in combination with the moderate CYP450 3A4 inhibitor
diltiazem (180 mg orally daily for 3 days) resulted in a nearly 60% increase in amlodipine peak plasma
concentration (Cmax) and systemic exposure (AUC). Associated systolic, diastolic, and standing blood
pressures decreased compared to those obtained with amlodipine alone. Erythromycin, another
moderate inhibitor, did not significantly alter amlodipine systemic exposure in healthy volunteers.
However, pharmacokinetic changes may be more pronounced in elderly patients.
MANAGEMENT: Close monitoring of clinical response and tolerance is recommended if amlodipine is

prescribed with potent or moderate CYP450 3A4 inhibitors. Dosage reduction may be required for
amlodipine. Patients should be advised to seek medical attention if they experience edema or
swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or
tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.
References
1. Sasaki M, Maeda A, Fujimura A "Influence of diltiazem on the pharmacokinetics of amlodipine in elderly hypertensive patients." Eur J Clin
Pharmacol 57 (2001): 85-6
2. Canadian Pharmacists Association "e-CPS. Available from: URL: http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink."
3. "Product Information. Norvasc (amlodipine)." Pfizer US Pharmaceuticals, New York, NY.
Moderate ciprofloxacin  ibuprofen

Applies to: ciprofloxacin, ibuprofen
MONITOR: Coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the
risk of central nervous system toxicity sometimes associated with fluoroquinolone use. The
interaction has been reported most often with enoxacin. It may occur with other fluoroquinolones as
well, but is poorly documented. The exact mechanism of interaction is unknown. Some investigators
suggest that the piperazine ring of fluoroquinolones may inhibit the binding of gamma-aminobutyric
acid (GABA) to brain receptors and that NSAIDs may synergistically add to this effect. Patients with a
history of seizures may be at greater risk.
MANAGEMENT: Clinical monitoring for signs of CNS stimulation such as tremors, involuntary muscle
movements, hallucinations, or seizures is recommended if fluoroquinolone antibiotics are prescribed
in combination with NSAIDs.
References
1. "Product Information. Raxar (grepafloxacin)." Glaxo Wellcome, Research Triangle Park, NC.
2. "Product Information. Avelox (moxifloxacin)" Bayer, West Haven, CT.
Moderate ciprofloxacin  sodium bicarbonate

Applies to: ciprofloxacin, sodium bicarbonate
GENERALLY AVOID: Urinary alkalinizers such as citrates may decrease the solubility of
fluoroquinolones in the urine and increase the risk of crystalluria.
MANAGEMENT: Concomitant use should generally be avoided. Patients receiving this combination
should be monitored for signs of renal toxicity and crystalluria.
References
Moderate ciprofloxacin  albuterol

Applies to: ciprofloxacin, albuterol
MONITOR: Beta-2 adrenergic agonists can cause dose-related prolongation of the QT interval and
potassium loss. Theoretically, coadministration with other agents that can prolong the QT interval
may result in additive effects and increased risk of ventricular arrhythmias including torsade de
pointes and sudden death. In general, the risk of an individual agent or a combination of agents
causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may
be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease,
and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-
induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the
drug(s). Clinically significant prolongation of QT interval and hypokalemia occur infrequently when
beta-2 agonists are inhaled at normally recommended dosages. However, these effects may be more
common when the drugs are administered systemically or when recommended dosages are
exceeded.
MANAGEMENT: Caution is recommended if beta-2 agonists are used in combination with other
drugs that can prolong the QT interval. Patients should be advised to seek prompt medical attention
if they experience symptoms that could indicate the occurrence of torsade de pointes such as
dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or
syncope.
References
1. "Product Information. Arcapta Neohaler (indacaterol)." Novartis Pharmaceuticals, East Hanover, NJ.
2. Ferguson GT, Funck-Brentano C, Fischer T, Darken P, Reisner C "Cardiovascular Safety of Salmeterol in COPD." Chest 123 (2003): 1817-24
3. Larsson S, Svedmyr N "Bronchodilating effect and side effects of beta2- adrenoceptor stimulants by different modes of administration (tablets,
metered aerosol, and combinations thereof). A study with salbutamol inasthmatics." Am Rev Respir Dis 116 (1977): 861-9
Moderate ciprofloxacin  aluminum hydroxide

Applies to: ciprofloxacin, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
ADJUST DOSING INTERVAL: Oral preparations that contain magnesium, aluminum, or calcium may
significantly decrease the gastrointestinal absorption of quinolone antibiotics. Absorption may also
be reduced by sucralfate, which contains aluminum, as well as other polyvalent cations such as iron
and zinc. The mechanism is chelation of quinolones by polyvalent cations, forming a complex that is
poorly absorbed from the gastrointestinal tract. The bioavailability of ciprofloxacin has been reported
to decrease by as much as 90% when administered with antacids containing aluminum or magnesium
hydroxide.
MANAGEMENT: When coadministration cannot be avoided, quinolone antibiotics should be dosed

either 2 to 4 hours before or 4 to 6 hours after polyvalent cation-containing products to minimize the
potential for interaction. Please consult individual product labeling for specific recommendations.
References
1. Teng R, Dogolo LC, Willavize SA, Friedman HL, Vincent J "Effect of Maalox and omeprazole on the bioavailability of trovafloxacin." J Antimicrob
Chemother 39 Suppl B (1997): 93-7
2. Nix DE, Wilton JH, Ronald B, Distlerath L, Williams VC, Norman A "Inhibition of norfloxacin absorption by antacids." Antimicrob Agents Chemother
34 (1990): 432-5
3. "Product Information. Factive (gemifloxacin)." GeneSoft Inc, San Francisco, CA.
Moderate ciprofloxacin  ferrous fumarate

Applies to: ciprofloxacin, ferrous fumarate / folic acid
hydroxide.

References
34 (1990): 432-5
Moderate ciprofloxacin  magnesium hydroxide

Applies to: ciprofloxacin, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
hydroxide.

References
34 (1990): 432-5
Moderate ciprofloxacin  calcium lactate

Applies to: ciprofloxacin, calcium lactate
hydroxide.

References
34 (1990): 432-5
Moderate ciprofloxacin  simvastatin

Applies to: ciprofloxacin, simvastatin
MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations
of HMG-CoA reductase inhibitors (i.e., statins) that are metabolized by the isoenzyme. Lovastatin and
simvastatin are particularly susceptible because of their low oral bioavailability, but others such as
atorvastatin and cerivastatin may also be affected. High levels of HMG-CoA reductase inhibitory
activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy
and may result in death. Clinically significant interactions have been reported with potent CYP450
3A4 inhibitors such as macrolide antibiotics, azole antifungals, protease inhibitors and nefazodone,
and moderate inhibitors such as amiodarone, cyclosporine, danazol, diltiazem and verapamil.
MANAGEMENT: Caution is recommended if atorvastatin, cerivastatin, lovastatin, simvastatin, or red

yeast rice (which contains lovastatin) is prescribed with a CYP450 3A4 inhibitor. It is advisable to
monitor lipid levels and use the lowest effective statin dose. All patients receiving statin therapy
should be advised to promptly report any unexplained muscle pain, tenderness or weakness,
particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be
discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if
myopathy is otherwise suspected or diagnosed. Fluvastatin, pravastatin, and rosuvastatin are not
expected to interact with CYP450 3A4 inhibitors.
References
1. Andreou ER, Ledger S "Potential drug interaction between simvastatin and danazol causing rhabdomyolysis." Can J Clin Pharmacol 10 (2003): 172-4
2. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE "Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients." Br J Clin Pharmacol 48 (1999):
610-5
3. Williams D, Feely J "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet 41 (2002):
343-70
Moderate
ciprofloxacin  kaolin
Applies to: ciprofloxacin, kaolin / pectin
hydroxide.

References
34 (1990): 432-5
Moderate ciprofloxacin  attapulgite

Applies to: ciprofloxacin, attapulgite
hydroxide.

References
34 (1990): 432-5
Moderate
ciprofloxacin  mefenamic acid
Applies to: ciprofloxacin, mefenamic acid
References
Moderate ciprofloxacin  zinc sulfate

Applies to: ciprofloxacin, Zinc (zinc sulfate)
hydroxide.

References
34 (1990): 432-5
Moderate ciprofloxacin  metFORMIN

Applies to: ciprofloxacin, metformin
MONITOR: Quinolone antibiotics may interfere with the therapeutic effects of insulin and other
antidiabetic agents. The use of quinolones has been associated with disturbances in blood glucose
homeostasis possibly stemming from effects on pancreatic beta cell ATP-sensitive potassium
channels that regulate insulin secretion. Both hyperglycaemia and hypoglycemia have been reported,
usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g.,
sulfonylurea) or insulin. Although hyperglycaemia is significantly more common and infection itself
may be an underlying risk factor, hypoglycemia may cause greater morbidity and mortality. An
internal safety review conducted by the U.S. Food and Drug Administration (FDA) identified at least
67 reports of severe hypoglycemia associated with quinolone use resulting in coma, death, or
permanent and disabling injuries, primarily in elderly and diabetic patients with renal impairment
and/or complicated infections. This is in addition to the numerous cases that have been reported for
gatifloxacin, which led to its withdrawal from the U.S. market in 2008. Of the five quinolones that the
FDA reviewed, levofloxacin had the most cases (44), followed by ciprofloxacin (12), moxifloxacin (9),
ofloxacin (2), and gemifloxacin (0). Other quinolones such as nalidixic acid and norfloxacin, as well as
some others that have never been marketed or are no longer marketed such as clinafloxacin and
temafloxacin, have also been associated with dysglycemia, thus it is generally believed to be a class
effect, albeit with varying risks amongst the individual agents. Available data also seem to indicate
different time frames for the development of hypo- and hyperglycaemia, with the former generally
occurring within 1 to 3 days following quinolone initiation and the latter within 4 to 10 days later.
MANAGEMENT: Blood glucose should be closely monitored whenever quinolones are prescribed to
diabetic patients, especially if they are elderly, have renal impairment, or are severely ill. Patients
should be apprised of the increased risk of dysglycemia and be particularly alert to potential signs
and symptoms of hypoglycemia such as headache, dizziness, drowsiness, nervousness, confusion,
tremor, hunger, weakness, perspiration, palpitation, and tachycardia. If hypoglycemia occurs, patients
should initiate appropriate remedial therapy immediately, discontinue the quinolone, and contact
their physician. Alternative antibiotics may need to be considered.
References
1. Gavin JR 3rd, Kubin R, Choudhri S, et al "Moxifloxacin and glucose homeostasis: a pooled-analysis of the evidence from clinical and postmarketing
studies." Drug Saf 27 (2004): 671-86
2. Kelesidis T, Canseco E "Quinolone-induced hypoglycemia: a life-threatening but potentially reversible side effect." Am J Med 123 (2010): e5-6
3. Baker SE, Hangii MC "Possible gatifloxacin-induced hypoglycemia." Ann Pharmacother 36 (2002): 1722-6
Moderate
ciprofloxacin  diclofenac
Applies to: ciprofloxacin, diclofenac
References
Moderate ciprofloxacin  ketoconazole

Applies to: ciprofloxacin, ketoconazole
MONITOR: Theoretically, concurrent use of two or more drugs that can cause QT interval
prolongation may result in additive effects and increased risk of ventricular arrhythmias including
torsade de pointes and sudden death. The risk of an individual agent or a combination of these
agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but
may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac
disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of
drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the
drug(s).
MANAGEMENT: Caution and clinical monitoring are recommended if multiple agents associated with
QT interval prolongation are prescribed together. Patients should be advised to seek prompt medical
attention if they experience symptoms that could indicate the occurrence of torsade de pointes such
as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or
syncope.
References
1. EMA. European Medicines Agency. European Union "EMA - List of medicines under additional monitoring. Available from: URL:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp&mid=WC0b01ac058067c852"
([2013 - ]):
2. Glassman AH, Bigger JT Jr "Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death." Am J Psychiatry 158 (2001): 1774-
82
3. Witchel HJ, Hancox JC, Nutt DJ "Psychotropic drugs, cardiac arrhythmia, and sudden death." J Clin Psychopharmacol 23 (2003): 58-77
Moderate
ibuprofen  dexamethasone
Applies to: ibuprofen, dexamethasone
MONITOR: The combined use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs)
may increase the potential for serious gastrointestinal (GI) toxicity, including inflammation, bleeding,
ulceration, and perforation. In a large, case-control study of elderly patients, those who used
corticosteroids and NSAIDs concurrently had an estimated relative risk (RR) for peptic ulcer disease
and GI hemorrhage of 14.6 compared to those who used neither. Corticosteroid use was associated
with a doubling of the risk (estimated RR = 2.0), but the risk was confined to those who also used
NSAIDs. It is possible that both categories of agents are ulcerogenic and have additive effects on the
GI mucosa during coadministration. Some investigators have also suggested that the primary effect
of corticosteroids in this interaction is to delay healing of erosions caused by NSAIDs rather than
cause de novo ulcerations.
MANAGEMENT: Caution is advised if corticosteroids and NSAIDs are used together, especially in
patients with a prior history of peptic ulcer disease or GI bleeding and in elderly and debilitated
patients. During concomitant therapy, patients should be advised to take the medications with food
and to immediately report signs and symptoms of GI ulceration and bleeding such as severe
abdominal pain, dizziness, lightheadedness, and the appearance of black, tarry stools. The selective
use of prophylactic anti-ulcer therapy (e.g., antacids, H2-antagonists) may be considered.
References
1. Wilcox CM, Shalek KA, Cotsonis G "Striking prevalence of over-the-counter nonsteroidal anti- inflammatory drug use in patients with upper
gastrointestinal hemorrhage." Arch Intern Med 154 (1994): 42-6
2. Stewart JT, Pennington CR, Pringle R "Anti-inflammatory drugs and bowel perforations and haemorrhage." Br Med J 290 (1985): 787-8
3. Messer J, Reitman D, Sacks HS, et al "Association of adrenocorticosteroid therapy and peptic-ulcer disease." N Engl J Med 309 (1983): 21-4
Moderate
ibuprofen  NIFEdipine
Applies to: ibuprofen, nifedipine
MONITOR: Limited data indicate that some cyclooxygenase inhibitors may attenuate the
antihypertensive effects of some calcium channel blockers. The mechanism appears to be related to
an alteration of vascular tone, which is dependent on prostacyclins and other vasodilatory
prostanoids. When a nonsteroidal anti-inflammatory drug (NSAID) is added to the regimen of a
patient who is already taking a calcium channel blocker, increased blood pressure may result. Also,
the clinician should be aware that the risk of hypotension is increased when NSAIDs are withdrawn
from the regimen.
MANAGEMENT: Monitoring for altered blood pressure control is recommended.
References
1. Cremer KF, Pieper JA, Joyal M, Mehta J "Effects of diltiazem, dipyridamole, and their combination on hemostasis." Clin Pharmacol Ther 36 (1984):
641-4
2. "Product Information. Arthrotec (diclofenac-misoprostol)." Searle, Skokie, IL.
3. Deleeuw PW "Nonsteroidal anti-inflammatory drugs and hypertension: the risks in perspective." Drugs 51 (1996): 179-87
Moderate ibuprofen  glimepiride

Applies to: ibuprofen, glimepiride

References
1298-301
Moderate
ibuprofen  amLODIPine
Applies to: ibuprofen, amlodipine
from the regimen.
References
641-4
Moderate ibuprofen  methylPREDNISolone

Applies to: ibuprofen, methylprednisolone
References
Moderate raNITIdine  glimepiride

Applies to: ranitidine, glimepiride
MONITOR: H2 antagonists such as cimetidine and ranitidine may increase plasma concentrations of
sulfonylureas and enhance hypoglycemic effects. The mechanism may be related to inhibition of liver
cytochrome P450 enzymes responsible for sulfonylurea metabolism or increased absorption due to
altered gastric pH. Cimetidine may also inhibit glucose metabolism. Other H2 antagonists may
interact in a similar manner, particularly if increased pH is involved.
MANAGEMENT: Clinical monitoring of patient response, tolerance, and glycemic control is

recommended. Patients receiving this combination should be advised to regularly monitor their
blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness,
drowsiness, nausea, tremor, hunger, weakness, or palpitations) and to notify their physician if it
occurs. The sulfonylurea dosage may require reduction in affected patients.
References
1. Dey NG, Castleden CM, Ward J, et al "The effect of cimetidine on tolbutamide kinetics." Br J Clin Pharmacol 16 (1983): 438-40
2. Lee K, Mize R, Lowenstein SR "Glyburide-induced hypoglycemia and ranitidine." Ann Intern Med 107 (1987): 261-2
3. Kubacka RT, Antal EJ, Juhl RP "The paradoxical effect of cimetidine and ranitidine on glibenclamide pharmacokinetics and pharmacodynamics." Br J
Clin Pharmacol 23 (1987): 743-51
Moderate
raNITIdine  aminophylline
Applies to: ranitidine, aminophylline
MONITOR: Cimetidine may increase theophylline plasma concentrations by as much as 70%. The
mechanism is related to inhibition of liver CYP450 enzymes responsible for theophylline metabolism.
Although controlled studies have not demonstrated an interaction with ranitidine, famotidine, or
nizatidine, and they do not have enzyme-inhibiting properties, there have been rare case reports of
increased theophylline concentrations and/or toxicity with each of these agents. Patients with chronic
obstructive pulmonary disease, congestive heart failure, or cirrhosis may have slower theophylline
clearance rates; therefore, they may be at greater risk of developing theophylline toxicity.
MANAGEMENT: Clinical monitoring of patient response, tolerance, and laboratory theophylline serum
concentrations is recommended. Patients should be advised to report any signs of theophylline
toxicity including nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat
to their physician.
References
1. Boehning W "Effect of cimetidine and ranitidine on plasma theophylline in patients with chronic obstructive airways disease treated with
theophylline and corticosteroids." Eur J Clin Pharmacol 38 (1990): 43-5
2. Roy AK, Cuda MP, Levine RA "Induction of theophylline toxicity and inhibition of clearance rates by ranitidine." Am J Med 85 (1988): 525-7
3. Schwartz JI, Bachmann KA, Bond LW, Mahajan VK "Impact of cimetidine on the pharmacokinetics of the theophylline." Clin Pharm 1 (1982): 534-8
Moderate raNITIdine  metFORMIN

Applies to: ranitidine, metformin
MONITOR: Ranitidine is a cationic drug and theoretically could decrease the excretion of metformin
by competing for renal tubular transport. Although this interaction has not been specifically reported
for ranitidine, cimetidine (also a cationic drug) has been reported to interact with metformin in this
manner. Increased metformin levels may increase the risk of lactic acidosis.
MANAGEMENT: If ranitidine and metformin must be used together, particularly slow and cautious
titration of metformin dosage is recommended. The maximal dose of metformin probably also should
be reduced until further information about this interaction is available. Patients should be advised to
monitor their blood glucose and to promptly notify their physician if they experience possible signs
of lactic acidosis such as malaise, myalgia, respiratory distress, hyperventilation, slow or irregular
heartbeat, somnolence, abdominal upset, or other unusual symptoms.
References
1. "Product Information. Glucophage (metformin)." Bristol-Myers Squibb, Princeton, NJ.
2. Somogyi A, Stockley C, Keal J, Rolan P, Bochner F "Reduction of metformin renal tubular secretion by cimetidine in man." Br J Clin Pharmacol 23
(1987): 545-51
Moderate raNITIdine  ketoconazole

Applies to: ranitidine, ketoconazole
GENERALLY AVOID: H2 antagonists may reduce the bioavailability of ketoconazole by 75% to 80%
resulting in decreased plasma ketoconazole concentrations and possible therapeutic failure. The
mechanism is related to an increase in gastric pH and a decrease in absorption of the antifungal
agent.
MANAGEMENT: Concomitant use is not recommended. Fluconazole absorption is not significantly

affected.
References
1. Carlson JA, Mann HJ, Canafax DM "Effect of pH on disintegration and dissolution of ketoconazole tablets." Am J Hosp Pharm 40 (1983): 1334-6
2. Van der Meer JW, Keuning JJ "The influence of gastric acidity on the bio-availability of ketoconazole." J Antimicrob Chemother 6 (1980): 552-4
3. Blum RA, D'Andrea DT, Florentino BM, et al "Increased gastric pH and the bioavailability of fluconazole and ketoconazole." Ann Intern Med 114
(1991): 755-7
Moderate
allopurinol  aluminum hydroxide
Applies to: allopurinol, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
ADJUST DOSING INTERVAL: Aluminum-containing oral medications may decrease the absorption of
allopurinol and reduce its therapeutic effect.
MANAGEMENT: Allopurinol should be administered at least one hour before or two hours after
aluminum-containing medications.
References
1. Weissman I, Krivoy N "Interaction of aluminum hydroxide and allopurinol in patients on chronic hemodialysis." Ann Intern Med 107 (1987): 787
Moderate allopurinol  kaolin

Applies to: allopurinol, kaolin / pectin
References
Moderate
allopurinol  attapulgite
Applies to: allopurinol, attapulgite
References
Moderate chloramphenicol  amLODIPine

Applies to: chloramphenicol, amlodipine
MONITOR: Coadministration with CYP450 3A4 inhibitors may increase the plasma concentrations of
amlodipine, which is a substrate of the isoenzyme. In 8 elderly hypertensive patients, administration
of a single 5 mg dose of amlodipine in combination with the moderate CYP450 3A4 inhibitor
diltiazem (180 mg orally daily for 3 days) resulted in a nearly 60% increase in amlodipine peak plasma
concentration (Cmax) and systemic exposure (AUC). Associated systolic, diastolic, and standing blood
pressures decreased compared to those obtained with amlodipine alone. Erythromycin, another
moderate inhibitor, did not significantly alter amlodipine systemic exposure in healthy volunteers.
However, pharmacokinetic changes may be more pronounced in elderly patients.
MANAGEMENT: Close monitoring of clinical response and tolerance is recommended if amlodipine is

prescribed with potent or moderate CYP450 3A4 inhibitors. Dosage reduction may be required for
amlodipine. Patients should be advised to seek medical attention if they experience edema or
swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or
tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.
References
1. Sasaki M, Maeda A, Fujimura A "Influence of diltiazem on the pharmacokinetics of amlodipine in elderly hypertensive patients." Eur J Clin
Pharmacol 57 (2001): 85-6
3. "Product Information. Norvasc (amlodipine)." Pfizer US Pharmaceuticals, New York, NY.
Moderate
chloramphenicol  simvastatin
Applies to: chloramphenicol, simvastatin
MONITOR: The risk of peripheral neuropathy may be increased during concurrent use of two or more
agents that are associated with this adverse effect. Patient risk factors include diabetes and age older
than 60 years. In some cases, the neuropathy may progress or become irreversible despite
discontinuation of the medications.
MANAGEMENT: Caution is advised during concomitant use of agents with neurotoxic effects. Patients
should be monitored closely for symptoms of neuropathy such as burning, tingling, pain, or
numbness in the hands and feet. Since the development of peripheral neuropathy may be dose-
related for many drugs, the recommended dosages should generally not be exceeded. Consideration
should be given to dosage reduction or immediate discontinuation of these medications in patients
who develop peripheral neuropathy to limit further damage. If feasible, therapy should generally be
reinstituted only after resolution of neuropathy symptoms or return of symptoms to baseline status.
In some cases, permanent dosage reductions may be required.
References
1. Carrion C, Espinosa E, Herrero A, Garcia B "Possible vincristine-isoniazid interaction." Ann Pharmacother 29 (1995): 201
2. Argov Z, Mastaglia FL "Drug-induced peripheral neuropathies." Br Med J 1 (1979): 663-6
3. Pharmaceutical Society of Australia "APPGuide online. Australian prescription products guide online. Available from: URL:
http://www.appco.com.au/appguide/default.asp." ([2006]):
Moderate chloramphenicol  ferrous fumarate

Applies to: chloramphenicol, ferrous fumarate / folic acid
MONITOR: Chloramphenicol can cause bone marrow depression and inhibit red blood cell
maturation, which may interfere with the therapeutic effects of iron or vitamin B12 in the treatment of
anemia. In a group of 22 patients receiving iron dextran for iron deficiency anemia, 10 patients who
also received chloramphenicol had inadequate hematologic response to the iron therapy. Four
patients receiving vitamin B12 for pernicious anemia were also unresponsive to the B12 therapy while
being treated with chloramphenicol. Reversible bone marrow depression is more likely to occur at
higher chloramphenicol dosages that produce serum levels of 25 mcg/mL or greater.
MANAGEMENT: Patients with preexisting anemia should preferably not receive chloramphenicol due
to the drug's depressive effect on bone marrow and reticulocytes. If use is unavoidable, the lowest
effective dosage of chloramphenicol should be given. Hematologic response to iron or vitamin B12
therapy should be closely monitored.
References
1. Scott JL, Finegold SY, Belkin GA, Lawrence JS "A controlled double-blind study of the hematologic toxicity of chloramphenicol." N Engl J Med 272
(1965): 1137-42
2. Saidi P, Wallerstein RO, Aggeler PM "Effect of chloramphenicol on erythropoiesis." J Lab Clin Med 57 (1961): 247-56
3. Haile CA "Chloramphenicol toxicity." South Med J 70 (1977): 479-80
Moderate chloramphenicol  cefixime

Applies to: chloramphenicol, cefixime
MONITOR: Limited, primarily in vitro, data suggest that chloramphenicol may antagonize the
bactericidal activity of cephalosporins against certain clinical isolates of gram-negative rods, group B
streptococci, and Staphylococcus aureus. This antagonism appears to occur against strains for which
chloramphenicol is bacteriostatic, and has been demonstrated with cefoperazone, cefotaxime, and
ceftriaxone. The proposed mechanism is inhibition of protein synthesis by chloramphenicol, resulting
in less protein substrate for cephalosporins to act on as inhibitors of bacterial cell wall synthesis. The
clinical relevance of these findings is unknown. Potential antagonism was suspected in two case
reports of treatment failure in patients with gram-negative bacterial meningitis who received a
cephalosporin in combination with chloramphenicol. One patient, a 2.5-month-old infant with
Salmonella enteritidis group D meningitis, was subsequently treated with the cephalosporin
(ceftazidime) alone and recovered uneventfully. The other, a 51-year-old male with Klebsiella
pneumoniae meningitis, was subsequently treated with the cephalosporin (cefotaxime) plus amikacin
and became afebrile, but later died with progressive neurologic disease. Autopsy findings were
consistent with subacute spongiform encephalopathy (Creutzfeldt-Jakob disease).
MANAGEMENT: The manufacturers recommend to avoid concomitant use . However, if concurrent

administration cannot be avoided, the possibility of antagonism should be considered, and patients
should be monitored for altered therapeutic effect.
References
1. Brown TH, Alford RH "Antagonism by chloramphenicol of broad-spectrum beta-lactam antibiotics against Klebsiella pneumoniae." Antimicrob
Agents Chemother 25 (1984): 405-7
2. Asmar BI, Prainito M, Dajani AS "Antagonistic effect of chloramphenicol in combination with cefotaxime or ceftriaxone." Antimicrob Agents
Chemother 32 (1988): 1375-8
3. Agencia Española de Medicamentos y Productos Sanitarios Healthcare "Centro de información online de medicamentos de la AEMPS - CIMA.
Available from: URL: https://cima.aemps.es/cima/publico/home.html." ([2018]):
Moderate
chloramphenicol  metroNIDAZOLE
Applies to: chloramphenicol, metronidazole
References
Moderate
chloramphenicol  cyanocobalamin
Applies to: chloramphenicol, Vitamin B12 (cyanocobalamin)
MONITOR: Chloramphenicol can cause bone marrow depression and inhibit red blood cell
maturation, which may interfere with the therapeutic effects of iron or vitamin B12 in the treatment of
anemia. In a group of 22 patients receiving iron dextran for iron deficiency anemia, 10 patients who
also received chloramphenicol had inadequate hematologic response to the iron therapy. Four
patients receiving vitamin B12 for pernicious anemia were also unresponsive to the B12 therapy while
being treated with chloramphenicol. Reversible bone marrow depression is more likely to occur at
higher chloramphenicol dosages that produce serum levels of 25 mcg/mL or greater.
MANAGEMENT: Patients with preexisting anemia should preferably not receive chloramphenicol due
to the drug's depressive effect on bone marrow and reticulocytes. If use is unavoidable, the lowest
effective dosage of chloramphenicol should be given. Hematologic response to iron or vitamin B12
therapy should be closely monitored.
References
1. Scott JL, Finegold SY, Belkin GA, Lawrence JS "A controlled double-blind study of the hematologic toxicity of chloramphenicol." N Engl J Med 272
(1965): 1137-42
2. Saidi P, Wallerstein RO, Aggeler PM "Effect of chloramphenicol on erythropoiesis." J Lab Clin Med 57 (1961): 247-56
3. Haile CA "Chloramphenicol toxicity." South Med J 70 (1977): 479-80
Moderate
chloramphenicol  glimepiride
Applies to: chloramphenicol, glimepiride
MONITOR: The hypoglycemic action of glimepiride may be potentiated by highly protein-bound

drugs. The mechanism is displacement of glimepiride from protein-binding sites, resulting in higher
plasma concentrations of unbound glimepiride available to act on pancreatic beta cells.
MANAGEMENT: Patients should be monitored closely for hypoglycemia during concomitant therapy,
particularly following addition of a highly protein-bound drug to a stabilized glimepiride regimen.
Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize
and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or
palpitations) and to notify their physician if it occurs. Likewise, such patients should be observed for
loss of glycemic control when the highly protein-bound drug is withdrawn.
References
1. "Product Information. Amaryl (glimepiride)." Hoechst Marion-Roussel Inc, Kansas City, MO.
Moderate
doxycycline  sodium bicarbonate
Applies to: doxycycline, sodium bicarbonate
ADJUST DOSING INTERVAL: Alkalinization of the urine may decrease the plasma concentration of
some tetracyclines. The mechanism is not completely understood, but may involve increased renal
elimination of tetracyclines when the urine becomes alkalinized. Information is available for
doxycycline, tetracycline, and sodium bicarbonate only.
MANAGEMENT: If these drugs must be used together, an alternating dosing schedule is

recommended (three to four hours apart).
References
1. Elliott GR "Sodium bicarbonate and oral tetracycline." Clin Pharmacol Ther 13 (1972): 459
2. Jaffe JM, Colaizzi JI, Poust RI, McDonald RH Jr "Effect of altered urinary pH on tetracycline and doxycycline excretion in humans." J Pharmacokinet
Biopharm 1 (1973): 267-82
3. Jaffe JM, Poust RI, Feld SL, Colaizzi JL "Influence of repetitive dosing and altered urinary pH on doxycycline excretion in humans." J Pharm Sci 63
(1974): 1256-60
Moderate doxycycline  magnesium hydroxide

Applies to: doxycycline, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
ADJUST DOSING INTERVAL: Administration of a tetracycline with aluminum, calcium, or magnesium
salts significantly decreases tetracycline serum concentrations. The proposed mechanism is chelation
of tetracycline by the cation, forming an insoluble complex that is poorly absorbed from the
gastrointestinal tract. The interaction has also been reported with parenteral doxycycline and oral
antacids.
MANAGEMENT: The administration of tetracyclines and preparations containing aluminum,

magnesium, or calcium should be separated by two to four hours.
References
1. Gotz VP, Ryerson GG "Evaluation of tetracycline on theophylline disposition in patients with chronic obstructive airways disease." Drug Intell Clin
Pharm 20 (1986): 694-6
2. Upton RA "Pharmacokinetic interactions between theophylline and other medication (Part I)." Clin Pharmacokinet 20 (1991): 66-80
3. "Product Information. Nuzyra (omadacycline)." Paratek Pharmaceuticals, Inc., Boston, MA.
Moderate doxycycline  attapulgite

Applies to: doxycycline, attapulgite
antacids.

References
Pharm 20 (1986): 694-6
Moderate doxycycline  aluminum hydroxide

Applies to: doxycycline, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
antacids.

References
Pharm 20 (1986): 694-6
Moderate doxycycline  ferrous fumarate

Applies to: doxycycline, ferrous fumarate / folic acid
GENERALLY AVOID: The bioavailability of oral tetracyclines and iron salts may be significantly
decreased during concurrent administration. Therapeutic failure may result. The proposed mechanism
is chelation of tetracyclines by the iron cation, forming an insoluble complex that is poorly absorbed
from the gastrointestinal tract. In ten healthy volunteers, simultaneous oral administration of ferrous
sulfate 200 mg and single doses of various tetracyclines (200 mg to 500 mg) resulted in reductions in
the serum levels of methacycline and doxycycline by 80% to 90%, oxytetracycline by 50% to 60%, and
tetracycline by 40% to 50%. In another study, 300 mg of ferrous sulfate reduced the absorption of
tetracycline by 81% and that of minocycline by 77%. Conversely, the absorption of iron has been
shown to be decreased by up to 78% in healthy subjects and up to 65% in patients with iron
depletion when ferrous sulfate 250 mg was administered with tetracycline 500 mg. Available data
suggest that administration of iron 3 hours before or 2 hours after a tetracycline largely prevents the
interaction with most tetracyclines except doxycycline. Due to extensive enterohepatic cycling, iron
binding may occur with doxycycline even when it is given parenterally. It has also been shown that
when iron is administered up to 11 hours after doxycycline, serum concentrations of doxycycline may
still be reduced by 20% to 45%.
MANAGEMENT: Coadministration of a tetracycline with any iron-containing product should be

avoided if possible. Otherwise, patients should be advised to stagger the times of administration by
at least three to four hours, although separating the doses may not prevent the interaction with
doxycycline.
References
1. Gothoni G, Neuvonen PJ, Mattila M, Hackman R "Iron-tetracycline interaction: effect of time interval between the drugs." Acta Med Scand 191
(1972): 409-11
2. Neuvonen PJ "Interactions with the absorption of tetracyclines." Drugs 11 (1976): 45-54
3. Neuvonen PJ, Penttila O "Effect of oral ferrous sulphate on the half-life of doxycycline in man." Eur J Clin Pharmacol 7 (1974): 361-3
Moderate
doxycycline  kaolin
Applies to: doxycycline, kaolin / pectin

antacids.

References
Pharm 20 (1986): 694-6
Moderate
doxycycline  calcium lactate
Applies to: doxycycline, calcium lactate

antacids.

References
Pharm 20 (1986): 694-6
Moderate
doxycycline  aminophylline
Applies to: doxycycline, aminophylline
MONITOR: Coadministration of a tetracycline may decrease theophylline plasma clearance and
increase theophylline levels. The mechanism is unknown. Data are available for minocycline,
tetracycline, and doxycycline, but are conflicting in some cases. This interaction appears to be more
problematic if a tetracycline is administered for more than five days. Patients with chronic obstructive
pulmonary disease, congestive heart failure, or cirrhosis may have slower theophylline clearance rates;
therefore, they may be at greater risk of developing theophylline toxicity.
MANAGEMENT: If these drugs are given concurrently, close clinical and laboratory monitoring of
response and tolerance is recommended. Patients should be advised to notify their physician if they
experience any signs of theophylline toxicity including nausea, vomiting, diarrhea, headache,
restlessness, insomnia, seizures, or irregular heartbeats. It may be necessary to reduce theophylline
dosage.
References
1. McCormack JP, Reid SE, Lawson LM "Theophylline toxicity induced by tetracycline." Clin Pharm 9 (1990): 546-9
Pharm 20 (1986): 694-6
Moderate doxycycline  amoxicillin

Applies to: doxycycline, amoxicillin
GENERALLY AVOID: Tetracyclines may reduce the effect of penicillins by inhibiting cellular protein
synthesis which is necessary for cell wall synthesis inhibition by penicillins. Antagonism is more likely
when low doses of either agent are administered. Therapeutic failure may result.
MANAGEMENT: This combination should be avoided if possible.
References
1. "Product Information. Seysara (sarecycline)." Allergan Inc, Irvine, CA.
2. "Product Information. Declomycin (demeclocycline)." Lederle Laboratories, Wayne, NJ.
3. Jawetz E "Synergism and antagonism among antimicrobial drugs: a personal perspective." West J Med 123 (1975): 87-91
Moderate clindamycin  attapulgite

Applies to: clindamycin, attapulgite
GENERALLY AVOID: Adsorbent antidiarrheal agents may significantly reduce the gastrointestinal
absorption of oral clindamycin and lincomycin, causing decreased serum levels and potential loss of
antimicrobial effectiveness. Kaolin-pectin has been associated with a 90% reduction in lincomycin
levels.
MANAGEMENT: The use of adsorbent antidiarrheals should be avoided if possible. If used

concurrently, the patient should be monitored closely for loss of antibiotic efficacy.
References
1. McGehee RF Jr, Smith CB, Wilcox C, Finland M "Comparative studies of antibacterial activity in vitro and absorption and excretion of lincomycin and
clindamycin." Am J Med Sci 256 (1968): 279-92
2. "Product Information. Lincocin (lincomycin)." Pharmacia and Upjohn, Kalamazoo, MI.
3. McCall CE, Steigbigel NH, Finland M "Lincomycin: activity in vitro and absorption and excretion in normal young men." Am J Med Sci 254 (1967):
144-55
Moderate
clindamycin  kaolin
Applies to: clindamycin, kaolin / pectin
GENERALLY AVOID: Adsorbent antidiarrheal agents may significantly reduce the gastrointestinal
absorption of oral clindamycin and lincomycin, causing decreased serum levels and potential loss of
antimicrobial effectiveness. Kaolin-pectin has been associated with a 90% reduction in lincomycin
levels.
MANAGEMENT: The use of adsorbent antidiarrheals should be avoided if possible. If used

concurrently, the patient should be monitored closely for loss of antibiotic efficacy.
References
1. McGehee RF Jr, Smith CB, Wilcox C, Finland M "Comparative studies of antibacterial activity in vitro and absorption and excretion of lincomycin and
clindamycin." Am J Med Sci 256 (1968): 279-92
2. "Product Information. Lincocin (lincomycin)." Pharmacia and Upjohn, Kalamazoo, MI.
3. McCall CE, Steigbigel NH, Finland M "Lincomycin: activity in vitro and absorption and excretion in normal young men." Am J Med Sci 254 (1967):
144-55
Moderate
NIFEdipine  dexamethasone
Applies to: nifedipine, dexamethasone

References
Moderate
NIFEdipine  methylPREDNISolone
Applies to: nifedipine, methylprednisolone
References
Moderate NIFEdipine  calcium lactate

Applies to: nifedipine, calcium lactate
MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers
by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe
verapamil toxicity.
MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker

therapy during coadministration with calcium products.
References
1. Oszko MA, Klutman NE "Use of calcium salts during cardiopulmonary resuscitation for reversing verapamil-associated hypotension." Clin Pharm 6
(1987): 448-9
2. Lipman J, Jardine I, Roos C, Dreosti L "Intravenous calcium chloride as an antidote to verapamil-induced hypotension." Intensive Care Med 8 (1982):
55-7
3. Schoen MD, Parker RB, Hoon TJ, et al "Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with
intravenous calcium chloride pretreatment in normal subjects." Am J Cardiol 67 (1991): 300-4
Moderate
NIFEdipine  ketoconazole
Applies to: nifedipine, ketoconazole
MONITOR: Coadministration with azole antifungal agents may increase the plasma concentrations of
calcium channel blockers (CCBs), especially the dihydropyridines (e.g., amlodipine, felodipine,
nicardipine, nifedipine, nisoldipine). The mechanism involves inhibition of intestinal and hepatic
CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of most CCBs. In a
pharmacokinetic study, nisoldipine mean peak plasma concentration (Cmax) and systemic exposure
(AUC) increased by 11- and 24-fold, respectively, during concomitant treatment with ketoconazole.
Significant increases of severalfold in felodipine and nifedipine plasma concentrations have also been
observed during coadministration with itraconazole. Theoretically, the interaction may potentiate the
risk of ventricular dysfunction, congestive heart failure, and peripheral and pulmonary edema,
particularly in patients with preexisting risk factors (e.g., a history of congestive heart failure; cardiac
disease such as ischemic and valvular disease; significant pulmonary disease such as chronic
obstructive pulmonary disorder; edematous disorders such as renal failure). There have been case
reports of leg and ankle edema in patients treated with various itraconazole-dihydropyridine
combinations.
MANAGEMENT: Close monitoring of clinical response and tolerance is recommended if calcium

channel blockers are used in combination with azole antifungal agents. Dosage reduction may be
required for the calcium channel blocker, particularly if it is a dihydropyridine. Patients should be
advised to seek medical attention if they experience edema or swelling of the lower extremities;
sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as
indicated by dizziness, fainting, or orthostasis.
References
1. Heinig R, Adelmann HG, Ahr G "The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine." Eur J Clin
Pharmacol 55 (1999): 57-60
2. Sandstrom R, Knutson TW, Knutson L, Jansson B, Lennernas H "The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of
(R/S)-verapamil in humans." Br J Clin Pharmacol 48 (1999): 180-9
3. Jalava KM, Olkkola KT, Neuvonen PJ "Itraconazole greatly increases plasma concentrations and effects of felodipine." Clin Pharmacol Ther 61
(1997): 410-5
Moderate NIFEdipine  simvastatin

Applies to: nifedipine, simvastatin
of HMG-CoA reductase inhibitors (i.e., statins) that are metabolized by the isoenzyme. Lovastatin and
simvastatin are particularly susceptible because of their low oral bioavailability, but others such as
atorvastatin and cerivastatin may also be affected. High levels of HMG-CoA reductase inhibitory
activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy
and may result in death. Clinically significant interactions have been reported with potent CYP450
3A4 inhibitors such as macrolide antibiotics, azole antifungals, protease inhibitors and nefazodone,
and moderate inhibitors such as amiodarone, cyclosporine, danazol, diltiazem and verapamil.
MANAGEMENT: Caution is recommended if atorvastatin, cerivastatin, lovastatin, simvastatin, or red

yeast rice (which contains lovastatin) is prescribed with a CYP450 3A4 inhibitor. It is advisable to
monitor lipid levels and use the lowest effective statin dose. All patients receiving statin therapy
should be advised to promptly report any unexplained muscle pain, tenderness or weakness,
particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be
discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if
myopathy is otherwise suspected or diagnosed. Fluvastatin, pravastatin, and rosuvastatin are not
expected to interact with CYP450 3A4 inhibitors.
References
1. Andreou ER, Ledger S "Potential drug interaction between simvastatin and danazol causing rhabdomyolysis." Can J Clin Pharmacol 10 (2003): 172-4
2. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE "Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients." Br J Clin Pharmacol 48 (1999):
610-5
3. Williams D, Feely J "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet 41 (2002):
343-70
Moderate NIFEdipine  diclofenac

Applies to: nifedipine, diclofenac
from the regimen.
References
641-4
Moderate
NIFEdipine  miconazole
Applies to: nifedipine, miconazole
combinations.

References
Pharmacol 55 (1999): 57-60
(1997): 410-5
Moderate
NIFEdipine  mefenamic acid
Applies to: nifedipine, mefenamic acid
from the regimen.
References
641-4
Moderate NIFEdipine  metFORMIN

Applies to: nifedipine, metformin
MONITOR: Nifedipine may increase plasma concentrations of metformin by increasing the extent of
absorption. Increased metformin levels may increase the risk of lactic acidosis.
MANAGEMENT: If nifedipine and metformin must be used together, cautious titration of metformin
dosage is recommended. Increased metformin levels may increase the risk of lactic acidosis. Patients
should be advised to monitor their blood glucose and to promptly notify their physician if they
experience possible signs of lactic acidosis such as malaise, myalgia, respiratory distress,
hyperventilation, slow or irregular heartbeat, somnolence, abdominal upset, or other unusual
symptoms.
References
Moderate
ketoconazole  lansoprazole
Applies to: ketoconazole, lansoprazole
GENERALLY AVOID: Proton pump inhibitors may decrease the gastrointestinal absorption of the azole
antifungal agents, itraconazole and ketoconazole, both of which require an acidic environment for
dissolution. By increasing gastric pH and reducing the acidity, proton pump inhibitors can decrease
bioavailability of the azoles by 75% to 80%.
MANAGEMENT: If coadministration is necessary, an acidic pH may be produced with two capsules of

glutamic acid hydrochloride administered 15 minutes before the azole dose. Administration with an
acidic beverage such as Coca-Cola(R) or Pepsi(R) may also help. However, clinicians should still
consider the possibility of a reduced or subtherapeutic antifungal effect. It may be appropriate to
switch to an agent like fluconazole or terbinafine whose absorption is not affected by stomach pH.
References
1. Piscitelli SC, Goss TF, Wilton JH, D'Andrea DT, Goldstein H, Schentag JJ "Effects of ranitidine and sucralfate on ketoconazole bioavailability."
Antimicrob Agents Chemother 35 (1991): 1765-71
3. "Product Information. Nexium (esomeprazole)" Astra-Zeneca Pharmaceuticals, Wilmington, DE.
Moderate ketoconazole  amLODIPine

Applies to: ketoconazole, amlodipine
combinations.

References
Pharmacol 55 (1999): 57-60
(1997): 410-5
Moderate
ketoconazole  dexamethasone
Applies to: ketoconazole, dexamethasone
and pharmacologic effects of corticosteroids, which are primarily metabolized by the isoenzyme. The
interaction has been reported with potent inhibitors such as clarithromycin, erythromycin,
itraconazole, nefazodone, cobicistat, and ritonavir during concomitant use of various corticosteroids,
including inhaled, nasal, and ophthalmic formulations. Systemic corticosteroid adverse effects may
occur following intensive or long-term continuous ophthalmic corticosteroid therapy. Cushing's
syndrome and adrenal insufficiency have been attributed to the interaction.
MANAGEMENT: The possibility of increased corticosteroid effects should be considered during

coadministration with potent and moderate CYP450 3A4 inhibitors. Some authorities advise against
concomitant use unless the potential benefit outweighs the risk. If the combination is considered
necessary, a lower dosage of the corticosteroid may be required. When indicated for intranasal or
inhalational use, alternative corticosteroids such as beclomethasone, which is less dependent on
CYP450 3A4 metabolism, should be considered, particularly if long term treatment is required.
Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning
of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased
appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting
and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual
disorders. Other systemic glucocorticoid effects may include adrenal suppression,
immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in
children and adolescents. Following extensive use with a potent CYP450 3A4 inhibitor, a progressive
dosage reduction may be required over a longer period if the corticosteroid is to be withdrawn from
therapy, as there may be a significant risk of adrenal suppression. Signs and symptoms of adrenal
insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue,
weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as inability to
respond to stress (e.g., illness, infection, surgery, trauma).
References
1. Edsbacker S, Andersson T "Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease." Clin Pharmacokinet 43 (2004): 803-21
2. Finkenbine RD, Frye MD "Case of psychosis due to prednisone-clarithromycin interaction." Gen Hosp Psychiat 20 (1998): 325-6
3. Varis T, Kivisto KT, Neuvonen PJ "The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone." Eur J Clin
Pharmacol 56 (2000): 57-60
Moderate ketoconazole  omeprazole

Applies to: ketoconazole, omeprazole
GENERALLY AVOID: Proton pump inhibitors may decrease the gastrointestinal absorption of the azole
antifungal agents, itraconazole (capsules only) and ketoconazole, both of which require an acidic
environment for dissolution. By increasing gastric pH and reducing the acidity, proton pump
inhibitors can decrease bioavailability of the azoles by 75% to 80%. Additionally, ketoconazole (a
potent CYP450 3A4 inhibitor) may increase serum omeprazole levels. The metabolism of omeprazole
includes hydroxylation catalyzed by CYP450 2C19 and, to a minor extent, sulfoxidation by CYP450
3A4. In a study involving ten subjects, ketoconazole 100 mg to 200 mg daily resulted in a marked
inhibition of the formation of the omeprazole sulfone in both extensive and poor metabolizers of
CYP450 2C19. In poor metabolizers, a doubling of omeprazole levels was observed. No adverse
effects were reported by any of the subjects.
MANAGEMENT: In general, the concomitant use of these drugs is not recommended. If

coadministration is necessary, an acidic pH may be produced with two capsules of glutamic acid
hydrochloride administered 15 minutes before the azole dose. Administration with an acidic beverage
such as Coca-Cola(R) may also help. Additionally, an increase of the antifungal dosage may be
required. However, clinicians should still consider the possibility of a reduced or subtherapeutic
antifungal effect. It may be appropriate to switch to itraconazole oral solution or an agent like
fluconazole whose absorption is not affected by stomach pH.
References
1. "Product Information. Aciphex (rabeprazole)" Janssen Pharmaceuticals, Titusville, NJ.
2. Bottiger Y, Tybring G, Gotharson E, Bertilsson L "Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers
of S-mephenytoin." Clin Pharmacol Ther 62 (1997): 384-91
Moderate ketoconazole  hyoscyamine

Applies to: ketoconazole, hyoscyamine
ADJUST DOSING INTERVAL: Theoretically, anticholinergic agents can reduce gastric acid secretion
and reduce the oral bioavailability of ketoconazole, which requires an acidic environment for
dissolution and absorption.
MANAGEMENT: Anticholinergic agents should be administered at least 2 hours after ketoconazole.
References
1. "Product Information. Nizoral (ketoconazole)." Janssen Pharmaceutica, Titusville, NJ.
Moderate ketoconazole  magnesium hydroxide

Applies to: ketoconazole, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
ADJUST DOSING INTERVAL: The dissolution of oral ketoconazole requires an acidic environment.
Medications that decrease the acidity of the stomach can reduce the bioavailability of ketoconazole
by 75% to 80%.
MANAGEMENT: Separation of doses by two or more hours is recommended.
References
3. Brass C, Galgiani JN, Blaschke TF, et al "Disposition of ketoconazole, an oral antifungal, in humans." Antimicrob Agents Chemother 21 (1982): 151-8
Moderate ketoconazole  aluminum hydroxide

Applies to: ketoconazole, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
by 75% to 80%.
References
ketoconazole  albuterol
Applies to: ketoconazole, albuterol

Moderate
MONITOR: Beta-2 adrenergic agonists can cause dose-related prolongation of the QT
interval and potassium loss. Theoretically, coadministration with other agents that can prolong the QT
interval may result in additive effects and increased risk of ventricular arrhythmias including torsade
de pointes and sudden death. In general, the risk of an individual agent or a combination of agents
causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may
be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease,
and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-
induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the
drug(s). Clinically significant prolongation of QT interval and hypokalemia occur infrequently when
beta-2 agonists are inhaled at normally recommended dosages. However, these effects may be more
common when the drugs are administered systemically or when recommended dosages are
exceeded.
MANAGEMENT: Caution is recommended if beta-2 agonists are used in combination with other
drugs that can prolong the QT interval. Patients should be advised to seek prompt medical attention
if they experience symptoms that could indicate the occurrence of torsade de pointes such as
dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or
syncope.
References
1. "Product Information. Arcapta Neohaler (indacaterol)." Novartis Pharmaceuticals, East Hanover, NJ.
2. Ferguson GT, Funck-Brentano C, Fischer T, Darken P, Reisner C "Cardiovascular Safety of Salmeterol in COPD." Chest 123 (2003): 1817-24
3. Larsson S, Svedmyr N "Bronchodilating effect and side effects of beta2- adrenoceptor stimulants by different modes of administration (tablets,
metered aerosol, and combinations thereof). A study with salbutamol inasthmatics." Am Rev Respir Dis 116 (1977): 861-9
Moderate ketoconazole  sodium bicarbonate

Applies to: ketoconazole, sodium bicarbonate
by 75% to 80%.
References
Moderate metroNIDAZOLE  simvastatin

Applies to: metronidazole, simvastatin
References
Moderate
metroNIDAZOLE  loperamide
Applies to: metronidazole, loperamide
References
Moderate sulfamethoxazole  glimepiride

Applies to: Cotrim (sulfamethoxazole / trimethoprim), glimepiride

References
1298-301
Moderate
trimethoprim  metFORMIN
Applies to: Cotrim (sulfamethoxazole / trimethoprim), metformin
MONITOR: Trimethoprim may decrease the excretion of metformin by competing for renal tubular
transport. The mechanism may involve trimethoprim inhibition of the organic cation transporter 2
(OCT2), thereby increasing metformin plasma concentration. Increased metformin levels may increase
the risk of lactic acidosis.
MANAGEMENT: If trimethoprim and metformin must be used together, particularly slow and cautious
titration of metformin dosage is recommended. The maximal dose of metformin probably also should
be reduced until further information about this interaction is available. Patients should be advised to
monitor their blood glucose and to promptly notify their physician if they experience possible signs
of lactic acidosis such as malaise, myalgia, respiratory distress, hyperventilation, slow or irregular
heartbeat, somnolence, abdominal upset, or other unusual symptoms.
References
1. Somogyi A, Stockley C, Keal J, Rolan P, Bochner F "Reduction of metformin renal tubular secretion by cimetidine in man." Br J Clin Pharmacol 23
(1987): 545-51
Moderate miconazole  amLODIPine

Applies to: miconazole, amlodipine
combinations.

References
Pharmacol 55 (1999): 57-60
(1997): 410-5
Moderate miconazole  simvastatin

Applies to: miconazole, simvastatin
GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 including azole antifungal
agents may significantly increase the plasma concentrations of HMG-CoA reductase inhibitors that
are substrates of the isoenzyme. High levels of HMG-CoA reductase inhibitory activity in plasma is
associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain
and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit
of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be
accompanied by acute renal failure secondary to myoglobinuria and may result in death. The
interaction has not been studied with clotrimazole troches or miconazole buccal tablets. Although
systemic absorption following mucous membrane exposure is limited, the potential for interaction
with drugs metabolized by CYP450 3A4 such as lovastatin, simvastatin, and atorvastatin cannot be
ruled out.
MANAGEMENT: Given the potential for serious and life-threatening musculoskeletal toxicity
associated with increased plasma levels of HMG-CoA reductase inhibitors, the concomitant use of
lovastatin, red yeast rice (which contains lovastatin), and simvastatin with clotrimazole or miconazole
mucous membrane preparations should be avoided if possible. Atorvastatin may be used with
caution, although the dosage should start low and probably not exceed 40 mg/day. All patients
treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained
muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should
be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if
myopathy is otherwise suspected or diagnosed. No interaction is expected with fluvastatin and
pravastatin, since they are not metabolized by CYP450 3A4.
References
2. Kantola T, Kivisto KT, Neuvonen PJ "Effect of itraconazole on cerivastatin pharmacokinetics." Eur J Clin Pharmacol 54 (1999): 851-5
3. Kivisto KT, Kantola T, Neuvonen PJ "Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin." Br J Clin Pharmacol 46
(1998): 49-53
Moderate miconazole  diclofenac

Applies to: miconazole, diclofenac
MONITOR: Coadministration with inhibitors of CYP450 2C9 may increase the plasma concentrations
of diclofenac, which is primarily metabolized by the isoenzyme. When the last dose of CYP450 2C9
inhibitor voriconazole (400 mg every 12 hours on day 1, followed by 200 mg every 12 hours on day 2)
was coadministered with a single dose of diclofenac (50 mg), the peak plasma concentration (Cmax)
and systemic exposure (AUC) of diclofenac increased by 114% and 78%, respectively, compared to
diclofenac alone.
MANAGEMENT: Caution is advised if diclofenac is prescribed in combination with an inhibitor of

CYP450 2C9. Some authorities recommend a reduction of the maximum diclofenac dose to 100 mg
per day when coadministered with a CYP450 2C9 inhibitor.
References
2. Cerner Multum, Inc. "Australian Product Information." O 0
Moderate chlorpheniramine  dimenhyDRINATE

Applies to: chlorpheniramine, dimenhydrinate
MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics;
neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may
have additive effects when used in combination. Excessive parasympatholytic effects may result in
paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral
symptoms of intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and
mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include
memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching
or jerking movements, stereotypy, and seizures. Central nervous system-depressant effects may also
be additively or synergistically increased when these agents are combined, especially in elderly or
debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic
agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic
antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or
more drugs that can cause QT interval prolongation may result in additive effects and increased risk
of ventricular arrhythmias including torsade de pointes and sudden death.
MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined,
particularly in the elderly and those with underlying organic brain disease, who tend to be more
sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be
easily overlooked. Patients should be advised to notify their physician promptly if they experience
potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance,
blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid
activities requiring mental alertness until they know how these agents affect them. A reduction in
anticholinergic dosages may be necessary if excessive adverse effects develop.
References
1. Kulik AV, Wilbur R "Delirium and stereotypy from anticholinergic antiparkinson drugs." Prog Neuropsychopharmacol Biol Psychiatry 6 (1982): 75-82
2. Hvizdos AJ, Bennett JA, Wells BG, Rappaport KB, Mendel SA "Anticholinergic psychosis in a patient receiving usual doses of haloperidol." Clin
Pharm 2 (1983): 174-8
3. Mann SC, Boger WP "Psychotropic drugs, summer heat and humidity, and hyperplexia: a danger restated." Am J Psychiatry 135 (1978): 1097-100
Moderate
chlorpheniramine  cetirizine
Applies to: chlorpheniramine, cetirizine
MONITOR: Concurrent use of cetirizine or levocetirizine with alcohol or other agents that exhibit
central nervous system (CNS) depressant effects may result in additive impairment of mental
alertness and performance. Several studies have shown no effect of racemic cetirizine on cognitive
function, motor performance, or sleep latency as indicated by objective measurements. However,
there have been reports of somnolence, fatigue, and asthenia in some patients treated with cetirizine
or levocetirizine in clinical trials.
MANAGEMENT: Concomitant use of cetirizine or levocetirizine with alcohol or other CNS depressants
should generally be avoided if possible. In the event that they are used together, patients should be
counseled to avoid hazardous activities requiring mental alertness and motor coordination until they
know how these agents affect them, and to notify their physician if they experience excessive or
prolonged CNS effects that interfere with their normal activities.
References
1. "Product Information. Zyrtec (cetirizine)." Pfizer US Pharmaceuticals, New York, NY.
2. "Product Information. Xyzal (levocetirizine)." UCB Pharma Inc, Smyrna, GA.
Moderate chlorpheniramine  hyoscyamine

Applies to: chlorpheniramine, hyoscyamine
References
Pharm 2 (1983): 174-8
Moderate chlorpheniramine  metoclopramide

Applies to: chlorpheniramine, metoclopramide
MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or
synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly
or debilitated patients.
MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially
excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required,
particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous
activities requiring mental alertness and motor coordination until they know how these agents affect
them, and to notify their physician if they experience excessive or prolonged CNS effects that
interfere with their normal activities.
References
1. "Product Information. Belsomra (suvorexant)." Merck & Company Inc, Whitehouse Station, NJ.
2. Divoll M, Greenblatt DJ, Lacasse Y, Shader RI "Benzodiazepine overdosage: plasma concentrations and clinical outcome." Psychopharmacology
(Berl) 73 (1981): 381-3
3. Plushner SL "Valerian: valeriana officinalis." Am J Health Syst Pharm 57 (2000): 328-35
Moderate chlorpheniramine  loperamide

Applies to: chlorpheniramine, loperamide
MONITOR: Coadministration with drugs that possess significant anticholinergic activity may
potentiate the antimotility effect of loperamide. An isolated case report describes an incident of fatal
gastroenteritis during concomitant treatment with clozapine and loperamide. A 36-year-old man who
had been treated with clozapine 500 mg/day and was previously in good health died after taking a
total of 6 mg of loperamide during an outbreak of intestinal disease in a Finnish hospital. The patient
received no other medications. The authors theorized that the anticholinergic effect of clozapine in
combination with the antimotility effect of loperamide may have led to toxic megacolon. However,
causality has not been determined.
MANAGEMENT: Until further information is available, loperamide should be used with caution in
combination with drugs that possess significant anticholinergic activity (e.g., antihistamines;
antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; class
IA antiarrhythmics especially disopyramide). Ambulatory patients should also be made aware of the
possibility of additive CNS effects (e.g., drowsiness, dizziness, lightheadedness, confusion) and
counseled to avoid activities requiring mental alertness until they know how these agents affect them.
References
1. Eronen M, Putkonen H, Hallikainen T, Vartiainen H "Lethal gastroenteritis associated with clozapine and loperamide." Am J Psychiatry 160 (2003):
2242-2243
Moderate dexamethasone  magnesium hydroxide

Applies to: dexamethasone, Almacone (aluminum hydroxide / magnesium hydroxide /
simethicone)
MONITOR: The overuse or abuse of laxatives can cause significant loss of electrolytes and potentiate
the risk of hypokalemia associated with corticosteroid therapy. Corticosteroids promote the retention
of sodium and water and the excretion of potassium. Although these effects are primarily associated
with mineralocorticoids like fludrocortisone, they may also occur with higher dosages of
glucocorticoids or adrenocorticotropic agents, particularly if given systemically for longer than brief
periods.
MANAGEMENT: In general, laxatives should only be used on a short-term, intermittent basis in

recommended dosages. During concomitant therapy with corticosteroids, particularly if
fludrocortisone or large doses of a glucocorticoid or adrenocorticotropic agent is given, patients
should be counseled to recognize potential signs and symptoms of hypokalemia such as fatigue,
myalgia, and muscle weakness. If maintenance of bowel regularity is required, patients should be
advised to exercise and increase fiber in the diet and/or consider the use of bulk-forming laxatives.
References
1. Chin RL "Laxative-induced hypokalemia." Ann Emerg Med 32 (1998): 517-8
2. Blumenthal M, Goldberg A, Brinckmann J, eds. "Herbal Medicine: Expanded Commission E Monographs." Newton, MA: Integrative Medicine
Communications (2000):
3. Seale JP, Compton MR "Side-effects of corticosteroid agents." Med J Aust 144 (1986): 139-42
Moderate dexamethasone  mefenamic acid

Applies to: dexamethasone, mefenamic acid
References
Moderate dexamethasone  diclofenac

Applies to: dexamethasone, diclofenac
References
Moderate dexamethasone  metFORMIN

Applies to: dexamethasone, metformin
MONITOR: The efficacy of insulin and other antidiabetic agents may be diminished by certain drugs,
including atypical antipsychotics, corticosteroids, diuretics, estrogens, gonadotropin-releasing
hormone agonists, human growth hormone, phenothiazines, progestins, protease inhibitors,
sympathomimetic amines, thyroid hormones, L-asparaginase, copanlisib, danazol, diazoxide,
isoniazid, megestrol, omacetaxine, phenytoin, tagraxofusp, temsirolimus, as well as pharmacologic
dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood
glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes
mellitus, and/or exacerbation of preexisting diabetes.
MANAGEMENT: Caution is advised when drugs that can interfere with glucose metabolism are
prescribed to patients with diabetes. Close clinical monitoring of glycemic control is recommended
following initiation or discontinuation of these drugs, and the dosages of concomitant antidiabetic
agents adjusted as necessary. Patients should be advised to notify their physician if their blood
glucose is consistently high or if they experience symptoms of severe hyperglycemia such as
excessive thirst and increases in the volume or frequency of urination. Likewise, patients should be
observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen.
References
1. Jori A, Carrara MC "On the mechanism of the hyperglycaemic effect of chlorpromazine." J Pharm Pharmacol 18 (1966): 623-4
2. "Product Information. Dymelor (acetohexamide)" Lilly, Eli and Company, Indianapolis, IN.
3. "Product Information. Elzonris (tagraxofusp)." Stemline Therapeutics, New York, NY.
Moderate dexamethasone  glimepiride

Applies to: dexamethasone, glimepiride

References
Moderate dexamethasone  aminophylline

Applies to: dexamethasone, aminophylline
MONITOR: The concomitant use of theophylline and corticosteroids may theoretically increase the
risk of hypokalemia due to additive potassium-lowering effects. Additionally, theophylline serum
concentrations may be altered. The mechanism is unknown and data have been limited and
conflicting; increased, decreased, and unchanged theophylline levels have all been reported.
MANAGEMENT: Monitoring for altered efficacy and safety of theophylline and altered serum
potassium and theophylline concentrations is advisable when these drugs are coadministered.
Patients should be advised to notify their physician if they experience signs of hypokalemia (e.g.,
weakness, lethargy, and muscle pains or cramps), worsening respiratory symptoms, or signs of
theophylline toxicity (e.g., nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular
heartbeat).
References
1. Fergusson RJ, Scott CM, Rafferty P, Gaddie J "Effect of prednisolone on theophylline pharmacokinetics in patients with chronic airflow obstruction."
Thorax 42 (1987): 195-8
2. Buchanan N, Hurwitz S, Butler P "Asthma - a possible interaction between hydrocortisone and theophylline." S Afr Med J 56 (1979): 1147-8
3. Tatsis G, Orphanidou D, Douratsos D, et al "The effect of steroids on theophylline absorption." J Int Med Res 19 (1991): 326-9
Moderate
dexamethasone  amLODIPine
Applies to: dexamethasone, amlodipine
References

Moderate mefenamic acid  glimepiride

Applies to: mefenamic acid, glimepiride

References
1298-301
Moderate mefenamic acid  amLODIPine

Applies to: mefenamic acid, amlodipine
from the regimen.
References
641-4
Moderate mefenamic acid  methylPREDNISolone

Applies to: mefenamic acid, methylprednisolone
References
Moderate methylPREDNISolone  magnesium hydroxide

Applies to: methylprednisolone, Almacone (aluminum hydroxide / magnesium hydroxide /
simethicone)
MONITOR: The overuse or abuse of laxatives can cause significant loss of electrolytes and potentiate
the risk of hypokalemia associated with corticosteroid therapy. Corticosteroids promote the retention
of sodium and water and the excretion of potassium. Although these effects are primarily associated
with mineralocorticoids like fludrocortisone, they may also occur with higher dosages of
glucocorticoids or adrenocorticotropic agents, particularly if given systemically for longer than brief
periods.
MANAGEMENT: In general, laxatives should only be used on a short-term, intermittent basis in

recommended dosages. During concomitant therapy with corticosteroids, particularly if
fludrocortisone or large doses of a glucocorticoid or adrenocorticotropic agent is given, patients
should be counseled to recognize potential signs and symptoms of hypokalemia such as fatigue,
myalgia, and muscle weakness. If maintenance of bowel regularity is required, patients should be
advised to exercise and increase fiber in the diet and/or consider the use of bulk-forming laxatives.
References
2. Blumenthal M, Goldberg A, Brinckmann J, eds. "Herbal Medicine: Expanded Commission E Monographs." Newton, MA: Integrative Medicine
Communications (2000):
Moderate methylPREDNISolone  aminophylline

Applies to: methylprednisolone, aminophylline
MONITOR: The concomitant use of theophylline and corticosteroids may theoretically increase the
risk of hypokalemia due to additive potassium-lowering effects. Additionally, theophylline serum
concentrations may be altered. The mechanism is unknown and data have been limited and
conflicting; increased, decreased, and unchanged theophylline levels have all been reported.
MANAGEMENT: Monitoring for altered efficacy and safety of theophylline and altered serum
potassium and theophylline concentrations is advisable when these drugs are coadministered.
Patients should be advised to notify their physician if they experience signs of hypokalemia (e.g.,
weakness, lethargy, and muscle pains or cramps), worsening respiratory symptoms, or signs of
theophylline toxicity (e.g., nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular
heartbeat).
References
1. Fergusson RJ, Scott CM, Rafferty P, Gaddie J "Effect of prednisolone on theophylline pharmacokinetics in patients with chronic airflow obstruction."
Thorax 42 (1987): 195-8
2. Buchanan N, Hurwitz S, Butler P "Asthma - a possible interaction between hydrocortisone and theophylline." S Afr Med J 56 (1979): 1147-8
3. Tatsis G, Orphanidou D, Douratsos D, et al "The effect of steroids on theophylline absorption." J Int Med Res 19 (1991): 326-9
Moderate
methylPREDNISolone  metFORMIN
Applies to: methylprednisolone, metformin
References
Moderate
methylPREDNISolone  amLODIPine
Applies to: methylprednisolone, amlodipine
References
Moderate methylPREDNISolone  diclofenac

Applies to: methylprednisolone, diclofenac
References
Moderate methylPREDNISolone  glimepiride

Applies to: methylprednisolone, glimepiride
References
Moderate metoclopramide  dimenhyDRINATE

Applies to: metoclopramide, dimenhydrinate
GENERALLY AVOID: Anticholinergic agents and other agents with significant anticholinergic activity
(e.g., clozapine, class IA antiarrhythmics especially disopyramide) may antagonize the pharmacologic
effects of gastrointestinal prokinetic agents. Gastrokinetic drugs such as domperidone and
metoclopramide increase gastrointestinal motility by blocking peripheral dopamine receptors.
Anticholinergic agents could negate this action.
MANAGEMENT: Concomitant use of gastrointestinal prokinetic agents with anticholinergic agents

should be avoided, if possible.
References
1. "Product Information. Reglan (metoclopramide)." Wyeth-Ayerst Laboratories, Philadelphia, PA.
2. "Product Information. Motilium (domperidone)." Janssen-Ortho Inc, Toronto, ON.
Moderate metoclopramide  cetirizine

Applies to: metoclopramide, cetirizine
References
Moderate metoclopramide  hyoscyamine

Applies to: metoclopramide, hyoscyamine
GENERALLY AVOID: Anticholinergic agents and other agents with significant anticholinergic activity
(e.g., clozapine, class IA antiarrhythmics especially disopyramide) may antagonize the pharmacologic
effects of gastrointestinal prokinetic agents. Gastrokinetic drugs such as domperidone and
metoclopramide increase gastrointestinal motility by blocking peripheral dopamine receptors.
Anticholinergic agents could negate this action.
MANAGEMENT: Concomitant use of gastrointestinal prokinetic agents with anticholinergic agents

should be avoided, if possible.
References
1. "Product Information. Reglan (metoclopramide)." Wyeth-Ayerst Laboratories, Philadelphia, PA.
2. "Product Information. Motilium (domperidone)." Janssen-Ortho Inc, Toronto, ON.
Moderate omeprazole  simvastatin

Applies to: omeprazole, simvastatin
MONITOR: A case report suggests that coadministration with esomeprazole may increase the plasma
concentrations of atorvastatin and the associated risk of myopathy. The proposed mechanism is
competitive inhibition of intestinal P-glycoprotein, resulting in decreased drug secretion into the
intestinal lumen and increased drug bioavailability. Another, perhaps minor mechanism is competitive
inhibition of CYP450 3A4 metabolism. The interaction was suspected in a patient treated with
atorvastatin (more than 1 year) and esomeprazole (6 weeks) who developed rhabdomyolysis with AV
block two days after the addition of clarithromycin. The patient reported experiencing symptoms of
increased fatigue, mild chest pain, and shortness of breath that coincided with the initiation of
esomeprazole approximately six weeks prior to admission. Theoretically, the interaction may also
occur with other proton pump inhibitors like lansoprazole, omeprazole, and pantoprazole and HMG-
CoA reductase inhibitors like lovastatin and simvastatin, since these drugs are all substrates of P-
glycoprotein and CYP450 3A4.
MANAGEMENT: Because of the increased risk of musculoskeletal toxicity associated with high levels
of HMG-CoA reductase inhibitory activity in plasma, patients treated with atorvastatin, lovastatin,
simvastatin, and red yeast rice (which contains lovastatin) should be monitored more closely during
concomitant use of proton pump inhibitors. All patients treated with HMG-CoA reductase inhibitors
should be advised to promptly report to their physician any unexplained muscle pain, tenderness, or
weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine
kinase is markedly elevated or if myopathy is suspected or diagnosed.
References
1. Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF "Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein." Naunyn
Schmiedebergs Arch Pharmacol 364 (2001): 551-7
2. Sipe BE, Jones RJ, Bokhart GH "Rhabdomyolysis Causing AV Blockade Due to Possible Atorvastatin, Esomeprazole, and Clarithromycin Interaction."
3. Bogman K, Peyer AK, Torok M, Kusters E, Drewe J "HMG-CoA reductase inhibitors and P-glycoprotein modulation." Br J Pharmacol 132 (2001):
1183-92
Moderate omeprazole  ferrous fumarate

Applies to: omeprazole, ferrous fumarate / folic acid
MONITOR: The profound hypochlorhydria induced by proton pump inhibitors (PPIs) may impair the
gastrointestinal absorption of nonheme iron, a process that is dependent on an acidic environment.
The interaction was suspected in two patients with iron deficiency anemia due to gastrointestinal
blood loss that were unresponsive to oral iron replacement therapy, even after the bleeding had
apparently stopped. Both patients had been on omeprazole for six months while being treated with
ferrous sulfate. An iron-loading test was performed on one of the patients and indicated iron
malabsorption. Within two months after discontinuation of omeprazole, notable improvements in
hemoglobin level and mean corpuscular volume (MCV) were observed in both patients, and iron
absorption was significantly increased in the patient who underwent absorption testing. In a case
review of patients with hereditary hemochromatosis treated at one institution, investigators observed
a reduced requirement for maintenance phlebotomy in seven patients following initiation of PPI
therapy (mean 2.5 L blood removed/year before PPI therapy vs. 0.5 L/year during PPI therapy),
presumably due to reduced tissue iron accumulation stemming from impaired absorption of dietary
nonheme iron. Mean annual phlebotomy requirement during PPI therapy in these patients was also
lower than that in controls who had never taken a PPI (mean 2.3 L blood removed/year). The same
group of investigators also studied iron absorption in 14 patients fed an iron-loaded meal before and
after PPI therapy for one week. PPI therapy was associated with a 51% reduction in area under the
serum iron concentration-time curve (AUC 0 to 4 hours); a 55% reduction in maximum increase of
serum iron following ingestion of iron-loaded meal; and a 46% reduction in percent recovery of
administered iron at peak serum iron concentration. Interestingly, the interaction has not been
reported in healthy, iron-replete individuals. In a study of 109 patients with Zollinger-Ellison
syndrome who had not undergone gastric resection, omeprazole treatment for an average of 5.7
years did not significantly decrease body iron stores or cause iron deficiency compared to H2-
receptor antagonist therapy or no gastric acid-suppressant treatment. It is possible that the
interaction may not affect people with healthy iron stores because of compensation by dietary heme
iron, which typically comprises only a small fraction of dietary iron but whose absorption is not
dependent on gastrointestinal pH. In contrast, dietary heme iron alone may not be sufficient to
restore normal iron balance in patients with anemia or those with defective regulatory mechanisms of
iron absorption.
MANAGEMENT: Patients with iron deficiency may not respond adequately to oral iron replacement
therapy during coadministration of proton pump inhibitors. If an interaction is suspected after ruling
out other causes, it may be appropriate to discontinue the proton pump inhibitor or consider
administering iron parenterally.
References
1. "Product Information. Prilosec (omeprazole)." Merck & Co, Inc, West Point, PA.
2. Hutchison C, Geissler CA, Powell JJ, Bomford A "Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary
haemochromatosis." Gut 56 (2007): 1291-5
3. "Product Information. Kapidex (dexlansoprazole)." Takeda Pharmaceuticals America, Lincolnshire, IL.
Moderate sodium bicarbonate  ferrous fumarate

Applies to: sodium bicarbonate, ferrous fumarate / folic acid
ADJUST DOSING INTERVAL: The bioavailability of orally administered iron may be reduced by
concomitant administration of antacids or other agents with acid-neutralizing effects. The exact
mechanism is unknown but may involve reduced iron solubility due to increase in gastric pH and/or
reduced absorption due to complexation or precipitation of the iron. Based on existing data, sodium
bicarbonate and calcium carbonate appear to have greater effects than antacids containing
magnesium and aluminum hydroxides. In a study of patients with mild iron deficiency anemia,
coadministration of ferrous sulfate with sodium bicarbonate 1 gram and calcium carbonate 500 mg
reduced iron absorption by 50% and 67%, respectively, while 5 mL of an antacid containing
magnesium and aluminum hydroxides had little effect. Another study also found no effect on iron
absorption when ferrous sulfate (equivalent to 10 mg/kg of elemental iron) was coadministered with
magnesium hydroxide (1 mg for every 5 mg of elemental iron ingested) in a group of healthy, fasting
male subjects. In contrast, absorption of iron from ferrous sulfate and ferrous fumarate tablets was
reduced by 37% and 31%, respectively, following administration of an antacid containing magnesium
carbonate, magnesium hydroxide, and aluminum hydroxide in a study of healthy, iron-replete
volunteers. Similarly, in a study of nine patients, coadministration of 5 mg of ferrous sulfate with a 35
gram dose of magnesium trisilicate was found to reduce iron absorption by an average of more than
70%. The interaction reportedly does not occur in the presence of ascorbic acid, which may
competitively bind with iron and prevent the interference with iron absorption.
MANAGEMENT: To minimize the potential for interaction, it may be appropriate to administer oral
iron preparations at least two hours apart from antacids or other agents with acid-neutralizing
effects.
References
1. Coste JF, De Barbi VA, Keil LB, Needle MA "In-vitro interactions of oral hemantics and antacid suspensions." Curr Ther Res Clin Exp 22 (1977): 205-
16
2. Coste JF, de Bari VA, Keil LB, Needle MA "In-vitro interactions of oral hematinics." Curr Ther Res Clin Exp 22 (1977): 205-15
3. Gugler R, Allgayer H "Effects of antacids on the clinical pharmacokinetics of drugs. An update." Clin Pharmacokinet 18 (1990): 210-9
Moderate amLODIPine  calcium lactate

Applies to: amlodipine, calcium lactate
MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers
by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe
verapamil toxicity.
MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker

therapy during coadministration with calcium products.
References
1. Oszko MA, Klutman NE "Use of calcium salts during cardiopulmonary resuscitation for reversing verapamil-associated hypotension." Clin Pharm 6
(1987): 448-9
2. Lipman J, Jardine I, Roos C, Dreosti L "Intravenous calcium chloride as an antidote to verapamil-induced hypotension." Intensive Care Med 8 (1982):
55-7
3. Schoen MD, Parker RB, Hoon TJ, et al "Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with
intravenous calcium chloride pretreatment in normal subjects." Am J Cardiol 67 (1991): 300-4
Moderate amLODIPine  diclofenac

Applies to: amlodipine, diclofenac
from the regimen.
References
641-4
Moderate simvastatin  pectin

Applies to: simvastatin, kaolin / pectin
GENERALLY AVOID: The concomitant use of HMG-CoA reductase inhibitors and the fiber pectin may
result in increased levels of low-density lipoprotein cholesterol. The beneficial effect of the HMG-CoA
reductase inhibitor may be reduced. The mechanism is decreased gastrointestinal absorption by the
fiber. A case report exists for lovastatin. A similar reaction may occur with other HMG-CoA reductase
inhibitors, although data is lacking.
MANAGEMENT: The clinician should consider avoiding coadministration, but if this is not possible the
administration times should be separated as much as possible. Patients should be monitored for
altered cholesterol-lowering effects.
References
1. Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706
Moderate simvastatin  lansoprazole

Applies to: simvastatin, lansoprazole
MONITOR: A case report suggests that coadministration with esomeprazole may increase the plasma
concentrations of atorvastatin and the associated risk of myopathy. The proposed mechanism is
competitive inhibition of intestinal P-glycoprotein, resulting in decreased drug secretion into the
intestinal lumen and increased drug bioavailability. Another, perhaps minor mechanism is competitive
inhibition of CYP450 3A4 metabolism. The interaction was suspected in a patient treated with
atorvastatin (more than 1 year) and esomeprazole (6 weeks) who developed rhabdomyolysis with AV
block two days after the addition of clarithromycin. The patient reported experiencing symptoms of
increased fatigue, mild chest pain, and shortness of breath that coincided with the initiation of
esomeprazole approximately six weeks prior to admission. Theoretically, the interaction may also
occur with other proton pump inhibitors like lansoprazole, omeprazole, and pantoprazole and HMG-
CoA reductase inhibitors like lovastatin and simvastatin, since these drugs are all substrates of P-
glycoprotein and CYP450 3A4.
MANAGEMENT: Because of the increased risk of musculoskeletal toxicity associated with high levels
of HMG-CoA reductase inhibitory activity in plasma, patients treated with atorvastatin, lovastatin,
simvastatin, and red yeast rice (which contains lovastatin) should be monitored more closely during
concomitant use of proton pump inhibitors. All patients treated with HMG-CoA reductase inhibitors
should be advised to promptly report to their physician any unexplained muscle pain, tenderness, or
weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine
kinase is markedly elevated or if myopathy is suspected or diagnosed.
References
1. Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF "Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein." Naunyn
Schmiedebergs Arch Pharmacol 364 (2001): 551-7
2. Sipe BE, Jones RJ, Bokhart GH "Rhabdomyolysis Causing AV Blockade Due to Possible Atorvastatin, Esomeprazole, and Clarithromycin Interaction."
3. Bogman K, Peyer AK, Torok M, Kusters E, Drewe J "HMG-CoA reductase inhibitors and P-glycoprotein modulation." Br J Pharmacol 132 (2001):
1183-92
Moderate
albuterol  glimepiride
Applies to: albuterol, glimepiride
References
Moderate albuterol  magnesium hydroxide

Applies to: albuterol, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
MONITOR: Bowel cleansing as well as overuse of certain laxatives may cause electrolyte loss and
increase the risk of torsade de pointes ventricular arrhythmia in patients treated with drugs that
prolong the QT interval. Electrolyte disturbances including hypokalemia and hypomagnesemia have
been reported with laxative abuse and are known risk factors for torsade de pointes associated with
QT interval prolongation.
MANAGEMENT: Patients treated with drugs that prolong the QT interval should exercise caution
when self-medicating with laxatives. The recommended dosage and duration of use should not be
exceeded. Patients treated with lactulose for more than six months should be monitored periodically
for electrolyte imbalance. Patients should be advised to seek prompt medical attention if they
lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.
References
Moderate albuterol  loperamide

Applies to: albuterol, loperamide
References
Moderate albuterol  aminophylline

Applies to: albuterol, aminophylline
MONITOR: Concomitant use of beta-2 adrenergic agonists with theophylline may increase the risk
and/or severity of hypokalemia and adverse cardiovascular effects such as palpitation, tachycardia,
and blood pressure elevation. Adverse events, especially hypokalemia, may be more likely with
systemic or nebulized formulations of beta-2 agonists or high dosages of theophylline. Beta-2
agonists can cause clinically significant but usually transient decreases in serum potassium
concentrations, while hypokalemia associated with theophylline often occurs in toxicity. Serious
events including rare cases of cardiorespiratory arrest and intestinal pseudo-obstruction have been
reported in association with hypokalemia induced by these agents. Moreover, since QT prolongation
is a possible side effect of beta-2 agonists, development of hypokalemia may potentiate the risk of
torsade de pointes and other serious arrhythmias. Pharmacokinetically, some beta-2 agonists given
systemically may decrease the plasma concentrations of theophylline. Albuterol, isoproterenol, and
terbutaline have been specifically implicated, usually increasing theophylline clearance by
approximately 10% to a third, although some studies with albuterol and terbutaline failed to
demonstrate a significant effect on theophylline pharmacokinetics. The interaction also did not occur
in studies with fenoterol, formoterol, and metaproterenol. A case report describes a significant
increase in theophylline clearance during intravenous administration of albuterol in a 19-month-old
child with severe asthma, who subsequently required a threefold increase in theophylline dosage.
Theophylline clearance decreased by 50% upon discontinuation of albuterol. In another case, a
greater than 4-fold increase in theophylline clearance was reported following the intravenous
administration of isoproterenol and methylprednisolone in a critically patient receiving aminophylline
and nebulized terbutaline.
MANAGEMENT: Although theophylline and beta-2 agonists are commonly used together to produce
bronchodilation, it may be appropriate to monitor patient response as well as serum potassium level,
blood pressure and heart rate during coadministration, especially if the beta-2 agonist is
administered systemically or by nebulizer. Close monitoring is particularly important in patients with
severe asthma, since the potential increases in blood pressure and heart rate may have more serious
consequences in the presence of hypoxemia or hypercapnia due to increased myocardial oxygen
consumption. Patients should be advised to notify their physician if they experience worsening of
their respiratory condition or potential signs and symptoms of hypokalemia such as fatigue,
weakness, myalgia, muscle cramps, numbness, tingling, abdominal pain, constipation, palpitation, and
irregular heartbeat.
References
1. Garty M, Paul-Keslin L, Ilfeld DN, et al "Increased theophylline clearance in asthmatic patients due to terbutaline." Eur J Clin Pharmacol 36 (1989):
25-8
2. Chow OK, Fung KP "Slow-release terbutaline and theophylline for the long-term therapy of children with asthma: a Latin square and factorial study
of drug effects and interactions." Pediatrics 84 (1989): 119-25
3. "Product Information. Striverdi Respimat (olodaterol)." Boehringer Ingelheim, Ridgefield, CT.
Moderate albuterol  metFORMIN

Applies to: albuterol, metformin
References
Moderate
diclofenac  glimepiride
Applies to: diclofenac, glimepiride

References
1298-301
Moderate
dimenhyDRINATE  hyoscyamine
Applies to: dimenhydrinate, hyoscyamine
References
Pharm 2 (1983): 174-8
Moderate
dimenhyDRINATE  cetirizine
Applies to: dimenhydrinate, cetirizine
References
Moderate dimenhyDRINATE  loperamide

Applies to: dimenhydrinate, loperamide
References
2242-2243
Moderate aluminum hydroxide  ferrous fumarate

Applies to: Almacone (aluminum hydroxide / magnesium hydroxide / simethicone), ferrous
fumarate / folic acid
effects.
References
16
Moderate magnesium hydroxide  ferrous fumarate

Applies to: Almacone (aluminum hydroxide / magnesium hydroxide / simethicone), ferrous
fumarate / folic acid
effects.
References
16
Moderate magnesium hydroxide  glimepiride

Applies to: Almacone (aluminum hydroxide / magnesium hydroxide / simethicone), glimepiride
ADJUST DOSING INTERVAL: Some antacids may significantly increase the absorption rate and in
some cases the extent of absorption of oral sulfonylureas. The hypoglycemic effects of these agents
may be altered.
MANAGEMENT: Sulfonylureas should be administered at least two hours before or after antacids.
Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize
and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or
palpitations) and to notify their physician if it occurs.
References
1. "Product Information. Diabeta (glyburide)." Hoechst Marion-Roussel Inc, Kansas City, MO.
2. Prendergast BD "Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents." Clin Pharm 3 (1984): 473-85
3. "Product Information. Glucotrol (glipizide)." Pfizer US Pharmaceuticals, New York, NY.
Moderate hyoscyamine  loperamide

Applies to: hyoscyamine, loperamide
References
2242-2243
Moderate
loperamide  cetirizine
Applies to: loperamide, cetirizine
References
Moderate metFORMIN  glimepiride

Applies to: metformin, glimepiride
MONITOR: Coadministration of metformin with an insulin secretagogue (e.g., sulfonylurea,
meglitinide) or insulin may potentiate the risk of hypoglycemia. Although metformin alone generally
does not cause hypoglycemia under normal circumstances of use, the added therapeutic effect when
combined with other antidiabetic agents may result in hypoglycemia. The risk is further increased
when caloric intake is deficient or when strenuous exercise is not compensated by caloric
supplementation.
MANAGEMENT: A lower dosage of the insulin secretagogue or insulin may be required when used
with metformin. Blood glucose should be closely monitored, and patients should be educated on the
potential signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nervousness,
confusion, tremor, hunger, weakness, perspiration, palpitation, tachycardia) and appropriate remedial
actions to take if it occurs. Patients should also be advised to take precautions to avoid hypoglycemia
while driving or operating hazardous machinery.
References
1. Wiernsperger N, Rapin JR "Metformin-insulin interactions: from organ to cell." Diabetes Metab Rev 11 Suppl (1995): s3-12
2. Okada S, Ishii K, Hamada H, Tanokuchi S, Ichiki K, Ota Z "Can alpha-glucosidase inhibitors reduce the insulin dosage administered to patients with
non-insulin-dependent diabetes mellitus?" J Int Med Res 23 (1995): 487-91
Moderate lansoprazole  ferrous fumarate

Applies to: lansoprazole, ferrous fumarate / folic acid
MONITOR: The profound hypochlorhydria induced by proton pump inhibitors (PPIs) may impair the
gastrointestinal absorption of nonheme iron, a process that is dependent on an acidic environment.
The interaction was suspected in two patients with iron deficiency anemia due to gastrointestinal
blood loss that were unresponsive to oral iron replacement therapy, even after the bleeding had
apparently stopped. Both patients had been on omeprazole for six months while being treated with
ferrous sulfate. An iron-loading test was performed on one of the patients and indicated iron
malabsorption. Within two months after discontinuation of omeprazole, notable improvements in
hemoglobin level and mean corpuscular volume (MCV) were observed in both patients, and iron
absorption was significantly increased in the patient who underwent absorption testing. In a case
review of patients with hereditary hemochromatosis treated at one institution, investigators observed
a reduced requirement for maintenance phlebotomy in seven patients following initiation of PPI
therapy (mean 2.5 L blood removed/year before PPI therapy vs. 0.5 L/year during PPI therapy),
presumably due to reduced tissue iron accumulation stemming from impaired absorption of dietary
nonheme iron. Mean annual phlebotomy requirement during PPI therapy in these patients was also
lower than that in controls who had never taken a PPI (mean 2.3 L blood removed/year). The same
group of investigators also studied iron absorption in 14 patients fed an iron-loaded meal before and
after PPI therapy for one week. PPI therapy was associated with a 51% reduction in area under the
serum iron concentration-time curve (AUC 0 to 4 hours); a 55% reduction in maximum increase of
serum iron following ingestion of iron-loaded meal; and a 46% reduction in percent recovery of
administered iron at peak serum iron concentration. Interestingly, the interaction has not been
reported in healthy, iron-replete individuals. In a study of 109 patients with Zollinger-Ellison
syndrome who had not undergone gastric resection, omeprazole treatment for an average of 5.7
years did not significantly decrease body iron stores or cause iron deficiency compared to H2-
receptor antagonist therapy or no gastric acid-suppressant treatment. It is possible that the
interaction may not affect people with healthy iron stores because of compensation by dietary heme
iron, which typically comprises only a small fraction of dietary iron but whose absorption is not
dependent on gastrointestinal pH. In contrast, dietary heme iron alone may not be sufficient to
restore normal iron balance in patients with anemia or those with defective regulatory mechanisms of
iron absorption.
MANAGEMENT: Patients with iron deficiency may not respond adequately to oral iron replacement
therapy during coadministration of proton pump inhibitors. If an interaction is suspected after ruling
out other causes, it may be appropriate to discontinue the proton pump inhibitor or consider
administering iron parenterally.
References
1. "Product Information. Prilosec (omeprazole)." Merck & Co, Inc, West Point, PA.
2. Hutchison C, Geissler CA, Powell JJ, Bomford A "Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary
haemochromatosis." Gut 56 (2007): 1291-5
3. "Product Information. Kapidex (dexlansoprazole)." Takeda Pharmaceuticals America, Lincolnshire, IL.
Minor acyclovir  aminophylline

Applies to: acyclovir, aminophylline
Limited data suggest that the combination of a methyl xanthine with acyclovir may lead to elevated
theophylline levels potentiating pharmacologic and adverse effects. The mechanism may be due to
inhibition of theophylline oxidative metabolism. Clinical and laboratory monitoring is warranted if
these agents are given concurrently. Patients receiving this combination should be advised to report
any signs of theophylline toxicity including nausea, vomiting, diarrhea, headache, restlessness,
insomnia, or irregular heartbeat to their physician.
References
1. Maeda Y, Konishi T, Omoda K, Takeda Y, Fukuhara S, Fukuzawa M, Ohune T, Tsuya T, Tsukiai S "Inhibition of theophylline metabolism by aciclovir."
Biol Pharm Bull 19 (1996): 1591-5
Minor captopril  magnesium hydroxide

Applies to: captopril, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
Coadministration with antacids may decrease the oral bioavailability of captopril and other
angiotensin converting enzyme (ACE) inhibitors due to delayed gastric emptying and/or elevated
gastric pH. In 10 healthy volunteers, 50 mL of an antacid suspension decreased the mean peak
plasma concentration (Cmax) and area under the concentration-time curve (AUC) of captopril (50 mg
single oral dose) by 50% and 42%, respectively, compared to administration after fasting. The relative
bioavailability of captopril was 0.66 with antacid, although its hypotensive activity did not seem to be
affected. Based on available data, the clinical significance of this interaction appears to be minor. As a
precaution, patients may want to consider separating the administration times of ACE inhibitors and
antacids or oral medications that contain antacids (e.g., didanosine buffered tablets or pediatric oral
solution) by 1 to 2 hours.
References
1. Mantyla R, Mannisto PT, Vuorela A, Sundberg S, Ottoila P "Impairment of captopril bioavailability by concomitant food and antacid intake." Int J
Clin Pharmacol Ther Toxicol 22 (1984): 626-9
Minor captopril  NIFEdipine

Applies to: captopril, nifedipine
Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors may have additive
hypotensive effects. While these drugs are often safely used together, careful monitoring of the
systemic blood pressure is recommended during coadministration, especially during the first one to
three weeks of therapy.
References
1. Di Somma S, et al "Antihypertensive effects of verapamil, captopril and their combination at rest and during dynamic exercise."
Arzneimittelforschung 42 (1992): 103
2. Kaplan NM "Amlodipine in the treatment of hypertension." Postgrad Med J 67 Suppl 5 (1991): s15-9
3. DeQuattro V "Comparison of benazepril and other antihypertensive agents alone and in combination with the diuretic hydrochlorothiazide." Clin
Cardiol 14 (1991): iv28-32;
Minor captopril  sodium bicarbonate

Applies to: captopril, sodium bicarbonate
References
Minor
captopril  aluminum hydroxide
Applies to: captopril, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
References
Minor captopril  amLODIPine

Applies to: captopril, amlodipine
Calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors may have additive
hypotensive effects. While these drugs are often safely used together, careful monitoring of the
systemic blood pressure is recommended during coadministration, especially during the first one to
three weeks of therapy.
References
1. Di Somma S, et al "Antihypertensive effects of verapamil, captopril and their combination at rest and during dynamic exercise."
Arzneimittelforschung 42 (1992): 103
2. Kaplan NM "Amlodipine in the treatment of hypertension." Postgrad Med J 67 Suppl 5 (1991): s15-9
3. DeQuattro V "Comparison of benazepril and other antihypertensive agents alone and in combination with the diuretic hydrochlorothiazide." Clin
Cardiol 14 (1991): iv28-32;
Minor ciprofloxacin  sulfamethoxazole

Applies to: ciprofloxacin, Cotrim (sulfamethoxazole / trimethoprim)
Limited data suggest that sulfamethoxazole-trimethoprim (SMX-TMP) may rarely prolong the QT
interval of the electrocardiogram. Theoretically, coadministration with other agents that can prolong
the QT interval may result in additive effects and increased risk of ventricular arrhythmias including
torsade de pointes and sudden death. There have been isolated reports of QT prolongation and
ventricular arrhythmias occurring in patients treated with SMX-TMP intravenously. However, a causal
relationship has not been established, and the risk of clinically significant QT prolongation is unlikely
at recommended dosages of SMX-TMP. In general, the risk of an individual agent or a combination of
drug(s). Patients should be advised to seek prompt medical attention if they experience symptoms
palpitation, irregular heart rhythm, shortness of breath, or syncope.
References
2. Crouch MA, Limon L, Cassano AT "Clinical relevance and management of drug-related QT interval prolongation." Pharmacotherapy 23 (2003): 881-
908
Minor ciprofloxacin  metoclopramide

Applies to: ciprofloxacin, metoclopramide
Metoclopramide increases the rate of absorption of oral ciprofloxacin, resulting in a shorter time to
reach maximum plasma concentrations. The bioavailability is not affected. The probable mechanism is
increased gastric motility by metoclopramide. The clinical significance are unknown.
References
Minor ciprofloxacin  omeprazole

Applies to: ciprofloxacin, omeprazole
According to the product labeling, absorption of the extended-release formulation of ciprofloxacin
was slightly diminished (20%) when given concomitantly with omeprazole. The mechanism and
clinical significance of this interaction are unknown.
References
1. "Product Information. Cipro XR (ciprofloxacin)." Bayer Pharmaceutical Inc, West Haven, CT.
Minor
ciprofloxacin  metroNIDAZOLE
Applies to: ciprofloxacin, metronidazole
Limited data suggest that metronidazole may rarely prolong the QT interval of the electrocardiogram.
Theoretically, coadministration with other agents that can prolong the QT interval may result in
additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden
death. There have been isolated reports of QT prolongation and ventricular arrhythmias occurring in
patients treated with metronidazole. However, a causal relationship has not been established, as
nearly all published reports have involved underlying conditions and/or concomitant medications
that predispose to QT prolongation. In general, the risk of an individual agent or a combination of
References
1. Kounas SP, Letsas KP, Sideris A, Efraimidis M, Kardaras F "QT interval prolongation and torsades de pointes due to a coadministration of
metronidazole and amiodarone." Pacing Clin Electrophysiol 28 (2005): 472-3
Minor ibuprofen  magnesium hydroxide

Applies to: ibuprofen, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
One study has suggested that coadministration of magnesium hydroxide and ibuprofen may
significantly increase the area under the plasma concentration-time curve for ibuprofen. This increase
may be clinically beneficial in circumstances in which a rapid response to ibuprofen is desirable.
References
1. "Product Information. Motrin (ibuprofen)." Pharmacia and Upjohn, Kalamazoo, MI.
Minor ibuprofen  raNITIdine

Applies to: ibuprofen, ranitidine
H2 antagonists may alter the disposition of nonsteroidal anti-inflammatory drugs (NSAIDs), resulting
in increased or decreased plasma concentrations. Data are varied, even for the same NSAID. The
mechanism may be related to inhibition of metabolism, changes in gastric pH that decrease
absorption, and/or reduced urinary elimination. Statistically significant changes have been small and
of limited clinical significance. Clinical monitoring of patient response and tolerance is recommended.
References
1. Scavone JM, Greenblatt DJ, Matlis R, Harmatz JS "Interaction of oxaprozin with acetaminophen, cimetidine, and ranitidine." Eur J Clin Pharmacol 31
(1986): 371-4
2. Said SA, Foda AM "Influence of cimetidine on the pharmacokinetics of piroxicam in rat and man." Arzneimittelforschung 39 (1989): 790-2
3. "Product Information. Daypro (oxaprozin)." Searle, Skokie, IL.
Minor raNITIdine  mefenamic acid

Applies to: ranitidine, mefenamic acid
References
(1986): 371-4

Minor raNITIdine  cyanocobalamin

Applies to: ranitidine, Vitamin B12 (cyanocobalamin)
By reducing or suppressing gastric acid secretion, H2-receptor antagonists and proton pump
inhibitors may interfere with the gastrointestinal absorption of vitamin B12, a process that is
dependent on the presence of gastric acid and pepsin. Clinical studies have shown that dietary (i.e.,
protein-bound) vitamin B12 malabsorption can occur during treatment with these agents, particularly
proton pump inhibitors, although the likelihood of developing clinically significant deficiency over
time is unknown. There has been one reported case of vitamin B12 deficiency with megaloblastic
anemia in a patient who received omeprazole at a minimum of 40 mg/day for 4 years. Also uncertain
is whether acid reduction or suppression can affect the absorption of vitamin B12 ingested in the
form of oral supplements such as cyanocobalamin. Non-oral routes of administration (e.g., parenteral,
intranasal, sublingual) are generally preferred in the treatment of B12 deficiency-related anemia.
References
1. Dutta SK "Vitamin b-12 malabsorption and omeprazole therapy." J Am Coll Nutr 13 (1994): 544-5
2. Bradford GS, Taylor CT "Omeprazole and vitamin B-12 deficiency." Ann Pharmacother 33 (1999): 641-3
3. Marcuard SP, Albernaz L, Khazanie PG "Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin-b12)." Ann Intern Med 120 (1994):
211-5
Minor raNITIdine  aluminum hydroxide

Applies to: ranitidine, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
Oral antacids and some aluminum, calcium, and magnesium salts may decrease oral H2 blocker
plasma concentrations. The mechanism may be related to reduced gastric absorption and
bioavailability due to acid-neutralizing effects. Data vary and the clinical significance has not been
clearly established. It is recommended that H2 blocker be administered one to two hours before one
of these preparations.
References
1. Bachmann KA, Sullivan TJ, Jauregui L, Reese J, Miller K, Levine L "Drug interactions of h-2-receptor antagonists." Scand J Gastroenterol 29 (1994):
14-9
2. Shelly DW, Doering PL, Russell WL, Guild RT, Lopez LM, Perrin J "Effect of concomitant antacid administration on plasma cimetidine concentrations
during repetitive dosing." Drug Intell Clin Pharm 20 (1986): 792-5
3. Albin H, Vincon G, Begaud B, Bistue C, Perez P "Effect of aluminum phosphate on the bioavailability of ranitidine." Eur J Clin Pharmacol 32 (1987):
97-9
Minor raNITIdine  magnesium hydroxide

Applies to: ranitidine, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
References
14-9
97-9
Minor
raNITIdine  diclofenac
Applies to: ranitidine, diclofenac
References
(1986): 371-4
Minor raNITIdine  acetaminophen

Applies to: ranitidine, Aceta (acetaminophen)
Animal studies have suggested that ranitidine may potentiate the hepatotoxicity of acetaminophen,
however, a double-blind placebo-controlled crossover study has failed to confirm this finding in
humans. Acetaminophen dosage adjustments are not indicated.
References
1. Rogers SA, Gale KC, Newton JF, et al "Inhibition by ranitidine of acetaminophen conjugation and its possible role in ranitidine potentiation of
acetaminophen-induced hepatotoxicity." J Pharmacol Exp Ther 245 (1988): 887-94
2. Jack D, Thomas M, Skidmore IF "Ranitidine and paracetamol metabolism." Lancet 2 (1985): 1067
Minor
raNITIdine  NIFEdipine
Applies to: ranitidine, nifedipine
The plasma concentration of some calcium channel blockers may be increased by H2 blockers such as
cimetidine and ranitidine. The mechanism is related to inhibition of liver cytochrome P450 enzymes
responsible for metabolism and/or increased gastric pH. Ranitidine is a much weaker inhibitor of the
cytochrome P450 system and effects are not expected to be clinically significant. Other H2 blockers,
antacids, and proton pump inhibitors that notably increase gastric pH would be expected to have a
similar effect. Clinical monitoring of patient response and tolerance is recommended and calcium
channel blocker dosage adjustments may be indicated.
References
1. "Product Information. Tagamet (cimetidine)." SmithKline Beecham, Philadelphia, PA.
2. "Product Information. Zantac (ranitidine)." Glaxo Wellcome, Research Triangle Park, NC.
Minor raNITIdine  sodium bicarbonate

Applies to: ranitidine, sodium bicarbonate
References
14-9
97-9
Minor allopurinol  aminophylline

Applies to: allopurinol, aminophylline
Allopurinol may inhibit the metabolism of the xanthines, possibly increasing serum concentrations
and the risk of toxicity. This interaction may be more likely to occur with daily allopurinol doses of
600 mg or more. The mechanism is unknown and data from controlled studies have been conflicting.
Patients receiving this combination should be advised to report any signs of theophylline toxicity
including nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat to their
physician.
References
1. Barry M, Feely J "Allopurinol influences aminophenazone elimination." Clin Pharmacokinet 19 (1990): 167
2. Upton RA "Pharmacokinetic interactions between theophylline and other medication (Part II)." Clin Pharmacokinet 20 (1991): 135-50
3. Manfredi RL, Vesell ES "Inhibition of theophylline metabolism by long-term allopurinol administration." Clin Pharmacol Ther 29 (1981): 224
Minor allopurinol  amoxicillin

Applies to: allopurinol, amoxicillin
Coadministration of allopurinol with ampicillin or amoxicillin may increase the risk of skin rash. The
mechanism of interaction is unknown, and it is unclear whether the condition of hyperuricemia or the
actual exposure to allopurinol is responsible. In a retrospective study, 15 out of 67 patients (22%) who
took ampicillin with allopurinol developed a skin rash, compared to 94 out of 1257 patients (7.5%)
who took ampicillin without allopurinol. An updated study by the same group of investigators
consisted of 252 patients who took ampicillin with allopurinol and 4434 who took ampicillin alone.
The incidence of rash was 13.9% in the allopurinol group and 5.7% in the ampicillin-only group.
Similar results were reported for amoxicillin. Specifically, 8 out of 36 patients (22%) treated
concomitantly with allopurinol developed a rash, compared to 52 out of 887 patients (5.9%) on
amoxicillin without allopurinol. There is probably no need to avoid concomitant use of these drugs in
patients who otherwise can take these drugs individually.
References
1. "Product Information. Zyloprim capsules (allopurinol)." Glaxo Wellcome, Research Triangle Park, NC.
2. Boston Collaborative Drug Surveillance Program "Excess of ampicillin rashes associated with allopurinol or hyperuricemia." N Engl J Med 286
(1972): 505-7
3. Jick H, Porter JB "Potentiation of ampicillin skin reactions by allopurinol or hyperuricemia." J Clin Pharmacol 21 (1981): 456-8
Minor acetaminophen  hyoscyamine

Applies to: Aceta (acetaminophen), hyoscyamine
Anticholinergic agents may delay and/or decrease the gastrointestinal absorption of acetaminophen
by reducing gastric motility and delaying gastric emptying. However, the clinical relevance is probably
minimal.
References
1. Clark JM, Seager SJ "Gastric emptying following premedication with glycopyrrolate or atropine." Br J Anaesth 55 (1983): 1195-9
2. "Product Information. Transderm Scop (scopolamine)." Ciba Self-Medication Inc, Woodbridge, NJ.
3. Nimmo J, Heading RC, Tothill P, Prescott LF "Pharmacological modification of gastric emptying: effects of propantheline and metoclopramide on
paracetamol absorption." Br Med J 1 (1973): 587-9
Minor NIFEdipine  cefixime

Applies to: nifedipine, cefixime
Nifedipine may increase the bioavailability of cefixime. The mechanism appears to be nifedipine
enhancement of cefixime absorption. This interaction appears to be clinically insignificant.
References
1. Duverne C, Bouten A, Deslandes A "Modification of cefixime bioavailabity by nifedipine in humans: involvement of the dipeptide carrier system."
Antimicrob Agents Chemother 36 (1992): 2462-7
Minor NIFEdipine  aminophylline

Applies to: nifedipine, aminophylline
Limited and controversial data suggest the following: either there is no significant interaction
between theophylline and dihydropyridine calcium channel blockers, or theophylline serum levels
increase after the addition of dihydropyridine calcium channel blockers. Data are available for
nifedipine. Theophylline dosage should be reduced if necessary, and plasma levels should be checked
when clinically necessary and appropriate. Patients should be advised to report any signs of
theophylline toxicity including nausea, vomiting, diarrhea, headache, restlessness, insomnia, or
irregular heartbeat to their physician.
References
1. Parrillo SJ, Venditto M "Elevated theophylline blood levels from institution of nifedipine therapy." Ann Emerg Med 13 (1984): 216-7
2. Upton RA "Pharmacokinetic interactions between theophylline and other medication (Part II)." Clin Pharmacokinet 20 (1991): 135-50
3. Harrod CS "Theophylline toxicity and nifedipine." Ann Intern Med 106 (1987): 480
Minor NIFEdipine  omeprazole

Applies to: nifedipine, omeprazole
Omeprazole may increase the absorption or interfere with the metabolism of at least one
dihydropyridine calcium channel blocker (CCB)--nifedipine. The pharmacologic effect of nifedipine
may be enhanced. Although unlikely to be of clinical significance, when omeprazole and a CCB are
coadministered, monitoring for CCB toxicity should be considered.
References
1. Andersson T "Omeprazole drug interaction studies." Clin Pharmacokinet 21 (1991): 195-212
3. "Product Information. Adalat (nifedipine)." Bayer, West Haven, CT.
Minor ketoconazole  aminophylline

Applies to: ketoconazole, aminophylline
Coadministration of ketoconazole with a slow-release preparation of theophylline has been reported
to decrease serum theophylline concentration. The mechanism may be related to decreased
absorption. Ketoconazole has not been shown to interfere with the pharmacokinetics of intravenous
theophylline. Theophylline dosages should be adjusted if necessary. Patients should be monitored for
altered efficacy of theophylline if ketoconazole is added to their regimen.
References
1. Heusner JJ, Dukes GE, Rollins DE, et al "Effect of chronically administered ketoconazole on the elimination of theophylline in man." Drug Intell Clin
Pharm 21 (1987): 514-7
2. Brown MW, Maldonado AL, Meredith CG, Speeg KV "Effect of ketoconazole on hepatic oxidative drug metabolism." Clin Pharmacol Ther 37 (1985):
290-7
Minor
ketoconazole  loratadine
Applies to: ketoconazole, loratadine
Ketoconazole has been reported to inhibit the metabolism of loratadine. Area under the plasma
concentration time curve (AUC) has increased 180% for loratadine and 56% for its active metabolite.
The mechanism of this interaction is inhibition of CYP450 3A4 metabolism by ketoconazole. No
adverse effects or cardiotoxicity were observed in this study. Loratadine and cetirizine appear to be
safe for use with ketoconazole. Terfenadine and astemizole should not be used with ketoconazole.
References
1. Woosley R, Carrow WR "Analysis of potential adverse drug reactions--a case of mistaken identity." Am J Cardiol 74 (1994): 208-9
2. Yumibe N, Huie K, Chen KJ, Clement RP, Cayen MN "Identification of human liver cytochrome P450s involved in the microsomal metabolism of the
antihistaminic drug loratadine." Int Arch Allery Immunol 207 (1995): 420
Minor ketoconazole  sulfamethoxazole

Applies to: ketoconazole, Cotrim (sulfamethoxazole / trimethoprim)
References
908
Minor ketoconazole  metroNIDAZOLE

Applies to: ketoconazole, metronidazole
References
Minor metroNIDAZOLE  sulfamethoxazole

Applies to: metronidazole, Cotrim (sulfamethoxazole / trimethoprim)
References
908
Minor metroNIDAZOLE  albuterol

Applies to: metronidazole, albuterol
References
Minor sulfamethoxazole  albuterol

Applies to: Cotrim (sulfamethoxazole / trimethoprim), albuterol
References
908
Minor miconazole  loratadine

Applies to: miconazole, loratadine
Ketoconazole has been reported to inhibit the metabolism of loratadine. Area under the plasma
concentration time curve (AUC) has increased 180% for loratadine and 56% for its active metabolite.
The mechanism of this interaction is inhibition of CYP450 3A4 metabolism by ketoconazole. No
adverse effects or cardiotoxicity were observed in this study. Loratadine and cetirizine appear to be
safe for use with ketoconazole. Terfenadine and astemizole should not be used with ketoconazole.
References
1. Woosley R, Carrow WR "Analysis of potential adverse drug reactions--a case of mistaken identity." Am J Cardiol 74 (1994): 208-9
2. Yumibe N, Huie K, Chen KJ, Clement RP, Cayen MN "Identification of human liver cytochrome P450s involved in the microsomal metabolism of the
antihistaminic drug loratadine." Int Arch Allery Immunol 207 (1995): 420
Minor
dexamethasone  sodium bicarbonate
Applies to: dexamethasone, sodium bicarbonate
Antacids and agents with acid-neutralizing effects may impair the absorption of dexamethasone,
prednisolone, prednisone, and other corticosteroids, although data from published studies are
somewhat conflicting. The mechanism of interaction and clinical significance are unknown. No
particular intervention is necessary during concomitant therapy with these agents, but clinicians
should be aware of the potential for interaction.
References
1. Naggar VF, Khalil SA, Gouda MW "Effect of concomitant administration of magnesium trisilicate on GI absorption of dexamethasone in humans." J
Pharm Sci 67 (1978): 1029-30
2. Tanner AR, Caffin JA, Halliday JW, Powell LW "Concurrent administration of antacids and prednisone: effect on serum levels of prednisolone." Br J
3. Albin H, Vincon G, Demotes-Mainard F, et al "Effect of aluminium phosphate on the bioavailability of cimetidine and prednisolone." Eur J Clin
Pharmacol 26 (1984): 271-3
Minor dexamethasone  albuterol

Applies to: dexamethasone, albuterol
Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic
agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can
sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk
of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the
potential significance is unknown. Patients who are receiving systemic or nebulized formulations of
beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be
at a greater risk of developing hypokalemia.
References
3. "Product Information. Foradil (formoterol)" Novartis Pharmaceuticals, East Hanover, NJ.
Minor
dexamethasone  aluminum hydroxide
Applies to: dexamethasone, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
References
Pharm Sci 67 (1978): 1029-30
Pharmacol 26 (1984): 271-3
Minor dexamethasone  zinc sulfate

Applies to: dexamethasone, Zinc (zinc sulfate)
Theoretically, agents that are thought to have immunostimulant properties such as echinacea, vitamin
E, cat's claw, and zinc may antagonize the pharmacologic effects of immunosuppressants. However,
clinical cases of drug interactions have not been reported.
References
1. Pepping J "Echinacea." Am J Health Syst Pharm 56 (1999): 121-2
2. Therapeutic Research Faculty "Natural Medicines Comprehensive Database. Available from: URL: http://www.naturaldatabase.com." ([1995-2008...]):
3. Izzo AA, Ernst E "Interactions between herbal medicines and prescribed drugs: a systematic review." Drugs 61 (2001): 2163-75
Minor isosorbide dinitrate  omeprazole

Applies to: isosorbide dinitrate, omeprazole
Omeprazole may inhibit the drug delivery of oral nitrates. Antianginal effects may be diminished, and
myocardial ischemia may be exacerbated. If an interaction is suspected, alternate acid-suppressant
therapy may be considered.
References
1. Kajinami K, Mabuchi H "Omeprazole and diminished antianginal drug delivery." Ann Intern Med 121 (1994): 385-6
Minor mefenamic acid  magnesium hydroxide

Applies to: mefenamic acid, Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
Orally administered magnesium-containing antacids may significantly increase the rate and extent of
the absorption of mefenamic acid. No special precautions appear to be necessary.
References
1. Neuvonen PJ, Kivisto KT "Effect of magnesium hydroxide on the absorption of tolfenamic and mefenamic acids." Eur J Clin Pharmacol 35 (1988):
495-501
Minor methylPREDNISolone  sodium bicarbonate

Applies to: methylprednisolone, sodium bicarbonate
References
Pharm Sci 67 (1978): 1029-30
Pharmacol 26 (1984): 271-3
Minor methylPREDNISolone  zinc sulfate

Applies to: methylprednisolone, Zinc (zinc sulfate)
Theoretically, agents that are thought to have immunostimulant properties such as echinacea, vitamin
E, cat's claw, and zinc may antagonize the pharmacologic effects of immunosuppressants. However,
clinical cases of drug interactions have not been reported.
References
1. Pepping J "Echinacea." Am J Health Syst Pharm 56 (1999): 121-2
2. Therapeutic Research Faculty "Natural Medicines Comprehensive Database. Available from: URL: http://www.naturaldatabase.com." ([1995-2008...]):
3. Izzo AA, Ernst E "Interactions between herbal medicines and prescribed drugs: a systematic review." Drugs 61 (2001): 2163-75
Minor methylPREDNISolone  albuterol

Applies to: methylprednisolone, albuterol
Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic
agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can
sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk
of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the
potential significance is unknown. Patients who are receiving systemic or nebulized formulations of
beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be
at a greater risk of developing hypokalemia.
References
3. "Product Information. Foradil (formoterol)" Novartis Pharmaceuticals, East Hanover, NJ.
Minor methylPREDNISolone  aluminum hydroxide

Applies to: methylprednisolone, Almacone (aluminum hydroxide / magnesium hydroxide /
simethicone)
References
Pharm Sci 67 (1978): 1029-30
Pharmacol 26 (1984): 271-3
Minor omeprazole  glimepiride

Applies to: omeprazole, glimepiride
Some benzimidazole proton pump inhibitors may increase sulfonylurea concentrations, and
hypoglycemic effects may be increased. The mechanism may be inhibition of CYP450 2C19 and/or
3A4 hepatic metabolism. The clinical significance of this interaction is unknown. Patients receiving
this combination should be advised to regularly monitor their blood sugar, counseled on how to
recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger,
weakness, or palpitations) and to notify their physician if it occurs. The sulfonylurea dosage may
require reduction in affected patients.
References
1. Toon S, Holt BL, Mullins FGP, Khan A "Effects of cimetidine, ranitidine and omeprazole on tolbutamide pharmacokinetics." J Pharm Pharmacol 47
(1995): 85-8
2. Humphries TJ "Clinical implications of drug interactions with the cytochrome P-450 enzyme system associated with omeprazole." Dig Dis Sci 36
(1991): 1665-9
3. "Product Information. Nexium (esomeprazole)" Astra-Zeneca Pharmaceuticals, Wilmington, DE.
Minor omeprazole  cyanocobalamin

Applies to: omeprazole, Vitamin B12 (cyanocobalamin)
References
211-5
Minor cyanocobalamin  lansoprazole

Applies to: Vitamin B12 (cyanocobalamin), lansoprazole
References
211-5
Minor aminophylline  lansoprazole

Applies to: aminophylline, lansoprazole
Lansoprazole may cause a minor decrease in the area under the plasma concentration-time curve of
theophylline and related drugs. This effect appears to be small (approximately a 13% decrease in one
study) and may be related either to a reduction in absorption or to enhanced clearance caused by
induction of hepatic enzymes by lansoprazole. Dosage adjustment is not believed to be necessary.

However, close observation for evidence of altered methylxanthine effect is recommended.
References
1. Kokufu T, Ihara N, Sugioka N, Koyama H, Ohta T, Mori S, Nakajima K "Effects of lansoprazole on pharmacokinetics and metabolism of theophylline."
Eur J Clin Pharmacol 48 (1995): 391-5
2. "Product Information. Prevacid (lansoprazole)." TAP Pharmaceuticals Inc, Deerfield, IL.
3. Granneman GR, Karol MD, Locke CS "Pharmacokinetic interaction between lansoprazole and theophylline." Ther Drug Monit 17 (1995): 460-4
Minor hydrocortisone topical  glimepiride

Applies to: hydrocortisone, glimepiride
The efficacy of insulin and other antidiabetic agents may be diminished by topical corticosteroids,
particularly during prolonged or indiscriminate use. Corticosteroids can raise blood glucose level by
antagonizing the action and suppressing the secretion of insulin, which results in inhibition of
peripheral glucose uptake and increased gluconeogenesis. Systemic absorption of topical
corticosteroids may occur depending on the vehicle and concentration of the preparation, the size of
the application area, the integrity of the skin, and the duration of administration. Use of occlusive
dressings over the applied areas may also increase percutaneous absorption. Given equivalent doses,
small children are generally at the greatest risk because of their larger skin surface to body mass
ratios. If possible, the use of highly potent agents (e.g., augmented betamethasone, clobetasol,
diflorasone, and halobetasol) should be avoided in children and limited to small areas for 2 weeks in
adults. Close clinical monitoring of glycemic control is recommended if topical corticosteroids are
administered chronically and/or to large areas in diabetic patients.
References
1. "Product Information. Temovate (clobetasol)." Glaxo Wellcome, Research Triangle Park, NC.
2. Ludvik B, Clodi M, Kautzky-Willer A, Capek M, Hartter E, Pacini G, Prager R "Effect of dexamethasone on insulin sensitivity, islet amyloid polypeptide
and insulin secretion in humans." Diabetologia 36 (1993): 84-7
Minor hydrocortisone topical  metFORMIN

Applies to: hydrocortisone, metformin
The efficacy of insulin and other antidiabetic agents may be diminished by topical corticosteroids,
particularly during prolonged or indiscriminate use. Corticosteroids can raise blood glucose level by
antagonizing the action and suppressing the secretion of insulin, which results in inhibition of
peripheral glucose uptake and increased gluconeogenesis. Systemic absorption of topical
corticosteroids may occur depending on the vehicle and concentration of the preparation, the size of
the application area, the integrity of the skin, and the duration of administration. Use of occlusive
dressings over the applied areas may also increase percutaneous absorption. Given equivalent doses,
small children are generally at the greatest risk because of their larger skin surface to body mass
ratios. If possible, the use of highly potent agents (e.g., augmented betamethasone, clobetasol,
diflorasone, and halobetasol) should be avoided in children and limited to small areas for 2 weeks in
adults. Close clinical monitoring of glycemic control is recommended if topical corticosteroids are
administered chronically and/or to large areas in diabetic patients.
References
1. "Product Information. Temovate (clobetasol)." Glaxo Wellcome, Research Triangle Park, NC.
2. Ludvik B, Clodi M, Kautzky-Willer A, Capek M, Hartter E, Pacini G, Prager R "Effect of dexamethasone on insulin sensitivity, islet amyloid polypeptide
and insulin secretion in humans." Diabetologia 36 (1993): 84-7
Minor ferrous fumarate  zinc sulfate

Applies to: ferrous fumarate / folic acid, Zinc (zinc sulfate)
Iron and zinc may reduce each other's absorption when they are coadministered orally. The
mechanism of interaction is unknown. In clinical studies, concurrent supplementation with iron and
zinc was associated with reduced efficacy in improving the growth and iron and zinc status of
malnourished infants compared to supplementation with either one alone. It is not known whether
the interaction occurs in adults. In any case, the clinical significance is probably minimal in healthy
individuals. However, monitoring for reduced therapeutic response may be advisable in malnourished
patients. Limited data suggest that the magnitude of the interaction may be lessened by separating
the times of administration of each by 12 hours.
References
1. Lind T, Lonnerdal B, Stenlund H, et al. "A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants:
interactions between iron and zinc." Am J Clin Nutr 77 (2003): 883-90
2. Sreedhar B "Conflicting evidence of iron and zinc interactions in humans: does iron affect zinc absorption?" Am J Clin Nutr 78 (2003): 1226; author
reply 1226-7
No other interactions were found between your selected drugs.

Note: this does not necessarily mean no interactions exist. Always consult with your doctor or
pharmacist.
Other drug and disease interactions

amoxicillin interacts with more than 30 other drugs and 5 diseases.
tranexamic acid interacts with more than 40 other drugs and 3 diseases.
glimepiride interacts with more than 400 other drugs and 5 diseases.
loperamide interacts with more than 300 other drugs and 1 diseases.
ibuprofen interacts with more than 300 other drugs and more than 10 diseases.
methylprednisolone interacts with more than 400 other drugs and more than 20 diseases.
omeprazole interacts with more than 100 other drugs and 3 diseases.
kaolin / pectin interacts with more than 90 other drugs and 1 diseases.
aminophylline interacts with more than 200 other drugs and 7 diseases.
acyclovir interacts with more than 50 other drugs and 4 diseases.
hydrocortisone interacts with more than 40 other drugs and 5 diseases.
gentamicin interacts with more than 20 other drugs and 1 diseases.
diclofenac interacts with more than 300 other drugs and more than 10 diseases.
ciprofloxacin interacts with more than 500 other drugs and 10 diseases.
attapulgite interacts with more than 70 other drugs.
amlodipine interacts with more than 300 other drugs and 4 diseases.
cefixime interacts with more than 30 other drugs and 5 diseases.
lansoprazole interacts with more than 100 other drugs and 4 diseases.
dimenhydrinate interacts with more than 200 other drugs and 5 diseases.
hyoscyamine interacts with more than 200 other drugs and more than 10 diseases.
metoclopramide interacts with more than 300 other drugs and 10 diseases.
acetylcysteine interacts with 3 other drugs and 4 diseases.
nifedipine interacts with more than 400 other drugs and 9 diseases.
captopril interacts with more than 300 other drugs and 8 diseases.
sodium bicarbonate interacts with more than 100 other drugs and 1 diseases.
metformin interacts with more than 300 other drugs and 4 diseases.
ketoconazole interacts with 1 diseases.
metronidazole interacts with more than 300 other drugs and 7 diseases.
nystatin interacts with 1 other drugs.
folic acid interacts with more than 10 other drugs and 1 diseases.
allopurinol interacts with more than 50 other drugs and 4 diseases.
doxycycline interacts with more than 100 other drugs and 3 diseases.
ketoconazole interacts with more than 500 other drugs and 4 diseases.
clindamycin interacts with more than 30 other drugs and 4 diseases.
chloramphenicol interacts with more than 300 other drugs and 3 diseases.
Cotrim (sulfamethoxazole / trimethoprim) interacts with more than 300 other drugs and more
than 10 diseases.
albuterol interacts with more than 300 other drugs and 5 diseases.
mefenamic acid interacts with more than 300 other drugs and more than 10 diseases.
Aceta (acetaminophen) interacts with more than 90 other drugs and 3 diseases.
Almacone (aluminum hydroxide / magnesium hydroxide / simethicone) interacts with more than
500 other drugs and 4 diseases.
ranitidine interacts with more than 100 other drugs and 6 diseases.
Zinc (zinc sulfate) interacts with more than 90 other drugs and 2 diseases.
isosorbide dinitrate interacts with more than 100 other drugs and 7 diseases.
chloramphenicol interacts with 4 other drugs and 1 diseases.
acyclovir interacts with 1 other drugs.
miconazole interacts with more than 200 other drugs and 2 diseases.
Vitamin C (ascorbic acid) interacts with more than 20 other drugs and 4 diseases.
Vitamin B12 (cyanocobalamin) interacts with more than 10 other drugs and 3 diseases.
Vitamin B1 (thiamine) interacts with 1 diseases.
Vitamin B6 (pyridoxine) interacts with more than 10 other drugs and 1 diseases.
Vitamin K (phytonadione) interacts with 9 other drugs and 1 diseases.
calcium lactate interacts with more than 80 other drugs and 4 diseases.
ferrous fumarate / folic acid interacts with more than 100 other drugs and 4 diseases.
simvastatin interacts with more than 200 other drugs and 6 diseases.
dexamethasone interacts with more than 600 other drugs and more than 20 diseases.
chlorpheniramine interacts with more than 300 other drugs and 4 diseases.
loratadine interacts with more than 60 other drugs and 1 diseases.
cetirizine interacts with more than 200 other drugs and 2 diseases.
Drug and food interactions
Major simvastatin  food

Applies to: simvastatin
GENERALLY AVOID: Coadministration with grapefruit juice may significantly increase the plasma
concentrations of lovastatin and simvastatin and their active acid metabolites. The proposed
mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain
compounds present in grapefruit. When a single 60 mg dose of simvastatin was coadministered with
200 mL of double-strength grapefruit juice three times a day, simvastatin systemic exposure (AUC)
increased by 16-fold and simvastatin acid AUC increased by 7-fold. Administration of a single 20 mg
dose of simvastatin with 8 ounces of single-strength grapefruit juice increased the AUC of simvastatin
and simvastatin acid by 1.9-fold and 1.3-fold, respectively. The interaction has also been reported
with lovastatin, which has a similar metabolic profile to simvastatin. Clinically, high levels of HMG-CoA
reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity.
Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine
kinase exceeding ten times the upper limit of normal has been reported occasionally.
Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure
secondary to myoglobinuria and may result in death.
ADJUST DOSING INTERVAL: Fibres such as oat bran and pectin may diminish the pharmacologic
effects of HMG-CoA reductase inhibitors by interfering with their absorption from the gastrointestinal
tract.
MANAGEMENT: Patients receiving therapy with lovastatin, simvastatin, or red yeast rice (which
contains lovastatin) should be advised to avoid the consumption of grapefruit and grapefruit juice.
Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized by other enzymes and may be
preferable alternatives in some individuals. All patients receiving statin therapy should be advised to
promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by
fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is
markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or
diagnosed. Also, patients should either refrain from the use of oat bran and pectin or, if concurrent
use cannot be avoided, to separate the administration times by at least 2 to 4 hours.
References
1. Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and
pravastatin." Clin Pharmacokinet 47 (2008): 463-74
2. Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706
3. Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-
CoA reductase inhibitors." Clin Pharmacol Ther 64 (1998): 477-83
Major metroNIDAZOLE  food

Applies to: metronidazole
CONTRAINDICATED: Use of alcohol or products containing alcohol during nitroimidazole therapy
may result in a disulfiram-like reaction in some patients. There have been a few case reports involving
metronidazole, although data overall are not convincing. The presumed mechanism is inhibition of
aldehyde dehydrogenase (ALDH) by metronidazole in a manner similar to disulfiram. Following
ingestion of alcohol, inhibition of ALDH results in increased concentrations of acetaldehyde, the
accumulation of which can produce an unpleasant physiologic response referred to as the 'disulfiram
reaction'. Symptoms include flushing, throbbing in head and neck, throbbing headache, respiratory
difficulty, nausea, vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation,
tachycardia, hypotension, syncope, weakness, vertigo, blurred vision, and confusion. Severe reactions
may result in respiratory depression, cardiovascular collapse, arrhythmia, myocardial infarction, acute
congestive heart failure, unconsciousness, convulsions, and death. However, some investigators have
questioned the disulfiram-like properties of metronidazole. One study found neither elevations in
blood acetaldehyde nor objective or subjective signs of a disulfiram-like reaction to ethanol in six
subjects treated with metronidazole (200 mg three times a day for 5 days) compared to six subjects
who received placebo.
MANAGEMENT: Because clear evidence is lacking concerning the safety of ethanol use during
nitroimidazole therapy, patients should be apprised of the potential for interaction. Consumption of
alcoholic beverages and products containing propylene glycol is specifically contraindicated during
and for at least 3 days after completion of metronidazole and benznidazole therapy according to
their product labeling.
References
1. Giannini AJ, DeFrance DT "Metronidazole and alcohol: potential for combinative abuse." J Toxicol Clin Toxicol 20 (1983): 509-15
2. "Product Information. Benznidazole (benznidazole)." Everett Laboratories Inc, West Orange, NJ.
3. Williams CS, Woodcock KR "Do ethanol and metronidazole interact to produce a disulfiram-like reaction?." Ann Pharmacother 34 (2000): 255-7
Major aluminum hydroxide  food

Applies to: Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)
GENERALLY AVOID: The concomitant administration of aluminum-containing products (e.g., antacids
and phosphate binders) and citrates may significantly increase serum aluminum concentrations,
resulting in toxicity. Citrates or citric acid are contained in numerous soft drinks, citrus fruits, juices,
and effervescent and dispersible drug formulations. Citrates enhance the gastrointestinal absorption
of aluminum by an unknown mechanism, which may involve the formation of a soluble aluminum-
citrate complex. Various studies have reported that citrate increases aluminum absorption by 4.6- to
50-fold in healthy subjects. Patients with renal insufficiency are particularly at risk of developing
hyperaluminemia and encephalopathy. Fatalities have been reported. Patients with renal failure or on
hemodialysis may also be at risk from soft drinks and effervescent and dispersible drug formulations
that contain citrates or citric acid. It is unknown what effect citrus fruits or juices would have on
aluminum absorption in healthy patients.
MANAGEMENT: The concomitant use of aluminum- and citrate-containing products and foods
should be avoided by renally impaired patients. Hemodialysis patients should especially be cautioned
about effervescent and dispersible over-the-counter remedies and soft drinks. Some experts also
recommend that healthy patients should separate doses of aluminum-containing antacids and
citrates by 2 to 3 hours.
ADJUST DOSING INTERVAL: The administration of aluminum-containing antacids with enteral

nutrition may result in precipitation, formation of bezoars, and obstruction of feeding tubes. The
proposed mechanism is the formation of an insoluble complex between the aluminum and the
protein in the enteral feeding. Several cases of esophageal plugs and nasogastric tube obstructions
have been reported in patients receiving high-protein liquids and an aluminum hydroxide-
magnesium hydroxide antacid or an aluminum hydroxide antacid.
MANAGEMENT: Some experts recommend that antacids should not be mixed with or given after high
protein formulations, that the antacid dose should be separated from the feeding by as much as
possible, and that the tube should be thoroughly flushed before administration.
References
2. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT "Recommendations for the use of medications with continuous enteral nutrition."
Am J Health Syst Pharm 66 (2009): 1438-67
Moderate metoclopramide  food

Applies to: metoclopramide
GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.
Use in combination may result in additive central nervous system depression and/or impairment of
judgment, thinking, and psychomotor skills.
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and
advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid
hazardous activities requiring complete mental alertness and motor coordination until they know
how these agents affect them, and to notify their physician if they experience excessive or prolonged
CNS effects that interfere with their normal activities.
References
1. Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15
(1986): 31-7
2. Gilman AG, Rall TW, Nies AS, Taylor P, eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed." New York, NY: Pergamon
Press Inc. (1990):
3. "Product Information. Fycompa (perampanel)." Eisai Inc, Teaneck, NJ.
Moderate methylPREDNISolone  food

Applies to: methylprednisolone
MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that
are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-
mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because
grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of
interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450
3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-,
dose- and preparation-dependent, and can vary widely among brands. Certain preparations of
grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of
CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated
moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high
degree of interpatient variability, thus the extent to which a given patient may be affected is difficult
to predict.
MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored
for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic
metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is
suspected. Orange juice is not expected to interact with these drugs.
References
1. Gunston GD, Mehta U "Potentially serious drug interactions with grapefruit juice." S Afr Med J 90 (2000): 41
2. Bailey DG, Arnold JMO, Spence JD "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8
3. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active
ingredients." Clin Pharmacol Ther 68 (2000): 468-77
Moderate chlorpheniramine  food

Applies to: chlorpheniramine
References
(1986): 31-7
Press Inc. (1990):
Moderate NIFEdipine  food

Applies to: nifedipine
GENERALLY AVOID: The consumption of grapefruit juice may be associated with significantly
increased plasma concentrations of some calcium channel blockers (CCBs) when they are
administered orally. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass
metabolism in the gut wall by certain compounds present in grapefruit. The interaction has been
reported with the dihydropyridine CCBs (in roughly decreasing order of magnitude) felodipine,
nisoldipine, nifedipine, and nimodipine, often with a high degree of interindividual variability.
Grapefruit juice caused more than twofold increases in felodipine, nifedipine, and nisoldipine AUCs.
MANAGEMENT: The manufacturers of nifedipine and nisoldipine recommend avoiding grapefruit

juice. Patients treated orally with other calcium channel blockers should be advised to avoid
consumption of large amounts of grapefruits and grapefruit juice to prevent any undue fluctuations
in serum drug levels. Increased effects on blood pressure may persist for up to 4 days after the
consumption of grapefruit juice. Monitoring for calcium channel blocker adverse effects (e.g.,
headache, hypotension, syncope, tachycardia, edema) is recommended.
References
1. Bailey DG, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit juice felodipine interaction: Effect of naringin and 6',7'-dihydroxybergamottin in
humans." Clin Pharmacol Ther 64 (1998): 248-56
2. "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4
3. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active
ingredients." Clin Pharmacol Ther 68 (2000): 468-77
Moderate loperamide  food

Applies to: loperamide
References
(1986): 31-7
Press Inc. (1990):
Moderate cetirizine  food

Applies to: cetirizine
References
(1986): 31-7
Press Inc. (1990):
Moderate captopril  food

Applies to: captopril
GENERALLY AVOID: Moderate-to-high dietary intake of potassium can cause hyperkalemia in some
patients who are using angiotensin converting enzyme (ACE) inhibitors. In some cases, affected
patients were using a potassium-rich salt substitute. ACE inhibitors can promote hyperkalemia
through inhibition of the renin-aldosterone-angiotensin (RAA) system.
MANAGEMENT: It is recommended that patients who are taking ACE inhibitors be advised to avoid
moderately high or high potassium dietary intake. Particular attention should be paid to the
potassium content of salt substitutes.
References
1. Ray K, Dorman S, Watson R "Severe hyperkalaemia due to the concomitant use of salt substitutes and ACE inhibitors in hypertension: a potentially
life threatening interaction." J Hum Hypertens 13 (1999): 717-20
2. "Product Information. Vasotec (enalapril)." Merck & Co, Inc, West Point, PA.
3. Good CB, McDermott L "Diet and serum potassium in patients on ACE inhibitors." JAMA 274 (1995): 538
Moderate ciprofloxacin  food

Applies to: ciprofloxacin
ADJUST DOSING INTERVAL: Concurrent ingestion of dairy products (milk, yogurt) or calcium-fortified
foods (i.e., cereal, orange juice) may decrease the activity of certain oral fluoroquinolone antibiotics.
The mechanism is chelation of calcium and the quinolone, resulting in decreased bioavailability. In
the case of orange juice, inhibition of intestinal transport mechanisms (P-glycoprotein or organic
anion-transporting polypeptides) by flavones may also be involved. One study reported an average
41% decrease in maximum plasma concentrations and a 38% decrease in AUC when ciprofloxacin
was given with calcium-fortified orange juice instead of water. Administration of ciprofloxacin tablets
with enteral nutrition may reduce its bioavailability and maximum serum concentrations. Data have
been conflicting and variable by the type of enteral nutrition product, location of the feeding tube,
and patient characteristics. Decreased absorption is expected if ciprofloxacin is given by jejunostomy
tube.
MANAGEMENT: Oral ciprofloxacin should not be taken with dairy products or calcium-fortified foods
alone, but may be taken with meals that contain these products. When taken alone, dairy products or
calcium-fortified foods should be ingested at least 2 hours before or after ciprofloxacin

administration. When ciprofloxacin tablets are administered to patients receiving continuous enteral
nutrition, some experts recommend that the tube feeding should be interrupted for at least 1 hour
before and 2 hours after the dose of ciprofloxacin is given. Patients should be monitored for altered
antimicrobial efficacy and switched to intravenous ciprofloxacin if necessary. If no enteral route
besides a jejunostomy tube is available, it is also recommended to switch to intravenous
ciprofloxacin. According to the manufacturer, ciprofloxacin oral suspension should not be
administered via nasogastric or feeding tubes due to its physical characteristics.
References
1. Yuk JH, Nightingale CH, Sweeney KR, Quintiliani R, Lettieri JT, Forst RW "Relative bioavailability in healthy volunteers of ciprofloxacin administered
through a nasogastric tube with and without enteral feeding." Antimicrob Agents Chemother 33 (1989): 1118-20
2. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT "Recommendations for the use of medications with continuous enteral nutrition."
Am J Health Syst Pharm 66 (2009): 1438-67
3. Noer BL, Angaran DW "The effect of enteral feedings on ciprofloxacin pharmacokinetics." Pharmacotherapy 10 (1990): 254
Minor ferrous fumarate  food

Applies to: ferrous fumarate / folic acid
Food taken in conjunction with oral iron supplements may reduce the bioavailability of the iron.
However, in many patients intolerable gastrointestinal side effects occur necessitating administration
with food. Some studies suggest administration of iron with ascorbic acid may enhance
bioavailability. Ideally, iron products should be taken on an empty stomach, but if this is not possible,
administer with meals and monitor the patient more closely for a subtherapeutic effect.
References
1. "Product Information. Feosol Tablets (ferrous sulfate)." SmithKline Beecham, Philadelphia, PA.
Minor loratadine  food

Applies to: loratadine
Theoretically, grapefruit juice may increase the plasma concentrations of loratadine as it does other
drugs that are substrates of the CYP450 3A4 enzymatic pathway. The proposed mechanism is
inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds
present in grapefruits. The clinical significance of this potential interaction is unknown. Reported
interactions with potent CYP450 3A4 inhibitors like clarithromycin, erythromycin and ketoconazole
have produced substantial increases in the area under the plasma concentration-time curve (AUC) of
loratadine and its active metabolite, descarboethoxyloratadine, without associated changes in the
overall safety profile of the drug.
References
1. Bailey DG, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit juice felodipine interaction: Effect of naringin and 6',7'-dihydroxybergamottin in
humans." Clin Pharmacol Ther 64 (1998): 248-56
2. "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4
3. Damkier P, Hansen LL, Brosen K "Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of
quinidine." Br J Clin Pharmacol 48 (1999): 829-38
Minor amLODIPine  food

Applies to: amlodipine
The consumption of grapefruit juice may slightly increase plasma concentrations of amlodipine. The
mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain
compounds present in grapefruits. Data have been conflicting and the clinical significance is
unknown. Monitoring for calcium channel blocker adverse effects (e.g., headache, hypotension,
syncope, tachycardia, edema) is recommended.
References
1. Kane GC, Lipsky JJ "Drug-grapefruit juice interactions." Mayo Clin Proc 75 (2000): 933-42
2. Josefsson M, Zackrisson AL, Ahlner J "Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers." Eur J Clin Pharmacol
51 (1996): 189-93
3. Bailey DG, Arnold JMO, Spence JD "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8
Therapeutic duplication warnings
Therapeutic duplication is the use of more than one medicine from the same drug category or
therapeutic class to treat the same condition. This can be intentional in cases where drugs with
similar actions are used together for demonstrated therapeutic benefit. It can also be
unintentional in cases where a patient has been treated by more than one doctor, or had
prescriptions filled at more than one pharmacy, and can have potentially adverse
consequences.
Duplication Cardiovascular agents

Therapeutic duplication
The recommended maximum number of medicines in the 'cardiovascular agents' category to be
taken concurrently is usually four. Your list includes five medicines belonging to the 'cardiovascular
agents' category:
amlodipine
nifedipine
captopril
isosorbide dinitrate
simvastatin
Note: The benefits of taking this combination of medicines may outweigh any risks associated with
therapeutic duplication. This information does not take the place of talking to your doctor. Always
check with your healthcare provider to determine if any adjustments to your medications are needed.
Duplication
Anti-infectives
The recommended maximum number of medicines in the 'anti-infectives' category to be taken
concurrently is usually three. Your list includes twelve medicines belonging to the 'anti-infectives'
category:
amoxicillin
acyclovir
ciprofloxacin
cefixime
metronidazole
nystatin
doxycycline
ketoconazole
clindamycin
chloramphenicol
Cotrim (sulfamethoxazole/trimethoprim)
miconazole
Duplication Analgesics
The recommended maximum number of medicines in the 'analgesics' category to be taken
concurrently is usually three. Your list includes five medicines belonging to the 'analgesics' category:
ibuprofen
diclofenac
allopurinol
mefenamic acid
Duplication Nutritionals
The recommended maximum number of medicines in the 'nutritionals' category to be taken
concurrently is usually three. Your list includes nine medicines belonging to the 'nutritionals'
category:
sodium bicarbonate
folic acid
Zinc (zinc sulfate)
calcium lactate
ferrous fumarate/folic acid
Duplication GI drugs
The recommended maximum number of medicines in the 'GI drugs' category to be taken
concurrently is usually three. Your list includes nine medicines belonging to the 'GI drugs' category:
loperamide
omeprazole
kaolin/pectin
attapulgite
lansoprazole
metoclopramide
sodium bicarbonate
Almacone (aluminum hydroxide/magnesium hydroxide/simethicone)
ranitidine
Duplication Topicals
The recommended maximum number of medicines in the 'topicals' category to be taken concurrently
is usually three. Your list includes seven medicines belonging to the 'topicals' category:
hydrocortisone
gentamicin
ketoconazole
nystatin
chloramphenicol
acyclovir
permethrin
Duplication Antihypertensives
The recommended maximum number of medicines in the 'antihypertensives' category to be taken
concurrently is usually two. Your list includes three medicines belonging to the 'antihypertensives'
category:
amlodipine
nifedipine
captopril
Duplication Calcium channel blockers

The recommended maximum number of medicines in the 'calcium channel blockers' category to be
taken concurrently is usually one. Your list includes two medicines belonging to the 'calcium channel
blockers' category:
amlodipine
nifedipine
Duplication Antibiotics
The recommended maximum number of medicines in the 'antibiotics' category to be taken
concurrently is usually three. Your list includes seven medicines belonging to the 'antibiotics'
category:
amoxicillin
ciprofloxacin
cefixime
doxycycline
clindamycin
chloramphenicol
Duplication Antifungals
The recommended maximum number of medicines in the 'antifungals' category to be taken
concurrently is usually two. Your list includes four medicines belonging to the 'antifungals' category:
nystatin
ketoconazole
miconazole
Duplication Beta-lactam antibiotics

The recommended maximum number of medicines in the 'beta-lactam antibiotics' category to be
taken concurrently is usually one. Your list includes two medicines belonging to the 'beta-lactam
antibiotics' category:
amoxicillin
cefixime
Duplication Non-narcotic analgesics

The recommended maximum number of medicines in the 'non-narcotic analgesics' category to be
taken concurrently is usually two. Your list includes five medicines belonging to the 'non-narcotic
analgesics' category:
ibuprofen
diclofenac
allopurinol
mefenamic acid
Duplication Nonsteroidal anti-inflammatories

The recommended maximum number of medicines in the 'nonsteroidal anti-inflammatories' category
to be taken concurrently is usually one. Your list includes three medicines belonging to the
'nonsteroidal anti-inflammatories' category:
ibuprofen
diclofenac
mefenamic acid
Duplication Antihistamines, antitussives and decongestants

The recommended maximum number of medicines in the 'antihistamines, antitussives and
decongestants' category to be taken concurrently is usually three. Your list includes four medicines
belonging to the 'antihistamines, antitussives and decongestants' category:
guaifenesin
chlorpheniramine
loratadine
cetirizine
Duplication Antihistamines
The recommended maximum number of medicines in the 'antihistamines' category to be taken

concurrently is usually one. Your list includes three medicines belonging to the 'antihistamines'
category:
chlorpheniramine
loratadine
cetirizine
Duplication Vitamins and minerals

The recommended maximum number of medicines in the 'vitamins and minerals' category to be
taken concurrently is usually three. Your list includes eight medicines belonging to the 'vitamins and
minerals' category:
folic acid
Zinc (zinc sulfate)
calcium lactate
Duplication Vitamins
The recommended maximum number of medicines in the 'vitamins' category to be taken
concurrently is usually three. Your list includes six medicines belonging to the 'vitamins' category:
folic acid
Duplication Acid suppressant agents

The recommended maximum number of medicines in the 'acid suppressant agents' category to be
taken concurrently is usually one. Your list includes three medicines belonging to the 'acid
suppressant agents' category:
omeprazole
lansoprazole
ranitidine
Duplication Antidiarrheal preparations

The recommended maximum number of medicines in the 'antidiarrheal preparations' category to be
taken concurrently is usually two. Your list includes three medicines belonging to the 'antidiarrheal
preparations' category:
loperamide
kaolin/pectin
attapulgite
Duplication Antidiarrheals
The recommended maximum number of medicines in the 'antidiarrheals' category to be taken
concurrently is usually one. Your list includes three medicines belonging to the 'antidiarrheals'
category:
loperamide
kaolin/pectin
attapulgite
Duplication Cortisones
The recommended maximum number of medicines in the 'cortisones' category to be taken
concurrently is usually one. Your list includes two medicines belonging to the 'cortisones' category:
methylprednisolone
dexamethasone
Duplication Skin preparations

The recommended maximum number of medicines in the 'skin preparations' category to be taken
concurrently is usually two. Your list includes five medicines belonging to the 'skin preparations'
category:
hydrocortisone
gentamicin
ketoconazole
acyclovir
permethrin
Duplication Antifungal agents

The recommended maximum number of medicines in the 'antifungal agents' category to be taken
concurrently is usually one. Your list includes three medicines belonging to the 'antifungal agents'
category:
nystatin
ketoconazole
miconazole
Duplication Folates
The recommended maximum number of medicines in the 'folates' category to be taken concurrently
is usually one. Your list includes two medicines belonging to the 'folates' category:
folic acid
Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is
difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special
circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take
steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.
Further information
Always consult your healthcare provider to ensure the information displayed on this page applies to
your personal circumstances.

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7/4/2019 Drug Interaction Report - Drugs.

Drug Interaction Report

My Interactions List: (Unsaved)

Cotrim (sulfamethoxazole / trimethoprim)

Almacone (aluminum hydroxide / magnesium hydroxide / simethicone)

Zinc (zinc sulfate)

Vitamin C (ascorbic acid)

Vitamin B12 (cyanocobalamin)

ferrous fumarate / folic acid

Interactions between your drugs

MONITOR CLOSELY: Coadministration of allopurinol with angiotensin converting enzyme (ACE)

MANAGEMENT: Caution is advised if allopurinol is prescribed in combination with an ACE inhibitor,

View all 6 references

View all 33 references

Major ciprofloxacin  methylPREDNISolone

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with

3. "Product Information. Cipro (ciprofloxacin)." Bayer, West Haven, CT.

View all 7 references

Major ciprofloxacin  glimepiride

View all 40 references

View all 29 references

MONITOR CLOSELY: Concomitant administration of corticosteroids may potentiate the risk of

MANAGEMENT: Caution is recommended if fluoroquinolones are prescribed in combination with

3. "Product Information. Cipro (ciprofloxacin)." Bayer, West Haven, CT.

View all 7 references

Major raNITIdine  loperamide

View all 6 references

Major ketoconazole  methylPREDNISolone

MANAGEMENT: The possibility of increased corticosteroid effects should be considered when

View all 8 references

Major ketoconazole  loperamide

3. "Product Information. Imodium (loperamide)." Janssen Pharmaceutica, Titusville, NJ.

View all 6 references

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly

View all 14 references

Major miconazole  glimepiride

View all 25 references

Major amLODIPine  simvastatin

Moderate captopril  methylPREDNISolone

2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

Moderate captopril  dexamethasone

2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

Moderate captopril  ibuprofen

3. Ahmad S "Indomethacin-enalapril interaction: an alert." South Med J 84 (1991): 411-2

View all 13 references

Moderate captopril  glimepiride

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these

View all 101 references

Moderate captopril  isosorbide dinitrate

MANAGEMENT: In general, this combination is used to clinical advantage; however, some

Moderate captopril  diclofenac

3. Ahmad S "Indomethacin-enalapril interaction: an alert." South Med J 84 (1991): 411-2

View all 13 references

Moderate captopril  mefenamic acid

3. Ahmad S "Indomethacin-enalapril interaction: an alert." South Med J 84 (1991): 411-2

View all 13 references

Moderate captopril  metFORMIN

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if ACE