Zafirlukast fills need for new asthma drug

Clinical trial indicates it improves symptoms

An agent belonging to a new class of drugs for treating asthma, zafirlukast (Accolate), recently was approved for the prevention and treatment of chronic asthma in adults and teenagers. The drug works by blocking the effect of leukotrienes, a naturally occurring substance that triggers anaphylaxis. Asthmatics are much more likely to be sensitive to the bronchoconstricting activity of leukotrienes.

"There is a need for new alternative asthma medications," says Jeffrey M. Drazen, MD, professor of medicine at Harvard Medical School in Boston and one of the drug’s investigators. "Some patients can’t control their asthma effectively with the medications that are currently available. In those patients, the addition of [zafirlukast] may provide an effective and generally well-tolerated approach to help control asthma symptoms."

Zafirlukast inhibits bronchoconstriction caused by sulfur dioxide and cold air as well as antigens such as grass, cat dander, and ragweed in asthmatics. The drug antagonizes the contractile activity of leukotrienes in conducting airway smooth muscle.

Three U.S. double-blind, randomized, placebo-controlled, 13-week clinical trials of 1,380 patients with mild to moderate asthma indicated that zafirlukast improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, and other problems. In a second, smaller study, zafirlukast was found to have efficacy parameters comparable to the active control (inhaled cromolyn sodium, 1,600 mcg four times a day) and superior to placebo at endpoint for decreasing rescue beta-agonist use.

In both trials, improvement in asthma symptoms occurred within one week of initiating treatment. The role of zafirlukast in treating patients with more severe asthma isn’t known.

Zafirlukast is contraindicated in patients who are hypersensitive to zafirlukast. It isn’t indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Therapy with zafirlukast can be continued during acute exacerbation of asthma.

When administered with warfarin, zafirlukast may result in a clinically significant increase in prothrombin time. Patients on oral warfarin therapy and zafirlukast should have their prothrombin times monitored closely, and the anticoagulant dose should be adjusted accordingly. Other drugs that may interact with zafirlukast include the following:

• terfenadine;

• erythromycin;

• aspirin;

• theophylline.

Providers should make sure patients know zafirlukast is indicated only for the chronic treatment of asthma and should be taken as prescribed, even when they are symptom-free.

Zafirlukast is contraindicated in women who are breast-feeding and in children below the age of 12.

Because the bioavailability of zafirlukast may be decreased when taken with food, patients should be instructed to take it at least one hour before or two hours after meals.

The most common side effects associated with zafirlukast in clinical trials were as follows:

• headache;

• infections;

• nausea;

• diarrhea.

Infections were more likely to occur in patients older than age 55 on zafirlukast than in patients on placebo, but the infections were mild to moderate in intensity and mostly affected the respiratory tract. Infections also were associated with coadministration of corticosteroids.

Enzymes return to normal

In the studies, one patient who was on 40 mg of zafirlukast a day for 100 days developed symptomatic hepatitis and hyperbilirubinemia, but the patient’s liver enzymes returned to normal within three months of stopping the drug.

The recommended dosage of zafirlukast is 20 mg twice daily in adults and children 12 years of age and older. Clinical trials of the drug did not indicate that the dose needs to be reduced in elderly patients. The clearance of zafirlukast is reduced in patients with stable alcoholic cirrhosis, but the drug hasn’t been evaluated long-term in those patients. Dosage adjustment isn’t required for patients with renal impairment.

Zafirlukast is supplied in 20 mg white, round, biconvex, coated tablets. They are supplied in bottles of 60 tables and in hospital unit dose blister packages of 100 tablets. Store the drug at controlled room temperature and protect from light and moisture. Dispense in the original air-tight container.

[Editor’s note: For more information on zafirlukast, contact: Linda Ziemba, Medical Information Office, Zeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850-5437. Telephone: (800) 456-3669, ext. 3838.]