Singulair Drug Information

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 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 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 (FEV 1 ) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV 1 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 results of the U.S. trial on the primary endpoint, morning FEV 1, 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 SINGULAIR 10-mg tablet daily in the evening resulted in a statistically significant increase in FEV 1 percent change from baseline (13.0%-change in the group treated with SINGULAIR vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV 1 for SINGULAIR was 0.32 liters compared with 0.10 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 FEV 1 were similar. Figure 2: FEV 1 Mean Percent Change from Baseline (U.S. Trial: SINGULAIR N=406; Placebo N=270) (ANOVA Model) The effect of SINGULAIR on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 6. Results on these endpoints were similar in the US study. Table 6: Effect of SINGULAIR on Primary and Secondary Endpoints in a Multinational Placebo-controlled Trial (ANOVA Model) SINGULAIR Placebo Endpoint N Baseline Mean Change from Baseline N Baseline Mean Change from Baseline Daytime Asthma Symptoms (0 to 6 scale) 372 2.35 -0.49 p<0.001, compared with placebo 245 2.40 -0.26 β-agonist (puffs per day) 371 5.35 -1.65 241 5.78 -0.42 AM PEFR (L/min) 372 339.57 25.03 244 335.24 1.83 PM PEFR (L/min) 372 355.23 20.13 244 354.02 -0.49 Nocturnal Awakenings (#/week) 285 5.46 -2.03 195 5.57 -0.78 Both studies evaluated the effect of SINGULAIR 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 SINGULAIR experienced asthma attacks compared with patients on placebo (27.3%, p<0.001). In the US study, 7.8% of patients on SINGULAIR 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 SINGULAIR were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25.7%, p<0.001). In the US study, 6.9% of patients on SINGULAIR 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 SINGULAIR, 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 SINGULAIR 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 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.

The patients had a mean baseline percent predicted FEV 1 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 SINGULAIR chewable tablet daily resulted in a significant improvement in mean morning FEV 1 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. 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 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. 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 SINGULAIR 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 SINGULAIR 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 SINGULAIR 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 FEV 1 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 92.0% 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 SINGULAIR 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 SINGULAIR to beclomethasone resulted in statistically significant improvements in FEV 1 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 SINGULAIR alone or placebo alone as indicated by FEV 1, 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 SINGULAIR, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of SINGULAIR in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of SINGULAIR on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated.

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 FEV 1 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. 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.

Table 7: Mean Maximum Percent Fall in FEV 1 Following Exercise Challenge in Study A (N=47) ANOVA Model Time of exercise challenge following medication administration Mean Maximum percent fall in FEV 1 Least squares-mean Treatment difference % for SINGULAIR versus Placebo (95% CI) SINGULAIR Placebo 2 hours 13 22 -9 (-12, -5) 8.5 hours 12 17 -5 (-9, -2) 24 hours 10 14 -4 (-7, -1) The efficacy of SINGULAIR 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 (SINGULAIR 5 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV 1 following the 2 hours post-dose exercise challenge. A single dose of SINGULAIR 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.

Table 8: Mean Maximum Percent Fall in FEV 1 Following Exercise Challenge in Pediatric Patients (N=64) ANOVA Model Time of exercise challenge following medication administration Mean Maximum percent fall in FEV 1 Least squares-mean Treatment difference % for SINGULAIR versus Placebo (95% CI) SINGULAIR Placebo 2 hours 15 20 -5 (-9, -1) 24 hours 13 17 -4 (-7, -1) The efficacy of SINGULAIR for prevention of EIB in patients below 6 years of age has not been established. Daily administration of SINGULAIR 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 FEV 1 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with SINGULAIR, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV 1 and mean time to recovery to within 5% of the pre-exercise FEV 1. 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. SINGULAIR did not, however, prevent clinically significant deterioration in maximal percent fall in FEV 1 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 SINGULAIR. 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).

Allergic Rhinitis (Seasonal and Perennial) 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.

The results of one trial are shown below. The median age in this trial was 35.0 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 SINGULAIR 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. Table 9: Effects of SINGULAIR on Daytime Nasal Symptoms Score Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0-3 categorical scale. in a Placebo- and Active-controlled Trial in Patients with Seasonal Allergic Rhinitis (ANCOVA Model) Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean SINGULAIR 10 mg 2.09 -0.39 -0.13 Statistically different from placebo (p≤0.001). (-0.21, -0.06) Placebo 2.10 -0.26 N.A. Active Control The study was not designed for statistical comparison between SINGULAIR and the active control (loratadine). (Loratadine 10 mg) 2.06 -0.46 -0.24 (-0.31, -0.17) 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. 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 1.0% other origins. SINGULAIR 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). Table 10: Effects of SINGULAIR on Daytime Nasal Symptoms Score Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0-3 categorical scale. in a Placebo-controlled Trial in Patients with Perennial Allergic Rhinitis (ANCOVA Model) Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean SINGULAIR 10 mg 2.09 -0.42 -0.08 Statistically different from placebo (p≤0.001). (-0.12, -0.04) Placebo 2.10 -0.35 N.A. The other 6-week study evaluated SINGULAIR 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 SINGULAIR vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between SINGULAIR and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing.

The estimated difference between SINGULAIR and placebo was -0.04 with a 95% CI of (-0.09, 0.01). The estimated difference between the active-control and placebo was -0.10 with a 95% CI of (-0.19, -0.01). image of figure 2