Indications : Asthma Pregnancy Category B Orphan Drugs; WHO Formulary FDA Approved 1998 Feb DRUG CLASS : : Antiasthmatics BRAND NAMES : Singulair (US); DESCRIPTION : Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor. Montelukast sodium is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt. The empirical formula is C35H35ClNNaO3S, and its molecular weight is 608.18. The structural formula is: Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile. Each 10-mg film-coated Singulair tablet contains 10.4 mg montelukast sodium, which is the molar equivalent to 10.0 mg of free acid, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red iron oxide, yellow iron oxide, and carnauba wax. Each 5-mg chewable Singulair tablet contains 5.2 mg montelukast sodium, which is the molar equivalent to 5.0 mg of free acid, and the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. CLINICAL PHARMACOLOGY : Mechanism of Action The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene receptors (CysLT) found in the human airway. Cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or beta-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity. Pharmacokinetics Absorption : Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning. For the 5-mg chewable tablet, the mean Cmax is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning. The safety and efficacy of montelukast were demonstrated in clinical trials in which both formulations were administered in the evening without regard to the timing of food ingestion. The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated. Distribution : Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues. Metabolism : Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients. In vitro studies using human liver microsomes indicate that cytochromes P450 3A4 and 2C9 are involved in the metabolism of montelukast. Clinical studies investigating the effect of known inhibitors of cytochromes P450 3A4 (e.g., ketoconazole, erythromycin) or 2C9 (e.g., fluconazole) on montelukast pharmacokinetics have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see DRUG INTERACTIONS). Elimination : The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile. In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (14%). Special Populations Gender : The pharmacokinetics of montelukast are similar in males and females. Elderly : The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required. Race : Pharmacokinetic differences due to race have not been studied. Hepatic Insufficiency : Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% Cl=7%, 85%) higher mean montelukast area under the plasma concentration curve (AUC) following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of montelukast in patients with more severe hepatic impairment or with hepatitis have not been evaluated. Renal Insufficiency : Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients. Adolescents and Pediatric Patients : The plasma concentration profile of montelukast following administration of the 10-mg film-coated tablet is similar in adolescents 15 years of age and young adults. The 10-mg film-coated tablet is recommended for use in patients 15 years of age. Pharmacokinetic studies show that the plasma profile of the 5-mg chewable tablet in pediatric patients 6 to 14 years of age is similar to that of the 10-mg film-coated tablet in adults. The 5-mg chewable tablet should be used in pediatric patients 6 to 14 years of age. Pharmacodynamics Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD4-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12). Montelukast inhibited early-and late-phase bronchoconstriction due to antigen challenge by 75% and 57% respectively. The effect of montelukast on eosinophils in the peripheral blood was examined in clinical trials in adults and pediatric asthmatic patients. Montelukast decreased mean peripheral blood eosinophils approximately 13 to 15% from baseline compared with placebo over the double-blind treatment periods. The relationship between this observation and the clinical benefits noted in the clinical trials is not known (see CLINICAL STUDIES). CLINICAL STUDIES : General There have been no clinical trials evaluating the relative efficacy of morning versus evening dosing. Although the pharmacokinetics of montelukast are similar whether dosed in the morning or the evening, efficacy was demonstrated in clinical trials in adults and pediatric patients in which montelukast was administered in the evening without regard to the time of food ingestion. Adolescents And Adults 15 Years Of Age And Older Clinical trials in adolescents and adults 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily. This was shown in two chronic asthma trials using doses up to 200 mg once daily and in one exercise challenge study using doses up to 50 mg, evaluated at the end of the once-daily dosing interval. The efficacy of montelukast for the chronic treatment of asthma in adolescents and adults 15 years of age and older was demonstrated in two (U.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with montelukast, 530 treated with placebo, and 251 treated with active control). The patients studied were mild and moderate, non-smoking asthmatics who required approximately 5 puffs of inhaled beta-agonist per day on an “as-needed” basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV1) of 66% (approximate range, 40 to 90%). The coprimary endpoints in these trials were FEV1 and daytime asthma symptoms. Secondary endpoints included morning and evening peak expiratory flow rates (AM PEFR, PM PEFR), rescue beta-agonist requirements, nocturnal awakening due to asthma, and other asthma-related outcomes. In both studies after 12 weeks, a random subset of patients receiving montelukast was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects. The effect of montelukast on other primary and secondary endpoints is shown in TABLE 1 as combined analyses of the U.S. and Multinational trials. TABLE 1 Effect of Montelukast on Primary and Secondary Endpoints in Placebo-controlled Trials (Combined Analyses – U.S. and Multinational Trials) Montelukast Placebo Endpoint Baseline Mean Change from Baseline Baseline Mean Change from Baseline Daytime Asthma Symptoms (0 to 6 scale) 2.43 -0.45* 2.45 -0.22 beta-agonist (puffs per day) 5.38 -1.56* 5.55 -0.41 AM PEFR (L/min) 361.3 24.5* 364.9 3.3 PM PEFR (L/min) 385.2 17.9* 389.3 2.0 Nocturnal Awakenings (#/week) 5.37 -1.84* 5.44 -0.79 * p<0.001, compared with placebo In adult patients, montelukast reduced “as-needed” beta-agonist use by 26.1% from baseline compared with 4.6% for placebo. In patients with nocturnal awakenings of at least 2 nights per week, montelukast reduced the nocturnal awakenings by 34% from baseline, compared with 15% for placebo (combined analysis). Montelukast, compared with placebo, significantly improved other protocol-defined, asthma-related outcome measurements (see TABLE 2). TABLE 2 Effect of Montelukast on Asthma-Related Outcome Measurements (Combined Analyses–U.S. and Multinational Trials) Montelukast Placebo Asthma Attack* (% of patients) 11.6 18.4 Oral Corticosteroid Rescue (% of patients) 10.7 17.5 Discontinuation Due to Asthma (% of patients) 1.4 4.0 Asthma Exacerbations§ (% of days) 12.8 20.5 Asthma Control Days¤ (% of days) 38.5 27.2 Physicians’ Global Evaluation (score)¶ 1.77 2.43 Patients’ Global Evaluation (score)** 1.60 2.15 * Asthma Attack defined as utilization of health-care resources such as an unscheduled visit to a doctor’s office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid. p<0.001, compared with placebo p<0.01, compared with placebo § Asthma Exacerbation defined by specific clinically important decreases in PEFR, increase in beta-agonist use, increases in day or nighttime symptoms, or the occurrence of an asthma attack. ¤ An Asthma Control Day defined as a day without any of the following: nocturnal awakening, use of more than 2 puffs of beta-agonist, or an asthma attack. ¶ Physicians’ evaluation of the patient’s asthma, ranging from 0 to 6 (“very much better” through “very much worse,” respectively). ** Patients’ evaluation of asthma, ranging from 0 to 6 (“very much better” through “very much worse,” respectively). In one of these trials, a non-U.S. formulation of inhaled beclomethasone dipropionate dosed at 200 mcg (two puffs of 100 mcg ex-valve) twice daily with a spacer device was included as an active control. Over the 12-week treatment period, the mean percentage change in FEV1 over baseline for montelukast and beclomethasone were 7.49% vs 13.3% (p<0.001) respectively; and the change in daytime symptom scores was -0.49 vs -0.70 on a 0 to 6 scale (p<0.001) for montelukast and beclomethasone, respectively. Onset of Action and Maintenance of Benefits In each placebo-controlled trial in adults, the treatment effect of montelukast, measured by daily diary card parameters, including symptom scores, “as-needed” beta-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in non-placebo-controlled extension trials for up to one year. Withdrawal of montelukast in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma. Pediatric Patients 6 To 14 Years Of Age The efficacy of montelukast in pediatric patients 6 to 14 years of age was demonstrated in one 8-week double-blind, placebo-controlled trial in 336 patients (201 treated with montelukast and 135 treated with placebo) using an inhaled beta-agonist on an “as-needed” basis. The patients had a mean baseline percent predicted FEV1 of 72% (approximate range, 45 to 90%) and a mean daily inhaled beta-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. Compared with placebo, treatment with one 5-mg montelukast chewable tablet daily, resulted in a significant improvement in mean morning FEV1 percent change from baseline (8.7% in the group treated with montelukast vs 4.2% change from baseline in the placebo group, p<0.001). There was a significant decrease in the mean percentage change in daily “as-needed” inhaled beta-agonist use (11.7% decrease from baseline in the group treated with montelukast vs 8.2% increase from baseline in the placebo group, p<0.05). This effect represents a mean decrease from baseline of 0.56 and 0.23 puffs per day for the montelukast and placebo groups, respectively. Subgroup analyses indicated that younger pediatric patients aged 6 to 11 had efficacy results comparable to those of the older pediatric patients aged 12 to 14. Montelukast, one 5-mg chewable tablet daily at bedtime, significantly decreased the percent of days asthma exacerbations occurred (montelukast 20.6% vs placebo 25.7%, p0.05). (See TABLE 2 for definition of asthma exacerbation.) Parents’ global asthma evaluations (parental evaluations of the patients’ asthma, see TABLE 2 for definition of score) were significantly better with montelukast compared with placebo (montelukast 1.34 vs placebo 1.69, p0.05). Similar to the adult studies, no significant change in the treatment effect was observed during continuous once-daily administration in one open-label extension trial without a concurrent placebo group for up to 6 months. Effects In Patients On Concomitant Inhaled Corticosteroids Separate trials in adults evaluated the ability of montelukast to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly. One randomized, placebo-controlled, parallel-group trial (n=226) enrolled stable asthmatic adults with a mean FEV1 of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone diproprionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5- to 7-week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose. Treatment with montelukast resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12-week active treatment period (p0.05). Approximately 40% of the montelukast-treated patients and 29% of the placebo-treated patients could be tapered off inhaled corticosteroids and remained off inhaled corticosteroids at the conclusion of the study (p=NS). It is not known whether the results of this study are generalizable to asthmatics who require higher doses of inhaled corticosteroids or systemic corticosteroids. In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast to beclomethasone resulted in statistically significant improvements in FEV1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast alone or placebo alone as indicated by FEV1, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-needed” beta-agonist requirements. In adult asthmatic patients with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week randomized, parallel-group trial (n=80) demonstrated that montelukast, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast in aspirin-sensitive patients was similar to the effect observed in the general population of asthmatic patients studied. The effect of montelukast on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated (see PRECAUTIONS, General). Effects on Exercise-Induced Bronchoconstriction (Adults and Pediatric Patients) In a 12-week, randomized, double-blind, parallel group study of 110 adolescent and adult asthmatics 15 years of age and older, with a mean baseline FEV1 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with montelukast, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV1 and mean time to recovery to within 5% of the pre-exercise FEV1. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. montelukast did not, however, prevent clinically significant deterioration in maximal percent fall in FEV1 after exercise (i.e., 20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10-mg doses of montelukast. In pediatric patients 6 to 14 years of age, using the 5-mg chewable tablet, a 2-day crossover study demonstrated effects similar to those observed in adults when exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). Montelukast should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled beta-agonists as prophylaxis and have available for rescue a short-acting inhaled beta-agonist (see PRECAUTIONS, General and PRECAUTIONS, Information for the Patient). INDICATIONS AND USAGE : Montelukast is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 6 years of age and older. CONTRAINDICATIONS : Hypersensitivity to any component of this product. PRECAUTIONS : General Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with montelukast can be continued during acute exacerbations of asthma. While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast should not be abruptly substituted for inhaled or oral corticosteroids. Montelukast should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled beta-agonists as prophylaxis and have available for rescue a short-acting inhaled beta-agonist. Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast. Although montelukast is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients (see CLINICAL STUDIES). The reduction in systemic corticosteroid dose in patients receiving another leukotriene antagonist has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. Although a causal relationship with leukotriene receptor antagonism has not been established and the phenomenon was not observed in clinical trials with montelukast, caution and appropriate clinical monitoring are recommended when systemic corticosteroid reduction is considered in patients receiving montelukast. Information for the Patient Patients should be advised to take montelukast daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled. Patients should be advised that oral tablets of montelukast are not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled beta-agonist medication available to treat asthma exacerbations. Patients should be advised that, while using montelukast, medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for 24-hour period are needed. Patients receiving montelukast should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. Patients who have exacerbations of asthma after exercise should be instructed to continue to use their usual regimen of inhaled beta-agonists as prophylaxis unless otherwise instructed by their physician. All patients should have available for rescue a short-acting inhaled beta-agonist. Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast. Chewable Tablets Phenylketonurics : Phenylketonuric patients should be informed that the chewable tablet contains phenylalanine (a component of aspartame) 0.842 mg per 5-mg chewable tablet. Carcinogenesis, Mutagenesis, and Impairment of Fertility No evidence of tumorigenicity was seen in a 2-year carcinogenicity study in Sprague Dawley rats, at oral (gavage) doses up to 200 mg/kg/day (approximately 160 times the maximum recommended daily oral dose in adults and 190 times the maximum recommended daily oral dose in children, on a mg/m2 basis) or in a 92-week carcinogenicity study in mice at oral doses up to 100 mg/kg/day (approximately 40 times the maximum recommended daily oral dose in adults and 50 times the maximum recommended daily oral dose in children, on a mg/m2 basis). Montelukast demonstrated no evidence of mutagenic or clastogenic activity in the following assays: the microbial mutagenesis assay, the V-79 mammalian cell mutagenesis assay, the alkaline elution assay in rat hepatocytes, the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse bone marrow chromosomal aberration assay. In fertility studies in female rats, montelukast produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (approximately 160 times the maximum recommended daily oral dose in adults, on a mg/m2 basis). No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (approximately 80 times the maximum recommended daily oral dose in adults, on a mg/m2 basis). Montelukast had no effects on fertility in male rats at oral doses up to 800 mg/kg (approximately 650 times the maximum recommended daily oral dose in adults, on a mg/m2 basis). Pregnancy, Teratogenic Effects, Pregnancy Category B No teratogenicity was observed in rats at oral doses up to 400 mg/kg/day (approximately 320 times the maximum recommended daily oral dose in adults, on a mg/m2 basis) and in rabbits at oral doses up to 300 mg/kg/day (approximately 490 times the maximum recommended daily oral dose in adults, on a mg/m2 basis). Montelukast crosses the placenta following oral dosing in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, montelukast should be used during pregnancy only if clearly needed. Nursing Mothers Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when montelukast is given to a nursing mother. Pediatric Use The safety and effectiveness in pediatric patients below the age of 6 years have not been established. Long-term trials evaluating the effect of chronic administration of montelukast on linear growth in pediatric patients have not been conducted. Geriatric Use Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. DRUG INTERACTIONS : Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State : did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State : did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. ADVERSE REACTIONS : Adolescents and Adults 15 Years of Age and Older Montelukast has been evaluated for safety in approximately 2600 adolescent and adult patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with montelukast occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo, regardless of causality assessment: TABLE 3 Adverse Experiences Occurring in 1% of Patients with an Incidence Greater than that in Patients Treated with Placebo, Regardless of Causality Assessment Montelukast Placebo 10 mg/day (%) (%) (n=1955) (n=1180) Body as a Whole Asthenia/fatigue 1.8 1.2 Fever 1.5 0.9 Pain, abdominal 2.9 2.5 Trauma 1.0 0.8 Digestive System Disorders Dyspepsia 2.1 1.1 Gastroenteritis, infectious 1.5 0.5 Pain, dental 1.7 1.0 Nervous System/Psychiatric Dizziness 1.9 1.4 Headache 18.4 18.1 Respiratory System Disorders Congestion, nasal 1.6 1.3 Cough 2.7 2.4 Influenza 4.2 3.9 Skin/Skin Appendages Disorder Rash 1.6 1.2 Laboratory Adverse Experiences* ALT increased 2.1 2.0 AST increased 1.6 1.2 Pyuria 1.0 0.9 * Number of patients tested (Montelukast and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159. The frequency of less common adverse events was comparable between montelukast and placebo. Cumulatively, 569 patients were treated with montelukast for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change. Pediatric Patients 6 to 14 Years of Age Montelukast has also been evaluated for safety in approximately 320 pediatric patients 6 to 14 years of age. Cumulatively, 169 pediatric patients were treated with montelukast for at least 6 months, and 121 for one year or longer in clinical trials. The safety profile of montelukast versus placebo in the double-blind, 8-week, pediatric efficacy trial was generally similar to the adult safety profile with the exception of the adverse events listed below. In pediatric patients receiving montelukast, the following events occurred with a frequency 2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: diarrhea, laryngitis, pharyngitis, nausea, otitis, sinusitis, and viral infection. The frequency of less common adverse events was comparable between montelukast and placebo. With prolonged treatment, the adverse experience profile did not significantly change. OVERDOSAGE : No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice (approximately 2000 times the maximum recommended daily oral dose in adults and 2400 times the maximum recommended daily oral dose in children, on a mg/m2 basis) and rats (approximately 4100 times the maximum recommended daily oral dose in adults and 4800 times the maximum recommended daily oral dose in children, on a mg/m2 basis). No specific information is available on the treatment of overdosage with montelukast. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for approximately a week without clinically important adverse experiences. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis. DOSAGE AND ADMINISTRATION : Adolescents and Adults 15 Years of Age and Older : The dosage for adolescents and adults 15 years of age and older is one 10-mg tablet daily to be taken in the evening. Pediatric Patients 6 to 14 Years of Age : The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet daily to be taken in the evening. No dosage adjustment within this age group is necessary. Safety and effectiveness in pediatric patients younger than 6 years of age have not been established. The safety and efficacy of montelukast was demonstrated in clinical trials where it was administered in the evening without regard to the time of food ingestion. There have been no clinical trials evaluating the relative efficacy of morning versus evening dosing. HOW SUPPLIED : Singulair tablets, 5 mg, are pink, round, biconvex-shaped chewable tablets, with code MRK 275 on one side and Singulair on the other. Singulair tablets, 10 mg, are beige, rounded square-shaped, film-coated tablets, with code MRK 117 on one side and Singulair on the other. Storage : Store at room temperature 15-30°C (59-86°F), protected from moisture and light.