Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action AIRDUO RESPICLICK: AIRDUO RESPICLICK contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to AIRDUO RESPICLICK. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices. Fluticasone Propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of 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. The clinical significance of these findings is unknown. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. 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 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 hyperresponsiveness. Pharmacodynamics AIRDUO RESPICLICK: Healthy Subjects: Cardiovascular Effects: There were no clinical trials conducted with AIRDUO RESPICLICK in healthy subjects. Other Fluticasone Propionate and Salmeterol Inhalation Powder Products: Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) trials were conducted with healthy adult subjects (1) a single-dose crossover trial using 2 inhalations of a fluticasone propionate and salmeterol powder product, fluticasone propionate powder 500 mcg and salmeterol powder 50 mcg given concurrently, or fluticasone propionate powder 500 mcg given alone, (2) a cumulative dose trial using 50 to 400 mcg of salmeterol powder given alone or as a fluticasone propionate 500 mcg and salmeterol 50 mcg powder product, (3) a repeat-dose trial for 11 days using 2 inhalations twice daily of fluticasone propionate 250 mcg and salmeterol 50 mcg powder product, fluticasone propionate powder 250 mcg, or salmeterol powder 50 mcg, and (4) a single-dose trial using 5 inhalations of fluticasone propionate 100 mcg and salmeterol powder 50 mcg product, fluticasone propionate powder 100 mcg alone, or placebo. In these trials, no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as fluticasone propionate and salmeterol powder, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in the fluticasone propionate and salmeterol powder product. AIRDUO RESPICLICK: Subjects with Asthma: Adults and Adolescents: Hypothalamic-Pituitary-Adrenal Axis Effects. There are no data from controlled trials using the AIRDUO RESPICLICK in healthy subjects or subjects with asthma in serum cortisol. Other Salmeterol Xinafoate Products: Subjects with Asthma: Cardiovascular Effects: Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium [see WARNINGS AND PRECAUTIONS]. The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration. The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50 mcg doses of salmeterol inhalation powder (N=60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted. Concomitant Use of AIRDUO RESPICLICK With Other Respiratory Medications: Other Fluticasone Propionate and Salmeterol Inhalation Powder Products: Short-Acting Beta2-Agonists: In clinical trials in subjects with asthma, the mean daily need for albuterol by 166 adult and adolescent subjects aged 12 years and older using a fluticasone propionate and salmeterol powder product was approximately 1.3 inhalations/day and ranged from 0 to 9 inhalations/day. Five percent (5%) of subjects using a fluticasone propionate and salmeterol powder product in these trials averaged 6 or more inhalations per day over the course of the 12-week trials. No increase in frequency of cardiovascular adverse events was observed among subjects who averaged 6 or more inhalations per day. Methylxanthines: In clinical trials in subjects with asthma, 39 subjects receiving fluticasone propionate and salmeterol powder product, fluticasone propionate 100 mcg and salmeterol 50 mcg, fluticasone propionate 250 mcg and salmeterol 50 mcg, or fluticasone propionate 500 mcg and salmeterol 50 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 304 subjects receiving fluticasone propionate and salmeterol powder product without theophylline. Similar results were observed in subjects receiving salmeterol 50 mcg plus fluticasone propionate 500 mcg twice daily concurrently with a theophylline product (n = 39) or without theophylline (n = 132). Pharmacokinetics Absorption Fluticasone Propionate AIRDUO RESPICLICK acts locally in the lung; therefore, plasma levels may not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate was negligible ( < 1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung was systemically absorbed. After administration of 232/14 mcg AIRDUO RESPICLICK to patients aged 12 years and older with persistent asthma in a clinical trial, the mean Cmax value of fluticasone propionate was 66 pg/mL with a median tmax value of approximately 2 hour. Salmeterol After administration of 232/14 mcg AIRDUO RESPICLICK to patients aged 12 years and older with persistent asthma, the mean Cmax values of salmeterol was 60 pg/mL. The median tmax was 5 minutes. Distribution Fluticasone Propionate Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin. Salmeterol Volume of distribution data are not available for salmeterol. The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol. Elimination Fluticasone Propionate Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Terminal half-life estimates of fluticasone propionate following oral inhalation administration of AIRDUO RESPICLICK were approximately 10.8 hours. Metabolism The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite has less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. Excretion 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. Salmeterol Terminal half-life estimates for salmeterol for AIRDUO RESPICLICK were approximately 12.6 hours. The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (greater than 99%) and has a long elimination half-life of 11 days. Metabolism Salmeterol base is extensively metabolized by hydroxylation. An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α hydroxysalmeterol in vitro. Excretion 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. Special Populations A population pharmacokinetic analysis was performed for fluticasone propionate and salmeterol utilizing data from 9 controlled clinical trials that included 350 subjects with asthma aged 4 to 77 years who received treatment with a combination dry powder inhaler of fluticasone propionate and salmeterol, the combination of HFA-propelled fluticasone propionate and salmeterol inhalation aerosol, fluticasone propionate inhalation powder, HFA-propelled fluticasone propionate inhalation aerosol, or CFC-propelled fluticasone propionate inhalation aerosol. The population pharmacokinetic analyses for fluticasone propionate and salmeterol showed no clinically relevant effects of age, gender, race, body weight, body mass index, or percent of predicted FEV1 on apparent clearance and apparent volume of distribution. Age: No pharmacokinetic studies have been performed with AIRDUO RESPICLICK in children or geriatric patients. A subgroup analysis was conducted to compare patients aged 12-17 (n=15) and ≥ 18 (n=23) years following administration of 232/14 mcg AIRDUO RESPICLICK. No overall differences in fluticasone propionate and salmeterolpharmacokinetics were observed. . Sex: A subgroup analysis was conducted to compare male (n=21) and female (n=16) patients following administration of 232/14 mcg AIRDUO RESPICLICK. No overall differences in fluticasone propionate and salmeterol pharmacokinetics were observed. Renal Impairment: The effect of renal impairment of the pharmacokinetics of AIRDUO RESPICLICK has not been evaluated. Hepatic Impairment: Formal pharmacokinetic studies using AIRDUO RESPICLICK have not been conducted in patients with hepatic impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Drug Interaction Studies: In a single-dose trial, the presence of salmeterol does not alter fluticasone propionate exposure. No studies have been performed with AIRDUO RESPICLICK to investigate the effect of fluticasone propionate on salmeterol pharmacokinetics when given in combination. Other Fluticasone Propionate and Salmeterol Inhalation Powder Products Drug Interactions: The population pharmacokinetic analysis from 9 controlled clinical trials in 350 subjects with asthma showed no significant effects on fluticasone propionate or salmeterol pharmacokinetics following co-administration with beta2-agonists, corticosteroids, antihistamines, or theophyllines. Inhibitors of Cytochrome P450 3A4: Ritonavir: Fluticasone Propionate: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable ( < 10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC0-∞ averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC0-∞ increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC. Ketoconazole: Fluticasone Propionate: In a placebo-controlled crossover trial in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Salmeterol: In a placebo-controlled, crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4-fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist-mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration. Erythromycin: Fluticasone Propionate: In a multiple-dose drug interaction trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. Salmeterol: In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P < 0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium. Animal Toxicology And/Or Pharmacology Preclinical: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown. Clinical Studies The safety and efficacy of AIRDUO RESPICLICK were evaluated in 3004 patients with asthma. The development program included 2 confirmatory trials of 12 weeks duration, a 26 week safety trial and three dose-ranging trials. The efficacy of AIRDUO RESPICLICK is based primarily on the dose-ranging trials and the confirmatory trials described below. Dose-Ranging Studies Six doses of fluticasone propionate ranging from 16 mcg to 434 mcg (expressed as metered doses) administered twice daily via multidose dry powder inhaler were evaluated in 2 randomized, double-blind, placebo-controlled 12 week trials. Trial 201 was conducted in patients who were uncontrolled at baseline and had been treated by short-acting beta2-agonist alone or in combination with non-corticosteroid asthma medication. Low dose ICS patients may have been included after a minimum of 2 weeks washout. This trial contained an open-label active comparator fluticasone propionate inhalation powder 100 mcg administered twice daily. Trial 202 was conducted in patients who were uncontrolled at baseline and had been treated with high dose ICS with or without a LABA. This study contained an open-label active comparator fluticasone propionate inhalation powder 250 mcg twice daily. The trials were dose-ranging trials of ARMONAIR RESPICLICK not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate inhalation powder. The metered doses for fluticasone multidose dry powder inhaler (16, 28, 59, 118, 225, 434 mcg) used in Trial 201 and Trial 202 (see Figure 2) are slightly different from the metered doses for the comparator products (fluticasone inhalation powder) and the Phase 3 investigational products which are the basis of the proposed commercial labeled claim (55, 113, 232 mcg for fluticasone). The changes in doses between Phase 2 and 3 resulted from optimization of the manufacturing process. Figure 2: Baseline Adjusted Least Square Mean Change in Trough Morning FEV1 (L) over 12 weeks (FAS)a FAS = full analysis set; aTrials were not designed to provide comparative effectiveness data and should not be interpreted as superiority/inferiority to fluticasone propionate inhalation powder The efficacy and safety of four doses of salmeterol xinafoate were evaluated in a double blind, 6period crossover study compared with single dose fluticasone propionate MDPI and open label fluticasone propionate/salmeterol 100/50 mcg dry powder inhaler as comparator in patients with persistent asthma. The trials were dose-ranging trials of the salmeterol component of AIRDUO RESPICLICK and not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority/inferiority to fluticasone propionate/salmeterol inhalation powder. The salmeterol doses studied were 6.8 mcg, 13.2 mcg, 26.8 mcg and 57.4 mcg in combination with fluticasone propionate 118 mcg delivered by MDPI (expressed as metered dose). The metered doses for salmeterol (6.8, 13.2, 26.8, 57.4 mcg) used in this study are slightly different from the metered doses for the comparator products (fluticasone/salmeterol inhalation powder) and the Phase 3 investigational products which are the basis of the proposed commercial labeled claim (55, 113, 232 mcg for fluticasone and 14 mcg for salmeterol). The phase 3 and commercial products were optimized to better match the strengths to the comparators. Plasma for pharmacokinetic characterization was obtained at each dosing period. Fluticasone propionate/salmeterol xinafoate MDPI 118/13.2 mcg had similar clinical efficacy with lower systemic exposure when compared to the 50 mcg of salmeterol in fluticasone propionate/salmeterol 100/50 mcg dry powder inhaler (Figure 3). Figure 3: Mean Baseline Adjusted FEV1 (mL) over 12 Hours (FAS)a FS MDPI = fluticasone propionate/salmeterol multidose dry powder inhaler: Fp MDPI = fluticasone propionate multidose dry powder inhaler; FS DPI = fluticasone propionate/salmeterol dry powder inhaler; FAS = full analysis set; FEV1 = forced expiratory volume in 1 second; aTrial was not designed to provide comparative effectiveness data and should not be interpreted as superiority/inferiority to fluticasone proprionate/salmeterol inhalation powder. Trials In The Maintenance Treatment Of Asthma Adult And Adolescent Patients Aged 12 Years And Older Two Phase 3 clinical trials were conducted; 2 trials comparing AIRDUO RESPICLICK with ARMONAIR RESPICLICK alone or placebo (Trial 1 and Trial 2). Trials Comparing AIRDUO RESPICLICK with Fluticasone Propionate Alone or Placebo Two double-blind, parallel-group clinical trials, Trial 1 and Trial 2, were conducted with AIRDUO RESPICLICK in 1375 adult and adolescent patients (aged 12 years and older, with baseline FEV1 40% to 85% of predicted normal) with asthma that was not optimally controlled on their current therapy. All treatments were given as 1 inhalation twice a day from the RESPICLICK inhaler, and other maintenance therapies were discontinued. Trial 1: This randomized, double-blind, placebo-controlled, 12-week, global efficacy and safety trial compared Fluticasone Propionate Multidose Dry Powder Inhaler (ARMONAIR RESPICLICK) 55 mcg and 113 mcg (1 inhalation twice a day) with Fluticasone/Salmeterol Multidose Dry Powder Inhaler (AIRDUO RESPICLICK) 55/14 mcg and 113/14 mcg (1 inhalation twice a day) and placebo in adolescents and adult patients with persistent symptomatic asthma despite low-dose or mid-dose inhaled corticosteroid or inhaled corticosteroid/LABA therapy. Patients received single-blinded placebo MDPI and were switched from their baseline ICS therapy to QVAR 40 mcg twice daily during the run-in period. Patients who met all randomization criteria were randomly assigned to receive treatment as follows: 130 received placebo, 129 received ARMONAIR RESPICLICK 55 mcg, 130 received ARMONAIR RESPICLICK 113 mcg, 129 received AIRDUO RESPICLICK 55/14 mcg, and 129 received AIRDUO RESPICLICK 113/14 mcg. Baseline FEV1 measurements were similar across treatments: ARMONAIR RESPICLICK 55 mcg 2.132 L, ARMONAIR RESPICLICK 113 mcg 2.166 L, AIRDUO RESPICLICK 55/14 mcg 2.302 L, AIRDUO RESPICLICK 113/14 mcg 2.162 L, and placebo 2.188 L. The primary endpoints for this trial were the change from baseline in trough FEV1 at week 12 for all patients and standardized baseline-adjusted FEV1 AUEC0-12h at week 12 analyzed for a subset of 312 patients who performed postdose serial spirometry. Patients receiving AIRDUO RESPICLICK 55/14 mcg and AIRDUO RESPICLICK 113/14 mcg had significantly greater improvements in trough FEV1 (AIRDUO RESPICLICK 55/14 mcg, LS mean change of 0.319 L at 12 weeks and AIRDUO RESPICLICK 113/14 mcg, LS mean change of 0.315 L at 12 weeks) compared with ARMONAIR RESPICLICK 55 mcg (LS mean change of 0.172 L at 12 weeks), ARMONAIR RESPICLICK 113 mcg (LS mean change of 0.204 L at 12 weeks), and placebo (LS mean change of 0.053 L at 12 weeks). Estimated mean differences between AIRDUO RESPICLICK 55/14 mcg and AIRDUO RESPICLICK 113/14 mcg compared to placebo are 0.266 L (95% CI: 0.172, 0.360) and 0.262 L (95% CI: 0.168, 0.356), respectively. The estimated mean differences between ARMONAIR RESPICLICK 55 mcg and ARMONAIR RESPICLICK 113 mcg compared to placebo are 0.119 L (95% CI: 0.025, 0.212) and 0.151 L (95% CI: 0.057, 0.244), respectively. The estimated mean difference between AIRDUO RESPICLICK 113/14 mcg and ARMONAIR RESPICLICK 113 mcg is 0.111 L (95% CI: 0.017, 0.206). The estimated mean difference between AIRDUO RESPICLICK 55/14 mcg and ARMONAIR RESPICLICK 55 mcg is 0.147 L (95% CI: 0.053, 0.242). In addition, the mean FEV1 results at each visit are displayed in Figure 4. Figure 4: Mean Change from Baseline in Trough FEV1 at Each Visit by Treatment Group Trial 1(FAS) There was supportive evidence of efficacy for AIRDUO RESPICLICK compared with placebo for secondary endpoints such as the weekly average of daily trough morning peak expiratory flow and total daily use of rescue medication. The Asthma Quality of Life Questionnaire (AQLQ) for patients age ≥ 18 years or the pediatric AQLQ (PAQLQ) for patients aged 12-17 were assessed in Trial 1. The responder rate for both measures was defined as an improvement in score of 0.5 or more as threshold. In Trial 1, the responder rate for patients receiving AIRDUO RESPICLICK 55/14 mcg and AIRDUO RESPICLICK 113/14 mcg was 51% and 57% , respectively, compared to 40% for patients receiving placebo, with an odds ratio of 1.53 (95% CI: 0.93, 2.55) and 2.04 (95% CI: 1.23, 3.41), respectively. Improvements in lung function occurred within 15 minutes of the first dose (15 minutes postdose, the difference in LS mean change from baseline in FEV1 was 0.216 and 0.164 L compared with placebo for AIRDUO RESPICLICK 55/14 mcg and 113/14 mcg, respectively; unadjusted p-value < 0.0001 for both doses compared with placebo. Refer to Figure 5 below. Maximum improvement in FEV1 generally occurred within 3 hours for AIRDUO RESPICLICK 55/14 mcg and within 6 hours for AIRDUO RESPICLICK 113/14 mcg and improvements were sustained over the 12 hours of testing at weeks 1 and 12 (Figure 5 and Figure 6). Following the initial dose, predose FEV1 relative to day 1 baseline improved markedly over the first week of treatment and the improvement was sustained over the 12 weeks of treatment in the trial. No diminution in the 12 hour bronchodilator effect was observed with either AIRDUO RESPICLICK dose as assessed by FEV1 following 12 weeks of therapy. Figure 5: Serial Spirometry: Mean Change from Baseline in FEV1 (L) at Day 1 by Time Point and Treatment Group Trial 1 (FAS; Serial Spirometry Subset) Figure 6: Serial Spirometry: Mean Change from Baseline in FEV1 (L) at Week 12 by Time Point and Treatment Group Trial 1 (FAS; Serial Spirometry Subset) Trial 2: This randomized, double-blind, placebo-controlled, 12-week, global efficacy and safety trial compared Fluticasone Propionate Multidose Dry Powder Inhaler (ARMONAIR RESPICLICK) 113 mcg and 232 mcg (1 inhalation twice a day) with Fluticasone/Salmeterol Multidose Dry Powder Inhaler (AIRDUO RESPICLICK) 113/14 mcg and 232/14 mcg (1 inhalation twice a day) and placebo in adolescents and adult patients with persistent symptomatic asthma despite inhaled corticosteroid or inhaled corticosteroid/LABA therapy. Patients received single-blinded placebo MDPI and were switched from their baseline ICS therapy to ARMONAIR RESPICLICK 55 mcg twice daily during the run-in period. Patients who met all randomization criteria were randomly assigned to receive treatment as follows: 145 patients received placebo, 146 patients received ARMONAIR RESPICLICK 113 mcg, 146 patients received ARMONAIR RESPICLICK 232 mcg, 145 patients received AIRDUO RESPICLICK 113/14 mcg, and 146 patients received AIRDUO RESPICLICK 232/14 mcg. Baseline FEV1 measurements were similar across treatments: ARMONAIR RESPICLICK 113 mcg 2.069 L, ARMONAIR RESPICLICK 232 mcg 2.075 L, AIRDUO RESPICLICK 113/14 mcg 2.157 L, AIRDUO RESPICLICK 232/14 mcg 2.083 L, and placebo 2.141 L. The primary endpoints for this trial were the change from baseline in trough FEV1 at week 12 for all patients and standardized baseline-adjusted FEV1 AUEC0-12h at week 12 analyzed for a subset of 312 patients who performed postdose serial spirometry. Efficacy results in this trial were similar to those observed in Trial 1. Patients receiving AIRDUO RESPICLICK 113/14 mcg and AIRDUO RESPICLICK 232/14 mcg had significantly greater improvements in trough FEV1 (AIRDUO RESPICLICK 113/14 mcg, LS mean change of 0.271 L at 12 weeks and AIRDUO RESPICLICK 232/14 mcg, LS mean change of 0.272 L at 12 weeks) compared with ARMONAIR RESPICLICK 113 mcg (LS mean change of 0.119 L at 12 weeks), ARMONAIR RESPICLICK 232 mcg (LS mean change of 0.179 L at 12 weeks), and placebo (LS mean change of -0.004 L at 12 weeks). Estimated mean differences between AIRDUO RESPICLICK 113/14 mcg and AIRDUO RESPICLICK 232/14 mcg compared to placebo are 0.274 L (95% CI: 0.189, 0.360) and 0.276 L (95% CI: 0.191, 0.361), respectively. The estimated mean differences between ARMONAIR RESPICLICK 113 mcg and ARMONAIR RESPICLICK 232 mcg compared to to placebo are 0.123 L (95% CI: 0.038, 0.208) and 0.183 L (95% CI: 0.098, 0.268), respectively. The estimated mean difference between AIRDUO RESPICLICK 232/14 mcg and ARMONAIR RESPICLICK 232 mcg is 0.093 L (95% CI: 0.009, 0.178). The estimated mean difference between AIRDUO RESPICLICK 113/14 mcg and ARMONAIR RESPICLICK 113 mcg is 0.152 L (95% CI: 0.066, 0.237). In addition, the mean FEV1 results at each visit are displayed in Figure 7. Figure 7: Mean Change from Baseline in Trough FEV1 at Each Visit by Treatment Group Trial 2 (FAS) There was supportive evidence of efficacy for AIRDUO RESPICLICK compared with placebo for secondary endpoints such as the weekly average of daily trough morning peak expiratory flow and total daily use of rescue medication. There were fewer withdrawals due to worsening asthma in patients treated with AIRDUO RESPICLICK than with placebo. The Asthma Quality of Life Questionnaire (AQLQ) for patients age ≥ 18 years or the pediatric AQLQ (PAQLQ) for patients aged 12-17 were assessed in Trial 2. The responder rate for both measures was defined as an improvement in score of 0.5 or more as threshold. In Trial 2, the responder rate for patients receiving AIRDUO RESPICLICK 113/14 mcg and AIRDUO RESPICLICK 232/14 mcg was 48% and 41%, respectively, compared to 27% for patients receiving placebo, with an odds ratio of 2.59 (95% CI: 1.56, 4.31) and 1.94 (95% CI: 1.16, 3.23), respectively. Improvements in lung function occurred within 15 minutes of the first dose (15 minutes postdose, the difference in LS mean change from baseline in FEV1 was 0.160 L and 0.187 L compared with placebo for AIRDUO RESPICLICK 113/14 mcg and 232/14 mcg, respectively; unadjusted p-value < 0.0001 for both doses compared with placebo. Maximum improvement in FEV1 generally occurred within 3 hours for both AIRDUO RESPICLICK dose groups, and improvements were sustained over the 12 hours of testing at weeks 1 and 12 (Figure 8 and Figure 9). Following the initial dose, predose FEV1 relative to day 1 baseline improved markedly over the first week of treatment and the improvement was sustained over the 12 weeks of treatment in the trial. No diminution in the 12 hour bronchodilator effect was observed with either AIRDUO RESPICLICK dose as assessed by FEV1 following 12 weeks of therapy. Figure 8: Serial Spirometry: Mean Change from Baseline in FEV1 (L) at Day 1 by Time Point and Treatment Group Trial 2 (FAS; Serial Spirometry Subset) Figure 9: Serial Spirometry: Mean Change from Baseline in FEV1 (L) at Week 12 by Time Point and Treatment Group Trial 2 (FAS; Serial Spirometry Subset)

CLINICAL PHARMACOLOGY Mechanism Of Action ADVAIR HFA ADVAIR HFA contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to ADVAIR HFA. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have different effects on clinical, physiologic, and inflammatory indices of asthma. Fluticasone Propionate Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of 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. The clinical significance of these findings is unknown. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. 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 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. Pharmacodynamics ADVAIR HFA Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) placebo-controlled crossover trials were conducted with healthy subjects: (1) a cumulative-dose trial using 42 to 336 mcg of salmeterol CFC inhalation aerosol given alone or as ADVAIR HFA 115/21, (2) a single-dose trial using 4 inhalations of ADVAIR HFA 230/21, salmeterol CFC inhalation aerosol 21 mcg, or fluticasone propionate CFC inhalation aerosol 220 mcg, (3) a single-dose trial using 8 inhalations of ADVAIR HFA 45/21, ADVAIR HFA 115/21, or ADVAIR HFA 230/21, and (4) a single-dose trial using 4 inhalations of ADVAIR HFA 230/21; 2 inhalations of ADVAIR DISKUS 500/50; 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg; or 1,010 mcg of fluticasone propionate given intravenously. In these trials pulse rate, blood pressure, QTc interval, glucose, and/or potassium were measured. Comparable or lower effects were observed for ADVAIR HFA compared with ADVAIR DISKUS or salmeterol alone. The effect of salmeterol on pulse rate and potassium was not altered by the presence of different amounts of fluticasone propionate in ADVAIR HFA. Hypothalamic-Pituitary-Adrenal Axis Effects: The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in 3 of these trials. Compared with fluticasone propionate CFC inhalation aerosol, ADVAIR HFA had less effect on 24-hour urinary cortisol excretion and less or comparable effect on 24-hour serum cortisol. In these crossover trials in healthy subjects, ADVAIR HFA and ADVAIR DISKUS had similar effects on urinary and serum cortisol. Subjects with Asthma: Cardiovascular Effects: In clinical trials with ADVAIR HFA in adult and adolescent subjects aged 12 years and older with asthma, systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) were similar to or slightly lower in patients treated with ADVAIR HFA compared with patients treated with salmeterol CFC inhalation aerosol 21 mcg. In 61 adult and adolescent subjects with asthma given ADVAIR HFA (45/21 or 115/21 mcg), continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of twice-daily therapy, and no clinically significant dysrhythmias were noted. The effect of 21 days of treatment with ADVAIR HFA 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. There were no notable changes from baseline for QTc, heart rate, or systolic and diastolic blood pressure. Hypothalamic-Pituitary-Adrenal Axis Effects: A 4-way crossover trial in 13 subjects with asthma compared pharmacodynamics at steady state following 4 weeks of twice-daily treatment with 2 inhalations of ADVAIR HFA 115/21, 1 inhalation of ADVAIR DISKUS 250/50 mcg, 2 inhalations of fluticasone propionate HFA inhalation aerosol 110 mcg, and placebo. No significant differences in serum cortisol AUC were observed between active treatments and placebo. Mean 12-hour serum cortisol AUC ratios comparing active treatment with placebo ranged from 0.9 to 1.2. No statistically or clinically significant increases in heart rate or QTc interval were observed for any active treatment compared with placebo. In a 12-week trial in adult and adolescent subjects with asthma, ADVAIR HFA 115/21 was compared with the individual components, fluticasone propionate CFC inhalation aerosol 110 mcg and salmeterol CFC inhalation aerosol 21 mcg, and placebo [see Clinical Studies]. All treatments were administered as 2 inhalations twice daily. After 12 weeks of treatment with these therapeutic doses, the geometric mean ratio of urinary cortisol excretion compared with baseline was 0.9 for ADVAIR HFA and fluticasone propionate and 1.0 for placebo and salmeterol. In addition, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation in 23 to 32 subjects per treatment group, remained intact for the majority of subjects and was similar across treatments. Three subjects who received ADVAIR HFA 115/21 had an abnormal response (peak serum cortisol less than 18 mcg/dL) after dosing, compared with 1 subject who received placebo, 2 subjects who received fluticasone propionate 110 mcg, and 1 subject who received salmeterol. In another 12-week trial in adult and adolescent subjects with asthma, ADVAIR HFA 230/21 (2 inhalations twice daily) was compared with ADVAIR DISKUS 500/50 (1 inhalation twice daily) and fluticasone propionate CFC inhalation aerosol 220 mcg (2 inhalations twice daily) [see Clinical Studies]. The geometric mean ratio of 24-hour urinary cortisol excretion at week 12 compared with baseline was 0.9 for all 3 treatment groups. The effect of 21 days of treatment with ADVAIR HFA 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) on serum cortisol was evaluated in 31 children aged 4 to 11 years with mild asthma. There were reductions in serum cortisol from baseline in all treatment groups (14%, 22%, and 13% for ADVAIR HFA, ADVAIR HFA with spacer, and ADVAIR DISKUS, respectively). Other Fluticasone Propionate Products Subjects with Asthma: Hypothalamic-Pituitary-Adrenal Axis Effects: In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol less than 18 mcg/dL assessed by radioimmunoassay) were noted both in subjects receiving fluticasone propionate and in subjects receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year trial carried out with the DISKHALER® inhalation device in 64 subjects with mild, persistent asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no subject receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol less than 18 mcg/dL). With a peak cortisol threshold of less than 35 mcg/dL, 1 subject receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another subject receiving fluticasone propionate (5%) had an abnormal response at 2 years. No subject on placebo had an abnormal response at 1 or 2 years. Other Salmeterol Xinafoate Products Subjects with Asthma: Cardiovascular Effects: Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium [see WARNINGS AND PRECAUTIONS]. The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration. The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). In 2 double-blind asthma trials, subjects receiving either 42 mcg of salmeterol inhalation aerosol twice daily (n = 81) or 180 mcg of albuterol inhalation aerosol 4 times daily (n = 80) underwent continuous electrocardiographic monitoring during four 24-hour periods; no clinically significant dysrhythmias were noted. Concomitant Use of ADVAIR HFA with Other Respiratory Medicines Short-Acting Beta2-Agonists: In three 12-week US clinical trials, the mean daily need for additional beta2-agonist use in 277 subjects receiving ADVAIR HFA was approximately 1.2 inhalations/day and ranged from 0 to 9 inhalations/day. Two percent (2%) of subjects receiving ADVAIR HFA in these trials averaged 6 or more inhalations per day over the course of the 12-week trials. No increase in frequency of cardiovascular adverse events was observed among subjects who averaged 6 or more inhalations per day. Methylxanthines: The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by subjects receiving ADVAIR HFA has not been completely evaluated. In five 12-week clinical trials (3 US and 2 non-US), 45 subjects receiving ADVAIR HFA 45/21, 115/21, or 230/21 twice daily concurrently with a theophylline product had adverse event rates similar to those in 577 subjects receiving ADVAIR HFA without theophylline. Fluticasone Propionate Nasal Spray: In subjects receiving ADVAIR HFA in three 12-week US clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between subjects receiving FLONASE® (fluticasone propionate) Nasal Spray, 50 mcg concurrently (n = 89) and those who were not (n = 192). Pharmacokinetics Absorption Fluticasone Propionate: Healthy Subjects: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Trials using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (less than 1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. Three single-dose placebo-controlled crossover trials were conducted in healthy subjects: (1) a trial using 4 inhalations of ADVAIR HFA 230/21, salmeterol CFC inhalation aerosol 21 mcg, or fluticasone propionate CFC inhalation aerosol 220 mcg, (2) a trial using 8 inhalations of ADVAIR HFA 45/21, ADVAIR HFA 115/21, or ADVAIR HFA 230/21, and (3) a trial using 4 inhalations of ADVAIR HFA 230/21; 2 inhalations of ADVAIR DISKUS 500/50; 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg; or 1,010 mcg of fluticasone propionate given intravenously. Peak plasma concentrations of fluticasone propionate were achieved in 0.33 to 1.5 hours and those of salmeterol were achieved in 5 to 10 minutes. Peak plasma concentrations of fluticasone propionate (N = 20 subjects) following 8 inhalations of ADVAIR HFA 45/21, ADVAIR HFA 115/21, and ADVAIR HFA 230/21 averaged 41, 108, and 173 pg/mL, respectively. Systemic exposure (N = 20 subjects) from 4 inhalations of ADVAIR HFA 230/21 was 53% of the value from the individual inhaler for fluticasone propionate CFC inhalation aerosol and 42% of the value from the individual inhaler for salmeterol CFC inhalation aerosol. Peak plasma concentrations from ADVAIR HFA for fluticasone propionate (86 versus 120 pg/mL) and salmeterol (170 versus 510 pg/mL) were significantly lower compared with individual inhalers. In 15 healthy subjects, systemic exposure to fluticasone propionate from 4 inhalations of ADVAIR HFA 230/21 (920/84 mcg) and 2 inhalations of ADVAIR DISKUS 500/50 (1,000/100 mcg) was similar between the 2 inhalers (i.e., 799 versus 832 pg•h/mL, respectively), but approximately half the systemic exposure from 4 inhalations of fluticasone propionate CFC inhalation aerosol 220 mcg (880 mcg, AUC = 1,543 pg•h/mL). Similar results were observed for peak fluticasone propionate plasma concentrations (186 and 182 pg/mL from ADVAIR HFA and ADVAIR DISKUS, respectively, and 307 pg/mL from the fluticasone propionate CFC inhalation aerosol). Absolute bioavailability of fluticasone propionate was 5.3% and 5.5% following administration of ADVAIR HFA and ADVAIR DISKUS, respectively. Subjects with Asthma: A double-blind crossover trial was conducted in 13 adult subjects with asthma to evaluate the steady-state pharmacokinetics of fluticasone propionate and salmeterol following administration of 2 inhalations of ADVAIR HFA 115/21 twice daily or 1 inhalation of ADVAIR DISKUS 250/50 twice daily for 4 weeks. Systemic exposure (AUC) to fluticasone propionate was similar for ADVAIR HFA (274 pg•h/mL [95% CI: 150, 502]) and ADVAIR DISKUS (338 pg•h/mL [95% CI: 197, 581]). The effect of 21 days of treatment with ADVAIR HFA 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) was evaluated in a trial of 31 children aged 4 to 11 years with mild asthma. Systemic exposure to fluticasone propionate was similar with ADVAIR DISKUS and ADVAIR HFA with a spacer (138 pg•h/mL [95% CI: 69, 273] and 107 pg•h/mL [95% CI: 46, 252], respectively) and lower with ADVAIR HFA without a spacer (24 pg•h/mL [95% CI: 10, 60]). Salmeterol Xinafoate: Healthy Subjects: Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Peak plasma concentrations of salmeterol (N = 20 subjects) following 8 inhalations of ADVAIR HFA 45/21, ADVAIR HFA 115/21, and ADVAIR HFA 230/21 ranged from 220 to 470 pg/mL. In 15 healthy subjects receiving ADVAIR HFA 230/21 (920/84 mcg) and ADVAIR DISKUS 500/50 (1,000/100 mcg), systemic exposure to salmeterol was higher (317 versus 169 pg•h/mL) and peak salmeterol concentrations were lower (196 versus 223 pg/mL) following ADVAIR HFA compared with ADVAIR DISKUS, although pharmacodynamic results were comparable. Subjects with Asthma: Because of the small therapeutic dosage, systemic levels of salmeterol are low or undetectable after inhalation of recommended dosages (42 mcg of salmeterol inhalation aerosol twice daily). Following chronic administration of an inhaled dosage of 42 mcg of salmeterol inhalation aerosol twice daily, salmeterol was detected in plasma within 5 to 10 minutes in 6 subjects with asthma; plasma concentrations were very low, with mean peak concentrations of 150 pg/mL at 20 minutes and no accumulation with repeated doses. A double-blind crossover trial was conducted in 13 adult subjects with asthma to evaluate the steady-state pharmacokinetics of fluticasone propionate and salmeterol following administration of 2 inhalations of ADVAIR HFA 115/21 twice daily or 1 inhalation of ADVAIR DISKUS 250/50 twice daily for 4 weeks. Systemic exposure to salmeterol was similar for ADVAIR HFA (53 pg•h/mL [95% CI: 17, 164]) and ADVAIR DISKUS (70 pg•h/mL [95% CI: 19, 254]). The effect of 21 days of treatment with ADVAIR HFA 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol was similar for ADVAIR HFA, ADVAIR HFA with spacer, and ADVAIR DISKUS (126 pg•h/mL [95% CI: 70, 225], 103 pg•h/mL [95% CI: 54, 200], and 110 pg•h/mL [95% CI: 55, 219], respectively). Distribution Fluticasone Propionate: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin. Salmeterol: The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol. Metabolism Fluticasone Propionate: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. 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. An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to α-hydroxysalmeterol (aliphatic oxidation) by CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of α-hydroxysalmeterol in vitro. Elimination Fluticasone Propionate: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 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 for ADVAIR HFA, ADVAIR DISKUS, and fluticasone propionate CFC inhalation aerosol were similar and 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 (greater than 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. Special Populations A population pharmacokinetic analysis was performed for fluticasone propionate and salmeterol utilizing data from 9 controlled clinical trials that included 350 subjects with asthma aged 4 to 77 years who received treatment with ADVAIR DISKUS, ADVAIR HFA, fluticasone propionate inhalation powder (FLOVENT® DISKUS®), HFA-propelled fluticasone propionate inhalation aerosol (FLOVENT HFA), or CFC-propelled fluticasone propionate inhalation aerosol. The population pharmacokinetic analyses for fluticasone propionate and salmeterol showed no clinically relevant effects of age, gender, race, body weight, body mass index, or percent of predicted FEV1 on apparent clearance and apparent volume of distribution. Hepatic and Renal Impairment: Formal pharmacokinetic studies using ADVAIR HFA have not been conducted in patients with hepatic or renal impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored. Drug Interactions In the repeat-and single-dose trials, there was no evidence of significant drug interaction in systemic exposure between fluticasone propionate and salmeterol when given alone or in combination via the DISKUS. Similar definitive studies have not been performed with ADVAIR HFA. The population pharmacokinetic analysis from 9 controlled clinical trials in 350 subjects with asthma showed no significant effects on fluticasone propionate or salmeterol pharmacokinetics following co-administration with beta2-agonists, corticosteroids, antihistamines, or theophyllines. Inhibitors of Cytochrome P450 3A4: Ritonavir: Fluticasone Propionate: Fluticasone propionate is a substrate of CYP3A4. Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor ritonavir is not recommended based upon a multiple-dose crossover drug interaction trial in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (less than 10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Cmax) averaged 11.9 pg/mL (range: 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•h/mL (range: 4.2 to 18.8 pg•h/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range: 110 to 648 pg/mL) and 3,102.6 pg•h/mL (range: 1,207.1 to 5,662.0 pg•h/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in serum cortisol AUC. Ketoconazole: Fluticasone Propionate: In a placebo-controlled crossover trial in 8 healthy adult volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol AUC, and no effect on urinary excretion of cortisol. Salmeterol: In a placebo-controlled crossover drug interaction trial in 20 healthy male and female subjects, coadministration of salmeterol (50 mcg twice daily) and the strong CYP3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a significant increase in plasma salmeterol exposure as determined by a 16-fold increase in AUC (ratio with and without ketoconazole 15.76 [90% CI: 10.66, 23.31]) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations were increased by 1.4fold (90% CI: 1.23, 1.68). Three (3) out of 20 subjects (15%) were withdrawn from salmeterol and ketoconazole coadministration due to beta-agonist–mediated systemic effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, mean blood potassium, or mean blood glucose. Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration. Erythromycin: Fluticasone Propionate: In a multiple-dose drug interaction trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. Salmeterol: In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol Cmax at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P less than 0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium. Animal Toxicology And/Or Pharmacology Preclinical Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown. Propellant HFA-134a In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation. Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (i.e., 380 to 1,300 times the maximum human exposure based on comparisons of area under the plasma concentration versus time curve [AUC] values), primarily producing ataxia, tremors, dyspnea, or salivation. These events are similar to effects produced by the structurally related CFCs, which have been used extensively in metered-dose inhalers. In drug interaction studies in male and female dogs, there was a slight increase in the salmeterol-related effect on heart rate (a known effect of beta2-agonists) when given in combination with high doses of fluticasone propionate. This effect was not observed in clinical trials. Clinical Studies ADVAIR HFA has been studied in subjects with asthma aged 12 years and older. ADVAIR HFA has not been studied in subjects younger than 12 years or in subjects with COPD. In clinical trials comparing ADVAIR HFA Inhalation Aerosol with its individual components, improvements in most efficacy endpoints were greater with ADVAIR HFA than with the use of either fluticasone propionate or salmeterol alone. In addition, clinical trials showed comparable results between ADVAIR HFA and ADVAIR DISKUS. Trials Comparing ADVAIR HFA With Fluticasone Propionate Alone Or Salmeterol Alone 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 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 45/21 Inhalation Aerosol This placebo-controlled 12-week, US trial 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 trial was stratified according to baseline asthma therapy: subjects using beta-agonists (albuterol alone [n = 142], salmeterol [n = 84], or inhaled corticosteroids [n = 134] [daily doses of beclomethasone dipropionate 252 to 336 mcg; budesonide 400 to 600 mcg; flunisolide 1,000 mcg; fluticasone propionate inhalation aerosol 176 mcg; fluticasone propionate inhalation powder 200 mcg; or triamcinolone acetonide 600 to 800 mcg]). 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. 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 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 medicine not allowed by the protocol. As shown in Table 3, statistically significantly fewer subjects receiving ADVAIR HFA 45/21 were withdrawn due to worsening asthma compared with salmeterol and placebo. Fewer subjects receiving ADVAIR HFA 45/21 were withdrawn due to worsening asthma compared with fluticasone propionate 44 mcg; however, the difference was not statistically significant. Table 3: Percent of Subjects Withdrawn due to Worsening Asthma in Subjects Previously Treated with Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Trial 1) ADVAIR HFA 45/21 Inhalation Aerosol (n = 92) Fluticasone Propionate CFC Inhalation Aerosol 44 mcg (n = 89) Salmeterol CFC Inhalation Aerosol 21 mcg (n = 92) Placebo HFA Inhalation Aerosol (n = 87) 2% 8% 25% 28% The FEV1 results are displayed in Figure 2. Because this trial used predetermined criteria for worsening asthma, which caused more subjects in the placebo group to be withdrawn, FEV1 results at Endpoint (last available FEV1 result) are also provided. 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 (albuterol alone, salmeterol, or inhaled corticosteroids). Figure 2: Mean Percent Change from Baseline in FEV1 in Subjects Previously Treated with Either Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Trial 1) The effect of ADVAIR HFA 45/21 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. Table 4: Secondary Efficacy Variable Results for Subjects Previously Treated with Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Trial 1) Efficacy Variablea ADVAIR HFA 45/21 Inhalation Aerosol (n = 92) Fluticasone Propionate CFC Inhalation Aerosol 44 mcg (n = 89) Salmeterol CFC Inhalation Aerosol 21 mcg (n = 92) Placebo HFA Inhalation Aerosol (n = 87) AM PEF (L/min) Baseline 377 369 381 382 Change from baseline 58 27 25 1 PM PEF (L/min) Baseline 397 387 402 407 Change from baseline 48 20 16 3 Use of VENTOLIN Inhalation Aerosol (inhalations/day) Baseline 3.1 2.4 2.7 2.7 Change from baseline -2.1 -0.4 -0.8 0.2 Asthma symptom score/day Baseline 1.8 1.6 1.7 1.7 Change from baseline -1.0 -0.3 -0.4 0 aChange from baseline = change from baseline at Endpoint (last available data). 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 45/21 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). Trial 2: Clinical Trial with ADVAIR HFA 45/21 Inhalation Aerosol This active-controlled, 12-week, US trial 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 subjects using as-needed albuterol alone. The primary efficacy endpoint was predose FEV1. Baseline FEV1 measurements were similar across treatments: ADVAIR HFA 45/21, 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. Subjects 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%). Trial 3: Clinical Trial with ADVAIR HFA 115/21 Inhalation Aerosol This placebo-controlled, 12-week, US trial 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 subjects using inhaled corticosteroids (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 FEV1 and withdrawals due to worsening asthma. Baseline FEV1 measurements were similar across treatments: ADVAIR HFA 115/21, 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. Subjects 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 subjects receiving ADVAIR HFA 115/21 were withdrawn from this trial for worsening asthma (7%) compared with salmeterol (24%) and placebo (54%). Fewer subjects 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. Trial 4: Clinical Trial with ADVAIR HFA 230/21 Inhalation Aerosol This active-controlled 12-week non-US trial 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 subjects using inhaled corticosteroids (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 230/21, 327 L/min; ADVAIR DISKUS 500/50, 341 L/min; and fluticasone propionate 220 mcg, 345 L/min. As shown in Figure 3, morning PEF improved significantly with ADVAIR HFA 230/21 compared with fluticasone propionate 220 mcg over the 12-week treatment period. Improvements in morning PEF observed with ADVAIR HFA 230/21 were similar to improvements observed with ADVAIR DISKUS 500/50. Figure 3: Mean Percent Change from Baseline in Morning Peak Expiratory Flow in Subjects Previously Treated with Inhaled Corticosteroids (Trial 4) One-Year Safety Trial Clinical Trial with ADVAIR HFA 45/21, 115/21, and 230/21 Inhalation Aerosol This 1-year, open-label, non-US trial evaluated the safety of ADVAIR HFA 45/21, 115/21, and 230/21 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 beta2-agonists alone (n = 42), salmeterol (n = 91), or inhaled corticosteroids (n = 277). Subjects treated with short-acting beta2-agonists alone, salmeterol, or low doses of inhaled corticosteroids with or without concurrent salmeterol received ADVAIR HFA 45/21. Subjects treated with moderate doses of inhaled corticosteroids with or without concurrent salmeterol received ADVAIR HFA 115/21. Subjects treated with high doses of inhaled corticosteroids with or without concurrent salmeterol received ADVAIR HFA 230/21. Baseline FEV1 measurements ranged from 2.3 to 2.6 L. 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 subjects (3%) were withdrawn due to worsening asthma over 1 year. Onset Of Action And Progression Of Improvement In Control The onset of action and progression of improvement in asthma control were evaluated in 2 placebo-controlled US trials and 1 active-controlled US trial. Following the first dose, the median time to onset of clinically significant bronchodilatation ( ≥ 15% improvement in FEV1) in most subjects was seen within 30 to 60 minutes. Maximum improvement in FEV1 occurred within 4 hours, and clinically significant improvement was maintained for 12 hours (see Figure 4). 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 all 3 trials. No diminution in the 12-hour bronchodilator effect was observed with either ADVAIR HFA 45/21 (Figures 4 and 5) or ADVAIR HFA 230/21 as assessed by FEV1 following 12 weeks of therapy. Figure 4: Percent Change in Serial 12-Hour FEV1 in Subjects Previously Using either Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Trial 1) Figure 5: Percent Change in Serial 12-Hour FEV1 in Subjects Previously Using either Beta2-Agonists (Albuterol or Salmeterol) or Inhaled Corticosteroids (Trial 1) Last Treatment Day (Week 12) 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.

AIRDUO RESPICLICK (fluticasone propionate and salmeterol) Inhalation Powder WARNING ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in AIRDUO RESPICLICK, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of salmeterol with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 subjects 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe AIRDUO RESPICLICK 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 AIRDUO RESPICLICK) 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 AIRDUO RESPICLICK for patients whose asthma is adequately controlled on low-or medium-dose inhaled corticosteroids [see WARNINGS AND PRECAUTIONS]. DESCRIPTION AIRDUO RESPICLICK 55/14 mcg, AIRDUO RESPICLICK 113/14 mcg and AIRDUO RESPICLICK 232/14 mcg are combinations of fluticasone propionate and salmeterol xinafoate. One active component of AIRDUO RESPICLICK is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11ß,17-dihydroxy-16α-methyl-3oxoandrosta-1,4-diene-17ß-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 AIRDUO RESPICLICK is salmeterol xinafoate, a beta2- adrenergic bronchodilator. Salmeterol xinafoate is the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. It has the chemical name 4-hydroxy-α -[[[6-(4phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2naphthalenecarboxylate and 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. AIRDUO RESPICLICK is a white multidose dry powder inhaler (MDPI) for oral inhalation only. It contains a formulation blend of fluticasone propionate, salmeterol xinafoate, and lactose monohydrate (which may contain milk proteins). The opening of the mouthpiece cover meters 5.5 mg of the formulation from the device reservoir, which contains 55 mcg, 113 mcg, or 232 mcg of fluticasone propionate, and 14 mcg of salmeterol base, equivalent to 20.3 mcg of salmeterol xinafoate. Patient inhalation through the mouthpiece causes the deagglomeration and aerosolization of the drug particles as the formulation moves through the cyclone component of the device. This is followed by dispersion into the airstream. Under standardized in vitro test conditions, the AIRDUO RESPICLICK inhaler delivers 49 mcg, 100 mcg, or 202 mcg of fluticasone propionate and 12.75 mcg of salmeterol base, equivalent to 18.5 mcg of salmeterol xinafoate, with lactose from the mouthpiece when tested at a flow rate of 85 L/min for 1.4 seconds. The amount of drug delivered to the lung will depend on patient factors such as inspiratory flow profiles. In adult subjects (N=50, aged 18 to 45 years) with asthma, mean peak inspiratory flow (PIF) through the AIRDUO RESPICLICK inhaler was 108.28 L/min (range: 70.37 to 129.24 L/min). In adolescent subjects (N=50, aged 12 to 17 years) with asthma, mean peak inspiratory flow (PIF) through the AIRDUO RESPICLICK inhaler was 106.72 L/min (range: 73.64 to 125.51 L/min).

Find Lowest Prices on ADVAIR HFA 45/21 (fluticasone propionate 45 mcg and salmeterol 21 mcg) Inhalation Aerosol ADVAIR HFA 115/21 (fluticasone propionate 115 mcg and salmeterol 21 mcg) Inhalation Aerosol ADVAIR HFA 230/21 (fluticasone propionate 230 mcg and salmeterol 21 mcg) Inhalation Aerosol WARNING ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in ADVAIR® HFA Inhalation Aerosol, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of salmeterol with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 subjects 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR HFA 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 HFA) 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 HFA for patients whose asthma is adequately controlled on low-or medium-dose inhaled corticosteroids [see WARNINGS AND PRECAUTIONS]. DESCRIPTION ADVAIR HFA 45/21 Inhalation Aerosol, ADVAIR HFA 115/21 Inhalation Aerosol, and ADVAIR HFA 230/21 Inhalation Aerosol are combinations of fluticasone propionate and salmeterol xinafoate. One active component of ADVAIR HFA is fluticasone propionate, a corticosteroid having the chemical name S-(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3oxoandrosta-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 HFA 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-(4phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2naphthalenecarboxylate, 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 HFA is a purple plastic inhaler with a light purple strapcap containing a pressurized metered-dose aerosol canister fitted with a counter. Each canister contains a microcrystalline suspension of micronized fluticasone propionate and micronized salmeterol xinafoate in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It contains no other excipients. After priming, each actuation of the inhaler delivers 50, 125, or 250 mcg of fluticasone propionate and 25 mcg of salmeterol in 75 mg of suspension from the valve. Each actuation delivers 45, 115, or 230 mcg of fluticasone propionate and 21 mcg of salmeterol from the actuator. Twenty-one micrograms (21 mcg) of salmeterol base is equivalent to 30.45 mcg of salmeterol xinafoate. The actual amount of drug delivered to the lung will depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. Prime ADVAIR HFA before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well for 5 seconds before each spray.

INDICATIONS AIRDUO™ RESPICLICK® is indicated for the treatment of asthma in patients aged 12 years and older. LABAs, such as salmeterol, one of the active ingredients in AIRDUO RESPICLICK, 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]. Therefore, when treating patients with asthma, physicians should only prescribe AIRDUO RESPICLICK 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 AIRDUO RESPICLICK) 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 AIRDUO RESPICLICK for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Important Limitation Of Use AIRDUO RESPICLICK is NOT indicated for the relief of acute bronchospasm. DOSAGE AND ADMINISTRATION General AIRDUO RESPICLICK should be administered as one inhalation twice daily by the orally inhaled route only. Advise the patient to rinse his/her mouth with water without swallowing after each dose. Dosing AIRDUO RESPICLICK should be administered as 1 inhalation twice daily (approximately 12 hours apart) by the orally inhaled route. AIRDUO RESPICLICK should be used at approximately the same time every day. Do not use AIRDUO RESPICLICK more than 2 times every 24 hours. The starting dosage for AIRDUO RESPICLICK is based upon patients' asthma severity . The usual recommended starting dose for patients not on inhaled corticosteroids is 55/14 mcg twice daily. For other patients, the starting dose should be based on previous asthma drug therapy and disease severity. For patients switching to AIRDUO RESPICLICK from another inhaled corticosteroid or combination product, select the low (55/14 mcg), medium (113/14 mcg) or high (232/14 mcg) dose strength of AIRDUO RESPICLICK based on the strength of the previous inhaled corticosteroid product or the strength of the inhaled corticosteroid from a combination product and disease severity. For patients who do not respond to AIRDUO RESPICLICK 55/14 mcg after 2 weeks of therapy, increasing the dose may provide additional asthma control. If a dosage regimen of AIRDUO RESPICLICK fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options (e.g., replacing the current strength of AIRDUO RESPICLICK with a higher strength, or adding additional controller therapies) should be considered. The highest recommended dose of AIRDUO RESPICLICK is 232/14 mcg twice daily. More frequent administration or a greater number of inhalations (more than one inhalation twice daily) of the prescribed strength of AIRDUO RESPICLICK is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using AIRDUO RESPICLICK should not use additional LABA for any reason [see WARNINGS AND PRECAUTIONS]. If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief. Improvement in asthma control following inhaled administration of AIRDUO RESPICLICK can occur within 15 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. After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. For patients who do not respond adequately to the starting dose after 2 weeks of therapy, replacing the current strength of AIRDUO RESPICLICK with a higher strength may provide additional improvement in asthma control. If a previously effective dosage regimen 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 AIRDUO RESPICLICK with a higher strength, adding additional controller therapies) should be considered. AIRDUO RESPICLICK does not require priming. Do not use AIRDUO RESPICLICK with a spacer or volume holding chamber. Cleaning Keep the inhaler in a cool dry place. Never wash or put any part of the inhaler in water. Routine maintenance is not required. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed. Dose Counter: The AIRDUO RESPICLICK inhaler has a dose counter. When the patient receives the inhaler, the number 60 will be displayed. The dose counter will count down each time the mouthpiece is opened and closed. The dose counter window displays the number of actuations (inhalations) left in the inhaler in units of two (e.g., 60, 58, 56, etc.). When the dose counter reaches 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red and the color of the numbers will change to black. HOW SUPPLIED Dosage Forms And Strengths Inhalation Powder. AIRDUO RESPICLICK is a multidose, inhalation-driven, dry powder inhaler for oral inhalation that meters 55 mcg, 113 mcg, or 232 mcg of fluticasone propionate with 14 mcg of salmeterol from the device reservoir and delivers 49 mcg, 100 mcg, or 202 mcg of fluticasone propionate with 12.75 mcg of salmeterol, respectively, from the mouthpiece per actuation. AIRDUO RESPICLICK is supplied as a white dry powder inhaler with a yellow cap in a sealed foil pouch with desiccant. AIRDUO RESPICLICK is supplied in the following three strengths as a white dry-powder inhaler. Each inhaler has a yellow cap and is packaged individually in a foil pouch in a carton. Each inhaler contains 0.45g of the formulation and provides 60 actuations: STRENGTH NDC CODE AIRDUO RESPICLICK 55/14 mcg NDC 59310-805-06 AIRDUO RESPICLICK 113/14 mcg NDC 59310-812-06 AIRDUO RESPICLICK 232/14 mcg NDC 59310-822-06 Each AIRDUO RESPICLICK inhaler has a dose counter attached to the actuator. Patients should never try to alter the numbers for the dose counter. Discard the inhaler when the counter displays 0, 30 days after opening the foil pouch or after the expiration date on the product, whichever comes first. The labeled amount of medication in each actuation cannot be assured after the counter displays 0, even though the inhaler is not completely empty and will continue to operate [see PATIENT INFORMATION]. Storage And Handling Store at room temperature (between 15° and 25°C; 59° and 77°F) in a dry place; excursions permitted from 59° F to 86° F (15°C to 30°C). Avoid exposure to extreme heat, cold, or humidity. Keep out of reach of children. AIRDUO RESPICLICK should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use. Discard AIRDUO RESPICLICK 30 days after opening the foil pouch or when the counter reads 0, whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart. Marketed by: Teva Respiratory, LLC Frazer, PA 19355. Manufactured by: Teva Pharmaceutical Industries Ltd. Jerusalem, Israel. Revised: Jan 2017

INDICATIONS ADVAIR HFA is indicated for the treatment of asthma in patients aged 12 years and older. LABA, such as salmeterol, one of the active ingredients in ADVAIR HFA, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see WARNINGS AND PRECAUTIONS]. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR HFA 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 HFA) 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 HFA for patients whose asthma is adequately controlled on low-or medium-dose inhaled corticosteroids. Important Limitation of Use ADVAIR HFA is NOT indicated for the relief of acute bronchospasm. DOSAGE AND ADMINISTRATION ADVAIR HFA should be administered as 2 inhalations twice daily by the orally inhaled route only. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis. More frequent administration or a greater number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of ADVAIR HFA is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using ADVAIR HFA should not use additional LABA for any reason. [See WARNINGS AND PRECAUTIONS] If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief. For patients aged 12 years and older, the dosage is 2 inhalations twice daily, approximately 12 hours apart. The recommended starting dosages for ADVAIR HFA for patients aged 12 years and older are based upon patients' asthma severity. The maximum recommended dosage is 2 inhalations of ADVAIR HFA 230/21 twice daily. Improvement in asthma control following inhaled administration of ADVAIR HFA 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 HFA with a higher strength may provide additional improvement in asthma control. If a previously effective dosage regimen 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 HFA with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be considered. Prime ADVAIR HFA before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well for 5 seconds before each spray. HOW SUPPLIED Dosage Forms And Strengths Inhalation Aerosol. Purple plastic inhaler with a light purple strapcap containing a pressurized metered-dose aerosol canister containing 60 or 120 metered inhalations and fitted with a counter. Each actuation delivers a combination of fluticasone propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) from the mouthpiece. Storage And Handling ADVAIR HFA 45/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0715-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0715-22). ADVAIR HFA 115/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0716-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0716-22). ADVAIR HFA 230/21 Inhalation Aerosol is supplied in 12-g pressurized aluminum canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0717-20) and 8-g pressurized aluminum canisters containing 60 metered actuations in institutional pack boxes of 1 (NDC 0173-0717-22). Each canister is fitted with a counter and supplied with a purple actuator with a light purple strapcap. Each inhaler is sealed in a plastic-coated, moisture-protective foil pouch with a desiccant that should be discarded when the pouch is opened. Each inhaler is packaged with a Medication Guide leaflet. The purple actuator supplied with ADVAIR HFA should not be used with any other product canisters, and actuators from other products should not be used with an ADVAIR HFA canister. The correct amount of medication in each actuation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000. Keep out of reach of children. Avoid spraying in eyes. Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire or incinerator. Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use. SHAKE WELL FOR 5 SECONDS BEFORE EACH SPRAY. Glaxo SmithKline, Research Triangle Park, NC 27709. Revised: November 2014

PATIENT INFORMATION No information provided. Please refer to the WARNINGS AND PRECAUTIONS sections.

PATIENT INFORMATION ADVAIR® [ad'vair] HFA 45/21 (fluticasone propionate 45 mcg and salmeterol 21 mcg) Inhalation Aerosol ADVAIR® HFA 115/21 (fluticasone propionate 115 mcg and salmeterol 21 mcg) Inhalation Aerosol ADVAIR® HFA 230/21 (fluticasone propionate 230 mcg and salmeterol 21 mcg) Inhalation Aerosol Read the Medication Guide that comes with ADVAIR HFA Inhalation Aerosol before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about ADVAIR HFA? ADVAIR HFA can cause serious side effects, including: People with asthma who take long-acting beta2-adrenergic agonist (LABA) medicines, such as salmeterol (one of the medicines in ADVAIR HFA), have an increased risk of death from asthma problems. It is not known whether fluticasone propionate, the other medicine in ADVAIR HFA, reduces the risk of death from asthma problems seen with salmeterol. Call your healthcare provider if breathing problems worsen over time while using ADVAIR HFA. You may need different treatment. Get emergency medical care if: your breathing problems worsen quickly. you use your rescue inhaler, but it does not relieve your breathing problems. ADVAIR HFA should be used only if your healthcare provider decides that your asthma is not well controlled with a long-term asthma control medicine, such as an inhaled corticosteroid. When your asthma is well controlled, your healthcare provider may tell you to stop taking ADVAIR HFA. Your healthcare provider will decide if you can stop ADVAIR HFA without loss of asthma control. Your healthcare provider may prescribe a different asthma control medicine for you, such as an inhaled corticosteroid. Children and adolescents who take LABA medicines may have an increased risk of being hospitalized for asthma problems. What is ADVAIR HFA? ADVAIR HFA combines the inhaled corticosteroid (ICS) medicine fluticasone propionate and the LABA medicine salmeterol. ICS medicines such as fluticasone propionate help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems. LABA medicines such as salmeterol help the muscles around the airways in your lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe. ADVAIR HFA is not used to relieve sudden breathing problems. It is not known if ADVAIR HFA is safe and effective in children younger than 12 years of age. ADVAIR HFA is used for asthma as follows: ADVAIR HFA is a prescription medicine used to control symptoms of asthma and to prevent symptoms such as wheezing in adults and adolescents aged 12 years and older. ADVAIR HFA contains salmeterol, the same medicine found in SEREVENT® DISKUS® (salmeterol xinafoate inhalation powder). LABA medicines such as salmeterol increase the risk of death from asthma problems. ADVAIR HFA is not for adults and adolescents with asthma who are well controlled with an asthma control medicine, such as a low to medium dose of an inhaled corticosteroid medicine. Who should not use ADVAIR HFA? Do not use ADVAIR HFA: if you are allergic to fluticasone propionate, salmeterol, or any of the ingredients in ADVAIR HFA. See “What are the ingredients in ADVAIR HFA?” below for a complete list of ingredients. What should I tell my healthcare provider before using ADVAIR HFA? Tell your healthcare provider about all of your health conditions, including if you: have heart problems. have high blood pressure. have seizures. have thyroid problems. have diabetes. have liver problems. have weak bones (osteoporosis). have an immune system problem. have eye problems such as glaucoma or cataracts. are allergic to any of the ingredients in ADVAIR HFA or any other medicines. See “What are the ingredients in ADVAIR HFA?” below for a complete list of ingredients. have any type of viral, bacterial, or fungal infection. are exposed to chickenpox or measles. have any other medical conditions. are pregnant or planning to become pregnant. It is not known if ADVAIR HFA may harm your unborn baby. are breastfeeding. It is not known if the medicines in ADVAIR HFA pass into your milk and if they can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ADVAIR HFA and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your healthcare provider if you take antifungal or anti-HIV medicines. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use ADVAIR HFA? Read the step-by-step instructions for using ADVAIR HFA at the end of this Medication Guide. Do not use ADVAIR HFA unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly. ADVAIR HFA comes in 3 different strengths. Your healthcare provider prescribed the strength that is best for you. Use ADVAIR HFA exactly as your healthcare provider tells you to use it. Do not use ADVAIR HFA more often than prescribed. Use 2 inhalations of ADVAIR HFA 2 times each day. Use ADVAIR HFA at the same time each day, about 12 hours apart. If you miss a dose of ADVAIR HFA, just skip that dose. Take your next dose at your usual time. Do not take 2 doses at 1 time. If you take too much ADVAIR HFA, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness. Do not use other medicines that contain a LABA for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA medicines. Do not stop using ADVAIR HFA, even if you are feeling better, unless your healthcare provider tells you to. Talk to your healthcare provider right away if you stop using ADVAIR HFA. ADVAIR HFA does not relieve sudden symptoms. Always have a rescue inhaler with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you. Call your healthcare provider or get medical care right away if: your breathing problems get worse. you need to use your rescue inhaler more often than usual. your rescue inhaler does not work as well to relieve your symptoms. you need to use 4 or more inhalations of your rescue inhaler in 24 hours for 2 or more days in a row. you use 1 whole canister of your rescue inhaler in 8 weeks. your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you. you have asthma and your symptoms do not improve after using ADVAIR HFA regularly for 1 week. What are the possible side effects with ADVAIR HFA? ADVAIR HFA can cause serious side effects, including: See “What is the most important information I should know about ADVAIR HFA?” fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using ADVAIR HFA to help decrease your chance of getting thrush. pneumonia. ADVAIR HFA contains the same medicine found in ADVAIR DISKUS® (fluticasone propionate and salmeterol inhalation powder). ADVAIR DISKUS is used to treat people with asthma and people with chronic obstructive pulmonary disease (COPD). People with COPD have a higher chance of getting pneumonia. ADVAIR DISKUS may increase the chance of you getting pneumonia. It is not known if ADVAIR HFA is safe and effective in people with COPD. Call your healthcare provider right away if you have any of the following symptoms: increase in mucus (sputum) production change in mucus color fever chills increased cough increased breathing problems weakened immune system and increased chance of getting infections (immunosuppression). reduced adrenal function (adrenal insufficiency). Adrenal insufficiency is a condition where the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking a medicine containing an inhaled steroid (such as ADVAIR HFA). When your body is under stress such as from fever, trauma (such as a car accident), infection, surgery, or worse COPD symptoms, adrenal insufficiency can get worse and may cause death. Symptoms of adrenal insufficiency include: feeling tired lack of energy weakness nausea and vomiting low blood pressure sudden breathing problems immediately after inhaling your medicine. serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction: rash hives swelling of your face, mouth, and tongue breathing problems effects on heart. increased blood pressure a fast or irregular heartbeat chest pain effects on nervous system. tremor nervousness bone thinning or weakness (osteoporosis). slowed growth in children. A child's growth should be checked often. eye problems including glaucoma and cataracts. You should have regular eye exams while using ADVAIR HFA. changes in laboratory blood levels (sugar, potassium, certain types of white blood cells). Common side effects of ADVAIR HFA include: upper respiratory tract infection throat irritation hoarseness and voice changes headache dizziness nausea and vomiting Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the side effects with ADVAIR HFA. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ADVAIR HFA? Store ADVAIR HFA at room temperature between 68°F and 77°F (20°C and 25°C) with the mouthpiece down. The contents of your ADVAIR HFA are under pressure: Do not puncture. Do not use or store near heat or open flame. Temperatures above 120°F may cause the canister to burst. Do not throw into fire or an incinerator. Safely throw away ADVAIR HFA in the trash when the counter reads 000. Keep ADVAIR HFA and all medicines out of the reach of children. General information about the safe and effective use of ADVAIR HFA. Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide. Do not use ADVAIR HFA for a condition for which it was not prescribed. Do not give your ADVAIR HFA to other people, even if they have the same condition that you have. It may harm them. This Medication Guide summarizes the most important information about ADVAIR HFA. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about ADVAIR HFA that was written for healthcare professionals. For more information about ADVAIR HFA, call 1-888-825-5249 or visit our website at www.advair.com. What are the ingredients in ADVAIR HFA? Active ingredients: fluticasone propionate, salmeterol xinafoate Inactive ingredient: propellant HFA-134a Instructions for Use For Oral Inhalation Only Your ADVAIR HFA inhaler The metal canister holds the medicine. See Figure A. Figure  A The canister has a counter to show how many sprays of medicine you have left. The number shows through a window in the back of the actuator. See Figure B. The counter starts at either 124 or 064, depending on which size inhaler you have. The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000. Do not try to change the numbers or take the counter off the metal canister. The counter cannot be reset, and it is permanently attached to the canister. The purple plastic actuator sprays the medicine from the canister. The actuator has a protective cap that covers the mouthpiece. See Figure A. Keep the protective cap on the mouthpiece when the canister is not in use. The strap keeps the cap attached to the actuator. Do not use the actuator with a canister of medicine from any other inhaler. Do not use an ADVAIR HFA canister with an actuator from any other inhaler. Figure B Before using your ADVAIR HFA inhaler Take ADVAIR HFA out of the foil pouch just before you use it for the first time. Safely throw away the pouch and the drying packet that comes inside the pouch. The inhaler should be at room temperature before you use it. Priming your ADVAIR HFA inhaler Before you use ADVAIR HFA for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it. To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray the inhaler 1 time into the air away from your face. See Figure C. Avoid spraying in eyes. Figure C Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read 120 or 060, depending on which size inhaler you have. See Figure D. Figure D You must prime your inhaler again if you have not used it in more than 4 weeks or if you drop it. Take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray it 1 time into the air away from your face. Shake and spray the inhaler like this 1 more time to finish priming it. How to use your ADVAIR HFA inhaler Follow these steps every time you use ADVAIR HFA. Step 1. Make sure the canister fits firmly in the actuator. The counter should show through the window in the actuator. Shake the inhaler well for 5 seconds before each spray. Take the cap off the mouthpiece of the actuator. Look inside the mouthpiece for foreign objects, and take out any you see. Step 2. Hold the inhaler with the mouthpiece down. See Figure E. Figure E Step 3. Breathe out through your mouth and push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your lips around it. See Figure F. Figure F Step 4. Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth. See Figure F. Step 5. After the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth. Step 6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe out slowly as long as you can. Wait about 30 seconds and shake the inhaler well for 5 seconds. Repeat steps 2 through 6. Step 7. Rinse your mouth with water after breathing in the medicine. Spit out the water. Do not swallow it. See Figure G. Figure G Step 8. Put the cap back on the mouthpiece after every time you use the inhaler. Make sure it snaps firmly into place. Cleaning your ADVAIR HFA inhaler Clean your inhaler at least 1 time each week after your evening dose. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See Figure H. Figure H Step 9. Take the cap off the mouthpiece. The strap on the cap will stay attached to the actuator. Do not take the canister out of the plastic actuator. Step 10. Use a dry cotton swab to clean the small circular opening where the medicine sprays out of the canister. Carefully twist the swab in a circular motion to take off any medicine. See Figure I. Figure I Step 11. Wipe the inside of the mouthpiece with a clean tissue dampened with water. Let the actuator air-dry overnight. Step 12. Put the cap back on the mouthpiece after the actuator has dried. Replacing your ADVAIR HFA inhaler When the counter reads 020, you should refill your prescription or ask your healthcare provider if you need another prescription for ADVAIR HFA. When the counter reads 000, throw the inhaler away. You should not keep using the inhaler when the counter reads 000 because you may not receive the right amount of medicine. Do not use the inhaler after the expiration date, which is on the packaging it comes in. For correct use of your ADVAIR HFA inhaler, remember: The canister should always fit firmly in the actuator. Breathe in deeply and slowly to make sure you get all the medicine. Hold your breath for about 10 seconds after breathing in the medicine. Then breathe out fully. After each dose, rinse your mouth with water and spit it out. Do not swallow the water. Do not take the inhaler apart. Always keep the protective cap on the mouthpiece when your inhaler is not in use. Always store your inhaler with the mouthpiece pointing down. Clean your inhaler at least 1 time each week. If you have questions about ADVAIR HFA or how to use your inhaler, call GlaxoSmithKline (GSK) at 1-888-825-5249 or visit www.advair.com. This Medication Guide and Instructions for Use have been approved by the U.S. Food and Drug Administration.

OVERDOSE AIRDUO RESPICLICK contains both fluticasone propionate and salmeterol; therefore, the risks associated with overdosage for the individual components described below apply to AIRDUO RESPICLICK. Treatment of overdosage consists of discontinuation of AIRDUO RESPICLICK together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage. Fluticasone Propionate Chronic overdosage of fluticasone propionate may result in signs/symptoms of hypercorticism [see WARNINGS AND PRECAUTIONS]. 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 subjects were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. 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 signs and symptoms of beta-adrenergic stimulation (e.g., 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, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval, which can produce ventricular arrhythmias. As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of salmeterol. CONTRAINDICATIONS Status Asthmaticus AIRDUO RESPICLICK is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required [see WARNINGS AND PRECAUTIONS]. Hypersensitivity AIRDUO RESPICLICK is contraindicated in patients with known severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to fluticasone propionate or any of the excipients [see WARNINGS AND PRECAUTIONS, DESCRIPTION].

SIDE EFFECTS LABA, such as salmeterol, one of the active ingredients in AIRDUO RESPICLICK, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol [see WARNINGS AND PRECAUTIONS]. 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see WARNINGS AND PRECAUTIONS]. Systemic and local corticosteroid use may result in the following: Candida albicans infection [see WARNINGS AND PRECAUTIONS] Immunosuppression [see WARNINGS AND PRECAUTIONS] Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS] Reduction in bone mineral density [see WARNINGS AND PRECAUTIONS] Growth effects in pediatrics [see WARNINGS AND PRECAUTIONS] Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience In Asthma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidence of adverse reactions associated with AIRDUO RESPICLICK in Table 2 is based upon two placebo-controlled, 12-week, clinical studies (Study 1 and 2). A total of 1,364 adolescent and adult patients previously treated with inhaled corticosteroids were treated twice daily ARMONAIR RESPICLICK 55 mcg, 113 mcg, 232 mcg or AIRDUO RESPICLICK 55/14 mcg, 113/14 mcg, 232/14 mcg, or placebo. Sixty percent of patients were female and 80% of patients were white. The average duration of exposure was 82 to 84 days in the active treatment groups compared with 75 days in the placebo group. Table 2: Adverse Reactions with ≥ 3% Incidence with AIRDUO RESPICLICK, and More Common than Placebo in Subjects with Asthma Adverse Reaction ARMONAIR RESPICLICK 55 mcg (n=129) % ARMONAIR RESPICLICK 113 mcg (n=274) % ARMONAIR RESPICLICK 232 mcg (n=146) % AIRDUO RESPICLICK 55/14 mcg (n=128) % AIRDUO RESPICLICK 113/14 mcg (n=269) % AIRDUO RESPICLICK 232/14 mcg (n=145) % Placebo (n=273) % Infections and infestations Nasopharyngitis 5.4 5.8 4.8 8.6 4.8 6.9 4.4 Oral candidiasis* 3.1 2.9 4.8 1.6 2.2 3.4 0.7 Musculoskeletal and connective tissue disorders Back pain 0 1.5 1.4 3.1 0.7 0 1.8 Nervous system disorders Headache 1.6 7.3 4.8 5.5 4.8 2.8 4.4 Respiratory disorders Cough 1.6 1.8 3.4 2.3 3.7 0.7 2.6 *Oral candidiasis includes oropharyngeal candidiasis, oral fungal infection, and oropharyngitis fungal Other adverse reactions not previously listed (and occurring in < 3% of patients and in three or more patients on AIRDUO RESPICLICK), whether considered drug-related or not by the investigators, that were reported more frequently by patients with asthma treated with AIRDUO RESPICLICK compared with patients treated with placebo include the following: Sinusitis, oropharyngeal pain, pharyngitis, dizziness, influenza, rhinitis allergic, respiratory tract infection, rhinitis, nasal congestion, abdominal pain upper, myalgia, pain in extremity, dyspepsia, laceration, dermatitis contact, and palpitations. Long Term Safety Study This was a 26-week, open labeled study of 674 patients previously treated with inhaled corticosteroids who were treated twice daily with ARMONAIR RESPICLICK 113 mcg, 232 mcg, AIRDUO RESPICLICK 113/14 mcg, 232/14 mcg, fluticasone propionate inhalation aerosol 110 mcg and 220 mcg, and fluticasone propionate 250 mcg and salmeterol 50 mcg inhalation powder, and fluticasone propionate 500 mcg and salmeterol 50 mcg inhalation powder. The types of adverse reactions were similar to those reported above in placebo controlled studies. Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of 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 fluticasone propionate and/or salmeterol or a combination of these factors. Cardiac Disorders: Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia. Endocrine Disorders: Cushing's syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism. Eye Disorders: Glaucoma. Gastrointestinal Disorders: Abdominal pain, dyspepsia, xerostomia. Immune System Disorders: Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction). Very rare anaphylactic reaction in patients with severe milk protein allergy. Infections and Infestations: Esophageal candidiasis. Metabolic and Nutrition Disorders: Hyperglycemia, weight gain. Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, cramps, myositis, osteoporosis. Nervous System Disorders: Paresthesia, restlessness. Psychiatric Disorders: Agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children. Reproductive System and Breast Disorders: Dysmenorrhea. Respiratory, Thoracic, and Mediastinal Disorders: Chest congestion; chest tightness, dyspnea; facial and oropharyngeal edema, immediate bronchospasm; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking. Skin and Subcutaneous Tissue Disorders: Ecchymoses, photodermatitis. Vascular Disorders: Pallor. DRUG INTERACTIONS AIRDUO RESPICLICK has been used concomitantly with other drugs, including short-acting beta2-agonists, and intranasal corticosteroids, commonly used in patients with asthma without adverse drug reactions [see CLINICAL PHARMACOLOGY]. No formal drug interaction trials have been performed with AIRDUO RESPICLICK. Inhibitors Of Cytochrome P450 3A4 Fluticasone propionate and salmeterol, the individual components of AIRDUO RESPICLICK, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with AIRDUO RESPICLICK is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur. Ritonavir: Fluticasone Propionate: A drug interaction trial 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]. 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 a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC) but had no effect on urinary excretion of cortisol. Salmeterol: In a drug interaction trial 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 [see CLINICAL PHARMACOLOGY]. Monoamine Oxidase Inhibitors And Tricyclic Antidepressants AIRDUO RESPICLICK 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 AIRDUO RESPICLICK, on the vascular system may be potentiated by these agents. Beta-Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of AIRDUO RESPICLICK, 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. Non-Potassium-Sparing Diuretics 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 AIRDUO RESPICLICK, 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 AIRDUO RESPICLICK with non-potassium-sparing diuretics.

SIDE EFFECTS LABA, such as salmeterol, one of the active ingredients in ADVAIR HFA, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol [see WARNINGS AND PRECAUTIONS]. 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see WARNINGS AND PRECAUTIONS]. Systemic and local corticosteroid use may result in the following: Candida albicans infection [see WARNINGS AND PRECAUTIONS] Pneumonia in patients with COPD [see WARNINGS AND PRECAUTIONS] Immunosuppression [see WARNINGS AND PRECAUTIONS] Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS] Reduction in bone mineral density [see WARNINGS AND PRECAUTIONS] Growth effects [see WARNINGS AND PRECAUTIONS] Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience 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. Adult and Adolescent Subjects Aged 12 Years and Older The incidence of adverse reactions associated with ADVAIR HFA in Table 2 is based upon two 12-week, placebo-controlled, US clinical trials (Trials 1 and 3) and 1 active-controlled 12-week US 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 inhaled corticosteroids were treated twice daily with 2 inhalations of ADVAIR HFA 45/21 or ADVAIR HFA 115/21, 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. Table 2: Adverse Reactions with ADVAIR HFA with ≥ 3% Incidence in Adult and Adolescent Subjects with Asthma Adverse Event ADVAIR HFA Inhalation Aerosol Fluticasone Propionate CFC Inhalation Aerosol Salmeterol CFC Inhalation Aerosol Placebo HFA Inhalation Aerosol 45/21 (n = 187) % 115/21 (n = 94) % 44 mcg (n = 186) % 110 mcg (n = 91) % 21 mcg (n = 274) % (n = 176) % Ear, nose, and throat Upper respiratory tract infection 16 24 13 15 17 13 Throat irritation 9 7 12 13 9 7 Upper respiratory inflammation 4 4 3 7 5 3 Hoarseness/dysphonia 3 1 2 0 1 0 Lower respiratory Viral respiratory infection 3 5 4 5 3 4 Neurology Headache 21 15 24 16 20 11 Dizziness 4 1 1 0 < 1 0 Gastrointestinal Nausea and vomiting 5 3 4 2 2 3 Viral gastrointestinal infection 4 2 2 0 1 2 Gastrointestinal signs and symptoms 3 2 2 1 1 1 Musculoskeletal Musculoskeletal pain 5 7 8 2 4 4 Muscle pain 4 1 1 1 3 < 1 The incidence of common adverse reactions reported in Trial 4, a 12-week non-US clinical trial in 509 subjects previously treated with inhaled corticosteroids who were treated twice daily with 2 inhalations of ADVAIR HFA 230/21, fluticasone propionate CFC inhalation aerosol 220 mcg, or 1 inhalation of ADVAIR DISKUS 500/50 was similar to the incidences reported in Table 2. Additional Adverse Reactions 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. Laboratory Test Abnormalities 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. Postmarketing Experience 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. Cardiovascular: Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), hypertension, ventricular tachycardia. Ear, Nose, and Throat: Aphonia, earache, facial and oropharyngeal edema, paranasal sinus pain, rhinitis, throat soreness, tonsillitis. Endocrine and Metabolic: Cushing's syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism, osteoporosis. Eye: Cataracts, glaucoma. Gastrointestinal: Dyspepsia, xerostomia. Hepatobiliary Tract and Pancreas: Abnormal liver function tests. Immune System: Immediate and delayed hypersensitivity reactions, including rash and rare events of angioedema, bronchospasm, and anaphylaxis. Infections and Infestations: Esophageal candidiasis. Musculoskeletal: Back pain, myositis. Neurology: Paresthesia, restlessness. Non-Site Specific: Fever, pallor. Psychiatry: Agitation, aggression, anxiety, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children. Respiratory: 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. Skin: Contact dermatitis, contusions, ecchymoses, photodermatitis, pruritus. Urogenital: Dysmenorrhea, irregular menstrual cycle, pelvic inflammatory disease, vaginal candidiasis, vaginitis, vulvovaginitis. DRUG INTERACTIONS ADVAIR HFA has been used concomitantly with other drugs, including short-acting beta2-agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma, without adverse drug reactions [see CLINICAL PHARMACOLOGY]. No formal drug interaction trials have been performed with ADVAIR HFA. Inhibitors Of Cytochrome P450 3A4 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. Ritonavir Fluticasone Propionate: A drug interaction trial 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]. 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 a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol. Salmeterol: In a drug interaction trial 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. Monoamine Oxidase Inhibitors And Tricyclic Antidepressants 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-Adrenergic Receptor Blocking 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 betaadrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution. Non–Potassium-Sparing Diuretics 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 betaagonists, 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.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Asthma-Related Death LABA, such as salmeterol, one of the active ingredients in AIRDUO RESPICLICK, 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe AIRDUO RESPICLICK 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 AIRDUO RESPICLICK) 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 AIRDUO RESPICLICK for patients whose asthma is adequately controlled on low-or medium-dose inhaled corticosteroids. A large placebo-controlled US trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol . The Salmeterol Multicenter Asthma Research Trial (SMART) was a randomized double-blind trial that enrolled LABA-naïve subjects with asthma to assess the safety of salmeterol 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 subjects had been enrolled (N=26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects 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 subjects 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 subjects treated with salmeterol than in subjects 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 subjects 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 subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (see Table 1). Given the similar basic mechanisms of action of beta2-agonists, the findings seen in the SMART trial are considered a class effect. Post-hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects 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 ( < 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]). The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other active ingredient in AIRDUO RESPICLICK, or other long-term asthma control therapy mitigates the risk of asthma-related death. Table 1: Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART) Salmeterol n (%a) Placebo n (%a) Relative Riskb (95% Confidence Interval) Excess Deaths Expressed per 10,000 Subjectsc (95% Confidence Interval) Total Populationd Salmeterol: n=13,176 Placebo: n=13,179 13 (0.10%) 3 (0.02%) 4.37 (1.25, 15.34) 8 (3, 13) Caucasian Salmeterol: n=9,281 Placebo: n=9,361 6 (0.07%) 1 (0.01%) 5.82 (0.70, 48.37) 6 (1, 10) African American Salmeterol: n=2,366 Placebo: n=2,319 7 (0.31%) 1 (0.04%) 7.26 (0.89, 58.94) 27 (8, 46) a Life-table 28-week estimate, adjusted according to the subjects' actual lengths of exposure to trial treatment to account for early withdrawal of subjects from the trial. b Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period. c Estimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000. d The Total Population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n=996, placebo n=999), Asian (salmeterol n=173, placebo n=149), or “Other” (salmeterol n=230, placebo n=224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n=130, placebo n=127). Figure 1: Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART), by Duration of Treatment A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial. In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy. Deterioration Of Disease And Acute Episodes AIRDUO RESPICLICK should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. AIRDUO RESPICLICK has not been studied in subjects with acutely deteriorating asthma. The initiation of AIRDUO RESPICLICK in this setting is not appropriate. Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of AIRDUO RESPICLICK, has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta2-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events. Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of AIRDUO RESPICLICK with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of AIRDUO RESPICLICK. AIRDUO RESPICLICK should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not AIRDUO RESPICLICK, should be used to relieve acute symptoms such as shortness of breath. When prescribing AIRDUO RESPICLICK, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily use of AIRDUO RESPICLICK. When beginning treatment with AIRDUO RESPICLICK, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. Excessive Use Of AIRDUO RESPICLICK And Use With Other Long-Acting Beta2-Agonists AIRDUO RESPICLICK should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using AIRDUO RESPICLICK should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. Local Effects Of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with AIRDUO RESPICLICK. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with AIRDUO RESPICLICK continues, but at times therapy with AIRDUO RESPICLICK may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible adolescents or adults using corticosteroids. In such patients who have not had these diseases or who have not been properly immunized, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although AIRDUO RESPICLICK may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a medical identification warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack. Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to AIRDUO RESPICLICK. Lung function (mean forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of systemic corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to AIRDUO RESPICLICK may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. Hypercorticism And Adrenal Suppression Fluticasone propionate, a component of AIRDUO RESPICLICK, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of AIRDUO RESPICLICK in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing AIRDUO RESPICLICK. Because of the possibility of significant systemic absorption of inhaled corticosteroids, patients treated with AIRDUO RESPICLICK should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, AIRDUO RESPICLICK should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and for management of asthma symptoms. Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with AIRDUO RESPICLICK is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY]. Paradoxical Bronchospasm And Upper Airway Symptoms As with other inhaled medicines, AIRDUO RESPICLICK can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs following dosing with inhaled fluticasone propionate/salmeterol medicines, it should be treated immediately with an inhaled, short-acting bronchodilator; inhaled fluticasone propionate/salmeterol medicines should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving inhaled fluticasone propionate/salmeterol medicines. Hypersensitivity Reactions, Including Anaphylaxis Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of AIRDUO RESPICLICK. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use AIRDUO RESPICLICK [see CONTRAINDICATIONS]. Cardiovascular And Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see OVERDOSAGE]. Therefore, AIRDUO RESPICLICK, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Salmeterol, a component of AIRDUO RESPICLICK, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Reduction In Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Effect On Growth Orally inhaled corticosteroids, including AIRDUO RESPICLICK, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving AIRDUO RESPICLICK routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including AIRDUO RESPICLICK, titrate each patient's dosage to the lowest dosage that effectively controls his/her symptoms [see DOSAGE AND ADMINISTRATION, Use in Specific Populations]. Glaucoma And Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of AIRDUO RESPICLICK. 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 other Fluticasone Propionate and Salmeterol Inhalation Powder 500/50, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on development of cataracts or glaucoma was evaluated in a subset of 658 subjects with COPD in the 3-year survival trial. Ophthalmic examinations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions about cataracts cannot be drawn from this trial because the high incidence of cataracts at baseline (61% to 71%) resulted in an inadequate number of subjects treated with other Fluticasone Propionate and Salmeterol Inhalation Powder 500/50 who were eligible and available for evaluation of cataracts at the end of the trial (n = 53). The incidence of newly diagnosed glaucoma was 2% with other Fluticasone Propionate and Salmeterol Inhalation Powder 500/50, 5% with fluticasone propionate, 0% with salmeterol, and 2% with placebo. Eosinophilic Conditions And Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate, a component of AIRDUO RESPICLICK, 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. Coexisting Conditions AIRDUO RESPICLICK, like all medicines 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. Hypokalemia And Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see CLINICAL PHARMACOLOGY]. 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 trials with AIRDUO RESPICLICK at recommended doses. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Patients should be given the following information: Asthma-Related Death Inform patients with asthma that salmeterol, one of the active ingredients in AIRDUO RESPICLICK, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Also inform them 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 LABA. Not For Acute Symptoms Inform patients that AIRDUO RESPICLICK is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used. Instruct patients to seek medical attention 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 Tell patients they should not stop therapy with AIRDUO RESPICLICK without physician/provider guidance since symptoms may recur after discontinuation. Do Not Use Additional Long-Acting Beta2-Agonists Instruct patients not to use other LABA for asthma. Local Effects Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with AIRDUO RESPICLICK, but at times therapy with AIRDUO RESPICLICK may need to be temporarily interrupted under close medical supervision. Rinsing the mouth with water without swallowing after inhalation is advised to help reduce the risk of thrush. Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Hypercorticism And Adrenal Suppression Advise patients that AIRDUO RESPICLICK may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients 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 AIRDUO RESPICLICK. Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of AIRDUO RESPICLICK. Patients should discontinue AIRDUO RESPICLICK if such reactions occur and contact their healthcare provider or get emergency medical help. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not take AIRDUO RESPICLICK. Reduction In Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including fluticasone propionate, may cause a reduction in growth velocity when administered to adolescent patients. Physicians should closely follow the growth of 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); consider regular eye examinations. Risks Associated With Beta-Agonist Therapy Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Pregnancy Inform patients who are pregnant or nursing that they should contact their physician about the use of AIRDUO RESPICLICK. Use Daily For Best Effect Patients should use AIRDUO RESPICLICK at regular intervals as directed. The daily dosage of AIRDUO RESPICLICK should not exceed 1 inhalation twice a day. Advise patients, if they miss a dose, to take their next dose at the same time they normally do and to not take 2 doses at one time. Individual patients will experience a variable time to onset and degree of symptom relief and full benefit may not be achieved until treatment has been administered for 1 to 2 weeks or longer. Patients should not increase the prescribed dosage but should contact their physicians if symptoms do not improve or if the condition worsens. Instruct patients not to stop use of AIRDUO RESPICLICK abruptly. Patients should contact their physicians immediately if they discontinue use of AIRDUO RESPICLICK. Caring For And Storing The Inhaler Instruct patients to not open their inhaler unless they are taking a dose. Repeated opening and closing the cover without taking medication will waste medication and may damage the inhaler. Advise patients to keep their inhaler dry and clean at all times. Never wash or put any part of the inhaler in water. Patient should replace inhaler if washed or placed in water. Advise patients to immediately replace inhaler if mouthpiece cover is damaged or broken. Gently wipe the mouthpiece with a dry cloth or tissue as needed. Instruct patients to store the inhaler at room temperature and to avoid exposure to extreme heat, cold, or humidity. Instruct patients to never take the inhaler apart. Inform patients that AIRDUO RESPICLICK has a dose counter. When the patient receives the inhaler, the number 60 will be displayed. The dose counter will count down each time the mouthpiece cap is opened and closed. The dose-counter window displays the number of actuations left in the inhaler in units of two (e.g., 60, 58, 56, etc.). When the counter displays 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red. Inform patients to discard AIRDUO RESPICLICK when the dose counter displays 0, 30 days after opening the foil pouch or after the expiration date on the product, whichever comes first. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1000 mcg/kg (approximately 10 times the MRHDID for adults on a mcg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately equivalent to the MRHDID for adults on a mcg/m² basis) for 104 weeks. Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test. Fertility and reproductive performance were unaffected in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately equivalent to the MRHDID for adults on a mcg/m² basis). Salmeterol In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1400 mcg/kg and above (approximately 240 times the MRHDID on a mcg/m² basis) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 200 mcg/kg (approximately 35 times the MRHDID on a mcg/m² basis). In a 24 month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 680 mcg/kg and above (approximately 240 times the MRHDID on a mcg/m² basis). No tumors were seen at 210 mcg/kg (approximately 75 times the MRHDID on a mcg/m² basis). These findings in rodents are similar to those reported previously for other beta adrenergic agonist drugs. The relevance of these findings to human use is unknown. Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. Fertility and reproductive performance were unaffected in male and female rats at oral doses up to 2000 mcg/kg (approximately 690 times the MRHDID for adults on a mcg/m² basis). Use In Specific Populations Pregnancy Risk Summary There are no randomized clinical studies of AIRDUO RESPICLICK or individual monoproducts, fluticasone propionate and salmeterol xinafoate, in pregnant women. There are clinical considerations with the use of AIRDUO RESPICLICK in pregnant women [see Clinical Considerations]. Animal reproduction studies are available with the combination of fluticasone propionate and salmeterol xinafoate as well as individual monoproducts. In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m² basis [see Data]. However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m² basis [see Data]. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. Oral administration of salmeterol to pregnant rabbits caused teratogenicity characteristic of beta-adrenoceptor stimulation at maternal doses approximately 700 times the MRHDID on a mcg/m² basis. These adverse effects generally occurred at large multiples of the MRHDID when salmeterol was administered by the oral route to achieve high systemic exposures. No such effects occurred at an oral salmeterol dose approximately 420 times the MRHDID [see Data]. The estimated risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Data Animal Data Fluticasone Propionate and Salmeterol: In an embryo/fetal development study with pregnant rats that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1000, 30/0, 10/100, 30/1000, and 100/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Omphalocele, increased embryo/fetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, when combining fluticasone propionate at a dose approximately 2 times the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 100 mcg/kg/day) and a dose of salmeterol at approximately 3500 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 10,000 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed when combining fluticasone propionate at a dose 0.6 times the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 30 mcg/kg/day) and a dose of salmeterol at approximately 350 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 1000 mcg/kg/day). In an embryo/fetal development study with pregnant mice that received the combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol at doses of 0/1400, 40/0, 10/200, 40/1400, or 150/10,000 mcg/kg/day (as fluticasone propionate/salmeterol) during the period of organogenesis, findings were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Cleft palate, fetal death, increased implantation loss, and delayed ossification were observed in mouse fetuses when combining fluticasone propionate at a dose approximately 1.4 times the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 150 mcg/kg/day) and salmeterol at a dose approximately 1470 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 10,000 mcg/kg/day). No developmental toxicity was observed at combination doses of fluticasone propionate up to approximately 0.8 times the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 420 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 1400 mcg/kg). Fluticasone Propionate: In embryo/fetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 2 times the MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat NOAEL was observed at approximately 0.6 times the MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.5 times the MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.16 times the MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 15 mcg/kg/day). In an embryo/fetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.5 times the MRHDID (on a mcg/m² basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.1 times the MRHDID (on a mcg/m² basis with a maternal inhalation dose of 5.5 mcg/kg/day). In an embryo/fetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity at doses approximately 0.02 times the MRHDID and higher (on a mcg/m² basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.2 times the MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.004 times the MRHDID (on a mcg/m² basis with a maternal subcutaneous dose of 0.08 mcg/kg/day). In a pre-and post-natal development study in pregnant rats dosed by the subcutaneous route from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to approximate equivalence to the MRHDID (on a mcg/m² basis with maternal subcutaneous doses up to 50 mcg/kg/day). Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. Salmeterol: In three embryo/fetal development studies, pregnant rabbits received oral administration of salmeterol at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. In pregnant Dutch rabbits administered salmeterol doses approximately 700 times the MRHDID (on a mcg/m² basis at maternal oral doses of 1000 mcg/kg/day and higher), fetal toxic effects were observed 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 a salmeterol dose approximately 420 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 600 mcg/kg/day). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 7,000 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 10,000 mcg/kg/day). In two embryo/fetal development studies, pregnant rats received salmeterol by oral administration at doses ranging from 100 to 10,000 mcg/kg/day during the period of organogenesis. Salmeterol produced no maternal toxicity or embryo/fetal effects at doses up to 3500 times the MRHDID (on a mcg/m² basis at maternal oral doses up to 10,000 mcg/kg/day). In a peri-and post-natal development study in pregnant rats dosed by the oral route from late gestation through delivery and lactation, salmeterol at a dose 3500 times the MRHDID (on mcg/m² basis with a maternal oral dose of 10,000 mcg/kg/day) was fetotoxic and decreased the fertility of survivors. Salmeterol xinafoate crossed the placenta following oral administration to mice and rats. Lactation Risk Summary There are no available data on the presence of fluticasone propionate or salmeterol in human milk, the effects on the breastfed child, or the effects on milk production. Other corticosteroids have been detected in human milk. However, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see CLINICAL PHARMACOLOGY]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AIRDUO RESPICLICK and any potential adverse effects on the breastfed child from AIRDUO RESPICLICK or from the underlying maternal condition. Data Animal Data Subcutaneous administration of tritiated fluticasone propionate at a dose in lactating rats approximately 0.2 times the MRHDID for adults (on a mcg/m² basis) resulted in measurable levels in milk. Oral administration of salmeterol at a dose in lactating rats approximately 2900 times the MRHDID for adults (on a mcg/m² basis) resulted in measurable levels in milk. Pediatric Use The safety and effectiveness of AIRDUO RESPICLICK in pediatric patients below the age of 12 years have not been established. Inhaled corticosteroids, including fluticasone propionate, a component of AIRDUO RESPICLICK, may cause a reduction in growth velocity in adolescents [see WARNINGS AND PRECAUTIONS]. The growth of pediatric patients receiving orally inhaled corticosteroids, including AIRDUO RESPICLICK, should be monitored. If an 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 AIRDUO RESPICLICK, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see DOSAGE AND ADMINISTRATION]. Geriatric Use No overall differences in safety or efficacy were observed in data collected in 54 subjects aged 65 years and older versus younger subjects who were treated with AIRDUO RESPICLICK in placebo-controlled Phase 2 and 3 studies. Hepatic Impairment Formal pharmacokinetic studies using AIRDUO RESPICLICK have not been conducted in patients with hepatic impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored. Renal Impairment Formal pharmacokinetic studies using AIRDUO RESPICLICK have not been conducted in patients with renal impairment.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Asthma-Related Death LABA, such as salmeterol, one of the active ingredients in ADVAIR HFA, 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR HFA 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 HFA) 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 HFA for patients whose asthma is adequately controlled on low-or medium-dose inhaled corticosteroids. A large placebo-controlled US trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol. The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized double-blind trial that enrolled LABA-naive subjects with asthma to assess the safety of salmeterol 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 subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects 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 subjects 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 subjects treated with salmeterol than in subjects 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 subjects 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 subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (see Table 1). Given the similar basic mechanisms of action of beta2-agonists, the findings seen in the SMART trial are considered a class effect. Post-hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects 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 (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]). The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids, such as fluticasone propionate, the other active ingredient in ADVAIR HFA, or other long-term asthma control therapy mitigates the risk of asthma-related death. Table 1: Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART) Salmeterol n (%a) Placebo n (%a) Relative Riskb (95% Confidence Interval) Excess Deaths Expressed per 10,000 Subjectsc (95% Confidence Interval) Total populationd Salmeterol: n = 13,176 13 (0.10%) 4.37 (1.25, 15.34) 8 (3, 13) Placebo: n = 13,179 3 (0.02%) Caucasian Salmeterol: n = 9,281 6 (0.07%) 5.82 (0.70, 48.37) 6 (1, 10) Placebo: n = 9,361 1 (0.01%) African American Salmeterol: n = 2,366 7 (0.31%) 7.26 (0.89, 58.94) 27 (8, 46) Placebo: n = 2,319 1 (0.04%) aLife-table 28-week estimate, adjusted according to the subjects' actual lengths of exposure to trial treatment to account for early withdrawal of subjects from the trial. bRelative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period. cEstimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000. dThe Total population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127). Figure 1: Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multi-center Asthma Research Trial (SMART), by Duration of Treatment A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial. In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy. Deterioration Of Disease And Acute Episodes ADVAIR HFA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. ADVAIR HFA has not been studied in subjects with acutely deteriorating asthma. The initiation of ADVAIR HFA in this setting is not appropriate. Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of ADVAIR HFA, has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta2-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events. Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of ADVAIR HFA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily of ADVAIR HFA. ADVAIR HFA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR HFA, should be used to relieve acute symptoms such as shortness of breath. When prescribing ADVAIR HFA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily use of ADVAIR HFA. When beginning treatment with ADVAIR HFA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. Excessive Use Of ADVAIR HFA And Use With Other Long-Acting Beta2Agonists ADVAIR HFA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR HFA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. Local Effects Of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with ADVAIR HFA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with ADVAIR HFA continues, but at times therapy with ADVAIR HFA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. Pneumonia Lower respiratory tract infections, including pneumonia, have been reported in patients with chronic obstructive pulmonary disease (COPD) following the inhaled administration of corticosteroids, including fluticasone propionate and ADVAIR DISKUS® (fluticasone propionate and salmeterol inhalation powder). In 2 replicate 1-year trials in 1,579 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in the subjects treated with ADVAIR DISKUS was higher in subjects older than 65 years (9%) compared with the incidence in subjects younger than 65 years (4%). In a 3-year trial in 6,184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% with ADVAIR DISKUS 500/50, 14% with fluticasone propionate 500 mcg, 11% with salmeterol 50 mcg, and 9% with placebo). Similar to what was seen in the 1-year trials with ADVAIR DISKUS 250/50, the incidence of pneumonia was higher in subjects older than 65 years (18% with ADVAIR DISKUS 500/50 versus 10% with placebo) compared with subjects younger than 65 years (14% with ADVAIR DISKUS 500/50 versus 8% with placebo). Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although ADVAIR HFA may control asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to ADVAIR HFA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with ADVAIR HFA. Lung function (mean forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [AM PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to ADVAIR HFA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. Hypercorticism And Adrenal Suppression Fluticasone propionate, a component of ADVAIR HFA, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of ADVAIR HFA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing ADVAIR HFA. Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with ADVAIR HFA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, ADVAIR HFA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of asthma symptoms should be considered. Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (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 [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY]. Paradoxical Bronchospasm And Upper Airway Symptoms As with other inhaled medicines, ADVAIR HFA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with ADVAIR HFA, it should be treated immediately with an inhaled, short-acting bronchodilator; ADVAIR HFA should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving ADVAIR HFA. Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of ADVAIR HFA [see CONTRAINDICATIONS]. Cardiovascular And Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see OVERDOSAGE]. Therefore, ADVAIR HFA, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Salmeterol, a component of ADVAIR HFA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, betaagonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Reduction In Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care. 2-Year Fluticasone Propionate Trial A 2-year trial in 160 subjects (females aged 18 to 40 years, males 18 to 50) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4. 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 HFA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including ADVAIR HFA, titrate each patient's dosage to the lowest dosage that effectively controls his/her symptoms [see DOSAGE AND ADMINISTRATION, Use in Specific Populations]. Glaucoma And Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR HFA. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. Eosinophilic Conditions And Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate, a component of ADVAIR HFA, 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. Coexisting Conditions ADVAIR HFA, like all medicines 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. Large doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. Hypokalemia And Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see CLINICAL PHARMACOLOGY]. 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 trials with ADVAIR HFA at recommended doses. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Asthma-Related Death Inform patients that salmeterol, one of the active ingredients in ADVAIR HFA, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Also inform them 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 LABA. Not for Acute Symptoms Inform patients that ADVAIR HFA is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Advise patients to treat acute asthma symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used. Instruct patients to seek medical attention 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 Tell patients they should not stop therapy with ADVAIR HFA without physician/provider guidance since symptoms may recur after discontinuation. Do Not Use Additional Long-Acting Beta2-Agonists Instruct patients not to use other LABA for asthma. Local Effects Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with ADVAIR HFA, but at times therapy with ADVAIR HFA may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush. Pneumonia Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia. Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Hypercorticism and Adrenal Suppression Advise patients that ADVAIR HFA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients 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 HFA. Immediate Hypersensitivity Reactions Advise patients that immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of ADVAIR HFA. Patients should discontinue ADVAIR HFA if such reactions occur. Reduction in Bone Mineral Density Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including fluticasone propionate, 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 Inform patients that long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations. Risks Associated with Beta-Agonist Therapy Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Fluticasone Propionate Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 5 times the MRHDID on a mg/m² basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (less than the MRHDID on a mg/m² basis) for 104 weeks. Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the in vivo mouse micronucleus test. No evidence of impairment of fertility was observed in rats at subcutaneous doses up to 50 mcg/kg (less than the MRHDID on a mg/m² basis). Prostate weight was significantly reduced. Salmeterol In an 18-month carcinogenicity study in CD-mice, salmeterol at oral doses of 1.4 mg/kg and above (approximately 10 times the MRHDID based on comparison of the plasma AUCs) caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. No tumors were seen at 0.2 mg/kg (approximately 2 times the MRHDID for adults based on comparison of the AUCs). In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 80 times the MRHDID on a mg/m² basis). No tumors were seen at 0.21 mg/kg (approximately 25 times the MRHDID on a mg/m² basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 230 times the MRHDID on a mg/m² basis). Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category C. There are no adequate and well-controlled trials with ADVAIR HFA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal reproduction studies are not always predictive of human response, ADVAIR HFA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while taking ADVAIR HFA. Fluticasone Propionate and Salmeterol: In the mouse reproduction assay, fluticasone propionate at a dose approximately equivalent to the maximum recommended human daily inhalation dose (MRHDID) (on a mcg/m² basis at a maternal subcutaneous dose of 150 mcg/kg) combined with salmeterol at a dose approximately 580 times the MRHDID (on a mg/m² basis at a maternal oral dose of 10 mg/kg) 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 up to approximately 1/5 the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 40 mcg/kg) and doses of salmeterol up to approximately 80 times the MRHDID (on a mg/m² basis at a maternal oral dose of 1.4 mg/kg). In rats, combining fluticasone propionate at a dose equivalent to the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 100 mcg/kg) and a dose of salmeterol at approximately 1,200 times the MRHDID (on a mg/m² basis at a maternal oral dose of 10 mg/kg) produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. No such effects were seen when combining fluticasone propionate at a dose less than the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 30 mcg/kg) and a dose of salmeterol at approximately 120 times the MRHDID (on a mg/m² basis at a maternal oral dose of 1 mg/kg). Fluticasone Propionate: Mice and rats at fluticasone propionate doses less than or equivalent to the MRHDID (on a mcg/m² basis at maternal subcutaneous doses of 45 and 100 mcg/kg, respectively) showed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity was seen in rats at doses approximately equivalent to the MRHDID (on a mcg/m² basis at maternal inhaled doses up to 68.7 mcg/kg). In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose less than the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 4 mcg/kg). However, no teratogenic effects were reported at fluticasone propionate doses up to approximately 6 times the MRHDID (on a mcg/m² basis at maternal oral doses up to 300 mcg/kg). No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see CLINICAL PHARMACOLOGY]. Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. 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 salmeterol doses approximately 230 times the MRHDID (on a mg/m² basis at maternal oral doses up to 2 mg/kg). In pregnant Dutch rabbits administered salmeterol doses approximately 25 times the MRHDID (on an AUC basis at maternal oral doses of 1 mg/kg and higher), 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 a salmeterol dose approximately 10 times the MRHDID (on an AUC basis at a maternal oral dose of 0.6 mg/kg). New Zealand White rabbits were less sensitive since only delayed ossification of the frontal cranial bones was seen at a salmeterol dose approximately 2,300 times the MRHDID (on a mg/m² basis at a maternal oral dose of 10 mg/kg). Salmeterol xinafoate crossed the placenta following oral administration to mice and rats. Nonteratogenic Effects Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. Labor And Delivery There are no well-controlled human trials that have investigated effects of ADVAIR HFA on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of ADVAIR HFA during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. Nursing Mothers Plasma levels of salmeterol, a component of ADVAIR HFA, 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 HFA, 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 HFA by nursing mothers, caution should be exercised when ADVAIR HFA is administered to a nursing woman. Pediatric Use Thirty-eight (38) subjects aged 12 to 17 years were treated with ADVAIR HFA in US pivotal clinical trials. Subjects in this age-group demonstrated efficacy results similar to those observed in subjects aged 18 years and older. There were no obvious differences in the type or frequency of adverse events reported in this age-group compared with subjects aged 18 years and older. In a 12-week trial, the safety of ADVAIR HFA 45/21 given as 2 inhalations twice daily was compared with that of fluticasone propionate 44 mcg HFA (FLOVENT® HFA) 2 inhalations twice daily in 350 subjects aged 4 to 11 years with persistent asthma currently being treated with inhaled corticosteroids. No new safety concerns were observed in children aged 4 to 11 years treated for 12 weeks with ADVAIR HFA 45/21 compared with adults and adolescents aged 12 years and older. Common adverse reactions (greater than or equal to 3%) seen in children aged 4 to 11 years treated with ADVAIR HFA 45/21 but not reported in the adult and adolescent clinical trials of ADVAIR HFA include: pyrexia, cough, pharyngolaryngeal pain, rhinitis, and sinusitis [see ADVERSE REACTIONS].This trial was not designed to assess the effect of salmeterol, a component of ADVAIR HFA, on asthma hospitalizations and death in subjects aged 4 to 11 years. The pharmacokinetics and pharmacodynamic effect on serum cortisol of 21 days of treatment with ADVAIR HFA 45/21 (2 inhalations twice daily with or without a spacer) or ADVAIR DISKUS 100/50 (1 inhalation twice daily) was evaluated in a trial of 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol xinafoate was similar for ADVAIR HFA, ADVAIR HFA delivered with a spacer, and ADVAIR DISKUS while the systemic exposure to fluticasone propionate was lower with ADVAIR HFA compared with that of ADVAIR HFA delivered with a spacer or ADVAIR DISKUS. There were reductions in serum cortisol from baseline in all treatment groups (14%, 22%, and 13% for ADVAIR HFA, ADVAIR HFA delivered with a spacer, and ADVAIR DISKUS, respectively) [see CLINICAL PHARMACOLOGY]. The safety and effectiveness of ADVAIR HFA in children younger than 12 years have not been established. Effects on Growth Inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR HFA, may cause a reduction in growth velocity in children and adolescents [see WARNINGS AND PRECAUTIONS]. The growth of pediatric patients receiving orally inhaled corticosteroids, including ADVAIR HFA, should be monitored. A 52-week placebo-controlled trial 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 trial 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 trial, 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 HFA, each patient should be titrated to the lowest strength that effectively controls his/her asthma [see DOSAGE AND ADMINISTRATION]. Geriatric Use Clinical trials of ADVAIR HFA did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects respond differently than younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In addition, as with other products containing beta2-agonists, special caution should be observed when using ADVAIR HFA in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Hepatic Impairment Formal pharmacokinetic studies using ADVAIR HFA have not been conducted in patients with hepatic impairment. However, since both fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored. Renal Impairment Formal pharmacokinetic studies using ADVAIR HFA have not been conducted in patients with renal impairment.