Montelukast Sodium (Page 6 of 8)

14.2 Exercise-Induced Bronchoconstriction (EIB)

Exercise-Induced Bronchoconstriction (Adults and Adolescents 15 years of age and older): The efficacy of montelukast sodium 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 sodium 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 sodium 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 3 and are representative of the results from the other two studies.

Table 3: Mean Maximum Percent Fall in FEV1 Following Exercise Challenge in Study A (N=47) ANOVA Model
*
Least squares‑mean

Time of exercise challenge following medication administration

Mean Maximum percent fall in FEV1 *

Treatment difference % for montelukast sodium versus placebo (95% CI)*

Montelukast Sodium

Placebo

2 hours

13

22

-9 (-12, -5)

8.5 hours

12

17

-5 (-9, -2)

24 hours

10

14

-4 (-7, -1)

Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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 sodium, 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 sodium.

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 0‑3 categorical scale.

Four of the five trials showed a significant reduction in daytime nasal symptoms scores with montelukast sodium 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 5. The remaining three trials that demonstrated efficacy showed similar results.

Table 5: Effects of Montelukast Sodium on Daytime Nasal Symptoms Score * in a Placebo- and Active-controlled Trial in Patients with Seasonal Allergic Rhinitis (ANCOVA Model)
*
Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0‑3 categorical scale.
Statistically different from placebo (p≤0.001).
The study was not designed for statistical comparison between montelukast sodium and the active control (loratadine).

Treatment Group (N)

Baseline Mean Score

Mean Change from Baseline

Difference Between Treatment and Placebo (95% CI) Least‑Squares Mean

Montelukast Sodium 10 mg (344)

2.09

-0.39

‑0.13 (‑0.21, ‑0.06)

Placebo (351)

2.1

-0.26

N.A.

Active Control (Loratadine 10 mg) (599)

2.06

-0.46

‑0.24 (‑0.31, ‑0.17)

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 sodium 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 sodium 10 mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6‑week treatment period (TABLE 6); 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 6: Effects of Montelukast Sodium on Daytime Nasal Symptoms Score * in a Placebo-controlled Trial in Patients with Perennial Allergic Rhinitis (ANCOVA Model)
*
Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0‑3 categorical scale.
Statistically different from placebo (p≤0.001).

Treatment Group (N)

Baseline Mean Score

Mean Change from Baseline

Difference Between Treatment and Placebo (95% CI) Least‑Squares Mean

Montelukast Sodium 10 mg (1000)

2.09

-0.42

‑0.08 (‑0.12, ‑0.04)

Placebo (980)

2.1

-0.35

N.A.

The other 6‑week study evaluated montelukast sodium 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).

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