Montelukast Sodium (Page 6 of 10)

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

No teratogenicity was observed at oral doses up to 400 mg/kg/day and 300 mg/kg/day in rats and rabbits, respectively. These doses were approximately 100 and 110 times the maximum recommended daily oral dose in adults, respectively, based on AUCs. Montelukast crosses the placenta following oral dosing in rats and rabbits [see Pregnancy (8.1)].

14 CLINICAL STUDIES

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 sodium 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 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 0.10 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 FEV1 were similar.

Figure 2: FEV1 Mean Percent Change from Baseline
(U.S. Trial: montelukast sodium N=406; Placebo N=270)
(ANOVA Model)

Figure 2

The effect of montelukast sodium on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 2. Results on these endpoints were similar in the US study.

Table 2: Effect of montelukast sodium on Primary and Secondary Endpoints in a Multinational Placebo-controlled Trial (ANOVA Model)

Montelukast Sodium 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*

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

* p<0.001, compared with placebo

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 US 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 US 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.

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