SINGULAIR (montelukast sodium) is a selective and orally active leukotriene receptor antagonist that specifically inhibits the cysteinyl leukotriene CysLT1
Montelukast causes potent inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4
in asthmatic patients. Doses as low as 5 mg cause substantial blockage of LTD4
Montelukast causes bronchodilation within 2 hours of oral administration; these effects were additive to the bronchodilation caused by a β-agonist.
Clinical studies in adults 15 years of age and older demonstrated that there is no additional clinical benefit to montelukast doses above 10 mg once daily. This was shown in two chronic asthma studies 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.
Mechanism of Action:
The cysteinyl leukotrienes (LTC4
), are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1
) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include a number of airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment.
Montelukast is a potent, orally active compound that significantly improves parameters of asthmatic inflammation. Based on biochemical and pharmacological bioassays, it binds with high affinity and selectivity to the CysLT1
receptor (in preference to other pharmacologically important airway receptors such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast potently inhibits physiologic actions of LTC4
, and LTE4
at the CysLT1
receptor without any agonist activity.
Clinical Studies: Adults ≥15 years:
The efficacy of Singulair for the chronic treatment of asthma in adults ≥15 years was demonstrated in 2 (US and Multinational) similarly designed 12-week double-blind, placebo-controlled studies in 1325 patients (795 treated with Singulair and 530 treated with placebo). Patients were symptomatic and using approximately 5 puffs of β-agonist per day on an "as-needed" basis. The mean baseline percent of predicted forced expiratory volume in 1 sec (FEV1
,) was 66% (approximate range 40-90%). In these studies, asthma symptoms, asthma-related outcomes, respiratory function and "as-needed" β-agonist use were measured. Endpoints were analyzed in each study and in a combined analysis according to a prespecified data analysis plan. The following clinical results were observed:
Asthma Symptoms and Asthma-Related Outcomes:
Singulair 10 mg once daily in the evening, significantly improved measurements of patient-reported daytime symptoms and night time awakenings in each study and in the combined analysis, compared with placebo. In patients with nocturnal awakenings of at least 2 nights per week, reduced the nocturnal awakenings by 34% from baseline, significantly better than the reduction of 14% for the placebo group (combined analysis). Singulair, compared with placebo, significantly improved asthma-related outcome measurements. In the combined analysis, Singulair compared with placebo, decreased asthma attacks by 37%, corticosteroid rescue by 39%, discontinuations due to worsening asthma by 65%, asthma exacerbations by 38% and increased asthma-free days by 42%. Physicians' and patients' global asthma evaluations and asthma-specific quality-of-life evaluations (in all domains, including normal daily activity and asthma symptoms) were significantly better with Singulair compared with placebo in each study and in the combined analysis.
Compared with placebo, Singulair caused significant improvements in parameters of respiratory function [FEV1
and peak expiratory flow rate (PEFR)] in each study and in the combined analysis (see Table 1).
Click on icon to see table/diagram/image
Compared with placebo, Singulair significantly decreased the use of "as-needed" β-agonist by 26.1% from baseline compared with 4.6% in the placebo group in the combined analysis. The decreases were also significant in each of the studies (p≤0.001).
Onset of Action and Maintenance of Benefits:
In each study and in the combined analysis, the treatment effect of Singulair measured by daily diary card parameters, including symptom scores, "as-needed" β-agonist use and PEFR measurements, was achieved after the 1st dose and was maintained throughout the dosing interval (24 hrs). Treatment effect also remained constant during continuous once-daily administration in extension studies for up to 1 year. Withdrawal of Singulair in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma (see Effects on Exercise-Induced Bronchoconstriction as follows).
Effects Relative to Inhaled Corticosteroids:
In one of the two 12-week double-blind studies in adults (Multinational), Singulair was compared with inhaled beclomethasone (200 mcg twice daily with a spacer device). Singulair demonstrated a more rapid initial response, although over the full duration of the study beclomethasone provided a greater average treatment effect. However, a high percent of patients treated with Singulair achieved similar clinical responses compared with inhaled beclomethasone.
Effects on Exercise-Induced Bronchoconstriction:
The efficacy of Singulair 10 mg when given as a single dose 2 hrs before exercise for the prevention of exercise-induced bronchospasm (EIB) was investigated in 3 (U.S. and Multinational), randomized, double-blind, placebo-controlled crossover studies that included a total of 160 adult and adolescent patients ≥15 years with EIB. Exercise challenge testing was conducted at 2 hrs, 8.5 or 12 hrs, and 24 hrs following administration of a single-dose of study drug (Singulair 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV1
following the 2 hrs post-dose exercise challenge in all 3 studies (Study A, Study B and Study C). In Study A, a single dose of Singulair 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hrs prior to exercise. Some patients were protected from EIB at 8.5 and 24 hrs after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in Table 2 and are representative of the results from the other 2 studies (see Table 2).
Click on icon to see table/diagram/image
In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics ≥15 years, with a mean baseline FEV1
percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with Singulair 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 (ie, 20-24 hrs after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. Singulair did not, however, prevent clinically significant deterioration in maximal percent fall in FEV1
after exercise (ie, ≥20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after 2 doses of Singulair 10 mg once-daily.
Effects on Asthmatic Inflammation:
Several studies have shown Singulair inhibits parameters of asthmatic inflammation. In a placebo-controlled crossover study (n=12), Singulair inhibited early and late phase bronchoconstriction due to antigen challenge by 75 and 57%, respectively.
Because inflammatory cell (eosinophil) infiltration is an important feature of asthma, the effects of Singulair on eosinophils in the peripheral blood and airway were examined. In Phase IIb/III clinical studies in adults, Singulair significantly decreased peripheral blood eosinophils approximately 15% from baseline, compared with placebo.
In a 4-week, randomized, parallel group study (n=40) in adults, Singulair significantly decreased airway eosinophils (as assessed in sputum) by 48% from baseline compared with an increase of 23% from baseline with placebo. In this study, peripheral blood eosinophils significantly decreased, and clinical asthma endpoints improved with treatment with Singulair.
Montelukast is rapidly and nearly completely absorbed following oral administration.
For the 4-mg chewable tablet, Cmax
is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.
The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. The coadministration of applesauce or a standard meal with the oral granule formulation did not have a clinically meaningful effect on the pharmacokinetics of montelukast as determined by AUC (1225.7 vs 1223.1 ng·hr/mL with and without applesauce, respectively, and 1191.8 vs 1148.5 ng·hr/mL with and without a standard meal, respectively).
Safety and efficacy were demonstrated in clinical studies where the 4-mg chewable tablet, were administered without regard to the timing of food ingestion. The safety of SINGULAIR was also demonstrated in a clinical study in which the 4-mg oral granules were administered without regard to the timing of food ingestion.
For the 10-mg film-coated tablet, the mean peak plasma concentration (Cmax
) is achieved 3 hrs time to peak plasma concentration (Tmax
) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax
are not influenced by a standard meal.
Safety and efficacy were demonstrated in clinical studies where the 10-mg film-coated tablet was administered without regard to the timing of food ingestion.
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.
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.
studies using human liver microsomes indicate that cytochrome P450 3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. 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.
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 montelukast and its metabolites are excreted almost exclusively via
In several studies, the mean plasma half-life (t½
) of montelukast ranged from 2.7-5.5 hrs in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. No difference in pharmacokinetics was noted between dosing in the morning or in the evening. During once-daily dosing with montelukast 10 mg, there is little accumulation of the parent drug in plasma (approximately 14%).
Characteristics in Patients:
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 t½
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. In clinical studies, there do not appear to be any differences in clinically important effects.
Hepatic Insufficiency: No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score >9).
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: The plasma concentration profile of montelukast following administration of the 10-mg film-coated tablet is similar in adolescents ≥15 years old and young adults. The 10-mg film-coated tablet is recommended for use in patients ≥15 years old.
Pediatric Patients: Pharmacokinetic studies show that the plasma profiles of the 4-mg chewable tablet in pediatric patients 2 to 5 years of age, were similar to the plasma profile of the 10-mg film-coated tablet in adults. 4-mg chewable tablet in pediatric patients 2 to 5 years of age. Since the 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet, it can also be used as an alternative formulation to the 4-mg chewable tablet in pediatric patients 2 to 5 years of age.
Drug Interactions: Montelukast 10 mg once daily to pharmacokinetic steady state: did not cause clinically significant changes in the kinetics of an intravenous dose of theophylline; did not change the pharmacokinetic profile of warfarin or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or International Normalized Ratio (INR); did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the plasma concentration profile of terfenadine or 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 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 µg; did not cause any clinically significant change in plasma profiles of either prednisone and 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 SINGULAIR is recommended (see Precautions).
Toxicology: Animal Toxicology:
Acute Toxicity: No mortality occurred following a single oral administration of montelukast sodium at doses up to 5000 mg/kg, in mice and rats, (15,000 mg/m2
and 29,500 mg/m2
in mice and rats, respectively) the maximum dose tested (oral LD50
>5000 mg/kg). This dose is equivalent to 25,000 times the recommended daily adult human dose*.
Chronic Toxicity: The toxic potential of montelukast sodium was evaluated in a series of repeated dose toxicity studies of up to 53 weeks in monkeys and rats and up to 14 weeks in infant monkeys and in mice. Montelukast sodium was well tolerated at doses which provide a wide margin of safety based on total dose administered. The no effect level for all toxicological parameters in any of the species tested was at least 125 times the recommended human dose*. There were no findings that would preclude administration at the therapeutic dosage level for both adults and pediatric patients.
Carcinogenicity: Montelukast sodium was not carcinogenic when administered at oral doses of up to 200 mg/kg/day in a 106-week study in rats, or at oral doses of up to 100 mg/kg/day in a 92-week study in mice. These doses are equivalent to 1000 times and 500 times the recommended adult human dose*.
Mutagenesis: Montelukast sodium was found to be neither genotoxic nor mutagenic. Montelukast sodium was negative in the in vitro
microbial mutagenesis assay and the V-79 mammalian cell mutagenesis assays, with and without metabolic activation. There was no evidence of genotoxicity in the in vitro
alkaline elution assay in rat hepatocytes and the in vitro
chromosomal aberration assays in Chinese hamster ovary cells, with or without a microsomal enzyme activation system. Similarly, there was no induction of chromosomal aberrations in bone marrow cells of male or female mice after the administration of oral doses of up to 1200 mg/kg (3600 mg/m2
) (6000 times the recommended daily adult dose*).
Reproduction: Fertility and reproductive performance were not affected in studies with male rats given oral doses of up to 800 mg/kg/day or with female rats given doses of up to 100 mg/kg/day. These dosages provide margins of 4000-fold and 500-fold, respectively, above the recommended adult human dose*.
*Based on an adult patient weight of 50 kg.
Development: In developmental toxicity studies, there were no treatment related adverse effects at doses up to 400 mg/kg/day in rats and up to 100 mg/kg/day in rabbits. Fetal exposure of montelukast sodium in rats and rabbits does occur and significant concentrations of drug were observed in milk of lactating rats.