, Volume 59, Issue 4, pp 891-928
Date: 27 Nov 2012

Montelukast

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Summary

Abstract

Montelukast is a cysteinyl leukotriene receptor antagonist used to treat persistent asthma in patients aged ≥6 years.

The drug has a rapid onset of action. Improvements in lung function and reductions in as-needed β2-agonist usage are apparent within 1 day of initiating montelukast treatment in adults and adolescents (aged ≥15 years treated with 10 mg/day) or children (aged 6 to 14 years treated with 5 mg/day) with persistent asthma as shown in clinical trials.

In two 12-week, multicentre, randomised, double-blind studies in adults and adolescents aged ≥15 years with persistent asthma [forced expiratory volume in 1 second (FEV1) = 50 to 85% predicted] there was significantly (p ≤ 0.05) greater improvement in FEV1, symptom scores, peak expiratory flow (PEF), as-needed β2-agonist use, peripheral eosinophil counts and health-related quality of life (QOL) in patients treated with montelukast 10 mg/day than in recipients of placebo. Improvements were significantly greater in patients treated with inhaled beclomethasone 400 μg/day than in recipients of montelukast 10 mg/day in 1 of these studies. Nonetheless, 42% of montelukast recipients experienced ≥11% improvement in FEV1, the median improvement in this parameter in beclomethasone-treated patients.

In an 8-week multicentre, randomised, double-blind, study in children aged 6 to 14 years with persistent asthma (FEV1 50 to 85% predicted), montelukast 5 mg/day produced significantly greater improvements in FEV1, clinic PEF, as-needed β2-agonist use, peripheral eosinophil counts, asthma exacerbations and QOL scores than placebo.

The combination of montelukast 10 mg/day plus inhaled beclomethasone 200μg twice daily provided significantly better asthma control than inhaled beclomethasone 200μg twice daily in adults with poorly controlled asthma (mean FEV1 = 72% predicted) despite 4 weeks treatment with inhaled beclomethasone. Patients receiving the combination experienced significant improvements in FEV1 and morning PEF, significant reductions in daytime symptom scores, as-needed β2 agonist usage and night-time awakenings with asthma, and had significantly lower peripheral blood eosinophil counts after 16 weeks in this multicentre, randomised, double-blind, placebo-controlled study.

Among adults (FEV1 ≥70%) treated with montelukast 10 mg/day for 12 weeks, inhaled corticosteroid dosages were titrated downward by 47% (vs 30% in placebo recipients), 40% of patients were tapered off of inhaled corticosteroids (vs 29%), and significantly fewer patients (16 vs 30%) experienced failed corticosteroid rescues in a multicentre, randomised, double-blind study.

During clinical studies, the frequency of adverse events in montelukast-treated adults, adolescents and children was similar to that in placebo recipients.

In conclusion, montelukast is well tolerated and effective in adults and children aged ≥6 years with persistent asthma including those with exercise-induced bronchoconstriction and/or aspirin sensitivity. Furthermore, montelukast has glucocorticoid sparing properties. Hence, montelukast, as monotherapy in patients with mild persistent asthma, or as an adjunct to inhaled corticosteroids is useful across a broad spectrum of patients with persistent asthma.

Pharmacodynamic Properties

Cysteinyl leukotrienes [leukotriene C4 (LTC4), D4 (LTD4) and E4 (LTE4)] are important pro-inflammatory mediators in asthma. Montelukast is a competitive antagonist of these substances at the cysteinyl leukotriene type 1 (cysLT1) receptor. The affinity of montelukast (50% inhibitory concentration = ≥2.3 nmol/L) for the cloned human cysLT1 receptor was 2.5 to 5-fold lower than that of LTD4 and was generally similar to that of other commercially available cysLT1 receptor antagonists.

Montelukast 5 mg/day for ≥2 weeks reduced nitric oxide levels in exhaled air, a marker of inflammation, by ≥20% in children with mild asthma.

Peripheral blood eosinophil levels were significantly reduced from baseline in adult and paediatric patients treated with clinically relevant dosages of montelukast for ≥4 weeks.

Over a broad dose range (5 to 250mg), and at both peak and trough plasma concentrations, montelukast inhibited acute LTD4-induced bronchoconstriction in patients with asthma. Moreover, the onset of the antagonist effect of montelukast was readily apparent after absorption of a single dose.

Significant improvements in FEV1 were noted within 15 minutes of administration of montelukast 7mg intravenously.

Single oral doses of montelukast 100 or 250mg produced significant improvements in forced expiratory volume in 1 second (FEV1) within 1 hour of drug administration in patients with asthma including those receiving ongoing inhaled corticosteroids. Importantly, these improvements did not preclude a bronchodilator response to inhaled salbutamol (albuterol).

After 2 doses, montelukast 10 mg/day provided a significant protective effect against both early (EAR) and late asthmatic responses (LAR) in patients with mild asthma (FEV1 = 79 to 109% predicted) after allergen challenge in a double-blind, placebo-controlled, crossover study.

Montelukast reduced the deterioration in lung function after a standard exercise challenge (6-minute treadmill test) in patients with persistent asthma and exercise-induced bronchoconstriction treated for 8 or 12 weeks in well-designed trials. There was no evidence of tolerance to the protective effects of montelukast 10 mg/day, which were apparent within 3 days, in patients with exercise-induced bronchoconstriction. However, in patients treated with inhaled salmeterol 42μg twice daily, tolerance became apparent after an initial favourable response.

The frequency of as-needed β2-agonist usage after exercise challenge was significantly lower among patients treated with montelukast than placebo or salmeterol.

In children aged 6 to 14 years with exercise-induced bronchoconstriction, montelukast 5 mg/day for 2 days had similar protective effects to those achieved to those achieved in adults with 10 mg/day.

Pharmacokinetic Properties

After oral administration, approximately 64% of a 10mg dose of montelukast is absorbed, and maximum plasma concentrations are achieved within 3 to 4 hours. Steady state plasma concentrations are achieved on the second day of administration in volunteers. Montelukast is eliminated primarily by biliary excretion and hepatic oxidative metabolism. Oxidative metabolism of montelukast was attributed to cytochrome P450 isozymes (CYP3A4 and CYP2C9).

The pharmacokinetics of oral montelukast 10mg were generally similar in elderly volunteers (aged ≥65 years) and younger adults (aged 20 to 45 years).

In children aged 6 to 14 years, a 5mg dose administered as a chewable tablet provided similar systemic exposure to that obtained in adults after a 10mg dose.

Montelukast appears to have a low potential for drug-drug interactions. No pharmacokinetic drug-drug interactions were evident in patients receiving clinically significant doses of montelukast (10 mg/day) and warfarin, digoxin, terfenadine, fexofenadine, combined oral contraceptives, theophylline, prednisone or prednisolone.

Phenobarbital appeared to increase the metabolism of montelukast; however, dosage adjustments are not warranted in patients receiving this combination.

Therapeutic Potential in Patients With Persistent Asthma

Montelukast has been evaluated in randomised, placebo-controlled studies in adults, adolescents and children with persistent asthma. The drug was administered in the evening in all clinical trials.

In multicentre randomised, double-blind, placebo-controlled trials of 8 or 12 weeks’ duration in adults (aged ≥15 years) or children (aged 5 to 14 years) montelukast had a rapid onset of action (i.e. within 1 day).

In Adults

Adult patients with persistent asthma (FEV1 = 50 to 85% predicted) received montelukast 10 mg/day or placebo (n = 681) in 1 study, and montelukast 10 mg/day, inhaled beclomethasone 400 μg/day or placebo in another trial (n = 895). After 12 weeks of treatment in both studies, significant improvements in all outcome variables (FEV1, daytime symptom scores, morning and evening peak expiratory flow rate (PEF), frequency of as-needed β2-agonist usage, frequency of nocturnal awakenings, health-related quality of life scores and peripheral eosinophil counts) were obtained in montelukast- or inhaled beclomethasone-treated patients, but not in recipients of placebo. Improvements with inhaled beclomethasone were significantly greater than with montelukast. Recipients of montelukast or inhaled beclomethasone experienced significantly more asthma control days and significantly fewer asthma exacerbation days than placebo recipients in these trials.

The combination of montelukast 10 mg/day plus inhaled beclomethasone 200μg twice daily provided significantly better asthma control than inhaled beclomethasone 200μg twice daily in patients with poorly controlled asthma (mean FEV1 = 72% predicted, n = 642) despite 4 weeks treatment with inhaled beclomethasone. Patients were randomised to 1 of 4 double-blind treatments (montelukast 10mg daily plus inhaled placebo, inhaled beclomethasone 200μgtwice daily plus oral placebo, montelukast plus beclomethasone, or oral and inhaled placebos) in the study. When compared with patients continuing on inhaled beclomethasone alone, patients receiving the combination experienced significant improvements in FEV1 and morning PEF, significant reductions in daytime symptom scores, as-needed β2 agonist usage and night-time awakenings with asthma, and had significantly lower peripheral blood eosinophil counts after 16 weeks. Asthma control generally deteriorated in patients assigned to placebo and the frequency of discontinuation from the study because of worsening asthma was 15, 11.4, 4 and 1%, respectively, among patients who received placebo, montelukast, inhaled beclomethasone or the 2 drugs combined. These findings indicate that montelukast is not suitable for monotherapy in patients with moderate or severe persistent asthma.

Montelukast 10 mg/day allowed for significant reductions in inhaled cortico-steroid dosages in patients with persistent asthma receiving ongoing treatment with inhaled corticosteroids. Between the start of treatment and the end of a randomised, double-blind, 12-week study, the mean daily dosage of inhaled corticosteroid was decreased by 47 and 30% in patients treated with montelukast or placebo, respectively. A higher proportion of montelukast (40%) than placebo recipients (29%) were successfully tapered off of inhaled corticosteroids and significantly fewer patients discontinued montelukast than placebo because of failed corticosteroid rescues (16 vs 30%).

Montelukast 10 mg/day plus loratadine 20 mg/day produced significantly greater improvements in FEV1, symptom scores and β2-agonist use than montelukast plus placebo in a 2-week, randomised, crossover study in patients with mild to severe persistent asthma.

Meta-analysis of data from 4 multicentre, placebo-controlled trials demonstrated that there was no apparent differences in the magnitude of improvement in clinical end-points between patients with or without a history of allergic rhinitis after treatment with montelukast 10 mg/day.

In aspirin-sensitive adults with persistent asthma, 4 weeks’ treatment with montelukast 10 mg/day produced significant improvements in most outcome measures (i.e. FEV1, morning PEF, β2-agonist usage and nocturnal, but not daytime symptom scores) compared with placebo.

In Children

In paediatric patients aged 6 to 14 years, montelukast 5 mg/day for 8 weeks produced significant improvements in FEV1, the primary outcome variable, in a multicentre, randomised, double-blind study. Significant improvement was also obtained in many (frequency of as-needed β2-agonist use, clinic PEF, Paediatric AQLQ scores and peripheral eosinophil counts) but not all secondary outcome variables (daytime symptom scores, morning and evening PEF in patient diaries, nocturnal awakenings). Montelukast significantly reduced the frequency of days with asthma exacerbations and the proportion of patients with asthma exacerbations compared with placebo.

Among children randomised to further treatment with montelukast or inhaled beclomethasone at the end of this study the mean change from baseline in FEV1 was similar (6.47 and 6.39%) after 1.4 years of follow-up.

Four weeks of treatment with montelukast 5 mg/day was compared with inhaled sodium cromoglycate 1.6 mg four times daily in 2 randomised, crossover studies in children aged 6 to 11 years with persistent asthma. Withdrawal rates were greater during treatment with sodium cromoglycate than montelukast. ≥86% of parents and ≥79% of patients expressed a preference for montelukast. In 1 of these studies, in which adherence with inhaled sodium cromoglycate was poor compared with montelukast (45 vs 82%, respectively), as-needed β2-agonist usage was significantly lower during treatment with montelukast.

Tolerability

During clinical trials in adults or children with persistent asthma the frequencyof adverse events in montelukast-treated patients was similar to that in placebo recipients. Headache was the most frequent adverse event, reported by 18.4 and 18.1% of adult recipients of montelukast and placebo, respectively.

In paediatric patients treated for 8 weeks, diarrhoea, laryngitis, pharyngitis, nausea, otitis, sinusitis and viral infections occurred in more than 2% of patients treated with montelukast and were more prevalent in recipients of montelukast 5 mg/day than placebo.

Churg-Strauss syndrome has been reported rarely in adult patients during treatment with montelukast; however, it is unlikely that there is a causal relationship between the drug and the emergence of this condition.

Dosage and Administration

Montelukast is indicated for the treatment of persistent asthma in patients aged ≥6 years. The recommended dosage of montelukast is 10 mg/day in adults and adolescents aged ≥15 years and 5 mg/day in children aged 6 to 14 years. The drug is administered in the evening with or without food. Dosage adjustments are not required in elderly patients or in those with renal or mild to moderate hepatic dysfunction.

Various sections of the manuscript reviewed by: N.C. Barnes, The Royal Hospitals NHS Trust, Department of Respiratory Medicine, The London Chest Hospital, London, England; P.J. Barnes, Department of Thoracic Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, London, England; E. Bateman, University of Cape Town and Respiratory Clinic Groote Schuur Hospital, Cape Town, South Africa; A. Becker, Section of Allergy and Clinical Immunology, Children’s Hospital of Winnipeg, Winnipeg, Manitoba, Canada; Z. Diamant, Department of Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands; P.H. Godard, Hopital Universitaire Aiguelongue, Montpellier, France; J.P. Kemp, Allergy and Asthma Medical Group and Research Center, San Diego, California, USA; G.G. Shapiro, A.S.T.H.M.A., Inc., Northwest Asthma and Allergy Center, Seattle, Washington, USA; R.G. Stirling, Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, England.

Data Selection

Sources: Medical literature published in any language since 1966 on montelukast, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: AdisBase, Medline and EMBASE search terms were ‘montelukast’, ‘MK-476’, ‘MK-0476’, ‘L-706631’, ‘Singulair’ and ‘asthma’. Searches were last updated 20 Mar 2000.
Selection: Studies in patients with asthma who received montelukast. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Asthma, montelukast, pharmacodynamics, pharmacokinetics, therapeutic use.