General Information

Singulair (montelukast sodium) is a leukotriene receptor antagonist.

Singulair is specifically indicated for:

• Prophylaxis and chronic treatment of asthma in patients 12 months of age and older
• Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older
• Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older
• Perennial allergic rhinitis (PAR) in patients 6 months of age and older.

Reserve use for patients who have an inadequate response or intolerance to alternative therapies.

Singulair is supplied as tablets, oral chewable tablets and oral granules. Dosing is as follows:

Administration (by indications):

• Asthma: Once daily in the evening for patients 12 months and older
• Acute prevention of EIB: One tablet at least 2 hours before exercise for patients 6 years of age and older
• Seasonal allergic rhinitis: Once daily for patients 2 years and older
• Perennial allergic rhinitis: Once daily for patients 6 months and older

Dosage (by age):

• 15 years and older: one 10-mg tablet
• 6 to 14 years: one 5-mg chewable tablet
• 2 to 5 years: one 4-mg chewable tablet or one packet of 4-mg oral granules
• 6 to 23 months: one packet of 4-mg oral granules

Patients with both asthma and allergic rhinitis should take only one dose daily in the evening. For oral granules: Must administer within 15 minutes after opening the packet (with or without mixing with food).

Mechanism of Action

Singulair (montelukast sodium) is a leukotriene receptor antagonist. 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 earlyand late-phase reactions and are associated with symptoms of allergic rhinitis.

Side Effects

Adverse effects may include the following:

• upper respiratory infection
• fever
• headache
• pharyngitis
• cough
• abdominal pain
• diarrhea
• otitis media
• influenza
• rhinorrhea
• sinusitis
• otitis

Clinical Trial Results

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 SINGULAIR 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 SINGULAIR, 530 treated with placebo, and 251 treated with active control). The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV1 ) of 66% 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 SINGULAIR was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects. The primary endpoint was morning FEV1 , expressed as mean percent change from baseline averaged over the 12-week treatment period. Compared with placebo, treatment with one SINGULAIR 10-mg tablet daily in the evening resulted in a statistically significant increase in FEV1 percent change from baseline (13.0%-change in the group treated with SINGULAIR vs. 4.2%-change in the placebo group); the change from baseline in FEV1 for SINGULAIR was 0.32 liters compared with 0.10 liters for placebo, corresponding to a between-group difference of 0.22 liters. The results of the Multinational trial on FEV1 were similar.

Pediatric Patients 6 to 14 Years of Age with Asthma

The efficacy of SINGULAIR 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 SINGULAIR and 135 treated with placebo) using an inhaled β-agonist on an “as-needed” basis. Compared with placebo, treatment with one 5-mg SINGULAIR chewable tablet daily resulted in a significant improvement in mean morning FEV1 percent change from baseline (8.7% in the group treated with SINGULAIR 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 SINGULAIR 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.

Pediatric Patients 2 to 5 Years of Age with Asthma

The efficacy of SINGULAIR 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 SINGULAIR. While the primary objective was to determine the safety and tolerability of SINGULAIR in this age group, the study included exploratory efficacy evaluations, including daytime and overnight asthma symptom scores, -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 SINGULAIR is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age.

Exercise-Induced Bronchoconstriction (EIB)

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

The efficacy of SINGULAIR, 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 (SINGULAIR 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 SINGULAIR 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.

Seasonal Allergic Rhinitis

The efficacy of SINGULAIR 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 SINGULAIR 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 0-3 categorical scale. Four of the five trials showed a significant reduction in daytime nasal symptoms scores with SINGULAIR 10-mg tablets compared with placebo.

Perennial Allergic Rhinitis

The efficacy of SINGULAIR 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 SINGULAIR 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. SINGULAIR 10-mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period; 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).