1.1 Asthma

Montelukast sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 2 years of age and older.

1.2 Exercise-Induced Bronchoconstriction (EIB)

Montelukast sodium is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older.

1.3 Allergic Rhinitis

Montelukast sodium is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 2 years of age and older. Because the benefits of montelukast sodium may not outweigh the risk of neuropsychiatric symptoms in patients with allergic rhinitis [see Warnings and Precautions (5.1)], reserve use for patients who have an inadequate response or intolerance to alternative therapies.

1.4 Limitations of Use

Montelukast sodium is not indicated for the treatment of an acute asthma attack.

2.1 Asthma

For asthma, administer montelukast sodium orally once daily in the evening, with or without food. There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing.

The following doses are recommended:

Table 1: Recommended Dosage in Asthma

Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

2.2 Exercise-Induced Bronchoconstriction (EIB)

For prevention of EIB, administer a single dose of montelukast sodium orally at least 2 hours, before exercise. The following doses are recommended:

Table 2: Recommended Dosage in Exercise-Induced Bronchoconstriction (EIB)

* Safety and effectiveness in patients younger than 6 years of age have not been established.

An additional dose of montelukast sodium should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist.

Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.

2.3 Allergic Rhinitis

For allergic rhinitis, administer montelukast sodium orally once daily without regard to time of food ingestion. Time of administration in patients with allergic rhinitis can be individualized to suit patient needs.

The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended:

Table 3: Recommended Dosage in Seasonal Allergic Rhinitis

* Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.

The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended:

Table 4: Recommended Dosage in Perennial Allergic Rhinitis

Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

2.4 Asthma and Allergic Rhinitis

For patients with both asthma and allergic rhinitis, administer only one montelukast sodium dose orally once daily in the evening.

Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

5.1 Neuropsychiatric Events

Serious neuropsychiatric (NP) events have been reported with use of montelukast sodium. 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 suicide), tic, and tremor. NP events have been reported in adult, adolescent, and pediatric patients with and without a previous history of psychiatric disorder. NP events have been reported mostly during montelukast sodium treatment, but some were reported after montelukast sodium discontinuation. Animal studies showed that montelukast distributes into the brain in rats [see Clinical Pharmacology (12.3)]; however, the mechanisms underlying montelukast sodium -associated NP events are currently not well understood. Based upon the available data, it is difficult to identify risk factors for or quantify the risk of NP events with montelukast sodium use.

Because of the risk of NP events, the benefits of montelukast sodium may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies. Reserve use of montelukast sodium for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies [see Indications and Usage (1.3)]. In patients with asthma or exercise-induced bronchoconstriction, consider the benefits and risks before prescribing montelukast sodium.

Discuss the benefits and risks of montelukast sodium use with patients and caregivers when prescribing montelukast sodium. Advise patients and/or caregivers to be alert for changes in behavior or for new NP symptoms when taking montelukast sodium. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue montelukast sodium and contact a healthcare provider immediately. In many cases, symptoms resolved after stopping montelukast sodium therapy; however, in some cases symptoms persisted after discontinuation of montelukast sodium. Therefore, continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting treatment with montelukast sodium if such events occur.

5.2 Acute Asthma

Montelukast sodium is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with montelukast sodium can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β-agonist.

5.3 Concomitant Corticosteroid Use

While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast sodium should not be abruptly substituted for inhaled or oral corticosteroids.

5.4 Aspirin Sensitivity

Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti­-inflammatory agents while taking montelukast sodium. Although montelukast sodium is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients [see Clinical Studies (14.1)].

5.5 Eosinophilic Conditions

Patients with asthma on therapy with montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between montelukast sodium and these underlying conditions has not been established [see Adverse Reactions (6.2)].

5.6 Risk in Patients with Phenylketonuria

Montelukast sodium contains aspartame, a source of phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria (PKU). Each 4 mg and 5 mg chewable tablet contains 0.674 mg and 0.842 mg of phenylalanine, respectively. Before prescribing montelukast sodium to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including montelukast sodium.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment.



The most common adverse reactions (incidence ≥5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.



Adults and Adolescents 15 Years of Age and Older with Asthma



Montelukast sodium has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse reactions reported with montelukast sodium occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:

The frequency of less common adverse reactions was comparable between montelukast sodium and placebo.



The safety profile of montelukast sodium, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for montelukast sodium.



Cumulatively, 569 patients were treated with montelukast sodium for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse reaction profile did not significantly change.



Pediatric Patients 6 to 14 Years of Age with Asthma



Montelukast sodium has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with montelukast sodium for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of montelukast sodium in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. In pediatric patients 6 to 14 years of age receiving montelukast sodium, the following reactions occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The frequency of less common adverse reactions was comparable between montelukast sodium and placebo. With prolonged treatment, the adverse reaction profile did not significantly change.



The safety profile of montelukast sodium, when administered as a single dose for prevention of EIB in pediatric patients 6 years of age and older, was consistent with the safety profile previously described for montelukast sodium. 



In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for montelukast sodium. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving montelukast sodium, the following reactions not previously observed with the use of montelukast sodium in this age group occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute bronchitis, tooth infection, skin infection, and myopia.



Pediatric Patients 2 to 5 Years of Age with Asthma



Montelukast sodium has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single- and multiple-dose studies. Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with montelukast sodium for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. In pediatric patients 2 to 5 years of age receiving montelukast sodium, the following reactions occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis.



Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis



Montelukast sodium has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. Montelukast sodium administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following reaction was reported with montelukast sodium with a frequency ≥1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving montelukast sodium vs. 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.



Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic Rhinitis



Montelukast sodium has been evaluated in 280 pediatric patients 2 to 14 years of age in a 2-week, multicenter, double-blind, placebo-controlled, parallel-group safety study. Montelukast sodium administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following reactions occurred with a frequency ≥2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection.



Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis



Montelukast sodium has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received montelukast sodium in two, 6-week, clinical studies. Montelukast sodium administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following reactions were reported with montelukast sodium with a frequency ≥1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.



Pediatric Patients 2 to 14 Years of Age with Perennial Allergic Rhinitis



The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of montelukast sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.



Blood and lymphatic system disorders



increased bleeding tendency, thrombocytopenia



Immune system disorders



hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration



Psychiatric disorders



including, but 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 thinking and behavior (including suicide), tic, and tremor [see Boxed Warning, Warnings and Precautions (5.1)]



Nervous system disorders



drowsiness, paraesthesia/hypoesthesia, seizures



Cardiac disorders



palpitations



Respiratory, thoracic and mediastinal disorders



epistaxis, pulmonary eosinophilia



Gastrointestinal disorders



diarrhea, dyspepsia, nausea, pancreatitis, vomiting



Hepatobiliary disorders



Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with montelukast sodium. Most of these occurred in combination with other confounding factors, such as use of other medications, or when montelukast sodium was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.



Skin and subcutaneous tissue disorders



angioedema, bruising, erythema multiforme, erythema nodosum, pruritus,  Stevens-Johnson syndrome/toxic epidermal necrolysis, urticaria



Musculoskeletal and connective tissue disorders



arthralgia, myalgia including muscle cramps



Renal and urinary disorders



enuresis in children.



General disorders and administration site conditions



edema



Patients with asthma on therapy with montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These reactions have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients [see Warnings and Precautions (5.5)].

8.1 Pregnancy

Risk Summary

Available data from published prospective and retrospective cohort studies over decades with montelukast use in pregnant women have not established a drug-associated risk of major birth defects [see Data]. In animal reproduction studies, no adverse developmental effects were observed with oral administration of montelukast to pregnant rats and rabbits during organogenesis at doses approximately 100 and 110 times, respectively, the maximum recommended human daily oral dose (MRHDOD) based on AUCs [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly or moderately controlled asthma in pregnancy increases the maternal risk of perinatal adverse outcomes such as preeclampsia and infant prematurity, low birth weight, and small for gestational age.

Data

Human Data  

Published data from prospective and retrospective cohort studies have not identified an association with montelukast sodium use during pregnancy and major birth defects. Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups.

Animal Data

In embryo-fetal development studies, montelukast administered to pregnant rats and rabbits during organogenesis (gestation days 6 to 17 in rats and 6 to 18 in rabbits) did not cause any adverse developmental effects at maternal oral doses up to 400 and 300 mg/kg/day in rats and rabbits, respectively (approximately 100 and 110 times the AUC in humans at the MRHDOD, respectively).

8.2 Lactation

Risk Summary

A published clinical lactation study reports the presence of montelukast in human milk. Data available on the effects of the drug on infants, either directly [see Use in Specific Populations (8.4)] or through breast milk, do not suggest a significant risk of adverse reactions from exposure to montelukast sodium. The effects of the drug on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for montelukast sodium and any potential adverse reactions on the breastfed infant from montelukast sodium or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of montelukast sodium for asthma have been established in pediatric patients 6 to 14 years of age. Use of montelukast sodium for this indication is supported by evidence from well-controlled studies. Safety and efficacy data in this age group are similar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology, Specific Populations (12.3), and Clinical Studies (14.1, 14.2)].

 

The effectiveness of montelukast sodium for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 2 to 14 years of age have been established and is supported by extrapolation from the demonstrated effectiveness in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.



The safety of montelukast sodium chewable tablets 4 mg in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data [see Adverse Reactions (6.1)]. Effectiveness of montelukast sodium in this age group is extrapolated from the demonstrated effectiveness in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Effectiveness in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age.



The safety of montelukast sodium chewable tablets 4 mg and 5 mg in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile [see Adverse Reactions (6.1)].



The safety and effectiveness in pediatric patients below the age of 12 months with asthma, 6 months with perennial allergic rhinitis, and 6 years with exercise-induced bronchoconstriction have not been established.



Growth Rate in Pediatric Patients



A 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study was conducted to assess the effect of montelukast sodium on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included montelukast 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. For each subject, a growth rate was defined as the slope of a linear regression line fit to the height measurements over 56 weeks. The primary comparison was the difference in growth rates between montelukast sodium and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the montelukast sodium, placebo, and beclomethasone treatment groups were 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 5.08), respectively. The differences in growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for montelukast sodium minus placebo, beclomethasone minus placebo, and montelukast sodium minus beclomethasone treatment groups were 0.03 (-0.26, 0.31), -0.78 (-1.06, -0.49); and 0.81 (0.53, 1.09), respectively. Growth rate (expressed as mean change in height over time) for each treatment group is shown in FIGURE 1.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetic profile and the oral bioavailability of a single 10 mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required.

8.6 Hepatic Impairment

No dosage adjustment is recommended in patients with mild-to-moderate hepatic insufficiency [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dosage adjustment is recommended in patients with renal insufficiency [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis.



Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.

12.2 Pharmacodynamics

Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD4-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), montelukast sodium inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.



The effect of montelukast sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received montelukast sodium, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received montelukast sodium, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of montelukast sodium. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known [see Clinical Studies (14)].

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of tumorigenicity was seen in carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The estimated exposure in rats was approximately 120 and 75 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose. The estimated exposure in mice was approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose.



Montelukast demonstrated no evidence of mutagenic or clastogenic activity in the following assays: 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, and in the in vivo mouse bone marrow chromosomal aberration assay.



In fertility studies in female rats, montelukast produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was approximately 70 times the AUC for adults at the maximum recommended daily oral dose). No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for adults at the maximum recommended daily oral dose). Montelukast had no effects on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was approximately 160 times the AUC for adults at the maximum recommended daily oral dose).

14.1 Asthma

Adults and Adolescents 15 Years of Age and Older with Asthma



Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily.



The efficacy of montelukast sodium for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two (U.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with montelukast sodium, 530 treated with placebo, and 251 treated with active control). The median age was 33 years (range 15 to 85); 56.8% were females and 43.2% were males. The ethnic/racial distribution in these studies was 71.6% Caucasian, 17.7% Hispanic, 7.2% other origins and 3.5% Black. Patients had mild or moderate asthma and were non­-smokers who required approximately 5 puffs of inhaled β-agonist per day on an “as-needed” basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV1) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV1 and daytime asthma symptoms. In both studies after 12 weeks, a random subset of patients receiving montelukast sodium was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects.



The results of the U.S. trial on the primary endpoint, morning FEV1, expressed as mean percent change from baseline averaged over the 12-week treatment period, are shown in FIGURE 2. Compared with placebo, treatment with one montelukast 10 mg tablet daily in the evening resulted in a statistically significant increase in FEV1 percent change from baseline (13%-change in the group treated with montelukast sodium vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV1 for montelukast sodium was 0.32 liters compared with 0.1 liters for placebo, corresponding to a between-group difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The results of the Multinational trial on FEV1 were similar.







The effect of montelukast sodium on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 6. Results on these endpoints were similar in the U.S. study.

Both studies evaluated the effect of montelukast sodium on secondary outcomes, including asthma attack (utilization of health-care resources such as an unscheduled visit to a doctor’s office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid), and use of oral corticosteroids for asthma rescue. In the Multinational study, significantly fewer patients (15.6% of patients) on montelukast sodium experienced asthma attacks compared with patients on placebo (27.3%, p<0.001). In the U.S. study, 7.8% of patients on montelukast sodium and 10.3% of patients on placebo experienced asthma attacks, but the difference between the two treatment groups was not significant (p=0.334). In the Multinational study, significantly fewer patients (14.8% of patients) on montelukast sodium were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25.7%, p<0.001). In the U.S. study, 6.9% of patients on montelukast sodium and 9.9% of patients on placebo were prescribed oral corticosteroids for asthma rescue, but the difference between the two treatment groups was not significant (p=0.196).



Onset of Action and Maintenance of Effects



In each placebo-controlled trial in adults, the treatment effect of montelukast sodium, measured by daily diary card parameters, including symptom scores, “as-needed” β-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in non­-placebo-controlled extension trials for up to one year. Withdrawal of montelukast sodium in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma.



Pediatric Patients 6 to 14 Years of Age with Asthma



The efficacy of montelukast sodium in pediatric patients 6 to 14 years of age was demonstrated in one 8-week, double-blind, placebo-controlled trial in 336 patients (201 treated with montelukast sodium and 135 treated with placebo) using an inhaled β-agonist on an “as-needed” basis. The patients had a mean baseline percent predicted FEV1 of 72% (approximate range, 45 to 90%) and a mean daily inhaled β-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. The median age was 11 years (range 6 to 15); 35.4% were females and 64.6% were males. The ethnic/racial distribution in this study was 80.1% Caucasian, 12.8% Black, 4.5% Hispanic, and 2.7% other origins.



Compared with placebo, treatment with one 5 mg montelukast chewable tablet daily resulted in a significant improvement in mean morning FEV1 percent change from baseline (8.7% in the group treated with montelukast sodium vs. 4.2% change from baseline in the placebo group, p<0.001). There was a significant decrease in the mean percentage change in daily "as-needed" inhaled β-agonist use (11.7% decrease from baseline in the group treated with montelukast sodium vs. 8.2% increase from baseline in the placebo group, p<0.05). This effect represents a mean decrease from baseline of 0.56 and 0.23 puffs per day for the montelukast and placebo groups, respectively. Subgroup analyses indicated that younger pediatric patients aged 6 to 11 had efficacy results comparable to those of the older pediatric patients aged 12 to 14.



Similar to the adult studies, no significant change in the treatment effect was observed during continuous once-daily administration in one open-label extension trial without a concurrent placebo group for up to 6 months.



Pediatric Patients 2 to 5 Years of Age with Asthma



The efficacy of montelukast sodium for the chronic treatment of asthma in pediatric patients 2 to 5 years of age was explored in a 12-week, placebo-controlled safety and tolerability study in 689 patients, 461 of whom were treated with montelukast sodium. The median age was 4 years (range 2 to 6); 41.5% were females and 58.5% were males. The ethnic/racial distribution in this study was 56.5% Caucasian, 20.9% Hispanic, 14.4% other origins, and 8.3% Black.



While the primary objective was to determine the safety and tolerability of montelukast sodium in this age group, the study included exploratory efficacy evaluations, including daytime and overnight asthma symptom scores, β-agonist use, oral corticosteroid rescue, and the physician's global evaluation. The findings of these exploratory efficacy evaluations, along with pharmacokinetics and extrapolation of efficacy data from older patients, support the overall conclusion that montelukast sodium is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age.



Effects in Patients on Concomitant Inhaled Corticosteroids



Separate trials in adults evaluated the ability of montelukast sodium to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly.



One randomized, placebo-controlled, parallel-group trial (n=226) enrolled adults with stable asthma with a mean FEV1 of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The median age was 41.5 years (range 16 to 70); 52.2% were females and 47.8% were males. The ethnic/racial distribution in this study was 92% Caucasian, 3.5% Black, 2.2% Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone dipropionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5- to 7-week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose. Treatment with montelukast sodium resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12-week active treatment period (p≤0.05). It is not known whether the results of this study can be generalized to patients with asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids.



In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast sodium alone or placebo alone as indicated by FEV1, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-needed” β-agonist requirements.



In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated [see Warnings and Precautions (5.4)].

14.2 Exercise-Induced Bronchoconstriction (EIB)

Exercise-Induced Bronchoconstriction (Adults, Adolescents, and Pediatric Patients 6 years of age and older)



The efficacy of montelukast, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo­-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and 24 hours following administration of a single dose of study drug (montelukast 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV1 following the 2 hours post-dose exercise challenge in all three studies (Study A, Study B, and Study C). In Study A, a single dose of montelukast 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in TABLE 7 and are representative of the results from the other two studies.

The efficacy of montelukast 5 mg chewable tablets, when given as a single dose 2 hours before exercise for the prevention of EIB, was investigated in one multinational, randomized, double-blind, placebo-controlled crossover study that included a total of 64 pediatric patients 6 to 14 years of age with EIB. Exercise challenge testing was conducted at 2 hours and 24 hours following administration of a single dose of study drug (montelukast 5 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV1 following the 2 hours post-dose exercise challenge. A single dose of montelukast 5 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise (TABLE 8). Similar results were shown at 24 hours post-dose (a secondary endpoint). Some patients were protected from EIB at 24 hours after administration; however, some patients were not. No timepoints were assessed between 2 and 24 hours post-dose.

The efficacy of montelukast sodium for prevention of EIB in patients below 6 years of age has not been established.



Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.



In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics 15 years of age and older, with a mean baseline FEV1 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with montelukast, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV1 and mean time to recovery to within 5% of the pre-exercise FEV1. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. Montelukast sodium did not, however, prevent clinically significant deterioration in maximal percent fall in FEV1 after exercise (i.e., ≥20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10 mg doses of montelukast.



In pediatric patients 6 to 14 years of age, using the 5 mg chewable tablet, a 2-day crossover study demonstrated effects similar to those observed in adults when exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose).

14.3 Allergic Rhinitis (Seasonal and Perennial)

Seasonal Allergic Rhinitis



The efficacy of montelukast sodium tablets for the treatment of seasonal allergic rhinitis was investigated in 5 similarly designed, randomized, double-blind, parallel-group, placebo- and active-controlled (loratadine) trials conducted in North America. The 5 trials enrolled a total of 5029 patients, of whom 1799 were treated with montelukast sodium tablets. Patients were 15 to 82 years of age with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study entry.



The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one trial. The primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0 to 3 categorical scale.



Four of the five trials showed a significant reduction in daytime nasal symptoms scores with montelukast 10 mg tablets compared with placebo. The results of one trial are shown below. The median age in this trial was 35 years (range 15 to 81); 65.4% were females and 34.6% were males. The ethnic/racial distribution in this study was 83.1% Caucasian, 6.4% other origins, 5.8% Black, and 4.8% Hispanic. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received montelukast sodium tablets, loratadine, and placebo are shown in TABLE 9. The remaining three trials that demonstrated efficacy showed similar results. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening.

Perennial Allergic Rhinitis



The efficacy of montelukast sodium tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3357 patients, of whom 1632 received montelukast 10 mg tablets. Patients 15 to 82 years of age with perennial allergic rhinitis as confirmed by history and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry, were enrolled.



In the study in which efficacy was demonstrated, the median age was 35 years (range 15 to 81); 64.1% were females and 35.9% were males. The ethnic/racial distribution in this study was 83.2% Caucasian, 8.1% Black, 5.4% Hispanic, 2.3% Asian, and 1% other origins. Montelukast 10 mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 10); in this study the primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, and sneezing).

The other 6-week study evaluated montelukast 10 mg (n=626), placebo (n=609), and an active-control (cetirizine 10 mg; n=120). The primary analysis compared the mean change from baseline in daytime nasal symptoms score for montelukast sodium vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between montelukast sodium and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between montelukast sodium and placebo was -0.04 with a 95% CI of (-0.09, 0.01). The estimated difference between the active-control and placebo was -0.1 with a 95% CI of (-0.19, -0.01).