Advair (fluticasone propionate and salmeterol)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved August 2000

Specific Treatments:

asthma and chronic obstructive pulmonary disease

Therapeutic Areas

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General Information

Advair is a combination of fluticasone propionate, a corticosteroid and salmeterol, a beta2-adrenergic bronchodilator. It is available as a metered-dose inhaler (HFA) or as an inhalation powder (Diskus).

Advair Diskus is specifically indicated for the treatment of asthma in patients aged 4 years and older and the maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease. Advair HFA is specifically indicated for treatment of asthma in patients aged 12 years and older.

Advair Diskus is supplied as an inhalation powder for oral inhalation only. The recommended dose for the treatment of asthma in patients aged 12 years and older is 1 inhalation of Advair Diskus 100/50, Advair Diskus 250/50, or Advair Diskus 500/50 twice daily. Starting dosage is based on asthma severity. The recommended dose for the treatment of asthma in patients aged 4 to 11 years is 1 inhalation of Advair Diskus 100/50 twice daily. The recommended dose for the maintenance treatment of COPD is 1 inhalation of Advair Diskus 250/50 twice daily.

Adviar HFA is supplied as a metered dose inhaler for oral inhalation only. The recommended dose for the treatment of asthma in patients aged 12 years and older is 2 inhalations of Advair HFA 45/21, 115/21, or 230/21 twice daily. The starting dosage is based on asthma severity.

Clinical Results

The FDA approval of Advair HFA Inhalation aerosol was based on the following studies:


Studies Comparing Advair HFA With Fluticasone Propionate Alone or Salmeterol Alone: Four double-blind, parallel-group clinical trials were conducted with comparing ADVAIR HFA to each individual component. The trials enrolled 1,517 adolescent and adult patients with asthma that was not optimally controlled on their current therapy. All metered-dose inhaler treatments were inhalation aerosols given as 2 inhalations twice daily. Study 1: Clinical Trial With ADVAIR HFA 45/21 Inhalation Aerosol: This placebo-controlled, 12-week, US study compared ADVAIR HFA 45/21 with fluticasone propionate CFC inhalation aerosol 44 mcg or salmeterol CFC inhalation aerosol 21 mcg, each given as 2 inhalations twice daily. The primary efficacy endpoints were predose FEV1 and withdrawals due to worsening asthma. This study was stratified according to baseline asthma therapy. Baseline FEV1 measurements were similar across treatments: ADVAIR HFA 45/21, 2.29 L; fluticasone propionate 44 mcg, 2.20 L; salmeterol, 2.33 L; and placebo, 2.27 L. Statistically significantly fewer patients receiving ADVAIR HFA 45/21 were withdrawn due to worsening asthma compared with salmeterol and placebo. Fewer patients receiving ADVAIR HFA 45/21 were withdrawn due to worsening asthma compared with fluticasone propionate 44 mcg; however, the difference was not statistically significant. In addition, subjects receiving ADVAIR HFA 45/21 had significantly greater improvements in FEV1 (0.58 L, 27%) compared with fluticasone propionate 44 mcg (0.36 L, 18%), salmeterol (0.25 L, 12%), and placebo (0.14 L, 5%). These improvements in FEV1 with ADVAIR HFA 45/21 were achieved regardless of baseline asthma therapy. Study 2: Clinical Trial With ADVAIR HFA 45/21 Inhalation Aerosol:This active-controlled, 12-week, US study compared ADVAIR HFA 45/21 with fluticasone propionate CFC inhalation aerosol 44 mcg and salmeterol CFC inhalation aerosol 21 mcg, each given as 2 inhalations twice daily, in 283 patients using as-needed albuterol alone. The primary efficacy endpoint was predose FEV1. Efficacy results were similar to those observed in Study 1. Patients receiving ADVAIR HFA 45/21 had significantly greater improvements in FEV1 (0.69 L, 33%) compared with fluticasone propionate 44 mcg (0.51 L, 25%) and salmeterol (0.47 L, 22%). Study 3: Clinical Trial With ADVAIR HFA 115/21 Inhalation Aerosol: This placebo-controlled, 12-week, US study compared ADVAIR HFA 115/21 with fluticasone propionate CFC inhalation aerosol 110 mcg or salmeterol CFC inhalation aerosol 21 mcg, each given as 2 inhalations twice daily, in 365 patients using inhaled corticosteroids. The primary efficacy endpoints were predose FEV1 and withdrawals due to worsening asthma. Patients receiving ADVAIR HFA 115/21 had significantly greater improvements in FEV1 (0.41 L, 20%) compared with fluticasone propionate 110 mcg (0.19 L, 9%), salmeterol (0.15 L, 8%), and placebo (-0.12 L, -6%). Significantly fewer patients receiving ADVAIR HFA 115/21 were withdrawn from this study for worsening asthma (7%) compared with salmeterol (24%) and placebo (54%). Fewer patients receiving ADVAIR HFA 115/21 were withdrawn due to worsening asthma (7%) compared with fluticasone propionate 110 mcg (11%); however, the difference was not statistically significant. Study 4: Clinical Trial With ADVAIR HFA 230/21 Inhalation Aerosol: This active-controlled, 12-week, non-US study compared ADVAIR HFA 230/21 with fluticasone propionate CFC inhalation aerosol 220 mcg, each given as 2 inhalations twice daily, and with ADVAIR DISKUS 500/50 given as 1 inhalation twice daily in 509 patients using inhaled corticosteroids. The primary efficacy endpoint was morning Peak Expiratory Flow (PEF). Morning PEF improved significantly with ADVAIR HFA 230/21 compared with fluticasone propionate 220 mcg over the 12-week treatment period.

The FDA approval of Advair Diskus was based on the following studies:

Asthma
Adults and Adolescents Aged 12 Years and Older:
Studies Comparing ADVAIR DISKUS to Fluticasone Propionate Alone or Salmeterol Alone: Three double-blind, parallel-group clinical trials were conducted with ADVAIR DISKUS in 1,208 adults and adolescents ( = 12 years) 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 One: 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) or salmeterol (N = 106). Statistically significantly fewer patients receiving ADVAIR DISKUS 100/50 were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo. 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).

Study Two: 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. 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.

Study Three:

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. 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 two 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. 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. 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. The primary objective 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. 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.

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 aged 40 years 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:

Trials One and Two:
These randomized, double-blind, parallel-group, 24-week trials were primarily designed to evaluate the efficacy of ADVAIR DISKUS on lung function in 1,414 patients with COPD associated with chronic bronchitis. One trial evaluated the efficacy of ADVAIR DISKUS 250/50 compared with its components fluticasone propionate 250 mcg and salmeterol 50 mcg and with placebo, and the other trial evaluated the efficacy of ADVAIR DISKUS 500/50 compared with its components fluticasone propionate 500 mcg and salmeterol 50 mcg and with placebo. Study treatments were inhalation powders given as 1 inhalation from the DISKUS device twice daily. Maintenance COPD therapies were discontinued. 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. 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. 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.

Trial Three:
This 1-year study 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:
ADVAIR DISKUS 250/50: Two studies were primarily designed to evaluate the effect of ADVAIR DISKUS 250/50 on exacerbations. In these two studies, exacerbations were defined as worsening of two or more major symptoms or worsening of any 1 major symptom together with any 1 minor symptom. These two trials 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 with an established history of COPD were enrolled. 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, p < 0.001) in the first study and (30.4% reduction, 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, p < 0.001) in the first study, and (34.3% reduction, 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.

ADVAIR DISKUS 500/50: 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. 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) but not when compared with its components (7.5% reduction compared with fluticasone propionate and 7% reduction compared with salmeterol). 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, 9.0% reduction compared with fluticasone propionate and 12.2% reduction compared with salmeterol ). 

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. 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.

Side Effects

Adverse effects associated with the use of Advair Diskus may include but are not limited to, the following:

Asthma:

  • Upper respiratory tract infection or inflammation
  • pharyngitis
  • dysphonia
  • oral candidiasis
  • bronchitis
  • cough
  • headaches
  • nausea
  • vomiting

COPD:

  • Pneumonia
  • oral candidiasis
  • throat irritation
  • dysphonia
  • viral respiratory infections
  • headaches
  • musculoskeletal pain

Adverse effects associated with the use of Advair HFA may include but are not limited to, the following:

  • upper respiratory tract infection or inflammation
  • throat irritation
  • dysphonia
  • headache
  • dizziness
  • nausea and vomiting

Advair HFA/Diskus comes with a boxed warning. Long-acting beta2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients, increase the risk of asthma-related death. Therefore, when treating patients with asthma, physicians should only prescribe Advair for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use ADVAIR for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Mechanism of Action

Advair is a combination of fluticasone propionate, a corticosteroid and salmeterol, a beta2-adrenergic bronchodilator.

Additional Information

For additional information regarding Advair, please visit http://www.advair.com/