Montelukast is used in the management of asthma and for the prevention of exercise-induced bronchospasm. Montelukast is also used for the symptomatic treatment of seasonal or perennial allergic rhinitis and has been evaluated for the management of urticaria.
Montelukast is used for the prevention and long-term symptomatic management of asthma.
Montelukast is not a bronchodilator and should not be used to relieve symptoms of acute asthma, including status asthmaticus; however, therapy with the drug can be continued during acute asthmatic attacks. All patients receiving montelukast should be provided with a short-acting, orally inhaled β2-adrenergic agonist (e.g., albuterol) to use as supplemental therapy for acute symptoms that may occur despite montelukast therapy. Patients receiving montelukast should be cautioned not to decrease the dose of, or discontinue therapy with, other antiasthmatic agents unless instructed to do so by a clinician.
Mild Persistent Asthma
Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma). When control of symptoms deteriorates in patients with intermittent asthma and symptoms become persistent (e.g., daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), current asthma management guidelines and most clinicians recommend initiation of an anti-inflammatory agent, preferably with a low-dose orally inhaled corticosteroid (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma, supplemented by as-needed use of a short-acting, inhaled β2-agonist. Alternatives to low-dose inhaled corticosteroids for mild persistent asthma include certain leukotriene modifiers (i.e., montelukast, zafirlukast), extended-release theophylline (in adults and children 5 years of age or older), or mast-cell stabilizers (e.g., cromolyn, nedocromil [preparation for oral inhalation no longer commercially available in the US]), but these agents are less effective and generally not preferred as initial therapy. Limited evidence suggests that montelukast may be considered for maintenance therapy in young children with mild persistent asthma when inhaled corticosteroid delivery is suboptimal as a result of poor technique or adherence.
Moderate Persistent Asthma
According to current asthma medication guidelines, therapy with a long-acting inhaled β2-agonist such as salmeterol or formoterol generally is recommended in adults and adolescents who have moderate persistent asthma and daily asthmatic symptoms that are inadequately controlled following addition of low-dose inhaled corticosteroids to as-needed inhaled β2-agonist treatment. However, the National Asthma Education and Prevention Program recommends that the beneficial effects of long-acting inhaled β2-agonists should be weighed carefully against the increased risk (although uncommon) of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.
Current asthma management guidelines also state that an alternative, but equally preferred option for management of moderate persistent asthma that is not adequately controlled with a low dosage of inhaled corticosteroid is to increase the maintenance dosage to a medium dosage (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adults and adolescents). Alternative less effective therapies that may be added to a low dosage of an inhaled corticosteroid include oral extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast). Considerations favoring these leukotriene modifiers in combination with orally inhaled corticosteroids include intolerance to long-acting β2-adrenergic agonists, marked preference for oral therapy, and demonstration of superior responsiveness to these leukotriene modifiers. Limited data are available in infants and children 11 years of age or younger with moderate persistent asthma, and recommendations of care are based on expert opinion and extrapolation from studies in adults. According to current asthma management guidelines, a long-acting inhaled β2-agonist (e.g., salmeterol, formoterol), a leukotriene modifier (i.e., montelukast, zafirlukast), or extended-release theophylline (with appropriate monitoring) may be added to low-dose inhaled corticosteroid therapy in children 5-11 years of age. Because comparative data establishing relative efficacy of these agents in this age group are lacking, there is no clearly preferred agent for use as adjunctive therapy with a low-dose inhaled corticosteroid for treatment of asthma in these children.
Severe Persistent Asthma
Maintenance therapy with an inhaled corticosteroid at medium (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate in adults and adolescents or 176 but not more than 352 mcg of the drug [or its equivalent] in children 5-11 years of age daily via a metered-dose inhaler) or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg of the drug [or its equivalent] in children 5-11 years of age daily via a metered-dose inhaler) and adjunctive therapy with a long-acting inhaled β2-agonist is the preferred treatment according to current asthma management guidelines in adults and children 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week). Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in older children and adults. Alternatives to a long-acting inhaled β2-agonist for severe persistent asthma in adults and children 5 years of age or older receiving medium-dose inhaled corticosteroids include certain leukotriene modifiers (i.e., montelukast, zafirlukast) or extended-release theophylline, but these therapies are generally not preferred. Omalizumab may be considered in adults and adolescents with severe persistent asthma with an allergic component who are inadequately controlled with high-dose inhaled corticosteroids and a long-acting β2-agonist. In infants and children 4 years of age or younger with severe asthma, maintenance therapy with an inhaled corticosteroid at medium (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) or high dosages (e.g., exceeding 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with either a long-acting inhaled β2-agonist or montelukast is the only preferred treatment according to current asthma management guidelines. Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in adolescents and adults. For additional details on the stepped-care approach to drug therapy in asthma, and .
Clinical Experience with Leukotriene Modifiers
While efficacy of montelukast in the management of asthma has not been directly compared with that of zafirlukast or zileuton, improvements in forced expiratory volume in 1 second (FEV1) and asthma symptoms reported with montelukast generally have been similar to those reported with zafirlukast or zileuton. For the management of mild persistent asthma, advantages of leukotriene modifiers relative to orally inhaled corticosteroids include ease of administration of an oral dosage form (and presumably improved compliance) and rapid onset of action (1 day versus a week or longer). The effects of montelukast appear to be additive with those of orally inhaled corticosteroids, and such combination therapy may improve asthma control in patients with moderate to severe asthma. In addition, montelukast therapy reduces the requirements for long-term inhaled corticosteroids in stable patients. Leukotriene modifiers may be especially useful in children and adults in whom disadvantages of using, continuing, or increasing the dose of orally inhaled corticosteroids have been identified. Additional clinical settings where therapy with a leukotriene modifier may be especially useful include patients with aspirin-induced asthma, exercise-induced bronchospasm (e.g., children who want to exercise at school without having to use an orally inhaled β2-adrenergic agonist, those whose jobs require exercise under atmospheric conditions likely to induce an asthmatic episode), nocturnal asthma, acute allergen-induced asthma, or coexisting allergic rhinitis. Conversely, because leukotrienes do not play a major role in asthma pathology in patients with naturally occurring mutations in the 5-lipoxygenase gene, such patients are unlikely to respond to therapy with leukotriene modifiers.
Current data indicate that leukotriene modifiers such as montelukast generally produce modest improvements in lung function, diminish asthma symptoms, and decrease the need for supplemental, short-acting β2-adrenergic agonist therapy in patients with mild to moderate persistent asthma. However, not all patients receiving leukotriene modifiers have substantial clinical improvement. While patients with aspirin-sensitive asthma generally respond to leukotriene modifiers, it currently is not possible to identify patients most likely to benefit from such therapy.
Clinical Efficacy of Montelukast
Efficacy of montelukast has been established in 2 clinical trials in adults and adolescents 15 years of age or older with mild to moderate intermittent or persistent asthma (i.e., a baseline FEV1 averaging 66% of the predicted normal value and an inhaled, short-acting β2-adrenergic agonist requirement averaging 5 puffs daily) who generally received montelukast for 12 weeks. Efficacy of montelukast also has been established in a clinical trial in children 6-14 years of age with mild to moderate intermittent or persistent asthma (i.e., a baseline FEV1 averaging 72% of the predicted normal value and an inhaled, short-acting β2-adrenergic agonist requirement averaging 3 or 4 puffs daily) who generally received montelukast for 8 weeks. Approximately 77-95% of children, adolescents, and adults enrolled in these studies had a history of exercise-induced bronchospasm, and 61-96% had a history of allergic rhinitis. In these clinical trials, adults and pediatric patients received montelukast once daily in the evening; evening administration was selected to provide high montelukast plasma concentrations in the early morning, the time of maximal airway narrowing. In these trials, montelukast was more effective than placebo in alleviating respiratory symptoms (i.e., daytime asthma symptoms, nighttime awakenings), improving pulmonary function (as measured by FEV1 and peak expiratory flow rate [PEFR]), and reducing the need for supplemental therapy with an orally inhaled β2-adrenergic agonist. The therapeutic effects of montelukast are evident after the first dose and persist for at least 24 hours.
Studies to date indicate that tolerance to montelukast does not occur and the therapeutic effect has been maintained for over 2.5 years in patients 15 years of age or older and at least 1.5 years in children 6-14 years of age. Discontinuance of long-term (i.e., 12 weeks) montelukast therapy is not associated with rebound deterioration in asthma symptoms. Efficacy of montelukast in the management of asthma in children 2-5 years of age is supported by evidence from studies in adults, adolescents, and children 6-14 years of age, the similar pathophysiology of asthma and the drug's effect in these populations, and data regarding the pharmacokinetics of montelukast in these patients.
Montelukast has been evaluated for the management of asthma in 2 randomized, controlled studies (the US study, the multinational study) that included 1576 patients 15 years of age or older with mild to moderate asthma who were allowed to receive an orally inhaled β2-adrenergic agonist on an as-needed basis. Patients in the US study were randomized to receive montelukast 10 mg daily or placebo; about 23% of these patients also received an orally inhaled corticosteroid on a routine basis. Patients in the multinational study were randomized to receive montelukast 10 mg daily, placebo, or active control (i.e., orally inhaled beclomethasone dipropionate 200 mcg [dose expressed as amount of drug released during actuation from the valve stem] twice daily). In these studies, therapy with montelukast was associated with greater improvement than placebo in daytime asthma symptom scores, fewer nighttime awakenings per week, and improvement in other asthma-related outcomes. Compared with baseline values, reductions in asthma symptom scores (on a scale of 0-6) averaged 0.45 or 0.22 for montelukast or placebo, respectively; nighttime awakenings per week were reduced by 1.84 or 0.79, respectively. Montelukast produced modest improvements in pulmonary function compared with baseline values in this study, with increases in FEV1, morning PEFR, and evening PEFR averaging 0.32 L, 24.5 L/minute, and 17.9 L/minute, respectively. In the US study, montelukast produced improvements in FEV1 of 13.1% versus 4.2% with placebo. Montelukast therapy also enabled a reduction averaging about 1.56 puffs/day in the use of supplemental orally inhaled β2-adrenergic agonist.
Therapy with montelukast in these studies was associated with a reduction in the number of patients experiencing an acute asthma episode (11.6% versus 18.4%), number of patients requiring oral corticosteroid rescue (10.7% versus 17.5%), fewer days with exacerbations (12.8% versus 20.5%), more days without symptoms (38.5% versus 27.2%), and greater improvement in physician and patient global evaluation scores than placebo. In the US study, the clinical effects of montelukast were not affected by gender, age, race, history of exercise-induced bronchoconstriction, history of allergic rhinitis, or concomitant use of orally inhaled corticosteroids. In patients 15 years of age and older, montelukast dosages exceeding 10 mg daily are not associated with additional clinical benefit.
In the multinational study, orally inhaled beclomethasone dipropionate 200 mcg (dose expressed as amount of drug released during actuation from the valve stem) twice daily was more effective in the management of asthma than montelukast. In patients 15 years of age or older, improvements in FEV1 reported with inhaled beclomethasone (13.3% versus 7.49%) and decreases in asthma symptom scores (0.7 versus 0.49) generally have been greater than those reported with montelukast.
In a randomized, placebo-controlled study in 336 children 6-14 years of age or older with mild to moderate asthma who were allowed to receive an orally inhaled β2-adrenergic agonist on an as-needed basis (36% also received an orally inhaled corticosteroid on a routine basis), therapy with montelukast 5 mg (chewable tablet) daily produced modest improvements in pulmonary function compared with baseline values, with increases in FEV1 and morning PEFR (determined in clinic setting) averaging 0.16 L and 27.85 L/minute, respectively. Montelukast produced improvements in FEV1 of 8.7% versus 8.2% with placebo. Montelukast therapy also enabled a reduction averaging about 0.56 puffs daily in the use of supplemental orally inhaled β2-adrenergic agonists. Therapy with montelukast and intermittent use of an orally inhaled β2-adrenergic agonist (with or without an orally inhaled corticosteroid) was associated with fewer days with asthma exacerbations (20.6% versus 25.7%) and greater improvement in clinician and parent global evaluation scores than intermittent use of a β2-adrenergic agonist (with or without an orally inhaled corticosteroid). Subgroup analysis indicates that improvement in FEV1 in children 6-11 years of age (7.7%) was essentially the same as in children 12-14 years of age (9.8%). In this study, the effects of montelukast on FEV1 and as-needed inhaled β2-adrenergic agonist use were not affected by gender, race, Tanner stage, history of allergic rhinitis, history of exercise-induced bronchospasm, or use of orally inhaled corticosteroids.
Montelukast has been evaluated for the management of asthma in children 2-5 years of age with mild persistent asthma. In a randomized, double-blind, placebo-controlled study, children received either montelukast 4 mg (as a chewable tablet) or placebo daily; about 27-29% of these patients also were receiving an orally inhaled corticosteroid on a routine basis. Patients were allowed to receive an orally inhaled β2-adrenergic agonist on an as-needed basis. The primary end point was determination of the safety profile of montelukast, and secondary end points evaluated asthma control. In this study, therapy with montelukast was associated with improvement in daytime asthma symptom scores, days without symptoms, and days requiring β-adrenergic agonist use. Therapy with montelukast also was associated with a reduction in the number of patients requiring oral corticosteroid rescue.
Concomitant Corticosteroid Therapy
The role of montelukast as a corticosteroid-sparing agent in patients receiving orally inhaled corticosteroids has been evaluated in asthmatic adults. In one study in adults with stable asthma (a baseline FEV1 averaging 84% of the predicted normal value), addition of montelukast to therapy with orally inhaled corticosteroids allowed a reduction in inhaled corticosteroid use while maintaining adequate asthma control. In this study, inhaled corticosteroids (i.e., metered-dose aerosol or dry powder for oral inhalation) used and their mean baseline requirement (dosage may not be expressed as dosage delivered from the mouthpiece) include beclomethasone dipropionate (1203 mcg/day), triamcinolone acetonide (2004 mcg/day), fluticasone propionate (1083 mcg/day), and budesonide (1192 mcg/day). Prior to study initiation, the dosage of orally inhaled corticosteroid was reduced to the lowest effective dosage, a reduction of 37%. An additional 47 or 30% reduction in corticosteroid dosage was reported in patients receiving montelukast or placebo for 12 weeks. In addition, about 40 or 29% of patients receiving montelukast or placebo reportedly were no longer receiving orally inhaled corticosteroids at study conclusion. Whether results of this study are applicable to patients who are maintained on higher doses of orally inhaled corticosteroids or systemic corticosteroid therapy remains to be determined.
Montelukast has been evaluated for use in combination with orally inhaled corticosteroids in asthmatic adults whose symptoms were not controlled by 336 mcg/day of beclomethasone dipropionate. Patients were randomized to receive combined therapy with beclomethasone and montelukast, beclomethasone alone, montelukast alone (beclomethasone withdrawn), or placebo (beclomethasone withdrawn). Treatment with beclomethasone and montelukast was more effective in improving pulmonary function (as measured by FEV1) than therapy with beclomethasone alone, montelukast alone, or placebo. In addition, beclomethasone alone was more effective than montelukast alone in alleviating respiratory symptoms (i.e., daytime asthma symptoms, nighttime awakenings), improving pulmonary function (as measured by FEV1 and PEFR), and reducing the need for supplemental therapy with an orally inhaled β2-adrenergic agonist. While combined therapy with orally inhaled corticosteroids and montelukast may improve asthma control in patients not adequately controlled with orally inhaled corticosteroids alone, substitution of montelukast for orally inhaled corticosteroids is not likely to result in improved asthma control in these patients. The relative merits of adding montelukast to a regimen of orally inhaled corticosteroids in patients whose symptoms are inadequately controlled versus doubling the dose of the orally inhaled corticosteroid remain to be determined.
In adults with documented aspirin sensitivity who were receiving orally inhaled and/or systemic corticosteroids, addition of montelukast improved asthma control compared with placebo. The magnitude of the effect of montelukast in aspirin-sensitive patients was similar to that observed in the general population of asthma patients enrolled in clinical trials. Montelukast-treated patients with aspirin sensitivity should avoid aspirin or nonsteroidal anti-inflammatory agents (NSAIAs) since montelukast has not been shown to truncate the bronchoconstrictor response to aspirin or other NSAIAs in aspirin-sensitive patients.
Montelukast is used for the prevention of exercise-induced bronchospasm. In adults and adolescents 15 years of age or older with a FEV1 averaging 83% of the predicted normal value and exercise-induced exacerbation of asthma, montelukast (10 mg daily 20-24 hours prior to exercise) reduced the mean maximal fall in FEV1 and time to recovery compared with placebo. In this study, the response to montelukast was similar after 4, 8, and 12 weeks; however, not all patients responded to montelukast. Montelukast did not prevent clinically important deterioration in the maximal fall in FEV1 after exercise (i.e., a 20% or greater decrease from baseline [before exercise]) in 52% of patients. While about 23% of patients experienced complete protection (i.e., a decrease in FEV1 of less than 10% after exercise), 25% had little or no response (i.e., decrease in FEV1 of more than 30% after exercise). Additional placebo-controlled, crossover studies in adults and in children 6-14 years of age with exercise-induced bronchospasm have reported similar results.
Results of 2 randomized, controlled studies in adults (15-46 years of age) with exercise-induced bronchospasm indicate that the bronchoprotective effect of montelukast is similar to that of salmeterol. Efficacy of montelukast in exercise-induced bronchoconstriction versus other therapies (e.g., orally inhaled albuterol, cromolyn sodium, or nedocromil [preparation for oral inhalation no longer commercially available in the US]) has not been established.
Advantages of montelukast for the management of exercise-induced bronchospasm compared with some other therapies (e.g., orally inhaled albuterol, cromolyn sodium, nedocromil [no longer commercially available in the US]) include oral administration and a protective effect that persists for 20-24 hours. While leukotriene modifiers are not included as first-line agents or as alternative agents to orally inhaled β2-adrenergic agonists for the prevention or treatment of exercise-induced bronchoconstriction in current guidelines, current evidence supports their bronchoprotective efficacy, and the addition of montelukast may provide an additional measure of control in patients currently maintained on long-term controller therapy. The National Collegiate Athletic Association, the US Olympic Committee, and the International Olympic Committee allow competitors to use leukotriene modifiers without prior approval. The manufacturer states that patients who experience exacerbations of asthma after exercise should have a short-acting orally inhaled β2-adrenergic agonist available for rescue. Daily administration of montelukast for the chronic treatment of asthma has not been established to prevent acute episodes of exercise-induced bronchospasm.
Montelukast is used for the symptomatic treatment of seasonal or perennial allergic rhinitis. Montelukast has been evaluated in a number of placebo-controlled or comparative trials with loratadine or cetirizine for the treatment of seasonal or perennial allergic rhinitis in patients 15-82 years of age. Therapy with montelukast generally has been associated with modest improvement in rhinitis end points (scores evaluating nasal congestion, nasal itching, rhinorrhea, nasal pruritus, sneezing) compared with placebo. Therapy with montelukast alone or in combination with loratadine has been associated with improved ocular manifestations, daytime nasal symptoms, nighttime symptoms, global evaluations, and quality of life compared with placebo.
Montelukast (5-20 mg daily) has been used successfully in a limited number of patients with chronic idiopathic urticaria; one retrospective analysis involving 18 patients indicated that many patients may benefit from the addition of a leukotriene modifier to existing therapy. Additional study is needed to elucidate further the role of leukotriene modifiers in the treatment of urticaria.