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montelukast sod 10 mg tablet (generic singulair)

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Uses

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.

Bronchospasm

Asthma

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.

Exercise-induced Bronchospasm

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.

Allergic Rhinitis

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.

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

Dosage and Administration

Administration

In patients with asthma with or without coexisting allergic rhinitis, montelukast is administered orally as a single daily dose in the evening. 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. Evening dosing has been employed so that achievement of peak plasma concentrations of the drug might coincide with peak airway reactivity in the morning. In patients with allergic rhinitis, the time of administration may be individualized to suit patient needs. Efficacy was demonstrated in patients with seasonal allergic rhinitis when montelukast was administered in the morning or evening without regard to food intake.

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.

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. Oral granules are not intended to be dissolved in any liquid other than baby formula or breast milk prior to administration. However, liquids may be taken subsequent to administration, and oral granules can be administered without regard to meals. The packet should not be opened until ready to use. 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. Any unused portions should be discarded.

Dosage

Dosage of montelukast sodium is expressed in terms of montelukast.

Asthma

Patients should be advised that montelukast must be taken at regular intervals (i.e., daily) to be therapeutically effective. 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. 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. No additional dosage is needed for the treatment of allergic rhinitis in patients already receiving chronic therapy for asthma.

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. 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.

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.

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. 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. 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.

Exercise-induced Bronchospasm

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

Adult Dosage

For the prevention of exercise-induced bronchospasm, the usual dosage of montelukast for adults and adolescents 15 years of age or older is 10 mg as film-coated tablets administered at least 2 hours prior to exercise; an additional dose should not be taken within 24 hours of the previous dose. 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.

Pediatric Dosage

For the prevention of exercise-induced bronchospasm, a montelukast dosage of 5 mg daily in children 6-14 years of age has been used.

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.

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.

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. 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. 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. 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.

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. However, the manufacturer makes no specific recommendations for adjustment of montelukast dosage in patients with mild to moderate hepatic impairment. The pharmacokinetics of montelukast in patients with severe hepatic impairment or with hepatitis have not been evaluated.

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

Cautions

Montelukast generally is well tolerated. 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. 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. The types of adverse effects reported in long-term studies were comparable to those reported in short-term, controlled studies.

A causal relationship between many adverse effects and montelukast has not been established. 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, 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. 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. 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.

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.

Nervous System Effects

Headache is the most frequently reported adverse effect with montelukast, occurring in 18-19% of children 6 years of age or older, adolescents, and adults. 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. 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. Dizziness or asthenia/fatigue has occurred in about 1.8-1.9% of patients 15 years of age or older receiving the drug in clinical studies. Dream abnormalities, hallucinations, agitation including aggressive behavior or hostility, anxiousness, paresthesia/hypoesthesia, seizures, drowsiness, insomnia, somnambulism, irritability, depression, suicidal thinking and behavior (including suicide), tremor, and restlessness also have been reported.(See Cautions: Precautions and Contraindications.)

GI Effects

Abdominal pain has occurred in 2.9% of patients 15 years of age or older receiving montelukast. Dyspepsia, infectious gastroenteritis, and dental pain have been reported in 2.1, 1.5, and 1.7% of patients in this age group, respectively. Diarrhea or nausea has been reported in at least 2% of children 6-14 years of age receiving montelukast. 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. 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. Nausea, vomiting, dyspepsia, pancreatitis (rarely), and diarrhea 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. 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. 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. Changes in laboratory values returned to normal despite continuing montelukast therapy or were not directly attributable to drug therapy. 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. Hepatic eosinophilic infiltration has been reported very rarely through postmarketing experience with montelukast.(See Dermatologic and Sensitivity Reactions.) Hepatocellular injury, cholestatic hepatitis, or mixed-pattern liver injury also has been reported rarely through postmarketing experience with montelukast. 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).

Dermatologic and Sensitivity Reactions

Rash has occurred in 1.6% of adults and adolescents 15 years of age or older receiving montelukast. Rash, eczema, dermatitis, or urticaria has been reported in at least 2% of children 2-5 years of age receiving the drug. 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. Hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, urticaria, and rarely hepatic eosinophilic infiltration, have been reported in patients receiving montelukast.

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), 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, pranlukast, zafirlukast); in almost all cases, these events were associated with a reduction (tapered dosage) or withdrawal of oral or high-dose inhaled corticosteroid therapy.

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. 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; 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]). 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.

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. 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. 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. 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.

Respiratory Effects

Influenza, cough, and nasal congestion have been reported in 4.2, 2.7, and 1.6%, respectively, of montelukast-treated patients with asthma 15 years of age or older. 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. Upper respiratory tract infection, wheezing, pharyngitis, tonsillitis, cough, and rhinitis occurred in at least 2% of patients 12-23 months of age with asthma. Pharyngitis occurred in at least 2% of patients 2-14 years of age with seasonal allergic rhinitis. Laryngitis, pharyngitis, sinusitis, and viral infection 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. Rhinorrhea, 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. 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. 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.

Other Adverse Effects

Fever or trauma occurred in 1.5 or 1% of patients 15 years of age or older receiving montelukast. Fever also has been reported in children 2-14 years of age. 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. 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. 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. Pyuria has occurred in 1% of patients 15 years of age or older and more frequently than with placebo. At least 2% of montelukast-treated children 2-5 years of age experienced conjunctivitis, varicella, leg pain, or thirst, each occurring more frequently than with placebo. 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. 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. Edema has been reported through postmarketing experience with montelukast. Myalgia (including muscle cramps) arthralgia, palpitations, bruising, edema, and an increased tendency for bleeding 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. 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. 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. 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.

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.(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. 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.

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. Montelukast should not be abruptly substituted for oral or inhaled corticosteroids.

Because of postmarketing reports of neuropsychiatric events (e.g., depression, anxiety, agitation, aggressive behavior, irritability, suicidal ideation and behavior [suicidality]) in adults, adolescents, and pediatric patients, the US Food and Drug Administration (FDA) reviewed the safety of montelukast and other leukotriene modifiers to evaluate a possible link between the use of these agents and such behavior or mood changes. Data from placebo-controlled trials with montelukast, zafirlukast, and zileuton submitted to FDA indicate that suicidal ideation occurred in 0.01% of 9929 patients treated with montelukast and in none of the patients treated with other leukotriene modifiers. In these studies, no completed suicide occurred during therapy with any leukotriene modifier. Following review of the postmarketing reports and analysis of available clinical data, FDA has concluded that some of the neuropsychiatric events reported during postmarketing surveillance with montelukast (e.g., agitation, aggressive behavior or hostility, anxiousness, depression, dream abnormalities, hallucinations, insomnia, irritability, somnambulism, restlessness, tremor) appear consistent with a drug-induced effect. The manufacturer of montelukast states that patients receiving the drug and their clinicians should be alert to the potential for neuropsychiatric events. Patients should be instructed to contact their clinician if behavior or mood changes occur during therapy with montelukast. Clinicians should carefully evaluate the risks and benefits of continuing montelukast therapy in patients who develop neuropsychiatric symptoms.

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). While a causal relationship between this syndrome and leukotriene modifiers has not been established, clinicians should be alert to the development of such manifestations in patients receiving leukotriene modifiers. 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.(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.

Montelukast is contraindicated in patients hypersensitive to the drug or any ingredient in the formulation. 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.

Pediatric Precautions

Safety and efficacy of montelukast for the treatment of asthma in children younger than 12 months of age have not been established. Safety and efficacy of montelukast for the prevention of exercise-induced bronchospasm in children and adolescents younger than 15 years of age have not been established. Safety and efficacy of montelukast in infants younger than 6 months of age with perennial allergic rhinitis have not been established. Safety and efficacy of montelukast in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established. 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. 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.

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. 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. Efficacy of montelukast in children 2-5 years of age is supported by exploratory efficacy assessments from a large, well-controlled safety study.

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. 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. 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. 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.

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. 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.

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. 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.

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

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.

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).

Pregnancy, Fertility, and Lactation

Pregnancy

Montelukast crosses the placenta following oral dosing in rats and rabbits. 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.

There are no adequate and well-controlled studies to date using montelukast in pregnant women, and the manufacturer states that montelukast should be used during pregnancy only when clearly needed. 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.(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. A causal relationship between montelukast use and the development of these congenital anomalies has not been established. The manufacturer maintains a registry to monitor pregnancy outcomes in women exposed to montelukast during pregnancy. Patients may be enrolled by calling 800-986-8999.

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. 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.

Lactation

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

Drug Interactions

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. 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.

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.

Nonsteroidal Anti-inflammatory Agents

Montelukast-treated patients with known aspirin sensitivity should continue to avoid aspirin and other NSAIAs. 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, and an anaphylactic reaction has been reported following exposure to a NSAIA (e.g., diclofenac) in at least one aspirin-sensitive individual receiving montelukast.

Drugs Affecting Hepatic Microsomal Enzymes

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

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.

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). The manufacturer of montelukast states that the drug can be administered without dosage adjustment in patients also receiving phenobarbital. 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.

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; however, the potential for an interaction exists with higher than recommended montelukast dosages. 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.

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. 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%.

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. Concomitant administration of montelukast and warfarin does not appear to affect the pharmacokinetics of warfarin. 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. 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.

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.

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., QTc interval).

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.

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.

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.

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. Pharmacokinetic studies have not revealed diurnal or gender-related differences in the pharmacokinetics of the drug; further study is needed to determine if there are race-related differences.

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. 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). In children 6-11 months of age, systemic exposure to montelukast and variability in plasma drug concentrations are greater than those observed in adults. 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. 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. Changes in disposition kinetics of montelukast occur in geriatric individuals but do not affect the dosing regimen. Pharmacokinetics of montelukast are linear for oral doses up to 50 mg.

Bioequivalence of the 10-mg film-coated tablet versus the 5-mg chewable tablet (2 tablets) has not been evaluated; 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. 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.

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. Oral bioavailability of montelukast administered as a 10-mg tablet in adults is 58-66%; 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. 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. 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%. Administration of montelukast granules with applesauce does not appear to have a clinically important effect on the pharmacokinetics of montelukast.

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. Trough concentrations on days 3-7 were essentially constant and ranged from 18-24 ng/mL. 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.

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.

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.

Distribution

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

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

Montelukast is more than 99% bound to plasma proteins.

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

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. Several metabolic pathways have been identified including acyl glucuronidation, and oxidation catalyzed by several cytochrome P-450 (CYP) isoenzymes. 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). Other identified metabolites include an acyl glucuronide (M1) and a 25-hydroxy (a phenol, M3) analog.

Following oral administration of 54.8 mg of radiolabeled montelukast, metabolites of the drug represented less than 2% of circulating radioactivity. 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. 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.

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. A plasma elimination half-life of 3.4-4.2 hours has been reported in children 6-14 years of age. 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. 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.

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

Following oral administration, montelukast is excreted principally in bile as unchanged drug and metabolites. 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.

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