Asthma/COPD:

Indications for: ADVAIR HFA

Treatment of asthma in patients not adequately controlled on a long-term asthma control medication [eg, inhaled corticosteroid (ICS)] or whose disease warrants initiation of both an ICS and LABA.

Limitations of Use:

Not for relief of acute bronchospasm.

Clinical Trials:

Four (4) double-blind, parallel-group clinical trials were conducted with Advair HFA in 1,517 adult and adolescent patients (aged ≥12 years, mean baseline FEV1 65% to 75% of predicted normal) 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, and other maintenance therapies were discontinued.

Trial 1: Clinical Trial with Advair HFA 45 mcg/21 mcg  

  • A placebo-controlled, 12-week, US trial compared Advair HFA 45 mcg/21 mcg 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 trial was stratified according to baseline asthma therapy: patients using beta-agonists (albuterol alone or salmeterol) or ICS.
  • Baseline FEV1 measurements were similar across treatments: Advair HFA 45 mcg/21 mcg, 2.29 L; fluticasone propionate 44 mcg, 2.20 L; salmeterol, 2.33 L; and placebo, 2.27 L. 
  • Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled trial.

Results showed statistically significantly fewer patients who received Advair HFA 45 mcg/21 mcg were withdrawn due to worsening asthma (2%) compared with salmeterol (25%) and placebo (28%). Fewer patients who received Advair HFA 45 mcg/21 mcg were withdrawn due to worsening asthma (2%) compared with fluticasone propionate 44 mcg (8%); however, the difference was not statistically significant. 

The FEV1 results at endpoint showed that patients who received Advair HFA 45 mcg/21 mcg 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 mcg/21 mcg were achieved regardless of baseline asthma therapy (albuterol alone, salmeterol, or ICS). 

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 HFA 45 mcg/21 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 1.14 [95% CI, 0.85-1.44] vs placebo).

Trial 2: Clinical Trial with Advair HFA 45 mcg/21 mcg 

  • An active-controlled, 12-week, US trial compared Advair HFA 45 mcg/21 mcg 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. Baseline FEV1 measurements were similar across treatments: Advair HFA 45 mcg/21 mcg, 2.37 L; fluticasone propionate 44 mcg, 2.31 L; and salmeterol, 2.34 L. 

Efficacy results in this trial were similar to those observed in Trial 1. Patients who received Advair HFA 45 mcg/21 mcg 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%).

Trial 3: Clinical Trial with Advair HFA 115 mcg/21 mcg 

  • A placebo-controlled, 12-week, US trial compared Advair HFA 115 mcg/21 mcg 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 ICS. 
  • The primary efficacy endpoints were predose FEV1 and withdrawals due to worsening asthma. Baseline FEV1 measurements were similar across treatments: Advair HFA 115 mcg/21 mcg, 2.23 L; fluticasone propionate 110 mcg, 2.18 L; salmeterol, 2.22 L; and placebo, 2.17 L. 

Efficacy results in this trial were similar to those observed in Trials 1 and 2. Patients who received Advair HFA 115 mcg/21 mcg 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 who received Advair HFA 115 mcg/21 mcg were withdrawn from this trial for worsening asthma (7%) compared with salmeterol (24%) and placebo (54%). Fewer patients who received Advair HFA 115 mcg/21 mcg were withdrawn due to worsening asthma (7%) compared with fluticasone propionate 110 mcg (11%); however, the difference was not statistically significant. 

Trial 4: Clinical Trial with Advair HFA 230 mcg/21 mcg 

  • A active-controlled, 12-week, non-US trial compared Advair HFA 230 mcg/21 mcg with fluticasone propionate CFC inhalation aerosol 220 mcg, each given as 2 inhalations twice daily, and with Advair Diskus 500 mcg /50 mcg given as 1 inhalation twice daily in 509 patients using ICS. 
  • The primary efficacy endpoint was morning peak expiratory flow (PEF). Baseline morning PEF measurements were similar across treatments: Advair HFA 230 mcg/21 mcg, 327 L/min; Advair Diskus 500 mcg/50 mcg, 341 L/min; and fluticasone propionate 220 mcg, 345 L/min. 

Results showed that the morning PEF improved significantly with Advair HFA 230 mcg/21 mcg compared with fluticasone propionate 220 mcg over the 12-week treatment period. Improvements in morning PEF observed with Advair HFA 230 mcg/21 mcg were similar to improvements observed with Advair Diskus 500 mcg/50 mcg. 

One-Year Safety Trial: Clinical Trial with Advair HFA 45 mcg/21 mcg, 115 mcg/21 mcg, and 230 mcg/21 mcg 

  • A 1-year, open-label, non-U.S. trial evaluated the safety of Advair HFA 45 mcg/21 mcg, 115 mcg/21 mcg, and 230 mcg/21 mcg given as 2 inhalations twice daily in 325 patients. 
  • This trial was stratified into 3 groups according to baseline asthma therapy: patients using short-acting beta2-agonists alone (n = 42), salmeterol (n = 91), or ICS (n = 277). 
  • Patients treated with short-acting beta2-agonists alone, salmeterol, or low doses of ICS with or without concurrent salmeterol received Advair HFA 45 mcg/21 mcg. 
  • Patients treated with moderate doses of ICS with or without concurrent salmeterol received Advair HFA 115 mcg/21 mcg. 
  • Patients treated with high doses of ICS with or without concurrent salmeterol received Advair HFA 230 mcg/21 mcg. 
  • Baseline FEV1 measurements ranged from 2.3 to 2.6 L. 

At study endpoint, improvements in FEV1 (0.17 to 0.35 L at 4 weeks) were seen across all 3 treatments and were sustained throughout the 52-week treatment period. Few patients (3%) were withdrawn due to worsening asthma over 1 year. 

 

Adult Dosage:

Allow approx. 12hrs between doses. Initially 2 inh of 45/21 or 115/21 or 230/21 twice daily, based on disease severity and previous asthma therapy. If insufficient response after 2wks, use next higher strength. Max: 2 inh of 230/21 twice daily. Rinse mouth after use.

Children Dosage:

<12yrs: not established.

ADVAIR HFA Contraindications:

Primary treatment of status asthmaticus or other acute episodes of asthma requiring intensive measures.

ADVAIR HFA Warnings/Precautions:

LABA monotherapy (without ICS) may increase risk of asthma-related events (death, hospitalizations, intubations). Do not initiate in rapidly or acutely deteriorating asthma. Not for use with other long-acting β2-agonists. Do not exceed recommended dose. Prescribe a short-acting, inhaled β2-agonist for acute symptoms; monitor for increased need. Monitor for signs/symptoms of pneumonia. Immunosuppressed. Tuberculosis. Systemic infections. Ocular herpes simplex. If exposed to chickenpox or measles, consider immune globulin prophylaxis or antiviral ­treatment. Monitor for adrenal insufficiency when transferring from systemic steroids. May need supplemental systemic corticosteroids during periods of stress or a severe asthma attack. May unmask previously suppressed allergic conditions. Reevaluate periodically. Monitor for hypercorticism and HPA axis suppression (if occurs, discontinue gradually), growth in children, IOP, glaucoma, or cataracts. Consider eye exams if ocular symptoms develop or in long-term use. Discontinue and treat if paradoxical bronchospasm occurs; use alternative therapy. Cardiovascular disease (esp. coronary insufficiency, arrhythmias, hypertension). Eosinophilic conditions. Convulsive disorders. Thyrotoxicosis. Hyperresponsiveness to sympathomimetics. Diabetes. Ketoacidosis. Hypokalemia. Hyperglycemia. Hepatic impairment; monitor. Assess bone mineral density if risk factors exist (eg, prolonged immobilization, osteoporosis, postmenopausal, advanced age, others). Labor & delivery. Pregnancy: monitor. Nursing mothers.

See Also:

    ADVAIR HFA Classification:

    Corticosteroid + long-acting beta-2 agonist (LABA).

    ADVAIR HFA Interactions:

    Concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, atazanavir, clarithromycin, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin): not recommended. Caution during or within 2 weeks of discontinuing MAOIs or tricyclic antidepressants, β-blockers (consider cardioselective), K+-depleting diuretics.

    Adverse Reactions:

    Upper respiratory tract infection or inflammation, throat irritation, dysphonia, headache, dizziness, nausea, vomiting; oral candidiasis, pneumonia, hypersensitivity reactions.

    Metabolism:

    Fluticasone Propionate: The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway.

    Salmeterol: Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces. 

    Drug Elimination:

    Fluticasone Propionate: After intravenous dosing, fluticasone propionate had a terminal elimination half-life of ~7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. Terminal half-life estimates of fluticasone propionate averaged 5.6 hours. 

    Salmeterol: In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only). 

    The xinafoate moiety has no apparent pharmacologic activity. 
    The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days. No terminal half-life estimates were calculated for salmeterol following administration of Advair HFA. 

    Generic Drug Availability:

    NO

    How Supplied:

    Inhaler—12g (120 inh)