Brands, Medical Use, Clinical Data
- Anti-Asthmatic Agents
- Leukotriene Antagonists
Brands / Synonyms
Accolate; Zafirlukast [Usan:Ban:Inn]
For the prophylaxis and chronic treatment of asthma.
Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA) indicated for the prophylaxis and chronic treatment of asthma. Patients with asthma were found in one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than nonasthmatic subjects. In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC4, LTD4 and LTE4) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD4-induced increases in cutaneous vascular permeability and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs.
Mechanism of Action
Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma.
Rapidly absorbed following oral administration, reduced following a high-fat or high-protein meal.
Side effects include rash and upset stomach.
Biotrnasformation / Drug Metabolism
ACCOLATE is contraindicated in patients who are hypersensitive to zafirlukast or any of its inactive
In a drug interaction study in 16 healthy male volunteers, coadministration of multiple doses of zafirlukast (160
mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a significant increase in the mean AUC
(+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time (PT) increased by approximately 35%. This
interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. Patients on
oral warfarin anticoagulant therapy and ACCOLATE should have their prothrombin times monitored closely and
anticoagulant dose adjusted accordingly. No formal drug-drug interaction studies with ACCOLATE and other drugs known
to be metabolized by the cytochrome P450 2C9 isoenzyme (eg, tolbu-tamide, phenytoin, carbamazepine) have been
conducted; however, care should be exercised when ACCOLATE is coadministered with these drugs.
In a drug interaction study in 11 asthmatic patients, coadministration of a single dose of zafirlukast (40 mg)
with erythromycin (500 mg three times daily for 5 days) to steady-state resulted in decreased mean plasma levels of
zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability.
Coadministration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of sustained release
theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in no
significant differences in the pharmacokinetic parameters of theophylline.
Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline
preparation (6 mg/kg) in 13 asthmatic patients, 18 to 44 years of age, resulted in decreased mean plasma levels of
zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed.
Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of
theophylline toxicity after the addition of ACCOLATE to an existing theophylline regimen have been reported. The
mechanism of the interaction between ACCOLATE and theophylline in these patients is unknown (see ADVERSE REACTIONS).
Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased
plasma levels of zafirlukast by approximately 45%.
In a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, 40 mg
twice daily of zafirlukast had no significant effect on ethinyl estradiol plasma concentrations or contraceptive
No formal drug-drug interaction studies between ACCOLATE and marketed drugs known to be metabolized by the P450
3A4 (CYP3A4) isoenzyme (eg, dihydropyridine calcium-channel blockers, cyclosporin, cisapride) have been conducted. As
ACCOLATE is known to be an inhibitor of CYP3A4 in vitro, it is reasonable to employ appropriate clinical
monitoring when these drugs are coadministered with ACCOLATE.