Fluticasone Propionate and Salmeterol DISKUS (Page 10 of 13)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone Propionate

Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 5 and 10 times the MRHDID for adults and children, respectively, on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than and approximately equivalent to the MRHDID for adults and children, respectively, on a mcg/m2 basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test.

Fertility and reproductive performance were unaffected in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 0.5 times the MRHDID for adults on a mcg/m2 basis).

Salmeterol

In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1,400 mcg/kg and above (approximately 20 times the MRHDID for adults and children based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 200 mcg/kg (approximately 3 times the MRHDID for adults and children based on comparison of the AUCs).

In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 680 mcg/kg and above (approximately 66 and 35 times the MRHDID for adults and children, respectively, on a mcg/m2 basis). No tumors were seen at 210 mcg/kg (approximately 20 and 10 times the MRHDID for adults and children, respectively, on a mcg/m2 basis). These findings in rodents are similar to those reported previously for other beta‑adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test.

Fertility and reproductive performance were unaffected in male and female rats at oral doses up to 2,000 mcg/kg (approximately 195 times the MRHDID for adults on a mcg/m2 basis).

13.2 Animal Toxicology and/or Pharmacology

Preclinical

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.

14 CLINICAL STUDIES

14.1 Asthma

Adult and Adolescent Subjects Aged 12 Years and Older

In clinical trials comparing fluticasone propionate/salmeterol DISKUS with its individual components, improvements in most efficacy endpoints were greater with fluticasone propionate/salmeterol DISKUS than with the use of either fluticasone propionate or salmeterol alone. In addition, clinical trials showed similar results between fluticasone propionate/salmeterol DISKUS and the concurrent use of fluticasone propionate plus salmeterol at corresponding doses from separate inhalers.

Trials Comparing Fluticasone Propionate/Salmeterol DISKUS with Fluticasone Propionate Alone or Salmeterol Alone: Three (3) double-blind, parallel-group clinical trials were conducted with fluticasone propionate/salmeterol DISKUS in 1,208 adult and adolescent subjects (aged 12 years and older, baseline FEV1 63% to 72% of predicted normal) with asthma that was not optimally controlled on their current therapy. All treatments were inhalation powders given as 1 inhalation from the DISKUS inhaler twice daily, and other maintenance therapies were discontinued.

Trial 1: Clinical Trial with Fluticasone Propionate/Salmeterol DISKUS 100/50 mcg: This placebo-controlled, 12-week, U.S. trial compared fluticasone propionate/salmeterol DISKUS 100/50 mcg with its individual components, fluticasone propionate 100 mcg and salmeterol 50 mcg. The trial was stratified according to baseline asthma maintenance therapy; subjects were using either ICS (n = 250) (daily doses of beclomethasone dipropionate 252 to 420 mcg; flunisolide 1,000 mcg; fluticasone propionate inhalation aerosol 176 mcg; or triamcinolone acetonide 600 to 1,000 mcg) or salmeterol (n = 106). Baseline FEV1 measurements were similar across treatments: fluticasone propionate/salmeterol DISKUS 100/50 mcg, 2.17 L; fluticasone propionate 100 mcg, 2.11 L; salmeterol, 2.13 L; and placebo, 2.15 L.

Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled trial. Worsening asthma was defined as a clinically important decrease in FEV1 or PEF, increase in use of VENTOLIN (albuterol, USP) Inhalation Aerosol, increase in night awakenings due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. As shown in Table 4, statistically significantly fewer subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo.

Table 4. Percent of Subjects Withdrawn due to Worsening Asthma in Subjects Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)

Fluticasone Propionate/

Salmeterol DISKUS

100/50 mcg

(n = 87)

Fluticasone

Propionate

100 mcg

(n = 85)

Salmeterol

50 mcg

(n = 86)

Placebo

(n = 77)

3%

11%

35%

49%

The FEV1 results are displayed in Figure 1. Because this trial used predetermined criteria for worsening asthma, which caused more subjects in the placebo group to be withdrawn, FEV1 results at Endpoint (last available FEV1 result) are also provided. Subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg had significantly greater improvements in FEV1 (0.51 L, 25%) compared with fluticasone propionate 100 mcg (0.28 L, 15%), salmeterol (0.11 L, 5%), and placebo (0.01 L, 1%). These improvements in FEV1 with fluticasone propionate/salmeterol DISKUS were achieved regardless of baseline asthma maintenance therapy (ICS or salmeterol).

Figure 1. Mean Percent Change from Baseline in FEV1 in Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)

Figure 1. Mean Percent Change from Baseline in FEV1 in Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)
(click image for full-size original)

The effect of fluticasone propionate/salmeterol DISKUS 100/50 mcg on morning and evening PEF endpoints is shown in Table 5.

Table 5. Peak Expiratory Flow Results for Subjects with Asthma Previously Treated with Either Inhaled Corticosteroids or Salmeterol (Trial 1)

Efficacy Variablea

Fluticasone Propionate/ Salmeterol DISKUS

100/50 mcg

(n = 87)

Fluticasone Propionate

100 mcg

(n = 85)

Salmeterol

50 mcg

(n = 86)

Placebo

(n = 77)

AM PEF (L/min)

Baseline

393

374

369

382

Change from baseline

53

17

-2

-24

PM PEF (L/min)

Baseline

418

390

396

398

Change from baseline

35

18

-7

-13

a Change from baseline = change from baseline at Endpoint (last available data).

The subjective impact of asthma on subjects’ perception of health was evaluated through use of an instrument called the Asthma Quality of Life Questionnaire (AQLQ) (based on a 7-point scale where 1 = maximum impairment and 7 = none). Subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg had clinically meaningful improvements in overall asthma-specific quality of life as defined by a difference between groups of ≥0.5 points in change from baseline AQLQ scores (difference in AQLQ score of 1.25 compared with placebo).

Trial 2: Clinical Trial with Fluticasone Propionate/Salmeterol DISKUS 250/50 mcg: This placebo-controlled, 12-week, U.S. trial compared fluticasone propionate/salmeterol DISKUS 250/50 mcg with its individual components, fluticasone propionate 250 mcg and salmeterol 50 mcg, in 349 subjects with asthma using ICS (daily doses of beclomethasone dipropionate 462 to 672 mcg; flunisolide 1,250 to 2,000 mcg; fluticasone propionate inhalation aerosol 440 mcg; or triamcinolone acetonide 1,100 to 1,600 mcg). Baseline FEV1 measurements were similar across treatments: fluticasone propionate/salmeterol DISKUS 250/50 mcg, 2.23 L; fluticasone propionate 250 mcg, 2.12 L; salmeterol, 2.20 L; and placebo, 2.19 L.

Efficacy results in this trial were similar to those observed in Trial 1. Subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg had significantly greater improvements in FEV1 (0.48 L, 23%) compared with fluticasone propionate 250 mcg (0.25 L, 13%), salmeterol (0.05 L, 4%), and placebo (decrease of 0.11 L, decrease of 5%). Statistically significantly fewer subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg were withdrawn from this trial for worsening asthma (4%) compared with fluticasone propionate (22%), salmeterol (38%), and placebo (62%). In addition, fluticasone propionate/salmeterol DISKUS 250/50 mcg was superior to fluticasone propionate, salmeterol, and placebo for improvements in morning and evening PEF. Subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg also had clinically meaningful improvements in overall asthma-specific quality of life as described in Trial 1 (difference in AQLQ score of 1.29 compared with placebo).

Trial 3: Clinical Trial with Fluticasone Propionate/Salmeterol DISKUS 500/50 mcg: This 28-week, non-U.S. trial compared fluticasone propionate/salmeterol DISKUS 500/50 mcg with fluticasone propionate 500 mcg alone and concurrent therapy (salmeterol 50 mcg plus fluticasone propionate 500 mcg administered from separate inhalers) twice daily in 503 subjects with asthma using ICS (daily doses of beclomethasone dipropionate 1,260 to 1,680 mcg; budesonide 1,500 to 2,000 mcg; flunisolide 1,500 to 2,000 mcg; or fluticasone propionate inhalation aerosol 660 to 880 mcg [750 to 1,000 mcg inhalation powder]). The primary efficacy parameter, morning PEF, was collected daily for the first 12 weeks of the trial. The primary purpose of weeks 13 to 28 was to collect safety data.

Baseline PEF measurements were similar across treatments: fluticasone propionate/salmeterol DISKUS 500/50 mcg, 359 L/min; fluticasone propionate 500 mcg, 351 L/min; and concurrent therapy, 345 L/min. Morning PEF improved significantly with fluticasone propionate/salmeterol DISKUS 500/50 mcg compared with fluticasone propionate 500 mcg over the 12-week treatment period. Improvements in morning PEF observed with fluticasone propionate/salmeterol DISKUS 500/50 mcg were similar to improvements observed with concurrent therapy.

Onset of Action and Progression of Improvement in Asthma Control: The onset of action and progression of improvement in asthma control were evaluated in the 2 placebo-controlled U.S. trials. Following the first dose, the median time to onset of clinically significant bronchodilatation (≥15% improvement in FEV1 ) in most subjects was seen within 30 to 60 minutes. Maximum improvement in FEV1 generally occurred within 3 hours, and clinically significant improvement was maintained for 12 hours (Figure 2). Following the initial dose, predose FEV1 relative to Day 1 baseline improved markedly over the first week of treatment and continued to improve over the 12 weeks of treatment in both trials. No diminution in the 12-hour bronchodilator effect was observed with either fluticasone propionate/salmeterol DISKUS 100/50 mcg (Figures 2 and 3) or fluticasone propionate/salmeterol DISKUS 250/50 mcg as assessed by FEV1 following 12 weeks of therapy.

Figure 2. Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Trial 1)

First Treatment Day

Figure 2. Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Trial 1)
(click image for full-size original)

Figure 3. Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Trial 1)

Last Treatment Day (Week 12)

Figure 3. Percent Change in Serial 12-Hour FEV1 in Subjects with Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Trial 1)
(click image for full-size original)

Reduction in asthma symptoms and use of rescue VENTOLIN Inhalation Aerosol and improvement in morning and evening PEF also occurred within the first day of treatment with fluticasone propionate/salmeterol DISKUS, and continued to improve over the 12 weeks of therapy in both trials.

Pediatric Subjects

In a 12-week U.S. trial, fluticasone propionate/salmeterol DISKUS 100/50 mcg twice daily was compared with fluticasone propionate inhalation powder 100 mcg twice daily in 203 children with asthma aged 4 to 11 years. At trial entry, the children were symptomatic on low doses of ICS (beclomethasone dipropionate 252 to 336 mcg/day; budesonide 200 to 400 mcg/day; flunisolide 1,000 mcg/day; triamcinolone acetonide 600 to 1,000 mcg/day; or fluticasone propionate 88 to 250 mcg/day). The primary objective of this trial was to determine the safety of fluticasone propionate/salmeterol DISKUS 100/50 mcg compared with fluticasone propionate inhalation powder 100 mcg in this age group; however, the trial also included secondary efficacy measures of pulmonary function. Morning predose FEV1 was obtained at baseline and Endpoint (last available FEV1 result) in children aged 6 to 11 years. In subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg, FEV1 increased from 1.70 L at baseline (n = 79) to 1.88 L at Endpoint (n = 69) compared with an increase from 1.65 L at baseline (n = 83) to 1.77 L at Endpoint (n = 75) in subjects receiving fluticasone propionate 100 mcg.

The findings of this trial, along with extrapolation of efficacy data from subjects aged 12 years and older, support the overall conclusion that fluticasone propionate/salmeterol DISKUS 100/50 mcg is efficacious in the treatment of asthma in subjects aged 4 to 11 years.

Safety and Efficacy Trials Comparing Fluticasone Propionate/Salmeterol DISKUS with Fluticasone Propionate

Serious Asthma-Related Events: Two 26-week, randomized, double-blind, parallel-group, active comparator trials were conducted to compare the safety and efficacy of fluticasone propionate/salmeterol DISKUS with fluticasone propionate inhalation powder in adult and adolescent subjects (Trial 4, NCT01475721) and in pediatric subjects aged 4 to 11 years (Trial 5, NCT01462344). The primary safety objective of both trials was to evaluate whether the addition of salmeterol xinafoate to fluticasone propionate therapy (fluticasone propionate/salmeterol DISKUS) was non-inferior to ICS fluticasone propionate in terms of the risk of a serious asthma-related event (hospitalization, endotracheal intubation, and death). The trials were designed to rule out pre-defined risk margins for serious asthma‑related events of 2.0 for Trial 4 and 2.7 for Trial 5. A blinded adjudication committee determined whether events were asthma related.

Trial 4 enrolled subjects with moderate to severe persistent asthma with a history of asthma‑related hospitalization or at least 1 asthma exacerbation in the previous year treated with systemic corticosteroids. A total of 11,679 adult and adolescent subjects [5,834 receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg, fluticasone propionate/salmeterol DISKUS 250/50 mcg, or fluticasone propionate/salmeterol DISKUS 500/50 mcg and 5,845 receiving fluticasone propionate inhalation powder (100, 250, or 500 mcg)] were included. Trial 5 enrolled subjects with a diagnosis of asthma and a history of at least 1 asthma exacerbation in the previous year treated with systemic corticosteroid. A total of 6,208 subjects aged 4 to 11 years [3,107 receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg or fluticasone propionate/salmeterol DISKUS 250/50 mcg and 3,101 receiving fluticasone propionate inhalation powder (100 or 250 mcg)] were included. In both trials, subjects with life-threatening asthma were excluded. In Trials 4 and 5, fluticasone propionate/salmeterol DISKUS was non-inferior to fluticasone propionate in terms of time to first serious asthma‑related events based on the pre-specified risk margins, with estimated hazard ratios of 1.03 (95% CI: 0.64, 1.66) and 1.29 (95% CI: 0.73, 2.27), respectively (Table 6).

Table 6. Serious Asthma-Related Events in the 26-Week Trials 4 and 5
a Number of subjects with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug treatment, whichever date was later. Subjects can have one or more events, but only the first event was counted for analysis. A blinded adjudication committee determined whether events were asthma related.b The hazard ratio for time to first event was based on a Cox proportional hazards model with a single covariate of treatment (fluticasone propionate/salmeterol DISKUS vs. fluticasone propionate) and baseline hazards stratified by incoming asthma medication/asthma control status. If the resulting upper 95% CI estimate for the relative risk was <2.0 (Trial 4) or <2.7 (Trial 5), then non-inferiority was concluded.

Adult and Adolescent Subjects Aged 12 Years and Older (Trial 4)

Pediatric Subjects Aged 4 to 11 Years (Trial 5)

Fluticasone Propionate/ Salmeterol DISKUS

(n = 5,834)

Fluticasone Propionate Inhalation Powder

(n = 5,845)

Fluticasone Propionate/ Salmeterol DISKUS

(n = 3,107)

Fluticasone Propionate Inhalation Powder

(n = 3,101)

Serious asthma-related event (hospitalization, endotracheal intubation, and death)a

34 (0.6%)

33 (0.6%)

27 (0.9%)

21 (0.7%)

Hazard ratio (Fluticasone propionate/salmeterol DISKUS/fluticasone propionate)

1.03

(0.64-1.66)b

1.29

(0.73-2.27)b

Asthma-related death

0

0

0

0

Asthma-related intubation (endotracheal)

0

2

0

0

Asthma-related hospitalization (≥24-hour stay)

34

33

27

21

Effect on Exacerbation: Trials 4 and 5 included time to first exacerbation as a secondary endpoint, where exacerbation was defined as a deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. In Trials 4 and 5, the hazard ratio for the time to first asthma exacerbation for fluticasone propionate/salmeterol DISKUS relative to fluticasone propionate inhalation powder was 0.79 (95% CI: 0.70, 0.89) and 0.86 (95% CI: 0.73, 1.01), respectively. The difference in exacerbations was primarily driven by a reduction in those requiring systemic corticosteroids only.

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