Singulair - Clinical Pharmacology

(Page 5)

Drug Interactions

Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state:

° did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate).

° did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP 2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio).

° did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin.

° did not change the plasma concentration profile of terfenadine (a substrate of CYP 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at doses of 100 mg daily dosed to pharmacokinetic steady state:

° did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ ethinyl estradiol 35 mcg.

° did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for SINGULAIR is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with SINGULAIR.

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), SINGULAIR inhibited early-and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of SINGULAIR on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received SINGULAIR, 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 SINGULAIR, 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 SINGULAIR. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known (see CLINICAL PHARMACOLOGY, Clinical Studies).

Clinical Studies – Asthma and Seasonal Allergic Rhinitis

GENERAL

There have been no clinical trials in asthmatics to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. Clinical Studies – Asthma

ADULTS AND ADOLESCENTS 15 YEARS OF AGE AND OLDER

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. This was shown in two chronic asthma trials using doses up to 200 mg once daily and in one exercise challenge study using doses up to 50 mg, evaluated at the end of the once-daily dosing interval. 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 studied were mild and moderate, non-smoking asthmatics who required approximately 5 puffs of inhaled -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. Secondary endpoints included morning and evening peak expiratory flow rates (AM PEFR, PM PEFR), rescue -agonist requirements, nocturnal awakening due to asthma, and other asthma-related outcomes. 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, FEV1 , expressed as mean percent change from baseline, are shown in FIGURE 1.

FIGURE 1 FEV1 Mean Percent Change from Baseline

(U. S. Trial)

The effect of SINGULAIR on other primary and secondary endpoints is shown in TABLE 1 as combined analyses of the U. S. and Multinational trials.

TABLE 1

Effect of SINGULAIR on Primary and Secondary Endpoints

in Placebo-controlled Trials

(Combined Analyses -U. S. and Multinational Trials)

SINGULAIR Placebo

Endpoint Baseline Mean

Change

from

Baseline

Baseline Mean

Change

from

Baseline

Daytime Asthma Symptoms

(0 to 6 scale)

2.43 -0.45* 2.45 -0.22

-agonist (puffs per day) 5.38 -1.56* 5.55 -0.41 AM PEFR (L/ min) 361.3 24.5* 364.9 3. 3

PM PEFR (L/ min) 385.2 17.9* 389.3 2. 0

Nocturnal Awakenings

(#/ week)

5.37 -1.84* 5.44 -0.79

* p< 0.001, compared with placebo

In adult patients, SINGULAIR reduced " as-needed" -agonist use by 26.1% from baseline compared with 4.6% for placebo. In patients with nocturnal awakenings of at least 2 nights per week, SINGULAIR reduced the nocturnal awakenings by 34% from baseline, compared with 15% for placebo (combined analysis). SINGULAIR, compared with placebo, significantly improved other protocol-defined, asthma-related outcome measurements (see TABLE 2).

TABLE 2

Effect of SINGULAIR on Asthma-Related Outcome Measurements

(Combined Analyses -U. S. and Multinational Trials)

SINGULAIR Placebo

Asthma Attack* (% of patients) 11.6 * 18.4

Oral Corticosteroid Rescue (% of patients) 10.7 * 17.5

Discontinuation Due to Asthma (% of patients) 1.4 * 4.0

Asthma Exacerbations** (% of days) 12.8 * 20.5

Asthma Control Days*** (% of days) 38.5 * 27.2

Physicians' Global Evaluation (score) § 1.77 * 2.43

Patients' Global Evaluation (score) §§ 1.60 * 2.15

* p< 0.001, compared with placebo

* p< 0.01, compared with placebo

SINGULAIR ® 9088817 (Montelukast Sodium)

Tablets, Chewable Tablets, and Oral Granules

* Asthma Attack defined as 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.

** Asthma Exacerbation defined by specific clinically important decreases in PEFR, increase in -agonist use, increases in day or nighttime symptoms, or the occurrence of an asthma attack.

*** An Asthma Control Day defined as a day without any of the following: nocturnal awakening, use of more than 2 puffs of -agonist, or an asthma attack. §

Physicians' evaluation of the patient's asthma, ranging from 0 to 6 (" very much better" through " very much worse" , respectively). §§

Patients' evaluation of asthma, ranging from 0 to 6 (" very much better" through " very much worse" , respectively).

In one of these trials, a non-U. S. formulation of inhaled beclomethasone dipropionate dosed at 200 mcg (two puffs of 100 mcg ex-valve) twice daily with a spacer device was included as an active control. Over the 12-week treatment period, the mean percentage change in FEV1 over baseline for SINGULAIR and beclomethasone were 7.49% vs 13.3% (p< 0.001) respectively, see FIGURE 2; and the change in daytime symptom scores was -0. 49 vs -0. 70 on a 0 to 6 scale (p< 0.001) for SINGULAIR and beclomethasone, respectively. The percentages of individual patients treated with SINGULAIR or beclomethasone achieving any given percentage change in FEV1 from baseline are shown in FIGURE 3.

FIGURE 2 FIGURE 3 FEV1 FEV1

Mean Percent Change From Baseline Distribution of Individual Patient Response (Multinational Trial) (Multinational Trial)

Onset of Action and Maintenance of Benefits

In each placebo-controlled trial in adults, the treatment effect of SINGULAIR, measured by daily diary card parameters, including symptom scores, " as-needed" -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

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 -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 -agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. 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 -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. SINGULAIR, one 5-mg chewable tablet daily at bedtime, significantly decreased the percent of days asthma exacerbations occurred (SINGULAIR 20.6% vs placebo 25.7%, p 0.05). (See TABLE 2 for definition of asthma exacerbation.) Parents' global asthma evaluations (parental evaluations of the patients' asthma, see TABLE 2 for definition of score) were significantly better with SINGULAIR compared with placebo (SINGULAIR 1.34 vs placebo 1.69, p 0.05). 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

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.

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 stable asthmatic adults 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 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 exactuator.

The prestudy 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). Approximately 40% of the montelukast-treated patients and 29% of the placebo-treated patients could be tapered off inhaled corticosteroids and remained off inhaled corticosteroids at the conclusion of the study (p= NS).

It is not known whether the results of this study can be generalized to asthmatics 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 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 SINGULAIR alone or placebo alone as indicated by FEV1 , daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and " as-needed" -agonist requirements. In adult asthmatic patients 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 asthmatic 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 (see PRECAUTIONS, General).

EFFECTS ON EXERCISE-INDUCED BRONCHOCONSTRICTION (ADULTS AND PEDIATRIC PATIENTS)

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 SINGULAIR, 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. SINGULAIR 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 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). SINGULAIR should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled -agonists as prophylaxis and have available for rescue a short-acting inhaled -agonist (see PRECAUTIONS, General and Information for Patients).

Clinical Studies – 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 efficacy results of one trial are shown below; the remaining three trials that demonstrated efficacy showed similar results. 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 3.

TABLE 3

Effects of SINGULAIR on Daytime Nasal Symptoms Score* in a Placebo-and Active-controlled Trial

in Patients with Seasonal Allergic Rhinitis

Treatment Group (N) Baseline Mean Score Mean Change from Baseline

Difference Between Treatment

and Placebo (95% CI)

Least-Squares Mean

SINGULAIR 10 mg

(344) 2.09 -0.39 -0.13

* (-0.21, -0.06)

Placebo

(351) 2.10 -0.26 N. A.

Active Control *

(Loratadine 10 mg)

(599)

2.06 -0.46 -0.24 * (-0.31, -0.17)

* Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0-3 categorical scale. *

The study was not designed for statistical comparison between SINGULAIR and the active control (loratadine). *

Statistically different from placebo (p 0.001).

SINGULAIR ® 9088817 (Montelukast Sodium)

Tablets, Chewable Tablets, and Oral Granules