ADVAIR DISKUS 100/50 MCG/INHAL Dry Powder Inhaler, 60 Blisters

Details

Generic Name: FLUTICASONE PROPIONATE AND SALMETEROL

Brand Name: ADVAIR DISKUS

Substance Name(s):
SALMETEROL XINAFOATE
FLUTICASONE PROPIONATE

DRUG INTERACTIONS

7 ADVAIR DISKUS has been used concomitantly with other drugs, including short-acting beta2-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD, without adverse drug reactions. No formal drug interaction studies have been performed with ADVAIR DISKUS. Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use not recommended. May cause systemic corticosteroid and cardiovascular effects. (7.1) Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of salmeterol on vascular system. (7.2) Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. (7.3) Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with nonpotassium-sparing diuretics may worsen with concomitant beta-agonists. (7.4) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate and salmeterol, the individual components of ADVAIR DISKUS, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with ADVAIR DISKUS is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur. Ritonavir: Fluticasone Propionate: A drug interaction study with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Ketoconazole: Fluticasone Propionate: Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate exposure and reduced plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol. Salmeterol: In a drug interaction study in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta2-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). 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. 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants ADVAIR DISKUS 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 DISKUS, on the vascular system may be potentiated by these agents. 7.3 Beta-Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with asthma or COPD 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. 7.4 Diuretics The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.

OVERDOSAGE

10 No human overdosage data has been reported for ADVAIR DISKUS. No deaths occurred in rats given an inhaled single-dose combination of salmeterol 3.6 mg/kg (approximately 290 and 140 times the MRHD for adults and children, respectively, on an mg/m2 basis) and 1.9 mg/kg of fluticasone propionate (approximately 15 and 35 times the MRHD for adults and children, respectively, on an mg/m2 basis). Fluticasone Propionate: Chronic overdosage with fluticasone propionate may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.7)]. Inhalation by healthy volunteers of a single dose of 4,000 mcg of fluticasone propionate inhalation powder or single doses of 1,760 or 3,520 mcg of fluticasone propionate CFC inhalation aerosol was well tolerated. Fluticasone propionate given by inhalation aerosol at dosages of 1,320 mcg twice daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily for 10 days in healthy volunteers and repeat oral doses up to 20 mg daily for 42 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. No deaths were seen in mice given an oral dose of 1,000 mg/kg (4,100 and 9,600 times the MRHD dose for adults and children, respectively, on an mg/m2 basis). No deaths were seen in rats given an oral dose of 1,000 mg/kg (8,100 and 19,200 times the MRHD for adults and children, respectively, on an mg/m2 basis). Salmeterol: The expected signs and symptoms with overdosage of salmeterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the following: seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. Other signs of overdosage may include hypokalemia and hyperglycemia. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of salmeterol. Treatment consists of discontinuation of salmeterol together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of salmeterol. Cardiac monitoring is recommended in cases of overdosage. No deaths were seen in rats given salmeterol at an inhalation dose of 2.9 mg/kg (approximately 240 and 110 times the MRHD for adults and children, respectively, on an mg/m2 basis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately 190 and 90 times the MRHD for adults and children, respectively, on an mg/m2 basis). By the oral route, no deaths occurred in mice at 150 mg/kg (approximately 6,100 and 2,900 times the MRHD for adults and children, respectively, on an mg/m2 basis) and in rats at 1,000 mg/kg (approximately 81,000 and 38,000 times the MRHD for adults and children, respectively, on an mg/m2 basis).

DESCRIPTION

11 ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, and ADVAIR DISKUS 500/50 are combinations of fluticasone propionate and salmeterol xinafoate. One active component of ADVAIR DISKUS is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure: Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. The other active component of ADVAIR DISKUS is salmeterol xinafoate, a beta2-adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. The chemical name of salmeterol xinafoate is 4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate, and it has the following chemical structure: Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C25H37NO4•C11H8O3. It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water. ADVAIR DISKUS 100/50, ADVAIR DISKUS 250/50, and ADVAIR DISKUS 500/50 are specially designed plastic devices containing a double-foil blister strip of a powder formulation of fluticasone propionate and salmeterol xinafoate intended for oral inhalation only. Each blister on the double-foil strip within the device contains 100, 250, or 500 mcg of microfine fluticasone propionate and 72.5 mcg of microfine salmeterol xinafoate salt, equivalent to 50 mcg of salmeterol base, in 12.5 mg of formulation containing lactose (which contains milk proteins). Each blister contains 1 complete dose of both medications. After a blister containing medication is opened by activating the device, the medication is dispersed into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, ADVAIR DISKUS delivers 93, 233, and 465 mcg of fluticasone propionate and 45 mcg of salmeterol base per blister from ADVAIR DISKUS 100/50, 250/50, and 500/50, respectively, when tested at a flow rate of 60 L/min for 2 seconds. In adult patients with obstructive lung disease and severely compromised lung function (mean FEV1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through a DISKUS® inhalation device was 82.4 L/min (range: 46.1 to 115.3 L/min). Inhalation profiles for adolescent (N = 13, aged 12 to 17 years) and adult (N = 17, aged 18 to 50 years) patients with asthma inhaling maximally through the DISKUS device show mean PIF of 122.2 L/min (range: 81.6 to 152.1 L/min). Inhalation profiles for pediatric patients with asthma inhaling maximally through the DISKUS device show a mean PIF of 75.5 L/min (range: 49.0 to 104.8 L/min) for the 4-year-old patient set (N = 20) and 107.3 L/min (range: 82.8 to 125.6 L/min) for the 8-year-old patient set (N = 20). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. fluticasone propionate chemical structure salmeterol xinafoate chemical structure

CLINICAL STUDIES

14 14.1 Asthma Adult and Adolescent Patients Aged 12 Years 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) ADVAIR DISKUS 100/50(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 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 5. Table 5. Peak Expiratory Flow Results for Patients With Asthma Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1) Efficacy Variablea ADVAIR DISKUS 100/50(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 aChange from baseline = change from baseline at Endpoint (last available data). 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. First Treatment Day Figure 3. Percent Change in Serial 12-hour FEV1 in Patients With Asthma Previously Using Either Inhaled Corticosteroids or Salmeterol (Study 1) Last Treatment Day (Week 12) 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 aged 12 years and older, support the overall conclusion that ADVAIR DISKUS 100/50 is efficacious in the treatment of asthma in patients aged 4 to 11 years. 14.2 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: 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 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, 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 aged 40 to 80 years 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 versus 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. Figure 2. Mean Percent Change From Baseline in FEV1 in Patients With Asthma Previously Treated With Either Inhaled Corticosteroids or Salmeterol (Study 1) 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) 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

HOW SUPPLIED

16 /STORAGE AND HANDLING ADVAIR DISKUS 100/50 is supplied as a disposable purple device containing 60 blisters. The DISKUS inhalation device is packaged within a plastic-coated, moisture-protective foil pouch (NDC 21695-361-60). Store at controlled room temperature (see USP), 20° to 25°C (68° to 77°F), in a dry place away from direct heat or sunlight. Keep out of reach of children. The DISKUS inhalation device is not reusable. The device should be discarded 1 month after removal from the moisture-protective foil overwrap pouch or after all blisters have been used (when the dose indicator reads “0”), whichever comes first. Do not attempt to take the device apart.

RECENT MAJOR CHANGES

Boxed Warning June 2010 Indications and Usage (1.1) June 2010 Dosage and Administration (2.1) June 2010 Warnings and Precautions, Asthma-Related Death (5.1) June 2010

GERIATRIC USE

8.5 Geriatric Use Clinical studies of ADVAIR DISKUS for asthma did not include sufficient numbers of patients aged 65 years and older to determine whether older patients with asthma respond differently than younger patients. Of the total number of patients in clinical studies receiving ADVAIR DISKUS for COPD, 1,621 were aged 65 years or older and 379 were aged 75 years or older. Patients with COPD aged 65 years and older had a higher incidence of serious adverse events compared with patients less than 65 years of age. Although the distribution of adverse events was similar in the 2 age-groups, patients over 65 years of age experienced more severe events. In two 1-year studies, the excess risk of pneumonia that was seen in patients treated with ADVAIR DISKUS compared with those treated with salmeterol was greater in patients over 65 years of age than in patients less than 65 years of age [see Adverse Reactions (6.2)]. As with other products containing beta2-agonists, special caution should be observed when using ADVAIR DISKUS in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for ADVAIR DISKUS or its active components, no adjustment of dosage of ADVAIR DISKUS in geriatric patients is warranted. No relationship between fluticasone propionate systemic exposure and age was observed in 57 patients with COPD (aged 40 to 82 years) given 250 or 500 mcg twice daily.

DOSAGE FORMS AND STRENGTHS

3 Disposable purple device with 60 blisters containing a combination of fluticasone propionate (100, 250, or 500 mcg) and salmeterol (50 mcg) as an oral inhalation powder formulation. An institutional pack containing 14 blisters is also available. DISKUS device containing a combination of fluticasone propionate (100, 250, or 500 mcg) and salmeterol (50 mcg) as an oral inhalation powder. (3)

MECHANISM OF ACTION

12.1 Mechanism of Action ADVAIR DISKUS: Since ADVAIR DISKUS contains both fluticasone propionate and salmeterol, the mechanisms of action described below for the individual components apply to ADVAIR DISKUS. These drugs represent 2 classes of medications (a synthetic corticosteroid and a selective LABA) that have different effects on clinical and physiological indices. Fluticasone Propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Inflammation is also a component in the pathogenesis of COPD. In contrast to asthma, however, the predominant inflammatory cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages. The effects of corticosteroids in the treatment of COPD are not well defined and inhaled corticosteroids and fluticasone propionate when used apart from ADVAIR DISKUS are not indicated for the treatment of COPD. Salmeterol Xinafoate: Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even highly selective beta2-agonists may have cardiac effects. The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.

INDICATIONS AND USAGE

1 ADVAIR DISKUS is a combination product containing a corticosteroid and a LABA indicated for: Treatment of asthma in patients aged 4 years and older. (1.1) Maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD). (1.2) Important limitation: Not indicated for the relief of acute bronchospasm. (1.1, 1.2) 1.1 Treatment of Asthma ADVAIR DISKUS is indicated for the treatment of asthma in patients aged 4 years and older. Long-acting beta2-adrenergic agonists (LABAs), such as salmeterol, one of the active ingredients in ADVAIR DISKUS, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1)]. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS 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 (e.g., discontinue ADVAIR DISKUS) 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 DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. Important Limitation of Use: ADVAIR DISKUS is NOT indicated for the relief of acute bronchospasm. 1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease ADVAIR DISKUS 250/50 is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. ADVAIR DISKUS 250/50 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. ADVAIR DISKUS 250/50 twice daily is the only approved dosage for the treatment of COPD because an efficacy advantage of the higher strength ADVAIR DISKUS 500/50 over ADVAIR DISKUS 250/50 has not been demonstrated. Important Limitation of Use: ADVAIR DISKUS is NOT indicated for the relief of acute bronchospasm.

PEDIATRIC USE

8.4 Pediatric Use Use of ADVAIR DISKUS 100/50 in patients aged 4 to 11 years is supported by extrapolation of efficacy data from older patients and by safety and efficacy data from a study of ADVAIR DISKUS 100/50 in children with asthma aged 4 to 11 years [see Adverse Reactions (6.1), Clinical Studies (14.1)]. The safety and effectiveness of ADVAIR DISKUS in children with asthma less than 4 years of age have not been established. Inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS, may cause a reduction in growth velocity in children and adolescents [see Warnings and Precautions (5.14)]. The growth of pediatric patients receiving orally inhaled corticosteroids, including ADVAIR DISKUS, should be monitored. A 52-week placebo-controlled study to assess the potential growth effects of fluticasone propionate inhalation powder (FLOVENT® ROTADISK®) at 50 and 100 mcg twice daily was conducted in the US in 325 prepubescent children (244 males and 81 females) aged 4 to 11 years. The mean growth velocities at 52 weeks observed in the intent-to-treat population were 6.32 cm/year in the placebo group (N = 76), 6.07 cm/year in the 50-mcg group (N = 98), and 5.66 cm/year in the 100-mcg group (N = 89). An imbalance in the proportion of children entering puberty between groups and a higher dropout rate in the placebo group due to poorly controlled asthma may be confounding factors in interpreting these data. A separate subset analysis of children who remained prepubertal during the study revealed growth rates at 52 weeks of 6.10 cm/year in the placebo group (n = 57), 5.91 cm/year in the 50-mcg group (n = 74), and 5.67 cm/year in the 100-mcg group (n = 79). In children aged 8.5 years, the mean age of children in this study, the range for expected growth velocity is: boys – 3rd percentile = 3.8 cm/year, 50th percentile = 5.4 cm/year, and 97th percentile = 7.0 cm/year; girls – 3rd percentile = 4.2 cm/year, 50th percentile = 5.7 cm/year, and 97th percentile = 7.3 cm/year. The clinical relevance of these growth data is not certain. If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect of corticosteroids should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including ADVAIR DISKUS, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see Dosage and Administration (2.1)].

PREGNANCY

8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled studies with ADVAIR DISKUS in pregnant women. ADVAIR DISKUS was teratogenic in mice and not in rats, although it lowered fetal weight in rats. Fluticasone propionate alone was teratogenic in mice, rats, and rabbits, and salmeterol alone was teratogenic in rabbits and not in rats. From the reproduction toxicity studies in mice and rats, no evidence of enhanced toxicity was seen using combinations of fluticasone propionate and salmeterol when compared with toxicity data from the components administered separately. ADVAIR DISKUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ADVAIR DISKUS: In the mouse reproduction assay, fluticasone propionate by the subcutaneous route at a dose approximately 3/5 the maximum recommended human daily inhalation dose (MRHD) on an mg/m2 basis combined with oral salmeterol at a dose approximately 410 times the MRHD on an mg/m2 basis produced cleft palate, fetal death, increased implantation loss, and delayed ossification. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses of fluticasone propionate subcutaneously up to approximately 1/6 the MRHD on an mg/m2 basis and oral doses of salmeterol up to approximately 55 times the MRHD on an mg/m2 basis. In rats, combining fluticasone propionate subcutaneously at a dose equivalent to the MRHD on an mg/m2 basis and an oral dose of salmeterol at approximately 810 times the MRHD on an mg/m2 basis produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were seen when combining fluticasone propionate subcutaneously at a dose less than the MRHD on an mg/m2 basis and an oral dose of salmeterol at approximately 80 times the MRHD on an mg/m2 basis. Fluticasone Propionate: Subcutaneous studies in mice at a dose less than the MRHD on an mg/m2 basis and in rats at a dose equivalent to the MRHD on an mg/m2 basis revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. In rabbits, fetal weight reduction and cleft palate were observed at a subcutaneous dose less than the MRHD on an mg/m2 basis. However, no teratogenic effects were reported at oral doses up to approximately 5 times the MRHD on an mg/m2 basis. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)]. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. Salmeterol: No teratogenic effects occurred in rats at oral doses approximately 160 times the MRHD on an mg/m2 basis. In pregnant Dutch rabbits administered oral doses approximately 50 times 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 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 cranial bones was seen at an oral dose approximately 1,600 times the MRHD on an mg/m2 basis. Extensive use of other beta-agonists has provided no evidence that these class effects in animals are relevant to their use in humans.

NUSRING MOTHERS

8.3 Nursing Mothers Plasma levels of salmeterol, a component of ADVAIR DISKUS, after inhaled therapeutic doses are very low. In rats, salmeterol xinafoate is excreted in the milk. There are no data from controlled trials on the use of salmeterol by nursing mothers. It is not known whether fluticasone propionate, a component of ADVAIR DISKUS, is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of tritiated fluticasone propionate resulted in measurable radioactivity in milk. Since there are no data from controlled trials on the use of ADVAIR DISKUS by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue ADVAIR DISKUS, taking into account the importance of ADVAIR DISKUS to the mother. Caution should be exercised when ADVAIR DISKUS is administered to a nursing woman.

BOXED WARNING

WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABAs), such as salmeterol, one of the active ingredients in ADVAIR DISKUS®, increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT ® Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks on salmeterol versus 3 out of 13,179 patients on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS 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 (e.g., discontinue ADVAIR DISKUS) 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 DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids [see Warnings and Precautions (5.1)]. WARNING: ASTHMA-RELATED DEATH See full prescribing information for complete boxed warning Long-acting beta2-adrenergic agonists (LABAs), such as salmeterol, one of the active ingredients in ADVAIR DISKUS, increase the risk of asthma-related death. A US study showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks on salmeterol versus 3 out of 13,179 patients on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1) When treating patients with asthma, only prescribe ADVAIR DISKUS 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 (e.g., discontinue ADVAIR DISKUS) 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 DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. (1.1, 5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Asthma-related death: LABAs increase the risk. Prescribe only for recommended patient populations. (5.1) Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or to treat acute symptoms. (5.2) Use with additional LABA: Do not use in combination because of risk of overdose. (5.3) Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation. (5.4) Pneumonia: Increased risk in patients with COPD. Monitor patients for signs and symptoms of pneumonia. (5.5) Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.6) Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to ADVAIR DISKUS. (5.7) Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue ADVAIR DISKUS slowly. (5.8) Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid and cardiovascular effects. Use not recommended with ADVAIR DISKUS. (5.9) Paradoxical bronchospasm: Discontinue ADVAIR DISKUS and institute alternative therapy if paradoxical bronchospasm occurs. (5.10) Patients with cardiovascular or central nervous system disorders: Use with caution because of beta-adrenergic stimulation. (5.12) Decreases in bone mineral density: Assess bone mineral density initially and periodically thereafter. (5.13) Effects on growth: Monitor growth of pediatric patients. (5.14) Glaucoma and cataracts: Close monitoring is warranted. (5.15) Metabolic effects: Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. (5.16, 5.18) Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.17) 5.1 Asthma-Related Death LABAs, such as salmeterol, one of the active ingredients in ADVAIR DISKUS, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR DISKUS 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 (e.g., discontinue ADVAIR DISKUS) 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 DISKUS for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. A large placebo-controlled US study that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol. The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized double-blind study that enrolled LABA-naive patients with asthma to assess the safety of salmeterol (SEREVENT® Inhalation Aerosol) 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,355), which led to premature termination of the study. The results of the interim analysis showed that patients receiving salmeterol were at increased risk for fatal asthma events (see Table 1 and Figure 1). In the total population, a higher rate of asthma-related death occurred in patients treated with salmeterol than those treated with placebo (0.10% versus 0.02%, relative risk: 4.37 [95% CI: 1.25, 15.34]). Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in patients treated with salmeterol than in patients treated with placebo (0.07% versus 0.01%, relative risk: 5.82 [95% CI: 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in patients treated with salmeterol than those treated with placebo (0.31% versus 0.04%, relative risk: 7.26 [95% CI: 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in patients treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American patients (see Table 1). Given the similar basic mechanisms of action of beta2-agonists, the findings seen in the SMART study are considered a class effect. Post-hoc analyses in pediatric patients aged 12 to 18 years were also performed. Pediatric patients accounted for approximately 12% of patients in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (50%) before the end of the follow-up and the maldistribution of covariates among the treatment groups that can affect BMD. Fracture risk was estimated for the entire population of patients with COPD in the survival study (N = 6,184). The probability of a fracture over 3 years was 6.3% for ADVAIR DISKUS, 5.4% for fluticasone propionate, 5.1% for salmeterol, and 5.1% for placebo. 5.14 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving ADVAIR DISKUS routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ADVAIR DISKUS, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms. [See Dosage and Administration (2.1), Use in Specific Populations (8.4).] 5.15 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. Effects of treatment with ADVAIR DISKUS 500/50, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on development of cataracts or glaucoma was evaluated in a subset of 658 patients with COPD in the 3-year survival study. Ophthalmic examinations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions about cataracts cannot be drawn from this study because the high incidence of cataracts at baseline (61% to 71%) resulted in an inadequate number of patients treated with ADVAIR DISKUS 500/50 who were eligible and available for evaluation of cataracts at the end of the study (n = 53). The incidence of newly diagnosed glaucoma was 2% with ADVAIR DISKUS 500/50, 5% with fluticasone propionate, 0% with salmeterol, and 2% with placebo. 5.16 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established. 5.17 Coexisting Conditions ADVAIR DISKUS, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.18 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with ADVAIR DISKUS at recommended doses. Figure 1. Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART), by Duration of Treatment

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide. 17.1 Asthma-Related Death Patients with asthma should be informed that salmeterol, one of the active ingredients in ADVAIR DISKUS, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. They should also be informed that currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABAs. 17.2 Not for Acute Symptoms ADVAIR DISKUS is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. The physician should provide the patient with such medication and instruct the patient in how it should be used. Patients should be instructed to notify their physician immediately if they experience any of the following: Decreasing effectiveness of inhaled, short-acting beta2-agonists Need for more inhalations than usual of inhaled, short-acting beta2-agonists Significant decrease in lung function as outlined by the physician Patients should not stop therapy with ADVAIR DISKUS without physician/provider guidance since symptoms may recur after discontinuation. 17.3 Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed ADVAIR DISKUS, other LABAs for asthma and COPD should not be used. 17.4 Risks Associated With Corticosteroid Therapy Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with ADVAIR DISKUS, but at times therapy with ADVAIR DISKUS may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised. Pneumonia: Patients with COPD have a higher risk of pneumonia and should be instructed to contact their healthcare provider if they develop symptoms of pneumonia. Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. Hypercorticism and Adrenal Suppression: Patients should be advised that ADVAIR DISKUS may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to ADVAIR DISKUS. Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk. Reduced Growth Velocity: Patients should be informed that orally inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route. Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered. 17.5 Risks Associated With Beta-Agonist Therapy Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. ADVAIR, ADVAIR DISKUS, DISKHALER, DISKUS, FLONASE, FLOVENT, ROTADISK, SEREVENT, and VENTOLIN are registered trademarks of GlaxoSmithKline. GlaxoSmithKline Research Triangle Park, NC 27709 ©2010, GlaxoSmithKline. All rights reserved. June 2010 ADD: 8PI Repackaged by: Rebel Distributors Corp Thousand Oaks, CA 91320

DOSAGE AND ADMINISTRATION

2 ADVAIR DISKUS should be administered twice daily every day by the orally inhaled route only. After inhalation, the patient should rinse the mouth with water without swallowing [see Patient Counseling Information (17.4)]. More frequent administration or a higher number of inhalations (more than 1 inhalation twice daily) of the prescribed strength of ADVAIR DISKUS is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using ADVAIR DISKUS should not use additional LABAs for any reason. [See Warnings and Precautions (5.3, 5.12).] For oral inhalation only. Treatment of asthma in patients ≥12 years: 1 inhalation of ADVAIR DISKUS 100/50, 250/50, or 500/50 twice daily. Starting dosage is based on asthma severity. (2.1) Treatment of asthma in patients aged 4 to 11 years: 1 inhalation of ADVAIR DISKUS 100/50 twice daily. (2.1) Maintenance treatment of COPD: 1 inhalation of ADVAIR DISKUS 250/50 twice daily. (2.2) 2.1 Asthma If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief. Adult and Adolescent Patients Aged 12 Years and Older: For patients aged 12 years and older, the dosage is 1 inhalation twice daily (morning and evening, approximately 12 hours apart). The recommended starting dosages for ADVAIR DISKUS for patients aged 12 years and older are based upon patients’ asthma severity. The maximum recommended dosage is ADVAIR DISKUS 500/50 twice daily. Improvement in asthma control following inhaled administration of ADVAIR DISKUS can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of ADVAIR DISKUS with a higher strength may provide additional improvement in asthma control. If a previously effective dosage regimen of ADVAIR DISKUS fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of ADVAIR DISKUS with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be considered. Pediatric Patients Aged 4 to 11 Years: For patients with asthma aged 4 to 11 years who are not controlled on an inhaled corticosteroid, the dosage is 1 inhalation of ADVAIR DISKUS 100/50 twice daily (morning and evening, approximately 12 hours apart). 2.2 Chronic Obstructive Pulmonary Disease The recommended dosage for patients with COPD is 1 inhalation of ADVAIR DISKUS 250/50 twice daily (morning and evening, approximately 12 hours apart). If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.