The Medical Letter On Drugs and Therapeutics Vol. 40 (issue 1031) July 17, 1998 MONTELUKAST FOR PERSISTENT ASTHMA Montelukast sodium (Singulair- Merck), a leukotriene receptor antagonist, has been approved by the US Food and Drug Administration (FDA) for oral prophylaxis and chronic treat- ment of asthma in adults and children at least 6 years old. It is the third "Ieukotriene modifier" to become available in the USA; zafirlukast (Accolate - Medical Letter, 38:111, 1996) and zileuton (Zyflo - Medical Letter, 39:18, 1997) were marketed previously. Neither zafirlukast nor zileuton has been approved by the FDA for use in children less than 12 years old. Leukotriene modifiers are not recommended for treatment of an acute asthma attack (Ex- pert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma, Bethesda: NIH, 1997;www.nhlbi.NIH.gov/nhlbi/lung/asthma/prof/asthgdln.htm). MECHANISM OF ACTION - Cysteinyl leukotrienes are products of arachidonic acid metabolism that increase eosinophil migration, mucus production and airway wall edema, and cause bronchoconstriction. Montelukast (mon tee loo' kast) selectively blocks binding of LTD 4 , the predominant cysteinyl Ieukotriene in the airways, to its receptor (TR Jones et al, Can J Physiol Pharmacol, 73:191, 1995). PHARMACOKINETICS - Montelukast is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentrations in 3 to 4 hours. Its mean plasma half-life is 2.7 to 5.5 hours. The drug is metabolized in the liver by cytochrome P450 enzymes 3A4 and 2C9 and ex- creted mainly in bile. CLINICAL TRIALS - A double-blind 12-week trial in 681 patients at least 15 years old with intermittent or persistent asthma, most not being treated with inhaled corticosteroids, found that 10 mg of montelukast nightly increased the morning FEV 1 (forced expiratory volume in one second) from a mean of 2.5 L to 2.8 L (a 13% increase), compared to an in- crease from 2.5 to 2.6 L (4%) with placebo. The drug also decreased nocturnal awakenings due to asthma by 1.7 nights/week, compared to 0.8 nights with placebo, and decreased use of a short-acting beta-agonist inhaler by 25%, compared to a 10% decrease with placebo. Treat- ment effects with the drug were near maximum within 24 hours after the first dose and were maintained for the full 12 weeks (TF Reiss et al, Arch Intern Med, 158:1213, 1998). An 8-week trial in 336 children 6 to 14 years old with intermittent or persistent asthma found that 5 mg of montelukast nightly increased the mean morning FEV 1 by about 8% compared to an increase of about 4% with placebo. Short-acting beta-agonist use, which averaged 3.3 puffs/day in both groups at baseline, decreased by 0.57 puffs/day in children taking montelukast and 0.22 puffs/day in those on placebo (B Knorr et air JAMA, 279:1181, 1998). Compared to Inhaled Corticosteroids - A 12-week double-blind trial in patients with moderate persistent asthma found 10 mg of montelukast once daily less effective than the in- haled corticosteroid beclomethasone 200 lag b.i.d. in increasing FEV1 (7.5% vs 13%), according to an unpublished study summarized in the manufacturer's package insert. In Addition to Corticosteroids - According to the package insert, a study in 642 patients not adequately controlled on inhaled beclomethasone found addition of montelukast more effective than placebo in improving lung function and decreasing symptoms. A 12-week double-blind trial in 226 adults with asthma well controlled on inhaled corticosteroids found that addition of montelukast permitted reduction of corticosteroid dosage by 47%, compared to a 30% reduction with placebo (JA Leff et al, Am J Respir Crit Care Med, 155:A976, 1997). In a 4-week double-blind study in 80 patients with aspirin-intolerant asthma being treated with inhaled or oral corticosteroids, addition of montelukast increased FEV 1 by 8.5%, compared to a 1.7% decrease with placebo (P Kuna et al, Am J Respir Crit Care Med, 155:A975, 1997). Exercise-induced Bronchospasm - In a two-day, placebo-controlled crossover trial in 27 children 6 to 14 years old with exercise-induced asthma, 5 mg of montelukast taken on 2 con- secutive nights attenuated the decrease in FEV 1 after a standardized exercise challenge 20 to 24 hours after the last dose (JP Kemp et al, J Allergy Clin Immunol, 99:S321, 1997). However, montelukast often does not prevent asthmatic symptoms after exercise, and should not be used alone for prophylaxis or treatment of exercise-induced bronchospasm. ADVERSE EFFECTS - In short-term studies, the frequency of adverse events with montelukast has been similar to that with placebo. Hepatic toxicity, which can occur with zileu- ton, has not been reported with montelukast. Churg-Strauss vasculitis, which has occurred in patients taking zafirlukast (RS Katz and M Papernik, JAMA, 279:1949, June 24, 1998), also has not been reported to date with montelukast. Higher-than-recommended doses of montelukast have not increased the incidence of adverse effects (EA Bronsky et al, Clin Pharmacol Ther, 62:556, 1997; MJ Noonan et al, Eur Respir J, 11:1232, 1998). DRUG INTERACTIONS - Montelukast has fewer drug interactions than zafirlukast or zileuton. In vitro studies using human liver microsomes indicate that montelukast does not inhibit CYP-450 enzymes. Clinical studies indicate that the drug does not interact with theo- phylline (K Malmstrom et al, Am J Ther, 5:189, May 1998), warfarin (Coumadin), digoxin (Lanoxin, and others), prednisone or either the estrogen or progestin components of combina- tion oral contraceptives. Phenobarbital decreases the area under the plasma concentration- time curve of montelukast by 40%. No information is available on the effects of other more potent CYP-450 enzyme inducers such as rifampin (Rifadin, Rimactane) or of potent CYP3A4 inhibitors such as ketoconazole (Nizoral) on elimination of montelukast. DOSAGE AND COST - Singulair is available in 10-mg tablets and 5-mg chewable ta- blets, which cost the same. The recommended dosage is 5 mg in children 6 to 14 years old and 10 mg in adults, taken daily in the evening without regard to food intake. CONCLUSION - Montelukast, a new leukotriene receptor antagonist, taken as a tablet once daily is modestly effective in controlling mild-to-moderate persistent asthma and is FDA-approved for use in children less than 12 years old. It might prove to be tolerated better than zafirlukast or zileuton, but more experience is needed. Montelukast is less effective than inhaled corticosteroids, but more convenient to take.