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Safe usage with maintenance of efficacy for periods up to 1 year has been documented. SEREVENT DISKUS and SEREVENT ® (salmeterol xinafoate) Inhalation Aerosol were compared to placebo in 2 additional randomized, double-blind clinical trials in adolescent and adult patients with mild-to-moderate asthma. SEREVENT DISKUS 50 mcg and SEREVENT Inhalation Aerosol 42 mcg, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period. While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results. Similar findings were noted in 2 randomized, single-dose, crossover comparisons of SEREVENT DISKUS and SEREVENT Inhalation Aerosol for the prevention of exercise-induced bronchospasm (EIB). Therefore, while SEREVENT DISKUS was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate patients with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all patients. In a randomized, double-blind, controlled study (N = 449), 50 mcg of SEREVENT DISKUS was administered twice daily to pediatric patients with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to periodic serial peak expiratory flow (PEF) (36% to 39% postdose increase from baseline) and FEV1 (32% to 33% postdose increase from baseline). Salmeterol was effective in demographic subgroup analyses (gender and age) and was effective when coadministered with other inhaled asthma medications such as short-acting bronchodilators and inhaled corticosteroids. A second randomized, double-blind, placebo-controlled study (N = 207) with 50 mcg of salmeterol inhalation powder via an alternate device supported the findings of the trial with the DISKUS. Text Continues Below
Effects in Patients With Asthma on Concomitant Inhaled Corticosteroids: In 4 clinical trials in adult and adolescent patients with asthma (N = 1,922), the effect of adding salmeterol to inhaled corticosteroid therapy was evaluated. The studies utilized the inhalation aerosol formulation of salmeterol xinafoate for a treatment period of 6 months. They compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose. Two randomized, double-blind, controlled, parallel-group clinical trials (N = 997) enrolled patients (ages 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all patients were switched to beclomethasone dipropionate 168 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of beclomethasone dipropionate to 336 mcg twice daily. As compared to the doubled dose of beclomethasone dipropionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of patients who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the group receiving SEREVENT Inhalation Aerosol versus 17.9% in the higher dose beclomethasone dipropionate group). Two randomized, double-blind, parallel-group clinical trials (N = 925) enrolled patients (ages 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior therapy. During the 2-to 4-week run-in period, all patients were switched to fluticasone propionate 88 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared to the increased (2.5 times) dose of fluticasone propionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reductions in supplemental albuterol use. Fewer patients receiving SEREVENT Inhalation Aerosol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%). Exercise-Induced Bronchospasm: In 2 randomized, single-dose, crossover studies in adolescents and adults with EIB (N = 53), 50 mcg of SEREVENT DISKUS prevented EIB when
dosed 30 minutes prior to exercise. For many patients, this protective effect against EIB was still apparent up to 8.5 hours following a single dose. Table 2. Results of 2 Exercise-Induced Bronchospasm Studies in Adolescents and Adults Placebo (N = 52) SEREVENT DISKUS (N = 52) n % Total n % Total 0.5-Hour postdose exercise challenge
% Fall in FEV1 <10% 10%, <20% 20%
15 3 34
29 6 65
31 11 10
60 21 19
Mean maximal % fall in FEV1 (SE) -25% (1.8) -11% (1.9) 8.5-Hour postdose exercise challenge
% Fall in FEV1 <10% 10%, <20% 20%
12 7 33
23 13 63
26 12 14
50 23 27
Mean maximal % fall in FEV1 (SE) -27% (1.5) -16% (2.0)
In 2 randomized studies in children 4 to 11 years old with asthma and EIB (N = 50), a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many patients. Salmeterol Multi-center Asthma Research Trial: The Salmeterol Multi-center Asthma Research Trial (SMART) enrolled long-acting beta2-agonist–naive patients with asthma (average age of 39 years, 71% Caucasian, 18% African-American, 8% Hispanic) to assess the safety of salmeterol (SEREVENT Inhalation Aerosol, 42 mcg twice daily over 28 weeks) compared to placebo when added to usual asthma therapy. The primary endpoint was the combined number of respiratory-related deaths or respiratory-related life-threatening experiences (intubation and mechanical ventilation). Other endpoints included combined asthma-related deaths or life-threatening experiences and asthma-related deaths. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,353). Due to the low rate of primary events in the study, the findings of the planned interim analysis were not conclusive. The analysis showed no significant difference for the primary endpoint for the total population. However, a higher number of asthma-related deaths or life-threatening experiences (36 vs. 23) and a higher number of asthma-related deaths (13 vs. 4) occurred in the patients treated with salmeterol. Post hoc subgroup analyses revealed no significant increase in respiratory-or asthma-related episodes, including deaths, in Caucasian patients. In African-Americans, the study showed a small, though statistically significantly greater, number of primary events (20 vs. 7), asthma-related deaths or life-threatening experiences (19 vs. 4), and asthma-related deaths (8 vs. 1) in patients taking salmeterol compared to those taking placebo. The numbers of patients from other ethnic groups were too small to draw any conclusions these populations. Even though SMART did not reach predetermined stopping criteria for the total population, the study was stopped due to the findings in African-American patients and difficulties in enrollment. Chronic Obstructive Pulmonary Disease: In 2 clinical trials evaluating twice-daily treatment with SEREVENT DISKUS 50 mcg (N = 336) compared to placebo (N = 366) in patients with chronic bronchitis with airflow limitation, with or without emphysema, improvements in pulmonary function endpoints were greater with salmeterol 50 mcg than with placebo. Treatment with SEREVENT DISKUS did not result in significant improvements in secondary endpoints assessing COPD symptoms in either clinical trial. Both trials were randomized, double-blind, parallel-group studies of 24 weeks’ duration and were identical in design, patient entrance criteria, and overall conduct. Figure 2 displays the integrated 2-hour postdose FEV1 results from the 2 clinical trials. The percent change in FEV1 refers to the change from baseline, defined as the predose value on Treatment Day 1. To account for patient withdrawals during the study, Endpoint (last evaluable FEV1) data are provided. Patients receiving SEREVENT DISKUS 50 mcg had significantly greater improvements in 2-hour postdose FEV1 at Endpoint (216 mL, 20%) compared to placebo (43 mL, 5%). Improvement was apparent on the first day of treatment and maintained throughout the 24 weeks of treatment. Figure 2. Mean Percent Change From Baseline in Postdose FEV1 Integrated Data From 2 Trials of Patients With Chronic Bronchitis and Airflow Limitation Onset of Action and Duration of Effect: The onset of action and duration of effect of SEREVENT DISKUS were evaluated in a subset of patients (n = 87) from 1 of the 2 clinical trials discussed above. Following the first 50-mcg dose, significant improvement in pulmonary function (mean FEV1 increase of 12% or more and at least 200 mL) occurred at 2 hours. The mean time to peak bronchodilator effect was 4.75 hours. As seen in Figure 3, evidence of bronchodilatation was seen throughout the 12-hour period. Figure 3 also demonstrates that the bronchodilating effect after 12 weeks of treatment was similar to that observed after the first dose. The mean time to peak bronchodilator effect after 12 weeks of treatment was 3.27 hours. Figure 3. Serial 12-Hour FEV1 on the First Day and at Week 12 of Treatment
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