Zafirlukast (Systemic)
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VA CLASSIFICATION
Primary: RE180
Commonly used brand name(s): Accolate.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Antiasthmatic (leukotriene receptor antagonist)—
Indications
Accepted
Asthma, chronic (prophylaxis and treatment)—Zafirlukast is indicated in patients with chronic asthma to improve daytime asthma symptoms, forced expiratory volume in 1 second (FEV 1), and morning peak expiratory flow rates, and to decrease nighttime awakenings, mornings with asthma symptoms, and use of a rescue beta 2 agonist {01} {02}. When used daily with an as-needed, inhaled beta 2 agonist in patients with mild-to-moderate asthma, zafirlukast significantly reduces asthma symptoms and use of an as-needed, inhaled beta 2 agonist as compared with use of an as-needed, inhaled beta 2 agonist alone {01} {03}.
—Only patients with mild-to-moderate asthma have been treated with zafirlukast in clinical trials; therefore, its use in the management of patients with more severe asthma and in those receiving antiasthma therapy other than as-needed, inhaled beta 2 agonists remains to be studied, as does use of zafirlukast as an oral or inhaled corticosteroid-sparing agent. {01}
Unaccepted
Zafirlukast is not indicated for the treatment of bronchospasm in acute asthma attacks, including status asthmaticus; however, use of zafirlukast can be continued during an acute exacerbation {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
575.69 {06}
Mechanism of action/Effect:
Zafirlukast is a selective and competitive receptor antagonist of the cysteinyl leukotrienes D 4 and E 4 {01}. The cysteinyl leukotrienes, originally described as slow-reacting substances of anaphylaxis, produce airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, all of which are associated with the pathophysiology of asthma {01} {04}. In humans, pretreatment with single oral doses of zafirlukast inhibited bronchoconstriction caused by sulfur dioxide and cold air and reduced the early- and late-phase reaction in patients with asthma caused by inhalation of various antigens, such as grass, cat dander, and ragweed. Zafirlukast reduced the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge. {01}
Absorption:
Rapid {01}.
Bioavailability is reduced following administration with a high-fat or high-protein meal {01}.
Protein binding:
High (more than 99% bound to plasma proteins, predominantly albumin) {01}.
Biotransformation:
Hepatic; extensively metabolized by the cytochrome P450 2C9 enzyme pathway to metabolites that are 90 times less potent antagonists of leukotriene D 4 receptors than zafirlukast in vitro {01}.
Half-life:
Elimination—The mean terminal elimination half-life is approximately 10 hours {01}.
Onset of action:
In clinical trials, improvement in asthma symptoms was seen within 1 week of starting treatment with zafirlukast {01}.
Time to peak plasma concentration
3 hours after dosing. {09}
Mean peak plasma concentration reached is 2.5 hours in children (between 7 and 11 years of age). {09}
Elimination:
Fecal—Approximately 90% {01}.
Renal—Approximately 10% {01}.
Precautions to Consider
Carcinogenicity/Tumorigenicity
A 2-year study in mice given zafirlukast orally in doses of 10, 100, and 300 mg per kg of body weight (mg/kg) per day showed a greater incidence of hepatocellular adenomas in males and whole-body histocytic sarcomas in females given the highest dose, as compared with controls. Plasma concentrations of zafirlukast following the 100- and 300-mg-per-kg-per-day doses were approximately 70 and 220 times, respectively, the plasma concentrations found at the maximum recommended human daily oral dose. {01}
A 2-year study in rats given zafirlukast orally in doses of 40, 400, and 2000 mg/kg per day found a greater incidence of urinary bladder transitional cell papillomas at doses of 2000 mg/kg per day, as compared with controls. Plasma concentrations of zafirlukast following the 400- and 2000-mg-per-kg-per-day doses were approximately 170 and 200 times, respectively, the plasma concentrations found at the maximum recommended human daily oral dose. {01}
Mutagenicity
Zafirlukast was not mutagenic in reverse or forward point mutation assays or in human and rat assays for chromosomal abnormalities {01}.
Pregnancy/Reproduction
Fertility—
Reproduction studies in rats given oral zafirlukast in doses approximately 400 times the maximum recommended human daily oral dose on a mcg per square meter of body surface area (mcg/m 2) basis showed no effect on fertility {01}.
Pregnancy—
Adequate and well-controlled studies have not been done in humans.
No teratogenicity was observed in mice, rats, or monkeys given oral zafirlukast in doses up to approximately 160, 400, and 800 times the maximum recommended human daily oral dose on a mg per square meter of body surface area (mg/m 2) basis. {01}
In rats given oral doses of 2000 mg/kg per day, maternal toxicity and deaths were seen, as well as an increased incidence of early fetal resorptions. In monkeys, the same dose resulted in maternal toxicity and an increased incidence of spontaneous abortions. {01}
FDA Pregnancy Category B {01}.
Breast-feeding
Zafirlukast is distributed into human breast milk. Steady-state concentrations of zafirlukast in breast milk and plasma were 50 and 255 nanograms per mL, respectively, after administration of 40 mg two times a day. Because of the potential for tumorigenicity and adverse effects in the neonate shown in animal studies, use of zafirlukast during breast-feeding is not recommended. {01}
Pediatrics
Appropriate studies on the relationship of age to the effects of zafirlukast have not been performed in the pediatric population. Safety and efficacy in children up to 7 years of age have not been established {01}.
Geriatrics
In patients 65 years of age and older, the clearance of zafirlukast is reduced, resulting in peak plasma concentration and area under the plasma concentration–time curve (AUC) values that are approximately two to three times greater than those of younger patients. However, the recommended dose of 20 mg two times a day did not result in increased adverse effects or withdrawal from the study in elderly patients during clinical trials when compared with patients younger than 65 years of age. {01}
In clinical trials, a greater incidence of mild or moderate infections, predominantly affecting the respiratory tract, occurred in patients older than 55 years of age treated with zafirlukast, as compared with other age groups and placebo-treated patients. The number of infections was proportional to the amount, in milligrams, of zafirlukast administered and was associated with concurrent use of inhaled corticosteroids. The clinical significance of this finding is unknown. {01}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: In in vitro studies using human liver microsomes, zafirlukast has been shown to inhibit the cytochrome P450 3A4 and 2C9 isoenzymes at concentrations close to those achieved following recommended dosing {01}.
In a 3-week study in females taking oral contraceptives, 40 mg of zafirlukast two times a day had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy {01}.
Aspirin (concurrent administration of 40 mg a day of zafirlukast with aspirin at a dosage of 650 mg four times a day increased mean plasma concentrations of zafirlukast by approximately 45% {01})
Astemizole or
Cisapride or
Cyclosporine or
Dihydropyridine calcium channel blocking agents, such as:
Felodipine
Isradipine
Nicardipine
Nifedipine
Nimodipine (although studies have not been done with zafirlukast and medications known to be metabolized by the cytochrome P450 3A4 isoenzyme, such as astemizole, cisapride, cyclosporine, and the dihydropyridine calcium channel blocking agents, concurrent use of these medications with zafirlukast should be monitored carefully, since zafirlukast is known to inhibit cytochrome P450 3A4 in vitro {01})
Carbamazepine or
Phenytoin or
Tolbutamide (although studies have not been done with zafirlukast and medications known to be metabolized by the cytochrome P450 2C9 isoenzyme, such as carbamazepine, phenytoin, and tolbutamide, patients in whom these medications are coadministered with zafirlukast should be appropriately monitored clinically, since zafirlukast is known to inhibit cytochrome P450 2C9 in vitro {01})
Erythromycin (administration of a single 40-mg dose of zafirlukast during steady-state erythromycin therapy resulted in a 40% decrease in the mean plasma concentration of zafirlukast, due to decreased zafirlukast bioavailability {01})
Terfenadine (concurrent administration of zafirlukast with terfenadine resulted in a 66% and 54% decrease in the mean peak plasma concentration and area under the plasma concentration–time curve, respectively, of zafirlukast; no effect was observed on terfenadine plasma concentrations or electrocardiogram results {01})
Theophylline (concurrent administration of 80 mg a day of zafirlukast with a single 6-mg-per-kg dose of theophylline decreased the mean plasma concentration of zafirlukast by approximately 30%; no effect on theophylline plasma concentration was observed {01})
» Warfarin (the concurrent use of a single 25-mg warfarin dose with multiple doses of zafirlukast resulted in an increase of approximately 35% in the mean prothrombin time, due to an inhibition of the cytochrome P450 2C9 isoenzyme; prothrombin times should be monitored closely and warfarin dose adjusted accordingly {01})
Side/Adverse Effects
Note: In clinical trials, a greater incidence of mild or moderate infections, predominantly affecting the respiratory tract, occurred in patients older than 55 years of age treated with zafirlukast, as compared with other age groups and placebo-treated patients. The number of infections was proportional to the amount, in milligrams, of zafirlukast administered and was associated with concurrent use of inhaled corticosteroids. The clinical significance of this finding is unknown. {01}
Rarely, elevation of one or more hepatic transaminases has occurred in patients receiving zafirlukast at doses four times higher than the recommended dose during controlled clinical trials. Most patients were asymptomatic. Hepatic enzyme values returned to normal after a variable period of time following discontinuation of zafirlukast. Rare cases of symptomatic hepatitis and hyperbilirubinemia have been reported in patients who received the recommended dosage of zafirlukast. In these patients, the hepatic transaminase elevations returned to normal or near-normal after discontinuation of the medication. {05}
Note: In rare cases, patients receiving zafirlukast therapy may present with systemic eosinophilia. Systemic eosinophilia sometimes is characterized by clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that often is treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy {08}. Churg-Strauss syndrome is a systemic eosinophilic vasculitis, which may present as generalized, flu-like symptoms (fever, muscle aches or pains, and weight loss), eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, or neuropathy. If left untreated, Churg-Strauss syndrome can result in damage to major organs and death. Although a causal relationship between the use of zafirlukast and the development of Churg-Strauss syndrome has not been established, adult asthma patients should be monitored carefully, especially {08} when corticosteroid therapy is being reduced or discontinued. {01} {07}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Headache
nausea {01}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zafirlukast (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Breast-feeding—Distributed into breast milk; use not recommended
Use in the elderly—Mild to moderate respiratory infections may be more likely to develop in patients older than 55 years of age; whether this is related to taking zafirlukast or to other factors, such as use of inhaled corticosteroids, is not clear
Other medications, especially warfarin
Proper use of this medication
» Importance of not using this medication to treat acute asthma symptoms
» Taking medication on an empty stomach, 1 hour before or 2 hours after meals
» Proper dosing
Missed dose: Taking as soon as possible; if almost time for next dose, skipping missed dose; not doubling doses
» Proper storage
Precautions while using this medication
» Compliance with therapy by using every day in regularly spaced doses, even during symptom-free periods
» Checking with health care professional before stopping or reducing therapy with any other asthma medications
Side/adverse effects
Signs of potential side effects, especially headache or nausea
General Dosing Information
Diet/Nutrition
In two separate studies, administration of zafirlukast with a high-fat meal and a high-protein meal resulted in a reduction of the mean bioavailability by approximately 40%; therefore, the medication should be taken on an empty stomach at least 1 hour before or 2 hours after meals {01} {08}.
Oral Dosage Forms
ZAFIRLUKAST TABLETS
Usual adult and adolescent dose
Antiasthmatic
Oral, 20 mg two times a day, one hour before or two hours after a meal {01}.
Usual adult and adolescent prescribing limits
20 mg two times a day.
Usual pediatric dose
Antiasthmatic
Children 12 years of age and older—See Usual adult and adolescent dose
Children 7 to 11 years of age—Oral, 10 mg two times a day, one hour before or two hours after a meal
Children up to 7 years of age—Safety and efficacy have not been established.
{09}
Usual geriatric dose
See Usual adult and adolescent dose {01}.
Strength(s) usually available
U.S.—
20 mg (Rx) [Accolate (film-coated)]
10 mg (Rx) [Accolate (film–coated)]
Canada—
Not commercially available.
Packaging and storage:
Store between 20 and 25 ºC (68 and 77 ºF). Protect from light and moisture. {01}
Auxiliary labeling:
• Take on empty stomach.
Revised: 01/13/2000
References
- Accolate package insert (Zeneca—US), Rev 7/97.
- Spector SL, Smith LJ, Glass M, et al. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D 4 receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med 1994; 150: 618-23.
- Suissa S, Dennis R, Ernst P, et al. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. Ann Intern Med 1997; 126: 177-83.
- Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy. J Allergy Clin Immunol 1996; 98: 1-13.
- Reviewer comment, 5/7/97.
- Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention Inc; 1996.
- Health advisory for new asthma drug. FDA Talk Paper 7/23/97. Available from: URL: http://www.fda.gov/bbs/topics/ANSWERS/ANS00810.html
- Accolate package insert (Zeneca—US), Rev 6/98, Rec 10/30/98.
- Product Information: Accolate, zafirlukast. Zeneca Pharmaceuticals, Wilmington, DE, USA, Sept 99.
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