VA Class:RE109

ATC Class:R03DC03

AHFS Class:

• Leukotriene Modifiers 48:10.24

Generic Name(s):

• Montelukast Sodium

Chemical Name:

• [ R -( E )]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl cyclopropane acetic acid sodium

Molecular Formula:

• C₃₅H₃₅ClNNaO₃S

Montelukast sodium, a synthetic leukotriene-receptor antagonist, is an antiasthmatic agent.1,2,3,4,5,6,7,8,9,10,11,12,13,14,30,31,44,45,53,54,71,105

Montelukast is used in the management of asthma and for the prevention of exercise-induced bronchospasm.1,31,40,43,45,50,51,52,53,54,55,56,57,58,59,60,69,70,77,78,105,110,119 Montelukast is also used for the symptomatic treatment of seasonal or perennial allergic rhinitis1,5,83,90,91,93 and has been evaluated for the management of urticaria†.83,87,90,91,93

Bronchospasm

Asthma

Montelukast is used for the prevention and long-term symptomatic management of asthma.1,31,40,43,45,51,53,54,55,56,57,58,59,60,69,70,105,109,110,119

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.1,53 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.1 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.1

Because of the risk of neuropsychiatric effects, the benefits and risks of montelukast treatment should be considered before prescribing the drug for patients with asthma.128,129 (See Cautions: Precautions and Contraindications.)

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).110,119 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.21,44,45,47,70,80,86,92,105,110,119 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]),44,70,80,86,87,88,91,98,99,105,110,119 but these agents are less effective and generally not preferred as initial therapy.110,119,121 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.119

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.110,119 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.119 (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects, in Salmeterol 12:12.08.12.)

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).110,119 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).110,119 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.119 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.110,119 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.110,119 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.119

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).110,119 Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in older children and adults.119 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.110,119 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.119 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.119 Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in adolescents and adults.119 For additional details on the stepped-care approach to drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12 and see Asthma under Uses: Respiratory Diseases, in the Corticosteroids General Statement 68:04.

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.1,31,32,33,34,35,36,43,44,45,98,99 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).31,44,57,58,70,80,87,88,92 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.1,6,31,44,45,53,55,56,57,58,70,92 In addition, montelukast therapy reduces the requirements for long-term inhaled corticosteroids in stable patients.1,6,31,40,44,53,55,58,92 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.92 Additional clinical settings where therapy with a leukotriene modifier may be especially useful include patients with aspirin-induced asthma,44,55,56,57,58,70,92 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),55,58,92 nocturnal asthma,92 acute allergen-induced asthma,92 or coexisting allergic rhinitis.92 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.55,56,68

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.1,21,22,31,32,33,34,35,36,43,44,45,47,51,53,54,55,56,57,58,59,60,69,70 However, not all patients receiving leukotriene modifiers have substantial clinical improvement.56,57,70 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.55,56,57,70

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.1,45,69 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.1,31,51,53,56 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.31,45,69 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.1,31,45 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.1,31,45,51,53,54,56,69,70 The therapeutic effects of montelukast are evident after the first dose and persist for at least 24 hours.1,8,31,45,53,69

Studies to date indicate that tolerance to montelukast does not occur1,45,69 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.1,98 Discontinuance of long-term (i.e., 12 weeks) montelukast therapy is not associated with rebound deterioration in asthma symptoms.1,45,69 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.1

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.1,45,53,56,69 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.45 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).1,69 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.1,44,45,53,69,70 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.1,45 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.1,45,53,98 In the US study, montelukast produced improvements in FEV₁ of 13.1% versus 4.2% with placebo.45,53 Montelukast therapy also enabled a reduction averaging about 1.56 puffs/day in the use of supplemental orally inhaled β₂-adrenergic agonist.1,45,53

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.1,44,45 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.45 In patients 15 years of age and older, montelukast dosages exceeding 10 mg daily are not associated with additional clinical benefit.1,6,7,10

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.1,53,69,70 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.1,53,69

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.1,31,53 Montelukast produced improvements in FEV₁ of 8.7% versus 8.2% with placebo.1,31,51,53 Montelukast therapy also enabled a reduction averaging about 0.56 puffs daily in the use of supplemental orally inhaled β₂-adrenergic agonists.1,31 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).1,31,53 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%).1,31 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.31

Montelukast has been evaluated for the management of asthma in children 2-5 years of age with mild persistent asthma.1,109 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.109 Patients were allowed to receive an orally inhaled β₂-adrenergic agonist on an as-needed basis.1,109 The primary end point was determination of the safety profile of montelukast, and secondary end points evaluated asthma control.1,109 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.109 Therapy with montelukast also was associated with a reduction in the number of patients requiring oral corticosteroid rescue.109

Concomitant Corticosteroid Therapy

The role of montelukast as a corticosteroid-sparing agent in patients receiving orally inhaled corticosteroids has been evaluated in asthmatic adults.1,40,53 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.1,40,53 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).1,40 Prior to study initiation, the dosage of orally inhaled corticosteroid was reduced to the lowest effective dosage, a reduction of 37%.1,40 An additional 47 or 30% reduction in corticosteroid dosage was reported in patients receiving montelukast or placebo for 12 weeks.1,40,53 In addition, about 40 or 29% of patients receiving montelukast or placebo reportedly were no longer receiving orally inhaled corticosteroids at study conclusion.1,40,44 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.1

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.1,79 Patients were randomized to receive combined therapy with beclomethasone and montelukast, beclomethasone alone, montelukast alone (beclomethasone withdrawn), or placebo (beclomethasone withdrawn).1,79 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.1,79 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.1,79 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.1 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.80

In adults with documented aspirin sensitivity who were receiving orally inhaled and/or systemic corticosteroids, addition of montelukast improved asthma control compared with placebo.1,44,46,51,53 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.1 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.1

Exercise-induced Bronchospasm

Montelukast is used for the prevention of exercise-induced bronchospasm.1,48,49,50,52 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.1,48,49,50 In this study, the response to montelukast was similar after 4, 8, and 12 weeks;49,50 however, not all patients responded to montelukast.1,50 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.1 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).50

In one multinational, randomized, double-blind, placebo-controlled crossover study, efficacy of montelukast was evaluated in 64 pediatric patients 6-14 years of age with exercise-induced bronchospasm who received a single dose of montelukast 5 mg as a chewable tablet or placebo administered 2 hours before exercise.128 Exercise challenge testing was conducted at 2 and 24 hours in these patients following administration of montelukast or placebo.128 In this study, the primary end point was the mean maximum percent fall in FEV₁ following the post-dose exercise challenge at 2 hours.128 Results of the study showed that montelukast 5 mg demonstrated a substantial protective effect against exercise-induced bronchospasm in these patients compared with placebo.128 Similar results were shown for the secondary end point of mean maximum percent fall in FEV₁ following the post-dose exercise challenge at 24 hours.128 However, the protective effect of montelukast for prevention of exercise-induced bronchospasm did not persist for all patients 24 hours following administration of the drug.128

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.77,78 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.98,99

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.50,52 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,21,22,70,92,110,119 current evidence supports their bronchoprotective efficacy,1,49,50,52,77,78,92,110 and the addition of montelukast may provide an additional measure of control in patients currently maintained on long-term controller therapy.88,98,99 The National Collegiate Athletic Association, the US Olympic Committee, and the International Olympic Committee allow competitors to use leukotriene modifiers without prior approval.50 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.1,98 Daily administration of montelukast for the chronic treatment of asthma has not been established to prevent acute episodes of exercise-induced bronchospasm.1

Because of the risk of neuropsychiatric effects, the benefits and risks of montelukast treatment should be considered before prescribing the drug for patients with exercise-induced bronchospasm.128,129 (See Cautions: Precautions and Contraindications.)

Allergic Rhinitis

Montelukast is used for the symptomatic treatment of seasonal or perennial allergic rhinitis.1,87,93,111 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.1,90,111 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.1,111 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.90,111

Because the benefits of montelukast treatment may not outweigh the risks of neuropsychiatric effects in patients with allergic rhinitis, use of the drug in such patients should be reserved for those who have an inadequate response or intolerance to alternative therapies.128,129 (See Cautions: Precautions and Contraindications.)

Urticaria

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.83 Additional study is needed to elucidate further the role of leukotriene modifiers in the treatment of urticaria.83,85

Administration

In patients with asthma with or without coexisting allergic rhinitis, montelukast is administered orally as a single daily dose in the evening.1,31,45 Safety and efficacy of montelukast in the management of asthma were established in clinical trials in which the drug was administered in the evening without regard to meals in adults, adolescents, and children 2-14 years of age.1,31,45,109 Evening dosing has been employed so that achievement of peak plasma concentrations of the drug might coincide with peak airway reactivity in the morning.1,31,45 In patients with allergic rhinitis, the time of administration may be individualized to suit patient needs.1 Efficacy was demonstrated in patients with seasonal allergic rhinitis when montelukast was administered in the morning or evening without regard to food intake.1

Pharmacokinetic and clinical data support use of the 10-mg film-coated tablet of montelukast in adults and adolescents 15 years of age or older, use of the 5-mg chewable tablet in children 6-14 years of age, use of the 4-mg chewable tablet or 4-mg oral granules formulation in children 2-5 years of age, and use of the 4-mg oral granules formulation in infants and children 12-23 months of age for the treatment of asthma and in infants and children 6-23 months of age for the treatment of perennial allergic rhinitis.1,31,45

Oral granules may be administered orally alone (directly in the mouth) or mixed with 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk, or a spoonful of cold or room temperature soft food (applesauce, carrots, rice, or ice cream only); the stability of the drug when mixed with other foods has not been determined.1 Oral granules are not intended to be dissolved in any liquid other than baby formula or breast milk prior to administration.1 However, liquids may be taken subsequent to administration, and oral granules can be administered without regard to meals.1 The packet should not be opened until ready to use.1 After opening the packet of granules, patients should receive the full dose within 15 minutes; do not store the opened packet or mixtures of the drug with food, breast milk, or baby formula.1 Any unused portions should be discarded.1

Dosage

Dosage of montelukast sodium is expressed in terms of montelukast.1

Asthma

Patients should be advised that montelukast must be taken at regular intervals (i.e., daily) to be therapeutically effective.1 In addition, patients should be advised that the drug will not provide immediate symptomatic relief and should not be used for relief of acute bronchospasm; however, montelukast therapy can be continued during acute exacerbations of asthma.1 Patients should not discontinue or reduce the dosage of other antiasthmatic agents, even if they feel better as a result of initiation of montelukast therapy, unless instructed to do so by their clinician.1 No additional dosage is needed for the treatment of allergic rhinitis in patients already receiving chronic therapy for asthma.1

Adult Dosage

For the prevention and long-term symptomatic control of asthma with or without allergic rhinitis, the usual dosage of montelukast for adults and adolescents 15 years of age or older is 10 mg once daily as film-coated tablets.1,45 The pharmacokinetic profile of montelukast in geriatric adults generally is similar to that in younger adults, and the manufacturer states that dosage of the drug in geriatric patients does not need to be modified based solely on age.1

Pediatric Dosage

Adolescents 15 years of age or older may receive the usual adult dosage of montelukast of 10 mg once daily as film-coated tablets.1,45

For the prevention and long-term symptomatic control of asthma with or without allergic rhinitis, the usual dosage of montelukast for children 6-14 years of age is 5 mg once daily as chewable tablets.1,31 The usual dosage of montelukast for the prevention and long-term symptomatic control of asthma with or without allergic rhinitis in children 2-5 years of age is 4 mg once daily as chewable tablets or oral granules.1,109 The usual dosage of montelukast for the prevention and long-term symptomatic control of asthma with or without allergic rhinitis in pediatric patients 12-23 months of age is 4 mg once daily as oral granules.1

Exercise-induced Bronchospasm

For the prevention of exercise-induced bronchospasm, montelukast should be administered at least 2 hours before exercise.1 Patients already taking montelukast for another indication, including chronic asthma, should not take an additional dose of the drug to prevent exercise-induced bronchospasm.1 All patients should have a short-acting β₂-adrenergic agonist available for exacerbations of asthma that may occur after exercise despite montelukast therapy.1

Adult Dosage

For the prevention of exercise-induced bronchospasm, the usual dosage of montelukast for adults and adolescents 15 years of age or older not already taking the drug for another indication is 10 mg as a film-coated tablet administered at least 2 hours prior to exercise; an additional dose should not be taken within 24 hours of the previous dose.1 The pharmacokinetic profile of montelukast in geriatric adults generally is similar to that in younger adults, and the manufacturer states that dosage of the drug in geriatric patients does not need to be modified based solely on age.1

Pediatric Dosage

For prevention of exercise-induced bronchospasm in children 6-14 years of age not already taking the drug for another indication, the usual dosage is 5 mg as a chewable tablet administered at least 2 hours prior to exercise; an additional dose should not be taken within 24 hours of the previous dose.128 Safety and efficacy of montelukast for exercise-induced bronchospasm in patients younger than 6 years of age have not been established.128

Allergic Rhinitis

Adult Dosage

For symptomatic control of seasonal or perennial allergic rhinitis with or without asthma, the usual dosage of montelukast is 10 mg once daily as film-coated tablets.1

Pediatric Dosage

Adolescents 15 years of age or older with allergic rhinitis with or without asthma may be given 10 mg once daily as film-coated tablets.1,45

For the symptomatic control of seasonal or perennial allergic rhinitis with or without asthma, the usual dosage of montelukast for children 6-14 years of age is 5 mg once daily as chewable tablets.1 In children 2-5 years of age with seasonal or perennial allergic rhinitis with or without asthma, the usual dosage is 4 mg once daily as chewable tablets or oral granules.1 In infants and children 12-23 months of age or older with allergic rhinitis and asthma, the usual dosage of montelukast is 4 mg once daily as oral granules.1 The usual dosage of montelukast in pediatric patients 6-23 months of age with perennial allergic rhinitis is 4 mg once daily as oral granules.1

Dosage in Renal and Hepatic Impairment

Limited evidence in patients with mild to moderate hepatic impairment and clinical evidence of cirrhosis indicate that area under the plasma concentration-time curve (AUC) of montelukast is increased 41% and plasma montelukast elimination half-life is prolonged in these patients relative to patients with normal hepatic function.1 However, the manufacturer makes no specific recommendations for adjustment of montelukast dosage in patients with mild to moderate hepatic impairment.1 The pharmacokinetics of montelukast in patients with severe hepatic impairment or with hepatitis have not been evaluated.1

The manufacturer makes no specific recommendations for dosage adjustment in patients with renal impairment.1 The drug is extensively metabolized and excreted principally in feces.1

Montelukast generally is well tolerated.1,6,8,9,10,11,31,37,40,45,51,52,53,59,60,69,79 Safety of montelukast has been evaluated in adults and adolescents 15 years of age or older with asthma or allergic rhinitis, in children 2-14 years of age with allergic rhinitis, in children 12 months of age or older with asthma, and in infants 6-23 months with perennial allergic rhinitis.1,31,45 While most adults and children 2 years of age or older with asthma received montelukast in clinical trials of 12 weeks' duration, safety data also have been collected from long-term studies lasting up to 2 years.1,45 The types of adverse effects reported in long-term studies were comparable to those reported in short-term, controlled studies.1

A causal relationship between many adverse effects and montelukast has not been established.1 In clinical studies in adults and adolescents 15 years of age or older with asthma, adverse effects occurring in at least 1% of patients receiving montelukast and more frequently than with placebo included headache, influenza, abdominal pain, cough, increased serum ALT or AST concentration, dyspepsia, dizziness, asthenia/fatigue, dental pain, nasal congestion, rash, fever, infectious gastroenteritis, trauma, and pyuria, 1,45,51,53,59,60,69 and the safety profile did not change substantially over time. In studies in asthmatic children 6-14 years of age, influenza, fever, dyspepsia, diarrhea, laryngitis, pharyngitis, nausea, otitis, sinusitis, and viral infection occurred in at least 2% of patients and more frequently in those receiving montelukast than in those receiving placebo; the safety profile in these children generally was similar to that in adults and did not change substantially over time.1 In clinical studies in asthmatic children 2-5 years of age, adverse effects occurring in at least 2% of patients receiving montelukast and more frequently than with placebo included fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, otic pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis.1 In clinical studies in asthmatic children 6-23 months of age, upper respiratory tract infection, wheezing, otitis media, pharyngitis, tonsillitis, cough, and rhinitis occurred in at least 2% of patients receiving montelukast and more frequently than with placebo.1

Discontinuance of montelukast therapy was required in about 2% of adolescents and adults and 4% of children 6-14 years of age in clinical studies, principally because of exacerbation of asthma.31,45

Nervous System Effects

Headache1,10,31,45,51,60,69,79 is the most frequently reported adverse effect with montelukast, occurring in 18-19% of children 6 years of age or older, adolescents, and adults.1,31,45 Headache has been reported in at least 2% of children 2-8 years of age with asthma receiving montelukast and in at least 1% (and more frequently than with placebo) of adults and adolescents 15 years of age or older with asthma.1 Sinus headache has been reported in at least 1% of adult and adolescent patients 15 years of age or older with perennial allergic rhinitis receiving montelukast and more frequently than in those receiving placebo.1 Dizziness1 or asthenia/fatigue1,79 has occurred in about 1.8-1.9% of patients 15 years of age or older receiving the drug in clinical studies.1 Dream abnormalities,1,125 hallucinations,1,125 agitation including aggressive behavior or hostility,1,125 anxiousness,1,125 paresthesia/hypoesthesia,1 seizures,1 drowsiness,1 insomnia,1,125 somnambulism,1,125 irritability,1,125 depression,1,120,125 suicidal thinking and behavior (including suicide),1,120,125,126 tremor,1,120,125 and restlessness1,125 also have been reported.1 (See Cautions: Precautions and Contraindications.)

GI Effects

Abdominal pain1,51 has occurred in 2.9% of patients 15 years of age or older receiving montelukast.1 Dyspepsia,1 infectious gastroenteritis,1 and dental pain have been reported in 2.1, 1.5, and 1.7% of patients in this age group, respectively.1 Diarrhea1,51 or nausea1 has been reported in at least 2% of children 6-14 years of age receiving montelukast.1 Abdominal pain, diarrhea, and gastroenteritis have been reported in at least 2% of children 2-5 years of age with asthma and more frequently than in those receiving placebo.1 Gastroenteritis has been reported in at least 2% of children 6-8 years of age with asthma and more frequently than in those receiving placebo.1 Nausea,1 vomiting,1 dyspepsia,1 pancreatitis (rarely),1 and diarrhea1 also have been reported with montelukast therapy during postmarketing experience.

Hepatic Effects

Elevations in the results of one or more liver function tests have occurred in patients receiving montelukast in clinical studies.1,31,45,69,79 Increases in serum ALT (SGPT) or AST (SGOT) concentrations occurred in 2.1 or 1.6%, respectively, of patients 15 years of age or older with asthma receiving montelukast in clinical studies.1,45 Increases in ALT occurred in at least 1% of adult and adolescent patients 15 years of age or older with perennial allergic rhinitis receiving montelukast in clinical studies and more frequently than in those receiving placebo.1 Changes in laboratory values returned to normal despite continuing montelukast therapy or were not directly attributable to drug therapy.45 Elevations in serum aminotransferase (transaminase) concentrations also have been reported in children 2-14 years of age receiving montelukast, but the incidence of these elevations was similar to that in children receiving placebo.31,85 Hepatic eosinophilic infiltration has been reported very rarely through postmarketing experience with montelukast.1 (See Dermatologic and Sensitivity Reactions.) Hepatocellular injury, cholestatic hepatitis, or mixed-pattern liver injury also has been reported rarely through postmarketing experience with montelukast.1 Confounding factors were present in most of these patients, such as the concomitant use of other drugs or alcohol or in the presence of coexisting conditions (e.g., other forms of hepatitis).1

Dermatologic and Sensitivity Reactions

Rash1,79 has occurred in 1.6% of adults and adolescents 15 years of age or older receiving montelukast.1 Rash,1 eczema,1 dermatitis,1 or urticaria1 has been reported in at least 2% of children 2-5 years of age receiving the drug.1 Atopic dermatitis, varicella, and skin infection have been reported in at least 2% of children 6-8 years of age with asthma receiving montelukast and more frequently than in those receiving placebo.1 Hypersensitivity reactions, including anaphylaxis,1 angioedema,1 pruritus,1 urticaria,1 and rarely hepatic eosinophilic infiltration,1 have been reported in patients receiving montelukast.1

Eosinophilia and Churg-Strauss Syndrome

Although montelukast therapy generally is associated with a decrease in peripheral blood eosinophil counts in asthmatic patients (see Pharmacology: Effects on Eosinophils),1,31,42,45,51 systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, has been reported rarely in patients receiving leukotriene modifiers (e.g., montelukast,1,39,72,96 pranlukast,72,96 zafirlukast33,39,61,62,63,64,65,66,67,72,85,96 ); in almost all cases, these events were associated with a reduction (tapered dosage) or withdrawal of oral or high-dose inhaled corticosteroid therapy.1,33,39,61,62,63,64,65,66,67,72,96

Churg-Strauss syndrome (allergic granulomatosis and angiitis) is an uncommon vasculitis of unknown etiology that is potentially fatal and characterized by at least 4 of the following 6 features: moderate to severe asthma, peripheral blood eosinophilia (greater than 10% on differential leukocyte count), mononeuropathy or polyneuropathy, nonfixed pulmonary infiltrates on radiograph, paranasal sinus abnormality, and blood vessel biopsy with extravascular eosinophils.39,79,94,95,96,97 The incidence of this syndrome in patients receiving leukotriene modifiers (e.g., zafirlukast) has been estimated to be approximately 60 cases/million patient-years of exposures;39,72 this is similar to the estimated incidence of this syndrome reported in patients receiving other antiasthmatic drugs (bambuterol, salmeterol, nedocromil [preparation for oral inhalation no longer commercially available in the US]).39,95 The onset of Churg-Strauss syndrome has been reported to range from 2 days to 10 months after initiation of leukotriene modifier therapy, and in most cases corticosteroid therapy had been withdrawn or dosage tapered within 3 months of the development of the syndrome.72,96

Although the exact mechanism of Churg-Strauss syndrome has not been determined, it is unlikely that its development during therapy with leukotriene modifiers is directly attributable to these drugs.1,31,33,39,61,62,63,64,65,66,67,72,96 Instead, the occurrence of Churg-Strauss syndrome in patients receiving leukotriene modifiers is believed to result from unmasking of an underlying vasculitic syndrome that initially was diagnosed as moderate to severe asthma.39,72,95,96,97 In such patients, it has been postulated that corticosteroid therapy had suppressed or delayed the development of overt Churg-Strauss syndrome, and initiation of therapy with leukotriene modifiers resulted in decreased steroid requirements, with a subsequent unmasking of the syndrome as corticosteroid therapy was tapered or withdrawn.39,72,95,96,97 Remission of the syndrome usually can be induced with systemic corticosteroid therapy alone, although other immunodulating agents (e.g., cyclophosphamide, methotrexate) may be necessary in some patients.96

Respiratory Effects

Influenza,1,51,69,79 cough,1,51,79 and nasal congestion1 have been reported in 4.2, 2.7, and 1.6%, respectively, of montelukast-treated patients with asthma 15 years of age or older.1 Upper respiratory tract infection occurred in 1.9 or at least 2% of patients 15 years of age or older or 2-14 years of age, respectively, with seasonal allergic rhinitis.1 Upper respiratory tract infection, wheezing, pharyngitis, tonsillitis, cough, and rhinitis occurred in at least 2% of patients 12-23 months of age with asthma.1 Pharyngitis occurred in at least 2% of patients 2-14 years of age with seasonal allergic rhinitis.1 Laryngitis,1 pharyngitis,1,31,69,79 sinusitis,1,79 and viral infection1,31 have occurred in at least 2% of children 6-14 years of age with asthma receiving montelukast and more frequently than in those receiving placebo.1 Rhinorrhea,1 cough, sinusitis, influenza, and pneumonia have been reported in at least 2% of montelukast-treated children 2-5 years of age with asthma and more frequently than in those receiving placebo.1 Sinusitis, upper respiratory tract infection, or cough occurred in at least 1% of adult and adolescent patients 15 years of age or older with perennial allergic rhinitis receiving montelukast and more frequently than in those receiving placebo.1 Infective rhinitis and acute bronchitis occurred in at least 2% of montelukast-treated children 6-8 years of age with asthma and more frequently than in those receiving placebo.1

Other Adverse Effects

Fever1 or trauma1 occurred in 1.5 or 1% of patients 15 years of age or older receiving montelukast.1 Fever also has been reported in children 2-14 years of age.31,85 Fever, otic pain, or otitis occurred in at least 2% of children 2-5 years of age with asthma and more frequently than in those receiving placebo.1 Otitis has occurred in at least 2% of the children 6-14 years of age with asthma and more frequently than in those receiving placebo.1 Otitis media has occurred in at least 2% of montelukast-treated patients 12-23 months of age with asthma or 2-14 years of age with seasonal allergic rhinitis and more frequently than in those receiving placebo.1 Pyuria1 has occurred in 1% of patients 15 years of age or older and more frequently than with placebo.1 At least 2% of montelukast-treated children 2-5 years of age experienced conjunctivitis,1 varicella,1 leg pain,1 or thirst, each occurring more frequently than with placebo.1 Tooth infection and myopia have been reported in at least 2% of montelukast-treated children 6-8 years of age with asthma and more frequently than in those receiving placebo.1 Epistaxis occurred in at least 1% of adult and adolescent patients 15 years of age or older with perennial allergic rhinitis receiving montelukast and more frequently than in those receiving placebo.1 Edema has been reported through postmarketing experience with montelukast.1 Myalgia (including muscle cramps)1 arthralgia,1 palpitations,1 bruising,1 edema,1 and an increased tendency for bleeding1 also has occurred in montelukast-treated patients.

Precautions and Contraindications

Patients should be advised that montelukast must be taken at regular intervals to be therapeutically effective.1 In addition, patients should be advised that the drug will not provide immediate symptomatic relief and should not be used for the relief of acute bronchospasm; however, montelukast therapy can be continued during acute exacerbations of asthma.1 Patients receiving montelukast should be provided with and instructed in the use of a short-acting, inhaled β₂-adrenergic bronchodilator as supplemental therapy for acute asthma symptoms.1 Patients should not discontinue or reduce the dosage of other antiasthmatic agents, even if they feel better as a result of initiation of montelukast therapy, unless instructed to do so by their clinician.1

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.1 (See Exercise-induced Bronchospasm under Uses: Bronchospasm.)

Patients in whom asthma is precipitated by aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs) should continue to avoid aspirin and NSAIAs while receiving montelukast.1,81,125 While montelukast can improve airway function in asthmatic patients with documented aspirin sensitivity, the drug has not been shown to truncate the bronchoconstrictor response to aspirin or other NSAIAs in such patients.1

Although orally inhaled corticosteroid requirements in patients with stable asthma may be reduced during montelukast therapy, only gradual (e.g., at 2-week intervals) reduction of the steroid dosage should be undertaken. 1,40,98,99 Montelukast should not be abruptly substituted for oral or inhaled corticosteroids.1

Serious neuropsychiatric effects have been reported during postmarketing experience with montelukast.128,129 These postmarketing reports have been highly variable and included, but were not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thoughts and behavior (including completed suicides), tic, and tremor in adults, adolescents, and pediatric patients with or without a history of psychiatric disorders.128,129 Neuropsychiatric effects have been reported mainly during montelukast treatment and resolved after the drug was discontinued; however, some of these effects developed or continued following discontinuance of the drug.128,129 Based on available data, it is difficult to identify risk factors for or to quantify the risk of neuropsychiatric effects with use of montelukast.128 The mechanisms underlying neuropsychiatric effects associated with use of montelukast are not well understood; however, it is known that montelukast distributes into the brain in rats.128,129 FDA evaluated reports for all neuropsychiatric adverse effects (including completed suicides) associated with use of montelukast from February 1998 (date of drug approval) through May 2019.129 A total of 82 cases of completed suicide associated with montelukast use were identified; many of these cases reported the development of concomitant neuropsychiatric symptoms prior to the event.129 Most of these reports did not contain sufficient information (e.g., time to onset of event, use of concomitant medications, presence of comorbidities or other risk factors) to determine the exact relationship between montelukast and these neuropsychiatric events.129 Following extensive review of the postmarketing reports and analysis of available clinical data, FDA convened a panel of outside experts to reevaluate the benefits and risks of montelukast and concluded that there was a need to strengthen existing warnings in the labeling for the drug, including restrictions for use in patients with allergic rhinitis.129 (See Uses: Allergic Rhinitis.) The manufacturer of montelukast states that patients receiving the drug and their caregivers and/or clinicians should be alert to the potential for neuropsychiatric effects, including changes in behavior or new neuropsychiatric symptoms.128 The benefits and risks of using montelukast should be considered when deciding to prescribe or continue therapy with the drug.128,129 Prior to initiation of therapy, patients should be asked about any history of psychiatric illness.129 Patients should be advised to discontinue montelukast and to contact their clinician immediately if changes in behavior, new neuropsychiatric symptoms, or suicidal thoughts and/or behavior occur during therapy with montelukast.128,129 Clinicians should provide patient monitoring and supportive care until such symptoms resolve, and should carefully evaluate the risks and benefits of reinitiating treatment with montelukast if such effects occur.128

Eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy consistent with Churg-Strauss syndrome, a systemic eosinophilic vasculitis, have been reported rarely in patients receiving leukotriene modifiers (e.g., montelukast, pranlukast, zafirlukast).1,31,33,39,61,62,63,64,65,66,67,72,96 While a causal relationship between this syndrome and leukotriene modifiers has not been established,1,31,33,39,61,62,63,64,65,66,67,72,96 clinicians should be alert to the development of such manifestations in patients receiving leukotriene modifiers.1,31,39,72,96 Patients should inform their clinician immediately if symptoms of Churg-Strauss syndrome (e.g., feeling of pins and needles or numbness of extremities, flu-like symptoms, rash, sinusitis) occur.125 (See Eosinophilia and Churg-Strauss Syndrome under Cautions: Dermatologic and Sensitivity Reactions.)

Patients should be advised that an increase in frequency of administration of short-acting inhaled bronchodilators or inadequate control of symptoms while receiving the maximum prescribed dosage of an inhaled bronchodilator may indicate substantial worsening of asthma that requires evaluation.1

Montelukast is contraindicated in patients hypersensitive to the drug or any ingredient in the formulation.1 Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be advised that montelukast chewable tablets contain aspartame (Nutrasweet^®), which is metabolized in the GI tract to provide 0.674 mg of phenylalanine for each 4-mg chewable tablet or 0.842 mg of phenylalanine for each 5-mg chewable tablet of montelukast.128

Pediatric Precautions

Safety and efficacy of montelukast for the treatment of asthma in children younger than 12 months of age have not been established.1 Safety and efficacy of montelukast for the prevention of exercise-induced bronchospasm in children younger than 6 years of age have not been established.128

Safety and efficacy of montelukast in infants younger than 6 months of age with perennial allergic rhinitis have not been established.1 Safety and efficacy of montelukast in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.1

Safety of montelukast oral granules in pediatric patients 12-23 months with asthma has been demonstrated in a placebo-controlled trial and other clinical experience.1 Efficacy of montelukast in this age group was explored as a secondary end point in a safety study and is extrapolated from demonstrated efficacy in patients 6 years of age or older based on similar mean systemic exposure to montelukast and the substantial similarity of the disease course, pathophysiology, and effects of the drug among these populations.1

Safety and efficacy of montelukast have been established in adequate and well-controlled studies in children 6-14 years of age with asthma and are similar to those reported in adults.1,31 Safety of the drug in children 2-5 years of age with asthma is extrapolated from demonstrated efficacy in asthmatic adults, adolescents, and children 6 years of age or older based on similar mean systemic exposure to montelukast and the substantial similarity of the disease course, pathophysiology, and effects of the drug among these populations.1 Efficacy of montelukast in children 2-5 years of age is supported by exploratory efficacy assessments from a large, well-controlled safety study.1,109

Efficacy of montelukast in pediatric patients 2-14 years or 6 months to 14 years of age with seasonal or perennial allergic rhinitis, respectively, is supported by extrapolation from demonstrated efficacy in patients 15 years of age and older with allergic rhinitis and the assumption that the disease course, pathophysiology, and drug's effect are substantially similar among these populations.1 Safety of the montelukast in pediatric patients aged 2-14 years of age with allergic rhinitis is supported by data from studies in pediatric patients 2-14 years of age with asthma.1 Data from a safety study of montelukast therapy in pediatric patients 2-14 years of age with seasonal allergic rhinitis demonstrated a safety profile similar to that of placebo.1 Safety of montelukast in pediatric patients 6-23 months with perennial allergic rhinitis is supported by data from studies in pediatric patients 6-23 months of age with asthma and by pharmacokinetic data comparing systemic exposure in such pediatric patients with that in adults.1

The effect of long-term therapy with montelukast on linear growth in pediatric patients has been assessed in a 56-week, multicenter, double-blind, randomized study with an active control (beclomethasone dipropionate) and placebo control in 360 children 6-8 years of age with mild asthma.1,112 Montelukast (5 mg once daily) did not affect growth rate in children compared with placebo; however, growth rate was slowed in children taking orally inhaled beclomethasone dipropionate (168 mcg twice daily) with chlorofluorocarbon propellants (no longer commercially available in the US) compared with placebo.1,112

Geriatric Precautions

When the total number of patients studied in clinical trials of montelukast is considered, 3.5% were 65 years of age or older, while 0.4% were 75 years of age or older.1 Although no overall differences in safety or efficacy were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.1

Changes in the plasma elimination half-life of montelukast occur in geriatric individuals but do not affect the dosing regimen.1,13

Mutagenicity and Carcinogenicity

Montelukast was not mutagenic or clastogenic in 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, or the in vivo mouse bone marrow chromosomal aberration assay.1

Montelukast was not tumorigenic in a 2-year carcinogenicity study in rats at oral (gavage) dosages up to 200 mg/kg daily (estimated exposure approximately 120 and 75 times the area under the plasma concentration-time curve [AUC] for adults and children, respectively, at the maximum recommended daily oral dose) or in a 92-week carcinogenicity study in mice at oral (gavage) dosages up to 100 mg/kg daily (estimated exposure approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose).1

Pregnancy, Fertility, and Lactation

Pregnancy

Montelukast crosses the placenta following oral dosing in rats and rabbits.1 Reproduction studies in rats using oral dosages up to 400 mg/kg daily (estimated exposure approximately 100 times the AUC for adults at the maximum recommended daily oral dose) and in rabbits using oral dosages up to 300 mg/kg daily (estimated exposure approximately 110 times the AUC for adults at the maximum recommended daily oral dose) have not revealed evidence of harm to the fetus.1

There are no adequate and well-controlled studies to date using montelukast in pregnant women,1,119 and the manufacturer states that montelukast should be used during pregnancy only when clearly needed.1 The American College of Obstetricians and Gynecologists (ACOG) generally recommends use of leukotriene modifiers as an alternative to a long-acting β₂-agonist in pregnant women with moderate persistent asthma who are inadequately controlled with low to medium dosages of an inhaled corticosteroid.107 (See Uses: Asthma.)

During postmarketing experience with montelukast, congenital limb defects have been reported rarely in the children of women treated with the drug; however, most of these women were receiving other antiasthmatic agents during their pregnancies.1 A causal relationship between montelukast use and the development of these congenital anomalies has not been established.1 The manufacturer maintains a registry to monitor pregnancy outcomes in women exposed to montelukast during pregnancy.1 Patients may be enrolled by calling 800-986-8999.1

Fertility

While reproduction studies in female rats using oral montelukast doses up to 100 mg/kg (estimated exposure approximately 20 times the AUC for adults at the maximum recommended daily oral dose) have not revealed evidence of impaired fertility, oral doses of 200 mg/kg (estimated exposure approximately 70 times the AUC for adults at the maximum recommended daily oral dose) have been associated with reduced fertility and fecundity indices.1 Reproduction studies in male rats using oral montelukast doses up to 800 mg/kg (estimated exposure approximately 160 times the AUC for adults at the maximum recommended daily oral dose) have not revealed evidence of impaired fertility.1

Lactation

Montelukast is distributed into milk in rats.1 Since it is not known whether montelukast is distributed in human milk, the drug should be used with caution in nursing women.1

Montelukast has been used concomitantly in clinical studies with other drugs used routinely for the prevention and long-term symptomatic management of asthma without an apparent increase in adverse effects.1,31,45 In addition, montelukast has been used concomitantly with benzodiazepines, decongestants, nonsteroidal anti-inflammatory agents (NSAIAs), sedative-hypnotics, or thyroid hormones without evidence of an increase in adverse effects.1

In drug-interaction studies, usual dosages of montelukast did not have clinically important effects on the pharmacokinetics of theophylline, warfarin, terfenadine (no longer commercially available in the US), digoxin, oral contraceptives (ethinyl estradiol with norethindrone), prednisone, or prednisolone.1,73,74,76

Nonsteroidal Anti-inflammatory Agents

Montelukast-treated patients with known aspirin sensitivity should continue to avoid aspirin and other NSAIAs.1,81 Although montelukast can improve airway function in asthmatics with aspirin sensitivity, the drug has not been shown to truncate the bronchoconstrictor response to aspirin or other NSAIAs in such patients,1 and an anaphylactic reaction has been reported following exposure to a NSAIA (e.g., diclofenac) in at least one aspirin-sensitive individual receiving montelukast.81

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of montelukast is mediated in part by the cytochrome P-450 (CYP) isoenzymes 3A4 and 2C9, 1,12 and the possibility exists that drugs that induce or inhibit these isoenzymes may alter the plasma concentrations of montelukast.1 Montelukast does not appear to have any inhibitory effect on CYP3A4, CYP2C9, CYP1A2, CYP2A6, CYP2C19, or CYP2D6.1 Data from in vitro studies indicate that montelukast is a potent inhibitor of CYP2C8.1 However, data from several clinical drug interaction studies evaluating montelukast and rosiglitazone or repaglinide, substrates for the CYP2C8 isoenzyme, indicate that montelukast does not inhibit CYP2C8 in vivo.1,113 Therefore, clinical drug interactions involving montelukast and CYP2C8 substrates (e.g., paclitaxel, rosiglitazone, repaglinide) are not anticipated.1,113

The effect of drugs that inhibit CYP3A4 (e.g., erythromycin, ketoconazole) or CYP2C9 (e.g., fluconazole) on the pharmacokinetics of montelukast remains to be determined.1

Phenobarbital

Administration of phenobarbital, which induces cytochrome P-450 isoenzymes, and a single 10-mg dose of montelukast resulted in a reduction of 40% in area under the plasma montelukast concentration-time curve (AUC).1,102 The manufacturer of montelukast states that the drug can be administered without dosage adjustment in patients also receiving phenobarbital.1,102 However, patients receiving montelukast with drugs that are potent inducers of cytochrome P-450 isoenzymes (e.g., phenobarbital) should be monitored for alterations in clinical response and/or adverse effects.1

Theophylline

Although theophylline may be metabolized to some extent via the CYP3A4 isoenzyme, drug interaction studies did not reveal evidence of a pharmacokinetic interaction with usual dosages of montelukast;1,76 however, the potential for an interaction exists with higher than recommended montelukast dosages.76 Following IV administration of a single theophylline dose (4.65 mg/kg of anhydrous drug) in healthy adults who had achieved steady-state plasma montelukast concentrations while receiving montelukast 10 mg daily, clinically important changes in the pharmacokinetics of theophylline were not observed.1,76

At daily montelukast dosages that were 20-fold higher (200 mg once daily) than the currently recommended dosage, montelukast decreased the peak concentration achieved with a single oral (250 mg) or IV (5 mg/kg) theophylline dose by 12 or 10% respectively, the AUC by 43 or 44%, respectively, and the elimination half-life by 44 or 39%, respectively.76 At a montelukast dosage that was 60-fold higher (200 mg 3 times daily) than recommended, the drug decreased the peak concentration of a single 250-mg oral dose of theophylline by 25%, AUC by 66%, and elimination half-life by 63%.76

Warfarin

Although warfarin is eliminated principally via CYP-dependent hepatic metabolism and montelukast is highly (99%) protein bound, drug interaction studies did not identify clinically important pharmacokinetic interactions between the drugs.1,73 Concomitant administration of montelukast and warfarin does not appear to affect the pharmacokinetics of warfarin.1,73 The effect of a single 30-mg dose of warfarin on prothrombin time (PT) or international normalized ratio (INR) was not altered in healthy adults who had achieved steady-state plasma montelukast concentrations while receiving montelukast 10 mg daily.1,73 Montelukast did not exhibit a clinically important effect on AUCs or peak plasma concentrations of R - or S -warfarin, although slight but statistically significant decreases in the time to peak for both warfarin enantiomers and in elimination half-life of the less potent R -enantiomer were observed; the latter changes were not considered clinically important.73

Rifampin

Although specific drug interaction studies have not been performed to date, the manufacturer states that it is reasonable to employ appropriate clinical monitoring when a potent cytochrome P-450 enzyme inducer such as rifampin is used concomitantly with montelukast.1

Antihistamines

Administration of terfenadine (60 mg twice daily; no longer commercially available in the US) following achievement of steady-state plasma montelukast concentrations in adults receiving montelukast 10 mg daily did not alter the plasma concentration profile of terfenadine or fexofenadine, the active carboxylated metabolite, and did not affect ECG parameters (i.e., QT_c interval).1,103

Digoxin

Administration of digoxin in adults who had achieved steady-state plasma montelukast concentrations while receiving montelukast 10 mg daily did not alter the pharmacokinetic profile or urinary excretion of digoxin.1,74

Estrogen-Progestin Combinations

Administration of an oral contraceptive (a fixed combination of ethinyl estradiol 35 mcg with norethindrone 1 mg) following achievement of steady-state plasma montelukast concentrations in women receiving montelukast 100 mg or more daily did not alter the plasma concentrations of either the estrogen or the progestin.1,104

Corticosteroids

Administration of oral prednisone or IV prednisolone in patients who had achieved steady-state plasma montelukast concentrations while receiving montelukast 100 mg or more daily did not result in clinically important changes in the plasma profiles of the corticosteroids.1

Acute Toxicity

Pathogenesis

Limited information is available on the acute toxicity of montelukast.1,75 Single oral doses of up to 5 g/kg in mice (estimated exposure approximately 335 and 210 times the area under the plasma concentration-time curve [AUC] for adults and children, respectively, at the maximum recommended daily oral dose) and rats (estimated exposure approximately 230 and 145 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose) were not lethal.1

Manifestations

Montelukast has been administered to adults with asthma in dosages up to 200 mg daily for 22 weeks, and in dosages up to 900 mg daily for approximately 1 week without clinically important adverse experiences.1

There have been reports of acute overdosage with montelukast doses of up to 1 g in adults and children.1,75 While adverse effects were not reported in most incidents of overdosage, the most frequently reported adverse experiences that were reported included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.1,75 Clinical and laboratory findings associated with these reports were consistent with the safety profile of the drug in adults and pediatric patients.1 In one 43-month-old child who ingested 65 mg of the drug and complained only of thirst, most of the ingested tablets were recovered via saline gastric lavage.75

Treatment

If acute overdosage of montelukast occurs, supportive and symptomatic treatment should be initiated and the patient closely observed.1,75 If indicated, unabsorbed material should be removed from the GI tract.1,75 Whether peritoneal dialysis or hemodialysis removes montelukast is unknown.1

Pharmacology

Anti-inflammatory Effects

Asthma and Allergic Rhinitis

Montelukast sodium, a selective, competitive leukotriene-receptor antagonist, affects inflammatory processes involved in asthma and allergic rhinitis.1,2,3,4,5,6,7,8,9,10,11,12,13,14,30,31,44,45,51,53,54,55,56,57,58,105 Current evidence indicates that asthma is a chronic inflammatory disorder of the airways involving the production and activity of several endogenous inflammatory mediators, including leukotrienes.1,2,4,5,6,7,8,9,10,11,12,13,14,23,24,30,44,47,53,54,55,56,57,58,105 Montelukast exerts beneficial effects in patients with asthma by inhibiting the action of leukotrienes at specific receptor sites (i.e., the cysteinyl leukotrienes C₄ [LTC₄], D₄ [LTD₄], and E₄ [LTE₄]) on airway smooth muscle and nasal mucosa.1,2,4,5,6,7,8,9,10,11,12,13,14,23,24,30,44,45,53,54,55,56,57,58,105 Cysteinyl leukotrienes are released from the nasal mucosa after allergen exposure and are associated with manifestations of allergic rhinitis (e.g., increased nasal airway resistance, nasal obstruction).1 Leukotriene modifiers (e.g., montelukast, zafirlukast, zileuton) have actions consistent with those of anti-inflammatory agents in that an expert panel of the National Asthma Education and Prevention Program has defined anti-inflammatory agents as those that reduce the markers of airway inflammation (e.g., eosinophils, mast cells, activated lymphocytes, macrophages, cytokines) in airway tissue or airway secretions and thereby reduce the intensity of airway hyperresponsiveness.1,21,22,44,45,57,105 However, the precise anti-inflammatory actions responsible for the therapeutic effects of drugs in asthma (e.g., symptom reduction, improvement in expiratory flow, reduction in airway hyperresponsiveness, prevention of exacerbations, prevention of airway wall remodeling) remain to be fully elucidated.21,22

Effects on Leukotrienes

Leukotrienes are products of arachidonic acid metabolism via the 5-lipoxygenase pathway; the contribution of this pathway to the inflammatory process is complemented by the cyclooxygenase pathway, which converts arachidonic acid into other biologic mediators (e.g., prostaglandins, thromboxanes).2,4,5,23,24,44,47,53,55,56,58 Arachidonic acid is liberated by cell membranes in response to various factors, such as antigen-antibody interactions, IgE-receptor activation, microorganisms, and physical stimuli (e.g., cold, altered ionic conditions).2,4,5,23,24 The cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) and leukotriene B₄ (LTB₄, a potent chemotactic mediator) are derived from the initial unstable product of arachidonic acid metabolism, leukotriene A₄ (LTA₄).2,4,5,23,24,44,45,56,58 Cysteinyl leukotrienes are produced by a number of cell types, including eosinophils, basophils, mast cells, macrophages, and monocytes; however, the physiologic effects of these leukotrienes appear to be mediated through binding to a common receptor, CysLT.1,2,4,5,23,24,45,47,58,100,106 While several other mediators (e.g., histamine, prostaglandins) also act on target cells within airways to induce manifestations typical of asthma, the cysteinyl leukotrienes (formerly referred to as “slow-reacting substance of anaphylaxis” [SRSA]) are especially important in the pathogenesis of this disease, causing increased mucus secretion and vascular permeability, airway edema, bronchoconstriction, and altered cellular activity associated with the inflammatory process.1,2,4,5,23,24,30,53,57,58

The involvement of leukotrienes in asthma is supported by evidence of increased concentrations of leukotrienes in biologic fluids (i.e., urine, bronchoalveolar lavage fluid, nasal fluid, plasma) of some patients with asthma compared with healthy individuals; increased urinary leukotriene concentrations also have been observed in patients following allergen challenge, episodes of asthma, and exercise or aspirin challenge.4,5,7,8,24,30,44,47,55 Compared with histamine or prostaglandins, cysteinyl leukotrienes are 100-1000 times more potent as bronchoconstrictors.2,4,5,24,45,55,57,58 In addition, patients with asthma are substantially more responsive to the effects of leukotrienes than are healthy individuals.4,24,25,26,27,28 In one study, patients with asthma were 25-100 times more sensitive to the bronchoconstrictor effects of inhaled LTD₄ than nonasthmatic individuals.28 However, there is substantial interindividual variability in airway sensitivity to the contractile effects of leukotrienes among both healthy individuals and patients with asthma.24,25,26,27,28

Because of the role of leukotrienes in the pathogenesis of asthma, modification of leukotriene activity may be used to reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control.1,2,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,30,44,45,47,58 Inhibition of leukotriene-mediated effects may be achieved by drugs that interrupt 5-lipoxygenase activity and prevent formation of leukotrienes (e.g., zileuton) or by antagonism of leukotriene activity at specific receptor sites in the airway (e.g., montelukast, zafirlukast).1,2,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,30,42,44,47,58,100 The antagonist activity of montelukast is selective, competitive, and reversible.1,2,4,5,6,7,8,9,10,11,12,13,14,30,45,51 Montelukast competitively inhibits the action of LTD₄ at a subgroup of CysLT receptors (CysLT₁) in airway smooth muscle.1,2,4,5,6,7,8,9,10,11,12,13,14,30,51,58,100 In vitro, montelukast possesses affinity for the CysLT₁ receptor that is similar to that of LTD₄.100 In in vitro studies, montelukast antagonized contraction of isolated animal smooth muscle produced by LTD₄, but did not antagonize contraction produced by LTC₄.30 In animal studies, montelukast antagonized contraction of airway smooth muscle produced by LTD₄ or antigen.2,30,51

Inhibition of Bronchoconstriction

In patients with asthma, oral montelukast inhibits bronchoconstriction induced by exposure to known precipitating factors (e.g., allergens, cold and/or dry air, exercise); in addition, both the acute bronchoconstrictor response (immediate/early asthmatic response [IAR, EAR]) and the delayed inflammatory response (late asthmatic response [LAR]) to inhaled antigen are inhibited.80,89 Montelukast reduces sensitivity to inhaled LTD₄ in patients with asthma.1,8,51 In studies evaluating the in vivo potency of montelukast, oral administration of a single 5-mg dose of montelukast attenuated LTD₄-induced bronchoconstriction.1,8,51 The effect of montelukast on LTD₄-induced bronchoconstriction is evident within 4 hours of drug administration and persists for 24 hours or longer.8 Montelukast is associated with a longer duration of inhibition of LTD₄-induced bronchoconstriction than oral zafirlukast.8,30 In addition, montelukast inhibits both the acute bronchoconstrictor response and the delayed inflammatory response to inhaled antigen.1,30,41,44,47,51,55 In one crossover, placebo-controlled study, montelukast inhibited the acute bronchoconstrictor and delayed inflammatory response to antigen by 75 and 57%, respectively.1,41,51 Following IV administration of montelukast 7 mg (not commercially available in the US) in patients with asthma, forced expiratory volume in 1 second (FEV₁) increased 15% over baseline at 15 minutes and 18.43% at 60 minutes; following administration of a single oral dose of montelukast 10 mg in patients with asthma, FEV₁ increased 4.67% at 15 minutes and 12.9% at 60 minutes.82

In a limited number of patients with asthma, single oral doses of montelukast 100 or 250 mg increased the FEV₁ regardless of concomitant use of inhaled corticosteroids.6 In addition, data from one clinical study indicate the bronchodilatory effects of inhaled corticosteroids and montelukast are additive.1,79

Effects on Eosinophils

Montelukast therapy decreased mean peripheral blood eosinophil count 9-15% from baseline in pediatric (at least 2 years of age) and adult patients with asthma.1,31,42,45,51 While a decrease in peripheral blood eosinophil count may indicate that montelukast has important effects on parameters of asthmatic inflammation,31,45 the clinical importance of changes in eosinophil counts in asthmatic patients remains to be determined.1

Similarly, therapy with montelukast in patients with seasonal allergic rhinitis (15 years of age or older) either prevented the rise in mean peripheral blood eosinophil counts observed with placebo1 or actually decreased mean peripheral blood eosinophil counts compared with placebo.111

Other Effects

Montelukast has essentially no affinity for prostanoid, cholinergic, or β-adrenergic receptors.1,30

Pharmacokinetics

While safety and efficacy of montelukast (10 or 5 mg daily) have been established in clinical studies in which the drug was administered in the evening without regard to meals, pharmacokinetics have been studied principally in healthy nonasthmatic adults and in asthmatic children who received the drug in the morning.1,11,12,13,14,20,37 Pharmacokinetic studies have not revealed diurnal or gender-related differences in the pharmacokinetics of the drug;1,12,14,37 further study is needed to determine if there are race-related differences.1

The plasma concentration profile following oral administration of montelukast 10 mg in adolescents 15 years of age or older is similar to that in young adults.1 In addition, the plasma concentration profile following oral administration of montelukast 4 or 5 mg chewable tablets in children 2-5 or 6-14 years of age, respectively, is similar to the profile in adults receiving montelukast 10 mg (as the commercially available film-coated tablet).1,37,101 In children 6-11 months of age, systemic exposure to montelukast and variability in plasma drug concentrations are greater than those observed in adults.1 Based on population analyses, the mean area under the plasma concentration-time curve (AUC) and the mean peak plasma drug concentration were 60 and 89% higher, respectively, than those observed in adults.1 Systemic exposure following administration of 4-mg granules in infants 12-23 months of age is less variable than that with the same formulation in younger children, but the mean AUC and mean peak plasma concentration were 33 and 60% higher, respectively, than that following administration of 10-mg film-coated tablets in adults.1 Changes in disposition kinetics of montelukast occur in geriatric individuals but do not affect the dosing regimen.1,13 Pharmacokinetics of montelukast are linear for oral doses up to 50 mg.1,37

Bioequivalence of the 10-mg film-coated tablet versus the 5-mg chewable tablet (2 tablets) has not been evaluated;1 however, limited data indicate that absorption of montelukast administered as a 10-mg chewable tablet (not commercially available) is more rapid and more complete than when the drug is administered as the commercially available film-coated tablet.37 The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to fasting adults, and the oral granules can be used as an alternative to the chewable tablets in patients 2-5 years of age.1

Absorption

Montelukast is rapidly absorbed from the GI tract, and peak plasma concentrations are attained within 3-4, 2-2.5, or 2 hours following oral administration in the fasted state of a single 10-mg film-coated (in adults), 5-mg chewable (in adults), or 4-mg chewable (in children 2-5 years of age) tablet, respectively.1,13,14,37,53 Oral bioavailability of montelukast administered as a 10-mg tablet in adults is 58-66%;1,13,14 presence of food in the GI tract does not affect bioavailability when the 10-mg film-coated tablet is administered with a standard meal in the morning.1 Oral bioavailability of the drug administered as a 5-mg chewable tablet in adults is 73% when the drug is administered in fasting individuals and 63% when the drug is administered with a standard meal in the morning.1 Ingestion of a high-fat meal in the morning with the 4-mg oral granules formulation had no effect on the AUC of montelukast; however, the time to peak plasma concentrations was prolonged from 2.3 hours to 6.4 hours and peak plasma concentrations were reduced by 35%.1 Administration of montelukast granules with applesauce does not appear to have a clinically important effect on the pharmacokinetics of montelukast.1

Following oral administration of montelukast 10 mg daily for 7 days in fasting young adults, peak plasma concentrations averaged 541 ng/mL on day 1 and 602.8 ng/mL on day 7.13,51 Trough concentrations on days 3-7 were essentially constant and ranged from 18-24 ng/mL.13 In this study, values for area under the plasma concentration-time curve (AUC) at steady-state were about 14-15% higher than those achieved with a single dose, and were reached within 2 days.1,13,51

The therapeutic effects of montelukast (e.g., as determined by improvements in asthma symptoms and/or lung function test results, decreased use of β-agonist bronchodilators) are evident after the first dose and persist for at least 24 hours.1,31,45

In patients receiving montelukast 10 mg daily with mild to moderate hepatic impairment and clinical evidence of cirrhosis, the AUC of the drug was increased by 41% compared with the AUC in healthy individuals receiving montelukast.1

Distribution

Distribution of montelukast in body tissues and fluids has not been fully characterized.98,99 The steady-state volume of distribution of montelukast is 8-11 L.1,13,14

Studies in rats indicate that only minimal amounts of radiolabeled material are detected in all tissues at 24 hours after administration of radiolabeled montelukast.1 Minimal amounts of radiolabeled montelukast cross the blood-brain barrier in rats.1

Montelukast is more than 99% bound to plasma proteins.1

It is not known whether montelukast crosses the placenta in humans; the drug crosses the placenta following oral administration in rats and rabbits.1 While it is not known whether montelukast is distributed in human milk, the drug is distributed into milk in rats.1

Elimination

The metabolic fate of montelukast has not been fully determined, but the drug is extensively metabolized in the GI tract and/or liver and excreted in bile.1,12,20 Several metabolic pathways have been identified including acyl glucuronidation, and oxidation catalyzed by several cytochrome P-450 (CYP) isoenzymes.1,12,20 In vitro studies indicate that the microsomal P-450 isoenzyme CYP3A4 is the major enzyme involved in formation of the 21-hydroxy metabolite (M5) and a sulfoxide metabolite (M2), and CYP2C9 is the major isoenzyme involved in the formation of the 36-hydroxy metabolite (M6).12 Other identified metabolites include an acyl glucuronide (M1) and a 25-hydroxy (a phenol, M3) analog.12

Following oral administration of 54.8 mg of radiolabeled montelukast, metabolites of the drug represented less than 2% of circulating radioactivity.1,12 Montelukast metabolites that have been identified in plasma in radiolabeled studies include the 21-hydroxy (diastereomers of a benzylic acid, M5a and M5b) and the 36-hydroxy (diastereomers of a methyl alcohol, M6a and M6b) metabolites.12 Following oral administration of therapeutic doses of montelukast, plasma concentrations of metabolites at steady-state in adults and children were below the level of detection.1

The mean plasma elimination half-life of montelukast in adults 19-48 years of age is 2.7-5.5 hours, and plasma clearance averages 45 mL/minute.1,13,14,37,51 A plasma elimination half-life of 3.4-4.2 hours has been reported in children 6-14 years of age.37 Limited data indicate that the plasma elimination half-life of montelukast is prolonged slightly in geriatric adults and in patients with mild to moderate hepatic impairment, although dosage adjustment is not required.1,13 A plasma elimination half-life of 6.6 or 7.4 hours has been reported in geriatric adults 65-73 years of age or patients with mild to moderate hepatic impairment, respectively.1,13,51

Pharmacokinetics of montelukast have not been evaluated in patients with renal impairment.1 It is not known whether montelukast is removed from the body by hemodialysis or peritoneal dialysis.1

Following oral administration, montelukast is excreted principally in bile as unchanged drug and metabolites.1,12,20 Following oral administration of radiolabeled montelukast, 86% of administered radioactivity was recovered in feces and less than 2% was recovered in urine over a 5-day collection period.1,12

Chemistry and Stability

Chemistry

Montelukast sodium, a synthetic leukotriene-receptor antagonist, is an antiasthmatic agent.1,2,3,4,5,6,7,8,9,10,11,12,13,14,30,31,44,45,53,54,71,105 Montelukast is a cysteinyl leukotriene analog that was developed based on a quinoline-containing compound that was modified with leukotriene structural elements.71 Structural modifications resulted in improved potency, oral bioavailability, clinical efficacy, and/or safety profile relative to early leukotriene antagonists (e.g., MK-571, verlukast).71 Montelukast consists of a 7-chloro-2-quinolinyl ethenylphenyl connected to a {[(1-hydroxy-1-methylethyl)phenyl]propyl}thiomethyl cyclopropaneacetic acid.1,2,3,12,13,14,20,71 Because montelukast contains polar and nonpolar groups at opposite ends of the molecule, the drug has amphophilic physicochemical properties.3

Montelukast is pharmacologically but not structurally related to zafirlukast.71,2 Montelukast, like zafirlukast, differs chemically and pharmacologically from other currently available antiasthmatic agents (e.g., corticosteroids, mast-cell stabilizers, β-adrenergic agonist bronchodilators, theophylline, zileuton).2

Montelukast sodium occurs as a hygroscopic, white to off-white powder.1 Montelukast sodium has solubilities of 0.2-0.5 mcg/mL in water at 25°C3 ; the drug is freely soluble in alcohol.1 The apparent pK_as of the drug in water are 2.8 and 5.7.3

Montelukast sodium chewable tablets contain aspartame (Nutrasweet^®).1 Following metabolism of aspartame in the GI tract, each 4- or 5-mg chewable tablet of montelukast provides 0.674 or 0.824 mg of phenylalanine, respectively.1,15,16,17,18,19

Stability

Commercially available montelukast sodium film-coated and chewable tablets and oral granules should be stored at 25°C and protected from light and moisture with exposure for short periods to temperatures of 15-30°C permitted.1 When stored as directed, montelukast sodium film-coated and chewable tablets have an expiration date of 2 years after the date of manufacture.98

1. Merck & Co. Singulair^® (montelukast sodium) tablets, chewable tablets, and oral granules prescribing information. Whitehouse Station, NJ; 2009 Aug.

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