Fluticasone Furoate and Vilanterol for COPD

INDICATIONS AND USAGE Fluticasone Furoate/Vilanterol ELLIPTA is a combination of fluticasone furoate, a corticosteroid, and vilanterol, a long‑acting beta 2 -adrenergic agonist (LABA), indicated for: • the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). ( 1.1 ) • the maintenance treatment of asthma in patients aged 5 years and older. ( 1.2 ) Limitations of Use: Not indicated for relief of acute bronchospasm. ( 1.3 , 5.2 ) 1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease Fluticasone Furoate/Vilanterol ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). 1.2 Maintenance Treatment of Asthma Fluticasone Furoate/Vilanterol ELLIPTA is indicated for the maintenance treatment of asthma in patients aged 5 years and older. 1.3 Limitations of Use Fluticasone Furoate/Vilanterol ELLIPTA is NOT indicated for the relief of acute bronchospasm.

DOSAGE AND ADMINISTRATION • For oral inhalation only. ( 2.3 ) • Maintenance treatment of COPD: 1 actuation of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg once daily administered by oral inhalation. ( 2.1 ) • Maintenance treatment of asthma in adult patients aged 18 years and older: 1 actuation of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg or Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg once daily administered by oral inhalation. ( 2.2 ) • Maintenance treatment of asthma in pediatric patients aged 12 to 17 years: 1 actuation of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg once daily administered by oral inhalation. ( 2.2 ) • Maintenance treatment of asthma in pediatric patients aged 5 to 11 years: 1 actuation of fluticasone furoate/vilanterol ELLIPTA 50/25 mcg once daily administered by oral inhalation. ( 2.2 ) 2.1 Recommended Dosage for Maintenance Treatment of Chronic Obstructive Pulmonary Disease The recommended dosage of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation. If shortness of breath occurs in the period between doses, an inhaled, short-acting beta 2 -agonist (rescue medicine, e.g., albuterol) should be used for immediate relief. 2.2 Recommended Dosage for Maintenance Treatment of Asthma Adult Patients Aged 18 Years and Older The recommended dosage of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation or Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg (containing fluticasone furoate 200 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation. • When choosing the starting dosage strength of Fluticasone Furoate/Vilanterol ELLIPTA, consider the patients’ disease severity, their previous asthma therapy, including the inhaled corticosteroid (ICS) dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation. • The median time to onset, defined as a 100-mL increase from baseline in mean forced expiratory volume in 1 second (FEV 1 ), was approximately 15 minutes after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief. • For patients who do not respond adequately to Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg once daily, increasing the dose to Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg once daily may provide additional improvement in asthma control. For patients who do not respond adequately to Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg once daily, re-evaluate and consider other therapeutic regimens and additional therapeutic options. • The maximum recommended dosage is 1 inhalation of Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg once daily. • If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist (rescue medicine, e.g., albuterol) should be used for immediate relief. Pediatric Patients Aged 12 to 17 Years The recommended dosage of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation [see Warnings and Precautions ( 5.14 )] . Pediatric Patients Aged 5 to 11 Years The recommended dosage of Fluticasone Furoate/Vilanterol ELLIPTA 50/25 mcg (containing fluticasone furoate 50 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation [see Warnings and Precautions ( 5.14 )] . 2.3 Administration Information • After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis [see Warnings and Precautions ( 5.4 )] . • Fluticasone Furoate/Vilanterol ELLIPTA should be used at the same time every day. Do not use Fluticasone Furoate/Vilanterol ELLIPTA more than 1 time every 24 hours. • More frequent administration or a greater number of inhalations (more than 1 inhalation daily) of the prescribed strength of Fluticasone Furoate/Vilanterol ELLIPTA is not recommended as some patients are more likely to experience adverse effects with higher doses.

WARNINGS AND PRECAUTIONS • LABA monotherapy increases the risk of serious asthma-related events. ( 5.1 ) • Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. ( 5.2 ) • Do not use in combination with additional therapy containing a LABA because of risk of overdose. ( 5.3 ) • Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) • Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.6 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Wean patients slowly from systemic corticosteroids if transferring to Fluticasone Furoate/Vilanterol ELLIPTA. ( 5.7 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Fluticasone Furoate/Vilanterol ELLIPTA slowly. ( 5.8 ) • If paradoxical bronchospasm occurs, discontinue Fluticasone Furoate/Vilanterol ELLIPTA and institute alternative therapy. ( 5.10 ) • Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) • Assess for decrease in bone mineral density (BMD) initially and periodically thereafter. ( 5.13 ) • Monitor growth of pediatric patients ( 5.14 ) • Glaucoma and cataracts may occur with long-term use of Inhaled Corticosteroid (ICS). Consider referral to an ophthalmologist in patients who develop ocular symptoms or use Fluticasone Furoate/Vilanterol ELLIPTA long term. ( 5.15 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.16 ) • Increased blood glucose levels have been reported. Also, be alert to hypokalemia. ( 5.17 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of Long-acting Beta 2 -adrenergic Agonist (LABA) as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)] . Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma‑related events (hospitalizations, intubations, death) compared with ICS alone (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-Acting Beta 2 -Adrenergic Agonists) . Serious Asthma-Related Events with Inhaled Corticosteroid/Long-Acting Beta 2 -Adrenergic Agonists Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed‑dose combination with ICS compared with ICS alone in patients with asthma. Three (3) trials included adult and pediatric patients aged 12 years and older: 1 trial compared budesonide/formoterol with budesonide, 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, and 1 trial compared mometasone furoate/formoterol with mometasone furoate. The fourth trial included pediatric patients aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related. The 3 adult and pediatric trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and pediatric trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone ( Table 1 ). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS. Table 1. Meta-Analysis of Serious Asthma-Related Events in Patients with Asthma Aged 12 Years and Older ICS = Inhaled Corticosteroid, LABA = Long-acting Beta 2 -adrenergic Agonist. a Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis. b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. c Number of patients with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Patients can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related. ICS/LABA (n = 17,537) a ICS (n = 17,552) a ICS/LABA vs. ICS Hazard Ratio (95% CI) b Serious asthma-related event c 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 The pediatric safety trial included 6,208 pediatric patients aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) patients randomized to ICS/LABA and 21/3,101 (0.7%) patients randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy. 5.2 Deterioration of Disease and Acute Episodes Fluticasone Furoate/Vilanterol ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. Fluticasone Furoate/Vilanterol ELLIPTA has not been studied in patients with acutely deteriorating COPD or asthma. The initiation of Fluticasone Furoate/Vilanterol ELLIPTA in this setting is not appropriate. In COPD, if Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting, re-evaluate the patient and the COPD treatment regimen at once. For COPD, the daily dose of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg should not be increased. Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate re

DRUG INTERACTIONS • Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid and cardiovascular effects. ( 7.1 ) • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of vilanterol on cardiovascular system. ( 7.2 ) • Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 ) • Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.4 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol are both substrates of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of Fluticasone Furoate/Vilanterol ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.3 )] . 7.2 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and QTc Prolonging Drugs Vilanterol, like other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. 7.3 Beta-Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, but may also produce severe bronchospasm in patients with COPD or asthma. Therefore, patients with COPD or 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. 7.4 Non–Potassium-Sparing Diuretics The electrocardiographic 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, 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 beta-agonists with non–potassium-sparing diuretics.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Serious Asthma-Related Events – Hospitalizations, Intubations, Death [see Warnings and Precautions ( 5.1 )] • Oropharyngeal Candidiasis [see Warnings and Precautions ( 5.4 )] • Pneumonia [see Warnings and Precautions ( 5.5 )] • Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.6 )] • Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.8 )] • Paradoxical Bronchospasm [see Warnings and Precautions ( 5.10 )] • Cardiovascular Effects [see Warnings and Precautions ( 5.12 )] • Reduction in Bone Mineral Density [see Warnings and Precautions ( 5.13 )] • Growth Effects [see Warnings and Precautions ( 5.14 )] • Glaucoma and Cataracts [see Warnings and Precautions ( 5.15 )] 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. • COPD: Most common adverse reactions (incidence ≥3%) are nasopharyngitis, upper respiratory tract infection, headache, oral candidiasis, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, and pyrexia. ( 6.1 ) • Asthma: Most common adverse reactions (incidence ≥2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease The safety data described below are based on two 6-month and two 12-month trials and one long-term mortality trial. In these studies, 5,356 patients with COPD received at least 1 dose of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg. Adverse reactions observed in other studies of fluticasone furoate/vilanterol ELLIPTA in COPD patients were similar to those observed in these 5 trials. 6-Month Trials The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in Table 2 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 patients, 70% were male and 84% were White. They had a mean age of 62 years and an average smoking history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV 1 /forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Patients received 1 inhalation once daily of the following: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo. Table 2. Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg with ≥3% Incidence and More Common than Placebo in Patients with Chronic Obstructive Pulmonary Disease a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis. Adverse Reaction Fluticasone Furoate/ Vilanterol ELLIPTA 100/25 mcg (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % Infections and infestations Nasopharyngitis 9 10 8 8 Upper respiratory tract infection 7 5 4 3 Oropharyngeal candidiasis a 5 2 3 2 Nervous system disorders Headache 7 9 7 5 12-Month Trials Long-term safety data are based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 patients, of which 57% were male and 85% were White. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV 1 /FVC ratio was 46% (range: 17% to 81%), indicating that the patient population had moderate to very severely impaired airflow obstruction. Patients received 1 inhalation once daily of the following: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 2 , adverse reactions occurring in ≥3% of the patients treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions ( 5.5 )] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia. Mortality Trial Safety data are available from a mortality trial in patients with moderate COPD (moderate airflow limitation [≥50% and ≤70% predicted FEV 1 ]) who either had a history of, or were at risk of, cardiovascular disease and were treated for up to 4 years (median treatment duration of 1.5 years). The trial included 16,568 patients, 4,140 of whom received fluticasone furoate/vilanterol ELLIPTA 100/25 mcg. In addition to the events in COPD trials shown in Table 2 , adverse reactions occurring in ≥3% of the patients treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg and more common than placebo included pneumonia, back pain, hypertension, and influenza. 6.2 Clinical Trials Experience in Asthma The safety data described below are based on trials that evaluated fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in 1,757 patients and fluticasone furoate/vilanterol ELLIPTA 200/25 mcg in 745 patients. While patients aged 12 to 17 years were included in these trials, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg is not approved for use in this age group [see Dosage and Administration ( 2.2 )] . One additional 24-week trial enrolled 902 pediatric patients with asthma. In this trial, fluticasone furoate/vilanterol ELLIPTA 100/25 mcg was studied in 117 patients aged 12 to 17 years and fluticasone furoate/vilanterol ELLIPTA 50/25 mcg was studied in 337 patients aged 5 to 11 years. Adult Patients The safety of fluticasone furoate/vilanterol ELLIPTA for the maintenance treatment of asthma in adult patients was based on the data from Trials 8, 9, 10, 11, and 12 [see Clinical Studies ( 14.2 )] . Trial 8 was a 12-week trial that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in patients with asthma compared with fluticasone furoate 100 mcg and placebo. The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg is shown in Table 3 . Table 3. Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg with ≥2% Incidence and More Common than Placebo in Patients with Asthma (Trial 8) a Includes oral candidiasis and oropharyngeal candidiasis. Adverse Reaction Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % Infections and infestations Nasopharyngitis 10 7 7 Oral candidiasis a 2 2 0 Nervous system disorders Headache 5 4 4 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 2 2 1 Dysphonia 2 1 0 Trial 9 was a 12-week trial that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, and fluticasone furoate 100 mcg in patients with asthma. This trial did not have a placebo arm. The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg and fluticasone furoate/vilanterol ELLIPTA 200/25 mcg is shown in Table 4 . Table 4. Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100