The population pharmacokinetic analysis included 160 patients with asthma aged 4 to 11 years who received ADVAIR DISKUS 100/50 or FLOVENT DISKUS 100 mcg. Higher fluticasone propionate exposure (AUC) was observed in children from ADVAIR DISKUS 100/50 compared with FLOVENT DISKUS 100 mcg (ratio 1.20 [90% CI: 1.06, 1.37]). Higher fluticasone propionate exposure (AUC) from ADVAIR DISKUS 100/50 was observed in children compared with adolescents and adults (ratio 1.63 [90% CI: 1.35, 1.96]). However, in clinical studies of up to 12 weeks' duration comparing ADVAIR DISKUS 100/50 and FLOVENT DISKUS 100 mcg in both adolescents and adults and in children, no differences in systemic effects of corticosteroid treatment (e.g., HPA axis effects) were observed.

Exposure to salmeterol was higher in children compared with adolescents and adults who received ADVAIR DISKUS 100/50 (ratio 1.23 [90% CI: 1.10, 1.38]). However, in clinical studies of up to 12 weeks' duration with ADVAIR DISKUS 100/50 in both adolescents and adults and in children, no differences in systemic effects of beta₂-agonist treatment (e.g., cardiovascular effects, tremor) were observed.

Gender: The population pharmacokinetic analysis involved 202 males and 148 females with asthma who received fluticasone propionate alone or in combination with salmeterol and showed no gender differences for fluticasone propionate pharmacokinetics.

The population pharmacokinetic analysis involved 76 males and 51 females with asthma who received salmeterol in combination with fluticasone propionate and showed no gender differences for salmeterol pharmacokinetics.

Hepatic and Renal Impairment: Formal pharmacokinetic studies using ADVAIR DISKUS have not been conducted in patients with hepatic or renal impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

Drug Interactions: In the repeat- and single-dose studies, there was no evidence of significant drug interaction in systemic exposure between fluticasone propionate and salmeterol when given as ADVAIR DISKUS. The population pharmacokinetic analysis from 9 controlled clinical trials in 350 patients with asthma showed no significant effects on fluticasone propionate or salmeterol pharmacokinetics following co-administration with beta₂-agonists, corticosteroids, antihistamines, or theophyllines.

Inhibitors of Cytochrome P450 3A4: Ritonavir: Fluticasone Propionate: Fluticasone propionate is a substrate of CYP 3A4. Coadministration of fluticasone propionate and the strong CYP 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable ( < 10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUC_(0-τ) averaged 8.43 pg•hr/mL (range, 4.2 to 18.8 pg•hr/mL). Fluticasone propionate Cmax and AUC_(0-τ) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC.

Ketoconazole: Fluticasone Propionate: In a placebo-controlled, crossover study in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol.

Salmeterol: In a placebo-controlled, crossover drug interaction study in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP 3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold [90% CI: 1.23, 1.68]. Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration.

Erythromycin: Fluticasone Propionate: In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

Salmeterol: In a repeat-dose study in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP 3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], p = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], p < 0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], p = 0.34), and no change in plasma potassium.

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.

Reproductive Toxicology Studies: ADVAIR DISKUS: In mice, combining 150 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m² basis) with 10 mg/kg orally of salmeterol (approximately 410 times the MRHD on a mg/m² basis) produced cleft palate, fetal death, increased implantation loss, and delayed ossification. No such effects were observed at combination subcutaneous doses up to 40 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m² basis) and up to 1.4 mg/kg orally doses of salmeterol (approximately 55 times the MRHD on a mg/m² basis).

In rats, combining 100 mcg/kg subcutaneously of fluticasone propionate (equivalent to the MRHD on a mg/m² basis) and 10 mg/kg orally of salmeterol (approximately 810 times the MRHD on a mg/m² basis) produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were observed at combination doses up to 30 mcg/kg subcutaneously of fluticasone propionate (less than the MRHD on a mg/m² basis) and up to 1 mg/kg orally of salmeterol (approximately 80 times the MRHD on a mg/m² basis).

Fluticasone Propionate: Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg (less than and equivalent to the MRHD on a mg/m² basis), respectively, revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose of 4 mcg/kg (less than the MRHD on a mg/m² basis). However, no teratogenic effects were reported at oral doses up to 300 mcg/kg (approximately 5 times the MRHD on a mg/m² basis) of fluticasone propionate. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see CLINICAL PHARMACOLOGY].

Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

Salmeterol: No teratogenic effects occurred in rats at oral doses up to 2 mg/kg (approximately 160 times the MRHD on a mg/m² basis).

In Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 50 times and above the MRHD based on comparison of the AUCs), salmeterol exhibited fetal toxic effects characteristically resulting from beta-adrenoceptor stimulation. These included precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No such effects occurred at an oral dose of 0.6 mg/kg (approximately 20 times the MRHD based on comparison of the AUCs). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal bones was seen at an oral dose of 10 mg/kg (approximately 1,600 times the MRHD on a mg/m² basis).

Salmeterol crossed the placenta following oral administration to mice and rats.

Clinical Studies

Asthma

Adult and Adolescent Patients 12 Years of Age and Older: In clinical trials comparing ADVAIR DISKUS with its individual components, improvements in most efficacy endpoints were greater with ADVAIR DISKUS than with the use of either fluticasone propionate or salmeterol alone. In addition, clinical trials showed similar results between ADVAIR DISKUS and the concurrent use of fluticasone propionate plus salmeterol at corresponding doses from separate inhalers.

Studies Comparing ADVAIR DISKUS to Fluticasone Propionate Alone or Salmeterol Alone: Three (3) double-blind, parallel-group clinical trials were conducted with ADVAIR DISKUS in 1,208 adolescent and adult patients ( 12 years, 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 device twice daily, and other maintenance therapies were discontinued.

Study 1: Clinical Trial With ADVAIR DISKUS 100/50: This placebo-controlled, 12-week, US study compared ADVAIR DISKUS 100/50 with its individual components, fluticasone propionate 100 mcg and salmeterol 50 mcg. The study was stratified according to baseline asthma maintenance therapy; patients were using either inhaled corticosteroids (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: ADVAIR DISKUS 100/50, 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 study. 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 patients receiving ADVAIR DISKUS 100/50 were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo.

Table 4. Percent of Patients Withdrawn Due to Worsening Asthma in Patients Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1)

The FEV₁ results are displayed in Figure 2. Because this trial used predetermined criteria for worsening asthma, which caused more patients in the placebo group to be withdrawn, FEV₁ results at Endpoint (last available FEV₁ result) are also provided. Patients receiving ADVAIR DISKUS 100/50 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 ADVAIR DISKUS were achieved regardless of baseline asthma maintenance therapy (inhaled corticosteroids or salmeterol).

Figure 2. Mean Percent Change From Baseline in FEV₁ in Patients With Asthma Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1)

The effect of ADVAIR DISKUS 100/50 on morning and evening PEF endpoints is shown in Table 2.

Table 5. Peak Expiratory Flow Results for Patients With Asthma Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1)

The subjective impact of asthma on patients' 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). Patients receiving ADVAIR DISKUS 100/50 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).

Study 2: Clinical Trial With ADVAIR DISKUS 250/50: This placebo-controlled, 12-week, US study compared ADVAIR DISKUS 250/50 with its individual components, fluticasone propionate 250 mcg and salmeterol 50 mcg, in 349 patients with asthma using inhaled corticosteroids (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: ADVAIR DISKUS 250/50, 2.23 L; fluticasone propionate 250 mcg, 2.12 L; salmeterol, 2.20 L; and placebo, 2.19 L.

Efficacy results in this study were similar to those observed in Study 1. Patients receiving ADVAIR DISKUS 250/50 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 patients receiving ADVAIR DISKUS 250/50 were withdrawn from this study for worsening asthma (4%) compared with fluticasone propionate (22%), salmeterol (38%), and placebo (62%). In addition, ADVAIR DISKUS 250/50 was superior to fluticasone propionate, salmeterol, and placebo for improvements in morning and evening PEF. Patients receiving ADVAIR DISKUS 250/50 also had clinically meaningful improvements in overall asthma-specific quality of life as described in Study 1 (difference in AQLQ score of 1.29 compared with placebo).

Study 3: Clinical Trial With ADVAIR DISKUS 500/50: This 28-week, non-US study compared ADVAIR DISKUS 500/50 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 patients with asthma using inhaled corticosteroids (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 study. The primary purpose of weeks 13 to 28 was to collect safety data.

Baseline PEF measurements were similar across treatments: ADVAIR DISKUS 500/50, 359 L/min; fluticasone propionate 500 mcg, 351 L/min; and concurrent therapy, 345 L/min. Morning PEF improved significantly with ADVAIR DISKUS 500/50 compared with fluticasone propionate 500 mcg over the 12-week treatment period. Improvements in morning PEF observed with ADVAIR DISKUS 500/50 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 US trials. Following the first dose, the median time to onset of clinically significant bronchodilatation ( ≥ 15% improvement in FEV₁) in most patients 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 (see Figure 3). 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 studies. No diminution in the 12-hour bronchodilator effect was observed with either ADVAIR DISKUS 100/50 (Figures 3 and 4) or ADVAIR DISKUS 250/50 as assessed by FEV₁ following 12 weeks of therapy.

Figure 3. Percent Change in Serial 12-hour FEV₁ in Patients With Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Study 1)

Figure 4. Percent Change in Serial 12-hour FEV₁ in Patients With Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Study 1)

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

Pediatric Patients: In a 12-week US study, ADVAIR DISKUS 100/50 twice daily was compared with fluticasone propionate inhalation powder 100 mcg twice daily in 203 children with asthma aged 4 to 11 years. At study entry, the children were symptomatic on low doses of inhaled corticosteroids (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 study was to determine the safety of ADVAIR DISKUS 100/50 compared with fluticasone propionate inhalation powder 100 mcg in this age-group; however, the study 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 patients receiving ADVAIR DISKUS 100/50, 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 patients receiving fluticasone propionate 100 mcg.

The findings of this study, along with extrapolation of efficacy data from patients 12 years of age and older, support the overall conclusion that ADVAIR DISKUS 100/50 is efficacious in the maintenance treatment of asthma in patients aged 4 to 11 years.

Chronic Obstructive Pulmonary Disease

The efficacy of ADVAIR DISKUS 250/50 and ADVAIR DISKUS 500/50 in the treatment of patients with COPD was evaluated in 6 randomized, double-blind, parallel-group clinical trials in adult patients 40 years of age and older. These trials were primarily designed to evaluate the efficacy of ADVAIR DISKUS on lung function (3 trials), exacerbations (2 trials), and survival (1 trial).

Lung Function: Two of the 3 clinical trials primarily designed to evaluate the efficacy of ADVAIR DISKUS on lung function were conducted in 1,414 patients with COPD associated with chronic bronchitis. In these 2 trials, all the patients had a history of cough productive of sputum that was not attributable to another disease process on most days for at least 3 months of the year for at least 2 years. The trials were randomized, double-blind, parallel-group, 24-week treatment duration. One trial evaluated the efficacy of ADVAIR DISKUS 250/50 compared with its components fluticasone propionate 250 mcg and salmeterol 50 mcg and to placebo, and the other trial evaluated the efficacy of ADVAIR DISKUS 500/50 compared with its components fluticasone propionate 500 mcg salmeterol 50 mcg and to placebo. Study treatments were inhalation powders given as 1 inhalation from the DISKUS device twice daily. Maintenance COPD therapies were discontinued, with the exception of theophylline. The patients had a mean pre-bronchodilator FEV₁ of 41% and 20% reversibility at study entry. Percent reversibility was calculated as 100 times (FEV₁ post-albuterol minus FEV₁ pre-albuterol)/FEV₁ pre-albuterol.

Improvements in lung function (as defined by predose and postdose FEV₁) were significantly greater with ADVAIR DISKUS than with fluticasone propionate, salmeterol, or placebo. The improvement in lung function with ADVAIR DISKUS 500/50 was similar to the improvement seen with ADVAIR DISKUS 250/50.

Figures 5 and 6 display predose and 2-hour postdose, respectively, FEV₁ results for the study with ADVAIR DISKUS 250/50. To account for patient withdrawals during the study, FEV₁ at Endpoint (last evaluable FEV₁) was evaluated. Patients receiving ADVAIR DISKUS 250/50 had significantly greater improvements in predose FEV₁ at Endpoint (165 mL, 17%) compared with salmeterol 50 mcg (91 mL, 9%) and placebo (1 mL, 1%), demonstrating the contribution of fluticasone propionate to the improvement in lung function with ADVAIR DISKUS (Figure 5). Patients receiving ADVAIR DISKUS 250/50 had significantly greater improvements in postdose FEV₁ at Endpoint (281 mL, 27%) compared with fluticasone propionate 250 mcg (147 mL, 14%) and placebo (58 mL, 6%), demonstrating the contribution of salmeterol to the improvement in lung function with ADVAIR DISKUS (Figure 6).

Figure 5. Predose FEV₁: Mean Percent Change From Baseline in Patients With Chronic Obstructive Pulmonary Disease

Figure 6. Two-Hour Postdose FEV₁: Mean Percent Changes From Baseline Over Time in Patients With Chronic Obstructive Pulmonary Disease

The third trial was a 1-year study that evaluated ADVAIR DISKUS 500/50, fluticasone propionate 500 mcg, salmeterol 50 mcg, and placebo in 1,465 patients. The patients had an established history of COPD and exacerbations, a pre-bronchodilator FEV₁ < 70% of predicted at study entry, and 8.3% reversibility. The primary endpoint was the comparison of pre-bronchodilator FEV₁ in the groups receiving ADVAIR DISKUS 500/50 or placebo. Patients treated with ADVAIR DISKUS 500/50 had greater improvements in FEV₁ (113 mL, 10%) compared with fluticasone propionate 500 mcg (7 mL, 2%), salmeterol (15 mL, 2%), and placebo (-60 mL, -3%).

Exacerbations: Two studies were primarily designed to evaluate the effect of ADVAIR DISKUS 250/50 on exacerbations. In these 2 studies, exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days. COPD exacerbations were considered of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered severe if hospitalization was required.

Exacerbations were also evaluated as a secondary outcome in the 1- and 3-year trials with ADVAIR DISKUS 500/50. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with antibiotics and/or systemic corticosteroids (moderately severe) or requiring hospitalization (severe).

The 2 exacerbation trials with ADVAIR DISKUS 250/50 were identical studies designed to evaluate the effect of ADVAIR DISKUS 250/50 and salmeterol 50 mcg, each given twice daily, on exacerbations of COPD over a 12-month period. A total of 1,579 patients had an established history of COPD (but no other significant respiratory disorders). Patients had a pre-bronchodilator FEV₁ of 33% of predicted, a mean reversibility of 23% at baseline, and a history of ≥ 1 COPD exacerbation in the previous year that was moderate or severe. All patients were treated with ADVAIR DISKUS 250/50 twice daily during a 4-week run-in period prior to being assigned study treatment with twice-daily ADVAIR DISKUS 250/50 or salmeterol 50 mcg. In both studies, treatment with ADVAIR DISKUS 250/50 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (30.5% reduction [95% CI: 17.0, 41.8], p < 0.001) in the first study and (30.4% reduction [95% CI: 16.9, 41.7], p < 0.001) in the second study. Patients treated with ADVAIR DISKUS 250/50 also had a significantly lower annual rate of exacerbations requiring treatment with oral corticosteroids compared with patients treated with salmeterol (39.7% reduction [95% CI: 22.8, 52.9], p < 0.001) in the first study, and (34.3% reduction [95% CI: 18.6, 47.0], p < 0.001) in the second study. Secondary endpoints including pulmonary function and symptom scores improved more in patients treated with ADVAIR DISKUS 250/50 than with salmeterol 50 mcg in both studies.

Exacerbations were evaluated in the 1- and the 3-year trials with ADVAIR DISKUS 500/50 as 1 of the secondary efficacy endpoints. In the 1-year trial, the group receiving ADVAIR DISKUS 500/50 had a significantly lower rate of moderate and severe exacerbations compared with placebo (25.4% reduction compared with placebo [95% CI: 13.5, 35.7]) but not when compared with its components (7.5% reduction compared with fluticasone propionate [95% CI: -7.3, 20.3] and 7% reduction compared with salmeterol [95% CI: -8.0, 19.9]). In the 3-year trial, the group receiving ADVAIR DISKUS 500/50 had a significantly lower rate of moderate and severe exacerbations compared with each of the other treatment groups (25.1% reduction compared with placebo [95% CI: 18.6, 31.1], 9.0% reduction compared with fluticasone propionate [95% CI: 1.2, 16.2], and 12.2% reduction compared with salmeterol [95% CI: 4.6, 19.2]).

There were no studies conducted to directly compare the efficacy of ADVAIR DISKUS 250/50 with ADVAIR DISKUS 500/50 on exacerbations. Across studies, the reduction in exacerbations seen with ADVAIR DISKUS 500/50 was not greater than the reduction in exacerbations seen with ADVAIR DISKUS 250/50.

Survival: A 3-year multicenter, international study evaluated the efficacy of ADVAIR DISKUS 500/50 compared with fluticasone propionate 500 mcg, salmeterol 50 mcg, and placebo on survival in 6,112 patients with COPD. During the study patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids and long-acting bronchodilators. The patients were 40 to 80 years of age with an established history of COPD, a pre-bronchodilator FEV₁ < 60% of predicted at study entry, and < 10% of predicted reversibility. Each patient who withdrew from double-blind treatment for any reason was followed for the full 3-year study period to determine survival status. The primary efficacy endpoint was all-cause mortality. Survival with ADVAIR DISKUS 500/50 was not significantly improved compared with placebo, or the individual components (all-cause mortality rate 12.6% ADVAIR DISKUS vs. 15.2% placebo). The rates for all-cause mortality were 13.5% and 16.0% in the groups treated with salmeterol 50 mcg and fluticasone propionate 500 mcg, respectively. Secondary outcomes, including pulmonary function (post-bronchodilator FEV₁), improved with ADVAIR DISKUS 500/50, salmeterol, and fluticasone propionate 500/50 compared with placebo.

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