Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The incidence of adverse reactions associated with ADVAIR HFA in Table 2 is based upon two 12-week, placebo-controlled, U.S. clinical trials (Trials 1 and 3) and 1 active-controlled 12-week U.S. clinical trial (Trial 2). A total of 1,008 adult and adolescent subjects with asthma (556 females and 452 males) previously treated with albuterol alone, salmeterol, or ICS were treated twice daily with 2 inhalations of ADVAIR HFA 45 mcg/21 mcg or ADVAIR HFA 115 mcg/21 mcg, fluticasone propionate CFC inhalation aerosol (44- or 110-mcg doses), salmeterol CFC inhalation aerosol 21 mcg, or placebo HFA inhalation aerosol. The average duration of exposure was 71 to 81 days in the active treatment groups compared with 51 days in the placebo group.

The incidence of common adverse reactions reported in Trial 4, a 12-week non-U.S. clinical trial in 509 subjects previously treated with ICS who were treated twice daily with 2 inhalations of ADVAIR HFA 230 mcg/21 mcg, fluticasone propionate CFC inhalation aerosol 220 mcg, or 1 inhalation of ADVAIR DISKUS 500 mcg/50 mcg was similar to the incidences reported in Table 2.

Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that occurred in the groups receiving ADVAIR HFA with an incidence of 1% to 3% and that occurred at a greater incidence than with placebo include the following: tachycardia, arrhythmias, myocardial infarction, postoperative complications, wounds and lacerations, soft tissue injuries, ear signs and symptoms, rhinorrhea/postnasal drip, epistaxis, nasal congestion/blockage, laryngitis, unspecified oropharyngeal plaques, dryness of nose, weight gain, allergic eye disorders, eye edema and swelling, gastrointestinal discomfort and pain, dental discomfort and pain, candidiasis mouth/throat, hyposalivation, gastrointestinal infections, disorders of hard tissue of teeth, abdominal discomfort and pain, oral abnormalities, arthralgia and articular rheumatism, muscle cramps and spasms, musculoskeletal inflammation, bone and skeletal pain, muscle injuries, sleep disorders, migraines, allergies and allergic reactions, viral infections, bacterial infections, candidiasis unspecified site, congestion, inflammation, bacterial reproductive infections, lower respiratory signs and symptoms, lower respiratory infections, lower respiratory hemorrhage, eczema, dermatitis and dermatosis, urinary infections.

In Trial 3, there were more reports of hyperglycemia among adults and adolescents receiving ADVAIR HFA, but this was not seen in Trials 1 and 2.

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of any formulation of ADVAIR, fluticasone propionate, and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to ADVAIR, fluticasone propionate, and/or salmeterol or a combination of these factors.

Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), hypertension, ventricular tachycardia.

Aphonia, earache, facial and oropharyngeal edema, paranasal sinus pain, rhinitis, throat soreness, tonsillitis.

Cushing’s syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, osteoporosis.

Cataracts, glaucoma.

Dyspepsia, xerostomia.

Abnormal liver function tests.

Immediate and delayed hypersensitivity reactions, including rash and rare events of angioedema, bronchospasm, and anaphylaxis.

Esophageal candidiasis.

Back pain, myositis.

Paresthesia, restlessness.

Fever, pallor.

Agitation, aggression, anxiety, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Asthma; asthma exacerbation; chest congestion; chest tightness; cough; dyspnea; immediate bronchospasm; influenza; paradoxical bronchospasm; tracheitis; wheezing; pneumonia; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Contact dermatitis, contusions, ecchymoses, photodermatitis, pruritus.

Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis.

Fluticasone propionate and salmeterol, the individual components of ADVAIR HFA, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with ADVAIR HFA is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.

ADVAIR HFA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR HFA, on the vascular system may be potentiated by these agents.

Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR HFA, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

The ECG changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as salmeterol, a component of ADVAIR HFA, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of ADVAIR HFA with non–potassium-sparing diuretics.

Four (4) double-blind, parallel-group clinical trials were conducted with ADVAIR HFA in 1,517 adult and adolescent subjects (aged 12 years and older, mean baseline FEV

This placebo-controlled, 12-week, U.S. 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 FEV

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 FEV

The FEV

Figure 1. Mean Percent Change from Baseline in FEV1 in Subjects Previously Treated with Either Beta

The effect of ADVAIR HFA 45 mcg/21 mcg on the secondary efficacy parameters, including morning and evening PEF, usage of VENTOLIN Inhalation Aerosol, and asthma symptoms over 24 hours on a scale of 0 to 5 is shown in Table 4.

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 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] compared with placebo).

This active-controlled, 12-week, U.S. 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 subjects using as-needed albuterol alone. The primary efficacy endpoint was predose FEV

Efficacy results in this trial were similar to those observed in Trial 1. Subjects receiving ADVAIR HFA 45 mcg/21 mcg had significantly greater improvements in FEV

This placebo-controlled, 12-week, U.S. 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 subjects using ICS (daily doses of beclomethasone dipropionate 378 to 840 mcg; budesonide 800 to 1,200 mcg; flunisolide 1,250 to 2,000 mcg; fluticasone propionate inhalation aerosol 440 to 660 mcg; fluticasone propionate inhalation powder 400 to 600 mcg; or triamcinolone acetonide 900 to 1,600 mcg). The primary efficacy endpoints were predose FEV

Efficacy results in this trial were similar to those observed in Trials 1 and 2. Subjects receiving ADVAIR HFA 115 mcg/21 mcg had significantly greater improvements in FEV

This active-controlled, 12-week, non-U.S. 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 subjects using ICS (daily doses of beclomethasone dipropionate CFC inhalation aerosol 1,500 to 2,000 mcg; budesonide 1,500 to 2,000 mcg; flunisolide 1,500 to 2,000 mcg; fluticasone propionate inhalation aerosol 660 to 880 mcg; or fluticasone propionate inhalation powder 750 to 1,000 mcg). The primary efficacy endpoint was morning 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. As shown in Figure 2, 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.

Figure 2. Mean Percent Change from Baseline in Morning Peak Expiratory Flow in Subjects Previously Treated with Inhaled Corticosteroids (Trial 4)

This 1-year, open-label, non-U.S. trial evaluated the safety of ADVAIR HFA 45 mcg/21 mcg, ADVAIR HFA 115 mcg/21 mcg, and ADVAIR HFA 230 mcg/21 mcg given as 2 inhalations twice daily in 325 subjects. This trial was stratified into 3 groups according to baseline asthma therapy: subjects using short-acting beta

Improvements in FEV

The onset of action and progression of improvement in asthma control were evaluated in 2 placebo-controlled U.S. trials and 1 active-controlled U.S. trial. Following the first dose, the median time to onset of clinically significant bronchodilatation (≥15% improvement in FEV

Following the initial dose, predose FEV

No diminution in the 12-hour bronchodilator effect was observed with either ADVAIR HFA 45 mcg/21 mcg (Figures 3 and 4) or ADVAIR HFA 230/21 as assessed by FEV

Figure 3. Percent Change in Serial 12-Hour FEV1 in Subjects Previously Using Either Beta

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 ADVAIR HFA and continued to improve over the 12 weeks of therapy in all 3 trials.