Breo Ellipta

6 ADVERSE REACTIONS • 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 GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. 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 BREO ELLIPTA 100/25 mcg. Adverse reactions observed in other studies of BREO ELLIPTA in COPD patients were similar to those observed in these 5 trials. 6-Month Trials The incidence of adverse reactions associated with BREO 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: BREO ELLIPTA 100/25 mcg, BREO 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 BREO 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 BREO 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: BREO ELLIPTA 100/25 mcg, BREO 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 BREO 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 BREO 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 BREO 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 were based on trials that evaluated BREO ELLIPTA 100/25 mcg in 1,757 patients and BREO ELLIPTA 200/25 mcg in 745 patients. While patients aged 12 to 17 years were included in these trials, BREO ELLIPTA 200/25 mcg is not approved for use in this age group [see Dosage and Administration ( 2.3 )] . One additional 24-week trial enrolled 902 pediatric patients with asthma. In this trial, BREO ELLIPTA 100/25 mcg was studied in 117 patients aged 12 to 17 years and BREO ELLIPTA 50/25 mcg was studied in 337 patients aged 5 to 11 years. Adult Patients The safety of BREO 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 BREO ELLIPTA 100/25 mcg in patients with asthma compared with fluticasone furoate 100 mcg and placebo. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 mcg is shown in Table 3 . Table 3. Adverse Reactions with BREO 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 BREO 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 BREO ELLIPTA 100/25 mcg, BREO 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 BREO ELLIPTA 100/25 mcg and BREO ELLIPTA 200/25 mcg is shown in Table 4 . Table 4. Adverse Reactions with BREO ELLIPTA 100/25 mcg and BREO ELLIPTA 200/25 mcg with ≥2% Incidence in Patients with Asthma (Trial 9) Adverse Reaction BREO ELLIPTA 200/25 mcg (n = 346) % BREO ELLIPTA 100/25 mcg (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % Nervous system disorders Headache 8 8 9 Infections and infestations Nasopharyngitis 7 6 7 Influenza 3 3 1 Upper respiratory tract infection 2 2 3 Sinusitis 2 1 <1 Bronchitis 2 <1 2 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 2 2 1 Cough 1 2 1 24-Week Trial Trial 10 was a 24-week trial that evaluated the efficacy of BREO ELLIPTA 200/25 mcg once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in patients with asthma. This trial did not have a placebo arm. In addition to the reactions shown in Tables 3 and 4 , adverse reactions occurring in ≥2% of patients treated with BREO ELLIPTA 200/25 mcg included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia. 12-Month Trial Long-term safety data are based on a 12-month trial that evaluated the safety of BREO ELLIPTA 100/25 mcg once daily (n = 201), BREO ELLIPTA 200/25 mcg once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in patients with asthma (Trial 11). In addition to the reactions shown in Tables 3 and 4 , adverse reactions occurring in ≥2% of the patients treated with BREO ELLIPTA 100/25 mcg or BREO ELLIPTA 200/25 mcg for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia. Adult and Pediatric Patients Aged 12 to 17 Years Exacerbation Trial Trial 12 included both adult and pediatric patients 12 years of age and older. Although this trial did not support efficacy of BREO ELLIPTA for maintenance treatment of asthma in pediatric patients 12 to 17 years of age, it was used to evaluate safety in both adult and pediatric patients 12 to 17 years of age. Patients received BREO ELLIPTA 100/25 mcg (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010). Patients participating in this trial had a history of 1 or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry. Asthma-related hospitalizations occurred in 10 patients (1%) treated with BREO ELLIPTA 100/25 mcg compared with 7 patients (0.7%) treated with fluticasone furoate 100 mcg. Among patients aged 12 to 17 years, asthma-related hospitalizations occurred in 4 patients (2.6%) treated with BREO ELLIPTA 100/25 mcg (n = 151) compared with 0 patients treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial. Pediatric Patients Aged 5 to 17 Years The safety of BREO ELLIPTA for the maintenance treatment of asthma in pediatric patients 5 years and older was based on the data from Trial 14, a 24-week clinical trial that enrolled 902 patients with asthma aged 5 to 17 years (aged 5 to 11 years [n = 673]; aged 12 to 17 years [n = 229]). Pediatric patients aged 12 to 17 years were randomized to BREO ELLIPTA 100/25 mcg (n = 117) or fluticasone furoate 100 mcg (n = 112). Pediatric patients aged 5 to 11 years were randomized to BREO ELLIPTA 50/25 mcg (n = 337) or fluticasone furoate 50 mcg (n = 336) [see Clinical Studies ( 14.2 )] . Adverse reactions reported in ≥3% of pediatric patients treated with BREO ELLIPTA is shown in Table 5 . Table 5. Adverse Reactions with BREO ELLIPTA with ≥3% Incidence in Pediatric Patients with Asthma (Trial 14) a The dose of BREO ELLIPTA was 100/25 mcg once daily for pediatric patients aged 12 to 17 years and 50/25 mcg once daily for pediatric patients aged 5 to 11 years. b The dose of fluticasone furoate was 100 mcg once daily for pediatric patients aged 12 to 17 years and 50 mcg once daily for pediatric patients aged 5 to 11 years. Adverse Reaction BREO ELLIPTA a (n = 454) % Fluticasone Furoate b (n = 448) % Infections and infestations Nasopharyngitis 10 8 Upper respiratory tract infection 7 6 Rhinitis 3 1 Viral upper respiratory tract infection 3 <1 Respiratory, thoracic, and mediastinal disorders Rhinitis allergic 4 1 Nervous system disorders Headache 3 2 6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of BREO ELLIPTA. 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 BREO ELLIPTA or a combination of these factors. Cardiac Disorders Palpitations, tachycardia. Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Metabolism and Nutrition Disorders Hyperglycemia. Musculoskeletal and Connective Tissue Disorders Muscle spasms. Nervous System Disorders Tremor. Psychiatric Disorders Nervousness. Respiratory, Thoracic, and Mediastinal Disorders Paradoxical bronchospasm.

4 CONTRAINDICATIONS BREO ELLIPTA is contraindicated in the following conditions: • Primary treatment of status asthmaticus or other acute episodes of COPD or asthma where intensive measures are required [see Warnings and Precautions ( 5.2 )] . • Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions ( 5.11 ), Description ( 11 )] . • Primary treatment of status asthmaticus or acute episodes of COPD or asthma requiring intensive measures. ( 4 ) • Severe hypersensitivity to milk proteins or any ingredients. ( 4 )

11 DESCRIPTION BREO ELLIPTA is an inhalation powder drug product for delivery of a combination of fluticasone furoate (an ICS) and vilanterol (a LABA) to patients by oral inhalation. Fluticasone furoate, a synthetic trifluorinated corticosteroid, has the chemical name (6α,11β,16α,17α)-6,9-difluoro-17-{[(fluoro-methyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl 2-furancarboxylate and the following chemical structure: Fluticasone furoate is a white powder with a molecular weight of 538.6, and the empirical formula is C 27 H 29 F 3 O 6 S. It is practically insoluble in water. Vilanterol trifenatate has the chemical name triphenylacetic acid-4-{(1 R )-2-[(6-{2-[2,6-dicholorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (1:1) and the following chemical structure: Vilanterol trifenatate is a white powder with a molecular weight of 774.8, and the empirical formula is C 24 H 33 Cl 2 NO 5 •C 20 H 16 O 2 . It is practically insoluble in water. BREO ELLIPTA is a light grey and pale blue plastic inhaler containing 2 foil blister strips. Each blister on one strip contains a white powder blend of micronized fluticasone furoate (50, 100, or 200 mcg) and lactose monohydrate (12.5, 12.4 or 12.3 mg, respectively), and each blister on the other strip contains a white powder blend of micronized vilanterol trifenatate (40 mcg equivalent to 25 mcg of vilanterol), magnesium stearate (125 mcg), and lactose monohydrate (12.34 mg). The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within both blisters is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, BREO ELLIPTA delivers 46, 92 or 184 mcg of fluticasone furoate and 22 mcg of vilanterol per dose when tested at a flow rate of 60 L/min for 4 seconds. In adult patients with obstructive lung disease and severely compromised lung function (COPD with FEV 1 /FVC <70% and FEV 1 <30% predicted or FEV 1 <50% predicted plus chronic respiratory failure), mean peak inspiratory flow through the ELLIPTA inhaler was 66.5 L/min (range: 43.5 to 81.0 L/min). In adult patients with severe asthma, mean peak inspiratory flow through the ELLIPTA inhaler was 96.6 L/min (range: 72.4 to 124.6 L/min). In pediatric patients with asthma aged 5 to 11 years, mean peak inspiratory flow through the ELLIPTA inhaler was 60.6 L/min (range: 36.3 to 82.5 L/min). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. fluticasone furoate chemical structure vilanterol trifenatate chemical structure

2 DOSAGE AND ADMINISTRATION • For oral inhalation only. ( 2.3 ) • Maintenance treatment of COPD: 1 actuation of BREO 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 BREO ELLIPTA 100/25 mcg or BREO 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 BREO 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 BREO 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 BREO 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 BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation or BREO 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 BREO 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 (FEV1), 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 BREO ELLIPTA 100/25 mcg once daily, increasing the dose to BREO ELLIPTA 200/25 mcg once daily may provide additional improvement in asthma control. For patients who do not respond adequately to BREO 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 BREO ELLIPTA 200/25 mcg once daily. • If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief. Pediatric Patients Aged 12 to 17 Years The recommended dosage of BREO 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 BREO 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 )] . • BREO ELLIPTA should be used at the same time every day. Do not use BREO 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 BREO ELLIPTA is not recommended as some patients are more likely to experience adverse effects with higher doses.

1 INDICATIONS AND USAGE BREO 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 BREO ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). 1.2 Maintenance Treatment of Asthma BREO ELLIPTA is indicated for the maintenance treatment of asthma in patients aged 5 years and older. 1.3 Limitations of Use BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm.

10 OVERDOSAGE BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA. Treatment of overdosage consists of discontinuation of BREO ELLIPTA 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 medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage. Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions ( 5.8 )] . Vilanterol The expected signs and symptoms with overdosage of vilanterol 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). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.

7 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 BREO 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action BREO ELLIPTA BREO ELLIPTA contains both fluticasone furoate and vilanterol. The mechanisms of action described below for the individual components apply to BREO ELLIPTA. These drugs represent 2 different classes of medications an ICS and a LABA), each having different effects on clinical and physiological indices. Fluticasone Furoate Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects COPD and asthma symptoms is not known. Inflammation is an important component in the pathogenesis of COPD and 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. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. Vilanterol Vilanterol is a LABA. In vitro tests have shown the functional selectivity of vilanterol was similar to salmeterol. The clinical relevance of this in vitro finding is unknown. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenergic agonist drugs, including vilanterol, 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. 12.2 Pharmacodynamics Cardiac Electrophysiology Healthy Subjects: QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled crossover study in 85 healthy volunteers. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 4.9 (7.5) milliseconds and 9.6 (12.2) milliseconds seen 30 minutes after dosing for fluticasone furoate/vilanterol 200/25 mcg and fluticasone furoate/vilanterol 800/100 mcg, respectively. A dose-dependent increase in heart rate was also observed. The maximum mean (95% upper confidence bound) difference in heart rate from placebo after baseline-correction was 7.8 (9.4) beats/min and 17.1 (18.7) beats/min seen 10 minutes after dosing for fluticasone furoate/vilanterol 200/25 mcg and fluticasone furoate/vilanterol 800/100 mcg, respectively. Hypothalamic-Pituitary-Adrenal Axis Effects Healthy Subjects: Inhaled fluticasone furoate at repeat doses up to 400 mcg was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects. Decreases in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose. Patients with Chronic Obstructive Pulmonary Disease: In a trial with patients with COPD, treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg, vilanterol 25 mcg, or fluticasone furoate (100 or 200 mcg) for 6 months did not affect 24-hour urinary cortisol excretion. A separate trial with patients with COPD demonstrated no effects on serum cortisol after 28 days of treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg. Patients with Asthma: A randomized, double-blind, parallel-group trial in 104 pediatric patients with asthma (aged 5 to 11 years) showed no difference between once-daily treatment with inhaled fluticasone furoate 50 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours) and serum cortisol AUC (0-24) following 6 weeks of treatment. A randomized, double-blind, parallel-group trial in 185 patients with asthma aged 12 to 65 years showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100/25 mcg or fluticasone furoate/vilanterol 200/25 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours), serum cortisol AUC (0-24) , and 24-hour urinary cortisol after 6 weeks of treatment, whereas prednisolone 10 mg given once daily for 7 days resulted in significant cortisol suppression. 12.3 Pharmacokinetics Linear pharmacokinetics was observed for fluticasone furoate (200 to 800 mcg) and vilanterol (25 to 100 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate and vilanterol plasma concentrations was achieved after 6 days, and the accumulation was up to 2.6-fold for fluticasone furoate and 2.4-fold for vilanterol as compared with single dose. Absorption Fluticasone Furoate: Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administered by inhalation was 15.2%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in patients with COPD or asthma was 46% or 7% lower, respectively, than observed in healthy subjects. Vilanterol: Vilanterol plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 10 minutes following inhalation. Absolute bioavailability of vilanterol when administered by inhalation was 27.3%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose of vilanterol is low (<2%) due to extensive first-pass metabolism. Systemic exposure (AUC) in patients with COPD was 24% higher than observed in healthy subjects. Systemic exposure (AUC) in patients with asthma was 21% lower than observed in healthy subjects. Distribution Fluticasone Furoate: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. Binding of fluticasone furoate to human plasma proteins was high (>99%). Vilanterol: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. Binding of vilanterol to human plasma proteins was on average 94%. Elimination Metabolism: Fluticasone Furoate: Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone. Vilanterol: Vilanterol is mainly metabolized, principally via CYP3A4, to a range of metabolites with significantly reduced β 1 - and β 2 -agonist activity. Excretion: Fluticasone Furoate: Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered doses, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered doses, respectively. Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours. Vilanterol: Following oral administration, vilanterol was eliminated mainly by metabolism followed by excretion of metabolites in urine and feces (approximately 70% and 30%, respectively, of the recovered radioactive dose). The plasma elimination half-life of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in patients with COPD and 16.0 hours in patients with asthma. Specific Populations The effects of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate and vilanterol are shown in Figure 1 . Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination a Severe renal impairment (CrCl <30 mL/min) compared with healthy subjects; mild (Child‑Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared with healthy subjects. b For COPD and asthma, the following comparisons were made: age compared with ≤65 years, gender compared with female, and ethnicity compared with White. Pediatric Patients: Fluticasone Furoate: A population pharmacokinetics analysis to assess impact of age on fluticasone furoate systemic exposure was conducted using combined data from clinical trials in pediatric patients aged 5 to 11 years (n = 306). There was no relevant effect of age on the apparent clearance of fluticasone furoate. The dose-adjusted fluticasone furoate systemic exposure at steady state in children aged 5 to 11 years following 50 mcg were comparable to that observed in adult and pediatric patients 12 years and older following dosing with fluticasone furoate 100 mcg monotherapy. Vilanterol: A population pharmacokinetic analysis was conducted to characterize vilanterol pharmacokinetics using combined data from clinical trials in pediatric patients aged 5 to 11 years (n = 142). There was no relevant effect of age, weight, body mass index, sex, ethnicity, and race on vilanterol clearance. A cross-study comparison in pediatric patients with asthma showed that at steady-state, when combined with fluticasone furoate, vilanterol had similar AUC values but lower C max values compared to vilanterol administered alone. Vilanterol systemic exposure at steady state, in patients with asthma aged 5 to 11 years, was similar to those observed in adult and pediatric patients 12 years and older with asthma following repeat dosing of BREO ELLIPTA 100/25 mcg. Racial or Ethnic Groups: Fluticasone Furoate: Systemic exposure [AUC (0-24) ] to inhaled fluticasone furoate 200 mcg was 27% to 49% higher in healthy subjects of Japanese, Korean, and Chinese heritage compared with White subjects. Similar differences were observed for patients with COPD or asthma ( Figure 1 ). However, there is no evidence that this higher exposure to fluticasone furoate results in clinically relevant effects on urinary cortisol excretion or on efficacy in these racial groups. Vilanterol: There was no effect of race on the pharmacokinetics of vilanterol in patients with COPD. In patients with asthma, vilanterol C max is estimated to be higher (3-fold) and AUC (0-24) comparable for those patients from an Asian heritage compared with patients from a non-Asian heritage. However, the higher C max values are similar to those seen in healthy subjects. Patients with Hepatic Impairment: Fluticasone Furoate: Following repeat dosing of fluticasone furoate/vilanterol 200/25 mcg (100/12.5 mcg in the severe impairment group) for 7 days, there was an increase of 34%, 83%, and 75% in fluticasone furoate systemic exposure (AUC) in patients with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects ( Figure 1 ). In patients with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (90% CI: 11%, 51%) compared with healthy subjects. In patients with severe hepatic impairment receiving fluticasone furoate/vilanterol 100/12.5 mcg, mean serum cortisol (0 to 24 hours) was increased by 14% (90% CI: -16%, 55%) compared with healthy subjects. Patients with moderate to severe hepatic disease should be closely monitored. Vilanterol: Hepatic impairment had no effect on vilanterol systemic exposure [C max and AUC (0-24) on Day 7] following repeat-dose administration of fluticasone furoate/vilanterol 200/25 mcg (100/12.5 mcg in the severe impairment group) for 7 days ( Figure 1 ). There were no additional clinically relevant effects of the fluticasone furoate/vilanterol combinations on heart rate or serum potassium in patients with mild or moderate hepatic impairment (vilanterol 25 mcg combination) or with severe hepatic impairment (vilanterol 12.5 mcg combination) compared with healthy subjects. Patients with Renal Impairment: Fluticasone furoate systemic exposure was not increased and vilanterol systemic exposure [AUC (0-24) ] was 56% higher in patients with severe renal impairment compared with healthy subjects ( Figure 1 ). There was no evidence of greater corticosteroid or beta-agonist class-related systemic effects (assessed by serum cortisol, heart rate, and serum potassium) in patients with severe renal impairment compared with healthy subjects. Drug Interaction Studies There were no clinically relevant differences in the pharmacokinetics or pharmacodynamics of either fluticasone furoate or vilanterol when administered in combination compared with administration alone. The potential for fluticasone furoate and vilanterol to inhibit or induce metabolic enzymes and transporter systems is negligible at low inhalation doses. Inhibitors of Cytochrome P450 3A4: The exposure (AUC) of fluticasone furoate and vilanterol were 36% and 65% higher, respectively, when coadministered with ketoconazole 400 mg compared with placebo ( Figure 2 ). The increase in fluticasone furoate exposure was associated with a 27% reduction in weighted mean serum cortisol (0 to 24 hours). The increase in vilanterol exposure was not associated with an increase in beta-agonist–related systemic effects on heart rate or blood potassium. Figure 2. Impact of Coadministered Drugs a on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination or Vilanterol Coadministered with a Long-acting Muscarinic Antagonist a Compared with placebo group. Inhibitors of P-glycoprotein: Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). Coadministration of repeat-dose (240 mg once daily) verapamil (a moderate CYP3A4 inhibitor and a P-gp inhibitor) did not affect the vilanterol C max or AUC in healthy subjects ( Figure 2 ). Drug interaction trials with a specific P-gp inhibitor and fluticasone furoate have not been conducted. Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination Figure 2. Impact of Coadministered Drugsa on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination or Vilanterol Coadministered with a Long-Acting Muscarinic Antagonist

12.1 Mechanism of Action BREO ELLIPTA BREO ELLIPTA contains both fluticasone furoate and vilanterol. The mechanisms of action described below for the individual components apply to BREO ELLIPTA. These drugs represent 2 different classes of medications an ICS and a LABA), each having different effects on clinical and physiological indices. Fluticasone Furoate Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects COPD and asthma symptoms is not known. Inflammation is an important component in the pathogenesis of COPD and 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. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. Vilanterol Vilanterol is a LABA. In vitro tests have shown the functional selectivity of vilanterol was similar to salmeterol. The clinical relevance of this in vitro finding is unknown. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenergic agonist drugs, including vilanterol, 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.

12.2 Pharmacodynamics Cardiac Electrophysiology Healthy Subjects: QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled crossover study in 85 healthy volunteers. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 4.9 (7.5) milliseconds and 9.6 (12.2) milliseconds seen 30 minutes after dosing for fluticasone furoate/vilanterol 200/25 mcg and fluticasone furoate/vilanterol 800/100 mcg, respectively. A dose-dependent increase in heart rate was also observed. The maximum mean (95% upper confidence bound) difference in heart rate from placebo after baseline-correction was 7.8 (9.4) beats/min and 17.1 (18.7) beats/min seen 10 minutes after dosing for fluticasone furoate/vilanterol 200/25 mcg and fluticasone furoate/vilanterol 800/100 mcg, respectively. Hypothalamic-Pituitary-Adrenal Axis Effects Healthy Subjects: Inhaled fluticasone furoate at repeat doses up to 400 mcg was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects. Decreases in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose. Patients with Chronic Obstructive Pulmonary Disease: In a trial with patients with COPD, treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg, vilanterol 25 mcg, or fluticasone furoate (100 or 200 mcg) for 6 months did not affect 24-hour urinary cortisol excretion. A separate trial with patients with COPD demonstrated no effects on serum cortisol after 28 days of treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg. Patients with Asthma: A randomized, double-blind, parallel-group trial in 104 pediatric patients with asthma (aged 5 to 11 years) showed no difference between once-daily treatment with inhaled fluticasone furoate 50 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours) and serum cortisol AUC (0-24) following 6 weeks of treatment. A randomized, double-blind, parallel-group trial in 185 patients with asthma aged 12 to 65 years showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100/25 mcg or fluticasone furoate/vilanterol 200/25 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours), serum cortisol AUC (0-24) , and 24-hour urinary cortisol after 6 weeks of treatment, whereas prednisolone 10 mg given once daily for 7 days resulted in significant cortisol suppression.

12.3 Pharmacokinetics Linear pharmacokinetics was observed for fluticasone furoate (200 to 800 mcg) and vilanterol (25 to 100 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate and vilanterol plasma concentrations was achieved after 6 days, and the accumulation was up to 2.6-fold for fluticasone furoate and 2.4-fold for vilanterol as compared with single dose. Absorption Fluticasone Furoate: Fluticasone furoate plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administered by inhalation was 15.2%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism. Systemic exposure (AUC) in patients with COPD or asthma was 46% or 7% lower, respectively, than observed in healthy subjects. Vilanterol: Vilanterol plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 10 minutes following inhalation. Absolute bioavailability of vilanterol when administered by inhalation was 27.3%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose of vilanterol is low (<2%) due to extensive first-pass metabolism. Systemic exposure (AUC) in patients with COPD was 24% higher than observed in healthy subjects. Systemic exposure (AUC) in patients with asthma was 21% lower than observed in healthy subjects. Distribution Fluticasone Furoate: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. Binding of fluticasone furoate to human plasma proteins was high (>99%). Vilanterol: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. Binding of vilanterol to human plasma proteins was on average 94%. Elimination Metabolism: Fluticasone Furoate: Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity. There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone. Vilanterol: Vilanterol is mainly metabolized, principally via CYP3A4, to a range of metabolites with significantly reduced β 1 - and β 2 -agonist activity. Excretion: Fluticasone Furoate: Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered doses, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered doses, respectively. Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours. Vilanterol: Following oral administration, vilanterol was eliminated mainly by metabolism followed by excretion of metabolites in urine and feces (approximately 70% and 30%, respectively, of the recovered radioactive dose). The plasma elimination half-life of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in patients with COPD and 16.0 hours in patients with asthma. Specific Populations The effects of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate and vilanterol are shown in Figure 1 . Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination a Severe renal impairment (CrCl <30 mL/min) compared with healthy subjects; mild (Child‑Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared with healthy subjects. b For COPD and asthma, the following comparisons were made: age compared with ≤65 years, gender compared with female, and ethnicity compared with White. Pediatric Patients: Fluticasone Furoate: A population pharmacokinetics analysis to assess impact of age on fluticasone furoate systemic exposure was conducted using combined data from clinical trials in pediatric patients aged 5 to 11 years (n = 306). There was no relevant effect of age on the apparent clearance of fluticasone furoate. The dose-adjusted fluticasone furoate systemic exposure at steady state in children aged 5 to 11 years following 50 mcg were comparable to that observed in adult and pediatric patients 12 years and older following dosing with fluticasone furoate 100 mcg monotherapy. Vilanterol: A population pharmacokinetic analysis was conducted to characterize vilanterol pharmacokinetics using combined data from clinical trials in pediatric patients aged 5 to 11 years (n = 142). There was no relevant effect of age, weight, body mass index, sex, ethnicity, and race on vilanterol clearance. A cross-study comparison in pediatric patients with asthma showed that at steady-state, when combined with fluticasone furoate, vilanterol had similar AUC values but lower C max values compared to vilanterol administered alone. Vilanterol systemic exposure at steady state, in patients with asthma aged 5 to 11 years, was similar to those observed in adult and pediatric patients 12 years and older with asthma following repeat dosing of BREO ELLIPTA 100/25 mcg. Racial or Ethnic Groups: Fluticasone Furoate: Systemic exposure [AUC (0-24) ] to inhaled fluticasone furoate 200 mcg was 27% to 49% higher in healthy subjects of Japanese, Korean, and Chinese heritage compared with White subjects. Similar differences were observed for patients with COPD or asthma ( Figure 1 ). However, there is no evidence that this higher exposure to fluticasone furoate results in clinically relevant effects on urinary cortisol excretion or on efficacy in these racial groups. Vilanterol: There was no effect of race on the pharmacokinetics of vilanterol in patients with COPD. In patients with asthma, vilanterol C max is estimated to be higher (3-fold) and AUC (0-24) comparable for those patients from an Asian heritage compared with patients from a non-Asian heritage. However, the higher C max values are similar to those seen in healthy subjects. Patients with Hepatic Impairment: Fluticasone Furoate: Following repeat dosing of fluticasone furoate/vilanterol 200/25 mcg (100/12.5 mcg in the severe impairment group) for 7 days, there was an increase of 34%, 83%, and 75% in fluticasone furoate systemic exposure (AUC) in patients with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects ( Figure 1 ). In patients with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (90% CI: 11%, 51%) compared with healthy subjects. In patients with severe hepatic impairment receiving fluticasone furoate/vilanterol 100/12.5 mcg, mean serum cortisol (0 to 24 hours) was increased by 14% (90% CI: -16%, 55%) compared with healthy subjects. Patients with moderate to severe hepatic disease should be closely monitored. Vilanterol: Hepatic impairment had no effect on vilanterol systemic exposure [C max and AUC (0-24) on Day 7] following repeat-dose administration of fluticasone furoate/vilanterol 200/25 mcg (100/12.5 mcg in the severe impairment group) for 7 days ( Figure 1 ). There were no additional clinically relevant effects of the fluticasone furoate/vilanterol combinations on heart rate or serum potassium in patients with mild or moderate hepatic impairment (vilanterol 25 mcg combination) or with severe hepatic impairment (vilanterol 12.5 mcg combination) compared with healthy subjects. Patients with Renal Impairment: Fluticasone furoate systemic exposure was not increased and vilanterol systemic exposure [AUC (0-24) ] was 56% higher in patients with severe renal impairment compared with healthy subjects ( Figure 1 ). There was no evidence of greater corticosteroid or beta-agonist class-related systemic effects (assessed by serum cortisol, heart rate, and serum potassium) in patients with severe renal impairment compared with healthy subjects. Drug Interaction Studies There were no clinically relevant differences in the pharmacokinetics or pharmacodynamics of either fluticasone furoate or vilanterol when administered in combination compared with administration alone. The potential for fluticasone furoate and vilanterol to inhibit or induce metabolic enzymes and transporter systems is negligible at low inhalation doses. Inhibitors of Cytochrome P450 3A4: The exposure (AUC) of fluticasone furoate and vilanterol were 36% and 65% higher, respectively, when coadministered with ketoconazole 400 mg compared with placebo ( Figure 2 ). The increase in fluticasone furoate exposure was associated with a 27% reduction in weighted mean serum cortisol (0 to 24 hours). The increase in vilanterol exposure was not associated with an increase in beta-agonist–related systemic effects on heart rate or blood potassium. Figure 2. Impact of Coadministered Drugs a on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination or Vilanterol Coadministered with a Long-acting Muscarinic Antagonist a Compared with placebo group. Inhibitors of P-glycoprotein: Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). Coadministration of repeat-dose (240 mg once daily) verapamil (a moderate CYP3A4 inhibitor and a P-gp inhibitor) did not affect the vilanterol C max or AUC in healthy subjects ( Figure 2 ). Drug interaction trials with a specific P-gp inhibitor and fluticasone furoate have not been conducted. Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination Figure 2. Impact of Coadministered Drugsa on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination or Vilanterol Coadministered with a Long-Acting Muscarinic Antagonist

20230512

25

3 DOSAGE FORMS AND STRENGTHS Inhalation powder: • 50 mcg fluticasone furoate and 25 mcg vilanterol (50/25 mcg) per actuation • 100 mcg fluticasone furoate and 25 mcg vilanterol (100/25 mcg) per actuation • 200 mcg fluticasone furoate and 25 mcg vilanterol (200/25 mcg) per actuation Inhalation powder: • 50 mcg fluticasone furoate and 25 mcg vilanterol (50/25 mcg) per actuation ( 3 ) • 100 mcg fluticasone furoate and 25 mcg vilanterol (100/25 mcg) per actuation ( 3 ) • 200 mcg fluticasone furoate and 25 mcg vilanterol (200/25 mcg) per actuation ( 3 )

Breo Ellipta fluticasone furoate and vilanterol trifenatate FLUTICASONE FUROATE FLUTICASONE VILANTEROL TRIFENATATE VILANTEROL LACTOSE MONOHYDRATE MAGNESIUM STEARATE Breo Ellipta fluticasone furoate and vilanterol trifenatate FLUTICASONE FUROATE FLUTICASONE VILANTEROL TRIFENATATE VILANTEROL LACTOSE MONOHYDRATE MAGNESIUM STEARATE Breo Ellipta fluticasone furoate and vilanterol trifenatate FLUTICASONE FUROATE FLUTICASONE VILANTEROL TRIFENATATE VILANTEROL LACTOSE MONOHYDRATE MAGNESIUM STEARATE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below. Fluticasone Furoate Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (both approximately 0.5 times the MRHDID of 200 mcg on a mcg/m 2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro . There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/day, respectively (approximately 3 and 8 times, respectively, the MRHDID of 200 mcg for adults on an AUC basis). Vilanterol In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhaled dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID on an AUC basis). No increase in tumors was seen at an inhaled dose of 615 mcg/kg/day (approximately 530 times the MRHDID on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhaled doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID on an AUC basis). These tumor 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. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay. No evidence of impairment of fertility was observed in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (both approximately 5,490 times the MRHDID based on AUC).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below. Fluticasone Furoate Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (both approximately 0.5 times the MRHDID of 200 mcg on a mcg/m 2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro . There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/day, respectively (approximately 3 and 8 times, respectively, the MRHDID of 200 mcg for adults on an AUC basis). Vilanterol In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhaled dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID on an AUC basis). No increase in tumors was seen at an inhaled dose of 615 mcg/kg/day (approximately 530 times the MRHDID on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhaled doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID on an AUC basis). These tumor 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. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay. No evidence of impairment of fertility was observed in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (both approximately 5,490 times the MRHDID based on AUC).

NDA204275

Breo Ellipta

fluticasone furoate and vilanterol trifenatate

0173-0882

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

PRINCIPAL DISPLAY PANEL NDC 0173-0916-10 BREO ELLIPTA (fluticasone furoate and vilanterol inhalation powder) 50 mcg/25 mcg Rx Only FOR ORAL INHALATION ONLY BREO ELLIPTA contains 2 foil strips of 30 blisters each. Each blister on one strip contains 50 mcg of fluticasone furoate and lactose monohydrate. Each blister on the other strip contains 25 mcg of vilanterol, magnesium stearate, and lactose monohydrate. 1 ELLIPTA Inhaler containing 30 doses (60 blisters total) GSK Trademarks are owned by or licensed to the GSK group of Companies. BREO ELLIPTA was developed in collaboration with Innoviva, Inc. ©2023 GSK group of companies or its licensor. Made in UK 62000000086025 Rev. 5/23 Breo Ellipta 50mcg-25mcg 30 dose carton

Indications and Usage, Maintenance Treatment of Asthma ( 1.2 ) 5/2023 Dosage and Administration, Recommended Dosage for Maintenance Treatment of Asthma ( 2.2 ) 5/2023 Warnings and Precautions, Effect on Growth ( 5.14 ) 5/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Serious Asthma-Related Events Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with BREO ELLIPTA, there is not a significant increase in the risk of these events. [See Warnings and Precautions ( 5.1 ).] Not for Acute Symptoms Inform patients that BREO ELLIPTA is not meant to relieve acute symptoms of COPD or asthma and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta 2 -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 beta 2 -agonists • Need for more inhalations than usual of inhaled, short-acting beta 2 -agonists • Significant decrease in lung function as outlined by the physician Tell patients they should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation. [See Warnings and Precautions ( 5.2 ).] Do Not Use Additional Long-acting Beta 2 -agonists Instruct patients not to use other LABA for COPD and asthma. [See Warnings and Precautions ( 5.3 ).] Oropharyngeal Candidiasis 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 BREO ELLIPTA, but at times therapy with BREO ELLIPTA 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. [See Warnings and Precautions ( 5.4 ).] Pneumonia Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia. [See Warnings and Precautions ( 5.5 ).] Immunosuppression and Risk of Infections 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. [See Warnings and Precautions ( 5.6 ).] Hypercorticism and Adrenal Suppression Advise patients that BREO ELLIPTA 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 BREO ELLIPTA. [See Warnings and Precautions ( 5.8 ).] Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue BREO ELLIPTA and contact their healthcare provider right away. [See Warnings and Precautions ( 5.10 ).] Hypersensitivity Reactions, including Anaphylaxis Advise patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) may occur after administration of BREO ELLIPTA. Instruct patients to discontinue BREO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA. [See Warnings and Precautions ( 5.11 ).] 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. [See Warnings and Precautions ( 5.13 ).] Reduced Growth Velocity Inform patients that orally inhaled corticosteroids, including fluticasone furoate, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children taking corticosteroids by any route. [See Warnings and Precautions ( 5.14 ).] Glaucoma and Cataracts Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations. [See Warnings and Precautions ( 5.15 ).] Risks Associated with Beta-agonist Therapy Inform patients of adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct patients to consult a healthcare practitioner immediately should any of these signs and symptoms develop. [See Warnings and Precautions ( 5.12 ).] Trademarks are owned by or licensed to the GSK group of companies. BREO ELLIPTA was developed in collaboration with Innoviva. GlaxoSmithKline Durham, NC 27701 ©2023 GSK group of companies or its licensor. BRE:12PI

INSTRUCTIONS FOR USE BREO ELLIPTA (BRE-oh e-LIP-ta) (fluticasone furoate and vilanterol inhalation powder) for oral inhalation use Read this before you start: • If you open and close the cover without inhaling the medicine, you will lose the dose. • The lost dose will be securely held inside the inhaler, but it will no longer be available to be inhaled. • It is not possible to accidentally take a double dose or an extra dose in 1 inhalation. Your BREO ELLIPTA inhaler How to use your inhaler • BREO ELLIPTA comes in a tray. • Peel back the lid to open the tray. See Figure A . • The tray contains a desiccant to reduce moisture. Do not eat or inhale. Throw it away in the household trash out of reach of children and pets. See Figure B . Figure A Figure B Important Notes: • Your inhaler contains 30 doses (14 doses if you have a sample or institutional pack). • Each time you fully open the cover of the inhaler (you will hear a clicking sound), a dose is ready to be inhaled. This is shown by a decrease in the number on the counter. • If you open and close the cover without inhaling the medicine, you will lose the dose. The lost dose will be held in the inhaler, but it will no longer be available to be inhaled. It is not possible to accidentally take a double dose or an extra dose in 1 inhalation. • Do not open the cover of the inhaler until you are ready to use it. To avoid wasting doses after the inhaler is ready, do not close the cover until after you have inhaled the medicine. • Write the “Tray opened” and “Discard” dates on the inhaler label. The “Discard” date is 6 weeks from the date you open the tray. Check the counter. See Figure C. Figure C • Before the inhaler is used for the first time, the counter should show the number 30 (14 if you have a sample or institutional pack). This is the number of doses in the inhaler. • Each time you open the cover, you prepare 1 dose of medicine. • The counter counts down by 1 each time you open the cover. Prepare your dose: Wait to open the cover until you are ready to take your dose. Figure D Step 1. Open the cover of the inhaler. See Figure D. • Slide the cover down to expose the mouthpiece. You should hear a “click.” The counter will count down by 1 number. You do not need to shake this kind of inhaler. Your inhaler is now ready to use. • If the counter does not count down as you hear the click, the inhaler will not deliver the medicine. Call your healthcare provider or pharmacist if this happens. Figure E Step 2. Breathe out. See Figure E. • While holding the inhaler away from your mouth, breathe out (exhale) fully. Do not breathe out into the mouthpiece. Figure F Step 3. Inhale your medicine. See Figure F. • Put the mouthpiece between your lips, and close your lips firmly around it. Your lips should fit over the curved shape of the mouthpiece. • Take one long, steady, deep breath in through your mouth. Do not breathe in through your nose. Figure G • Do not block the air vent with your fingers. See Figure G. Figure H • Remove the inhaler from your mouth and hold your breath for about 3 to 4 seconds (or as long as comfortable for you). See Figure H. Figure I Step 4. Breathe out slowly and gently. See Figure I. • You may not taste or feel the medicine, even when you are using the inhaler correctly. • Do not take another dose from the inhaler even if you do not feel or taste the medicine. Figure J Step 5. Close the inhaler. See Figure J. • You can clean the mouthpiece if needed, using a dry tissue, before you close the cover. Routine cleaning is not required. • Slide the cover up and over the mouthpiece as far as it will go. Figure K Step 6. Rinse your mouth. See Figure K. • Rinse your mouth with water after you have used the inhaler and spit the water out. Do not swallow the water. Important Note: When should you get a refill? Figure L • When you have fewer than 10 doses remaining in your inhaler, the left half of the counter shows red as a reminder to get a refill. See Figure L. • After you have inhaled the last dose, the counter will show “0” and will be empty. • Throw the empty inhaler away in your household trash out of reach of children and pets. For more information about BREO ELLIPTA or how to use your inhaler, call 1-888-825-5249. Trademarks are owned by or licensed to the GSK group of companies. BREO ELLIPTA was developed in collaboration with Innoviva. GlaxoSmithKline, Durham, NC 27701 ©2023 GSK group of companies or its licensor. BRE:4IFU This Instructions for Use has been approved by the U.S. Food and Drug Administration Revised: May 2023 Parts figure Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Fig K Figure K

14 CLINICAL STUDIES 14.1 Chronic Obstructive Pulmonary Disease Four trials evaluated the efficacy of BREO ELLIPTA on lung function (Trial 1, NCT01053988 and Trial 2, NCT01054885) and exacerbations (Trial 3, NCT01009463 and Trial 4, NCT01017952). Lung Function: Trials 1 and 2 were 24-week, randomized, double-blind, placebo-controlled trials designed to evaluate the efficacy of BREO ELLIPTA on lung function in patients with COPD. In Trial 1, patients were randomized to BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, and placebo. In Trial 2, patients were randomized to BREO ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, fluticasone furoate 100 mcg, vilanterol 25 mcg, and placebo. All treatments were administered as 1 inhalation once daily. 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%), mean postbronchodilator FEV 1 /FVC ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). The co-primary efficacy variables in both trials were weighted mean FEV 1 (0 to 4 hours) postdose on Day 168 and change from baseline in trough FEV 1 on Day 169 (the mean of the FEV 1 values obtained 23 and 24 hours after the final dose on Day 168). The weighted mean comparison of the fluticasone furoate/vilanterol combination with fluticasone furoate was assessed to evaluate the contribution of vilanterol to BREO ELLIPTA. The trough FEV 1 comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA. BREO ELLIPTA 100/25 mcg demonstrated a larger increase in the weighted mean FEV 1 (0 to 4 hours) relative to placebo and fluticasone furoate 100 mcg at Day 168 ( Table 6 ). Table 6. Least Squares Mean Change from Baseline in Weighted Mean FEV 1 (0-4 h) and Trough FEV 1 at 6 Months FEV 1 = Forced Expiratory Volume in 1 second. a At Day 168. b At Day 169. Treatment N Weighted Mean FEV 1 (0-4 h) a (mL) Trough FEV 1 b (mL) Difference from Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Placebo (95% CI) Vilanterol 25 mcg (95% CI) Trial 1 BREO ELLIPTA 100/25 mcg 204 214 (161, 266) 168 (116, 220) –– 144 (91, 197) 45 (-8, 97) BREO ELLIPTA 200/25 mcg 205 209 (157, 261) –– 168 (117, 219) 131 (80, 183) 32 (-19, 83) Trial 2 BREO ELLIPTA 100/25 mcg 206 173 (123, 224) 120 (70, 170) –– 115 (60, 169) 48 (-6, 102) Serial spirometric evaluations were performed predose and up to 4 hours after dosing. Results from Trial 1 at Day 1 and Day 168 are shown in Figure 3 . Similar results were seen in Trial 2 (not shown). Figure 3. Raw Mean Change from Baseline in Postdose Serial FEV 1 (0-4 h) (mL) on Days 1 and 168 Day 1 Day 168 The second co-primary variable was change from baseline in trough FEV 1 following the final treatment day. At Day 169, both Trials 1 and 2 demonstrated significant increases in trough FEV 1 for all strengths of the fluticasone furoate/vilanterol combination compared with placebo ( Table 7 ). The comparison of BREO ELLIPTA 100/25 mcg with vilanterol did not achieve statistical significance ( Table 7 ). Trials 1 and 2 evaluated FEV 1 as a secondary endpoint. Peak FEV 1 was defined as the maximum postdose FEV 1 recorded within 4 hours after the first dose of trial medicine on Day 1 (measurements recorded at 5, 15, and 30 minutes and 1, 2, and 4 hours). In both trials, differences in mean change from baseline in peak FEV 1 were observed for the groups receiving BREO ELLIPTA 100/25 mcg compared with placebo (152 and 139 mL, respectively). The median time to onset, defined as a 100-mL increase from baseline in FEV 1 , was 16 minutes in patients receiving BREO ELLIPTA 100/25 mcg. Exacerbations: Trials 3 and 4 were randomized, double-blind, 52-week trials designed to evaluate the effect of BREO ELLIPTA on the rate of moderate and severe COPD exacerbations. All patients were treated with fluticasone propionate/salmeterol 250/50 mcg twice daily during a 4-week run-in period prior to being randomly assigned to 1 of the following treatment groups: BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, or vilanterol 25 mcg. The primary efficacy variable in both trials was the annual rate of moderate/severe exacerbations. The comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA. In these 2 trials, exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days. COPD exacerbations were considered to be of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if hospitalization was required. 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 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. The mean percent reversibility was 15% (range: -65% to 313%). Patients treated with BREO ELLIPTA 100/25 mcg had a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol in both trials ( Table 7 ). Table 7. Moderate and Severe Chronic Obstructive Pulmonary Disease Exacerbations Treatment n Mean Annual Rate (exacerbations/year) Ratio vs. Vilanterol 95% CI Trial 3 BREO ELLIPTA 100/25 mcg 403 0.90 0.79 0.64, 0.97 BREO ELLIPTA 200/25 mcg 409 0.79 0.69 0.56, 0.85 Fluticasone furoate/vilanterol 50/25 mcg 412 0.92 0.81 0.66, 0.99 Vilanterol 25 mcg 409 1.14 –– –– Trial 4 BREO ELLIPTA 100/25 mcg 403 0.70 0.66 0.54, 0.81 BREO ELLIPTA 200/25 mcg 402 0.90 0.85 0.70, 1.04 Fluticasone furoate/vilanterol 50/25 mcg 408 0.92 0.87 0.72, 1.06 Vilanterol 25 mcg 409 1.05 –– –– Comparator Trials Three 12-week, randomized, double-blind, double-dummy trials were conducted with BREO ELLIPTA 100/25 mcg once daily versus fluticasone propionate/salmeterol 250/50 mcg twice daily to evaluate the efficacy of serial lung function of BREO ELLIPTA in patients with COPD. The primary endpoint of each trial was change from baseline in weighted mean FEV 1 (0 to 24 hours) on Day 84. Of the 519 patients in Trial 5 (NCT01323634), 64% were male and 97% were White; mean age was 61 years; average smoking history was 40 pack years, with 55% identified as current smokers. At screening in the treatment group using BREO ELLIPTA 100/25 mcg, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 19% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.51 (0.11), and the mean percent reversibility was 11% (range: -12% to 83%). At screening in the treatment group using fluticasone propionate/salmeterol 250/50 mcg, the mean postbronchodilator percent predicted FEV 1 was 47% (range: 14% to 71%), the mean (SD) FEV 1 /FVC ratio was 0.49 (0.10), and the mean percent reversibility was 11% (range: -13% to 50%). Of the 511 patients in Trial 6 (NCT01323621), 68% were male and 94% were White; mean age was 62 years; average smoking history was 35 pack years, with 52% identified as current smokers. At screening in the treatment group using BREO ELLIPTA 100/25 mcg, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 18% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.51 (0.10), and the mean percent reversibility was 12% (range: -56% to 77%). At screening in the treatment group using fluticasone propionate/salmeterol 250/50 mcg, the mean postbronchodilator percent predicted FEV 1 was 49% (range: 15% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.50 (0.10), and the mean percent reversibility was 12% (range: -66% to 72%). Of the 828 patients in Trial 7 (NCT01706328), 72% were male and 98% were White; mean age was 61 years; average smoking history was 38 pack years, with 60% identified as current smokers. At screening in the treatment group using BREO ELLIPTA 100/25 mcg, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 18% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.52 (0.10), and the mean percent reversibility was 12% (range: -26% to 84%). At screening in the treatment group using fluticasone propionate/salmeterol 250/50 mcg, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 16% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.51 (0.10), and the mean percent reversibility was 12% (range: -15% to 67%). In Trial 5, the mean (SE) change from baseline in weighted mean FEV 1 (0 to 24 hours) with BREO ELLIPTA 100/25 mcg was 174 (15) mL compared with 94 (16) mL with fluticasone propionate/salmeterol 250/50 mcg (treatment difference 80 mL; 95% CI: 37, 124; P <0.001). In Trials 6 and 7, the mean (SE) change from baseline in weighted mean FEV 1 (0 to 24 hours) with BREO ELLIPTA 100/25 mcg was 142 (18) mL and 168 (12) mL, respectively, compared with 114 (18) mL and 142 (12) mL, respectively, for fluticasone propionate/salmeterol 250/50 mcg (Trial 6 treatment difference 29 mL; 95% CI: -22, 80; P = 0.267; Trial 7 treatment difference 25 mL; 95% CI: -8, 59; P = 0.137). Mortality Trial A randomized, double-blind, multicenter, multinational trial (NCT01313676) prospectively evaluated the efficacy of BREO ELLIPTA 100/25 mcg compared with placebo on survival. The trial was event-driven, and patients were followed until a sufficient number of deaths occurred. In this trial, 16,568 patients aged 40 to 80 years received BREO ELLIPTA 100/25 mcg (n = 4,140), fluticasone furoate 100 mcg (n = 4,157), vilanterol 25 mcg (n = 4,140), or placebo (n = 4,131). Patients were treated for up to 4 years, with a median treatment duration of 1.5 years. Median duration of follow-up for the endpoint of survival was 1.8 years for all treatment groups. All patients had COPD with moderate airflow limitation (≥50% and ≤70% predicted FEV 1 ) and either had a history of, or were at risk of, cardiovascular disease. The primary endpoint was all-cause mortality. Secondary efficacy endpoints included the rate of decline in FEV 1 , annual rate of moderate/severe COPD exacerbations, and health-related quality of life as measured by the St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C). Survival: Survival with BREO ELLIPTA 100/25 mcg was not significantly improved compared with placebo (hazard ratio 0.88; 95% CI: 0.74, 1.04). Mortality per 100 patient-years was 3.1 for BREO ELLIPTA 100/25 mcg, 3.5 for placebo, 3.2 for fluticasone furoate, and 3.4 for vilanterol. Lung Function: A reduction of 8 mL/year was estimated on-treatment for BREO ELLIPTA 100/25 mcg compared with placebo in the rate of lung function decline as measured by FEV 1 (95% CI: 1, 15). Exacerbations: Treatment with BREO ELLIPTA 100/25 mcg reduced the on-treatment annual rate of moderate/severe exacerbations by 29% compared with placebo (95% CI: 22, 35). Treatment with BREO ELLIPTA 100/25 mcg reduced the annual rate of moderate/severe exacerbations by 19% compared with fluticasone furoate (95% CI: 12, 26) and by 21% compared with vilanterol (95% CI: 14, 28). The on-treatment annual rate of moderate/severe exacerbations was 0.25 for BREO ELLIPTA 100/25 mcg, 0.35 for placebo, 0.31 for fluticasone furoate, and 0.31 for vilanterol. Treatment with BREO ELLIPTA 100/25 mcg reduced the on-treatment annual rate of severe exacerbations (i.e., requiring hospitalization) by 27% compared with placebo (95% CI: 13, 39). Treatment with BREO ELLIPTA 100/25 mcg reduced the on-treatment annual rate of exacerbations requiring hospitalization by 11% compared with fluticasone furoate (95% CI: -6, 25) and by 9% compared with vilanterol (95% CI: -8, 24). Health-Related Quality of Life: The St. George’s Respiratory Questionnaire (SGRQ) is a disease-specific patient-reported instrument that measures symptoms, activities, and impact on daily life. The SGRQ-C, a shorter version derived from the original SGRQ, was used in this trial. Results were transformed to the SGRQ for reporting purposes. In a subset of 4,443 patients, the on-treatment SGRQ responder rates at 1 year (defined as a change in score of 4 or more as threshold) were 49% for BREO ELLIPTA 100/25 mcg, 47% for placebo, 48% for fluticasone furoate, and 48% for vilanterol (odds ratio 1.18; 95% CI: 0.97, 1.44 for BREO ELLIPTA 100/25 mcg compared with placebo). Figure 3. Day 1 Figure 3. Day 168 14.2 Asthma Adult Patients The efficacy of BREO ELLIPTA for the maintenance treatment of asthma was based on data from 4 randomized, double-blind, parallel-group clinical trials (Trial 8 [NCT01165138], Trial 9 [NCT01686633], Trial 10 [NCT01134042] and Trial 12 [NCT01086384]). While these 4 trials enrolled pediatric patients 12 to 17 years of age, these trials only support efficacy in adults [see Use in Specific Populations ( 8.4 )] . In addition, patients in these trials were treated with BREO ELLIPTA 200/25 mcg once daily by oral inhalation, which is not the approved recommended dosage for pediatric patients 12 years of age and older [see Dosage and Administration ( 2.3 )] . Trials 8, 9, and 10 were designed to evaluate the safety and efficacy of BREO ELLIPTA given once daily in patients who were not controlled on their current treatments of ICS or combination therapy consisting of an ICS plus a LABA. Trial 12 (24- to 76-week exacerbation trial) was designed to demonstrate that treatment with BREO ELLIPTA 100/25 mcg significantly decreased the risk of asthma exacerbations as measured by time to first asthma exacerbation when compared with fluticasone furoate 100 mcg. This trial enrolled patients who had 1 or more asthma exacerbations in the year prior to trial entry. The demographics of these 4 trials and the comparator trial (Trial 13, NCT01147848) are provided in Table 8 . Table 8. Demography of Asthma Trials 8, 9, 10, 12, and 13 N/A = Data not collected. a Trials did not include current smokers; past smokers had fewer than 10 packs per year history. Parameter Trial 8 n = 609 Trial 9 n = 1,039 Trial 10 n = 586 Trial 12 n = 2,019 Trial 13 n = 806 Mean age (years) (range) for all patients 40 (12, 84) 46 (12, 82) 46 (12, 76) 42 (12, 82) 43 (12, 80) Mean age (years) (range) for adult patients 44 (18, 84) 48 (18, 82) 47 (18, 76) 46 (18, 82) 46 (18, 80) Female (%) 58 60 59 67 61 White (%) 84 88 84 73 59 Duration of asthma (years) 12 18 16 16 21 Never smoked a (%) N/A 84 N/A 86 81 Predose FEV 1 (L) at baseline 2.32 1.97 2.15 2.20 2.03 Mean percent predicted FEV 1 at baseline (%) 70 62 67 72 68 % Reversibility 29 30 29 24 28 Absolute reversibility (mL) 614 563 571 500 512 Trials 8, 9, and 10 were 12- or 24-week trials that evaluated the efficacy of BREO ELLIPTA on lung function in patients with asthma. In Trial 8, patients were randomized to BREO ELLIPTA 100/25 mcg, fluticasone furoate 100 mcg, or placebo. In Trial 9, patients were randomized to BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, or fluticasone furoate 100 mcg. In Trial 10, patients were randomized to BREO ELLIPTA 200/25 mcg, fluticasone furoate 200 mcg, or fluticasone propionate 500 mcg. All inhalations were administered once daily, with the exception of fluticasone propionate, which was administered twice daily. Patients receiving an ICS or an ICS plus a LABA (doses of ICS varied by trial and asthma severity) entered a 4-week run-in period during which LABA treatment was stopped. Patients reporting symptoms and/or rescue beta 2 -agonist medication use during the run-in period were continued in the trial. In Trials 8 and 10, change from baseline in weighted mean FEV 1 (0 to 24 hours) and change from baseline in trough FEV 1 at approximately 24 hours after the last dose at study endpoint (12 and 24 weeks, respectively) were co-primary efficacy endpoints. In Trial 9, change from baseline in weighted mean FEV 1 (0 to 24 hours) at Week 12 was the primary efficacy endpoint; change from baseline in trough FEV 1 at approximately 24 hours after the last dose at Week 12 was a secondary endpoint. Table 9 provides the change from baseline in weighted mean FEV 1 in mL (0 to 24 hours) and trough FEV 1 in mL at study endpoint. Weighted mean FEV 1 (0 to 24 hours) was derived from serial measurements taken within 30 minutes prior to dosing and post-dose assessments at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours after the final dose. Other secondary endpoints included change from baseline in percentage of rescue-free 24-hour periods and percentage of symptom-free 24-hour periods over the treatment period. Table 9. Change from Baseline in Weighted Mean FEV 1 (0-24 h) (mL) and Trough FEV 1 (mL) at Study Endpoint (Trials 8, 9, and 10) a FEV 1 = Forced Expiratory Volume in 1 second, ICS = inhaled corticosteroid, LABA = long-acting beta 2 -adrenergic agonist. a Although these trials included pediatric patients 12 to 17 years of age, they only support the efficacy in adult patients. Study (Duration) Background Treatment n Weighted Mean FEV 1 (0-24 h) (mL) Treatment Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Trial 8 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA BREO ELLIPTA 100/25 mcg 108 302 (178, 426) 116 (-5, 236) –– Trial 9 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 100/25 mcg 312 –– 108 (45, 171) –– Trial 10 (24 Weeks) High-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 200/25 mcg 89 –– –– 136 (1, 270) Study (Duration) Background Treatment n Trough FEV 1 (mL) Treatment Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Trial 8 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA BREO ELLIPTA 100/25 mcg 200 172 (87, 258) 36 (-48, 120) –– Trial 9 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 100/25 mcg 334 –– 77 (16, 138) –– Trial 10 (24 Weeks) High-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 200/25 mcg 187 –– –– 193 (108, 277) In Trial 8, weighted mean FEV 1 (0 to 24 hours) was assessed in a subset of patients (n = 309). At Week 12, change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 100/25 mcg compared with placebo (302 mL; 95% CI: 178, 426; P <0.001) ( Table 9 ); change from baseline in weighted mean FEV 1 (0 to 24 hours) for BREO ELLIPTA 100/25 mcg was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (116 mL; 95% CI: -5, 236). At Week 12, change from baseline in trough FEV 1 was significantly greater for BREO ELLIPTA 100/25 mcg compared with placebo (172 mL; 95% CI: 87, 258; P <0.001) ( Table 9 ); change from baseline in trough FEV 1 for BREO ELLIPTA 100/25 mcg was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (36 mL; 95% CI: -48, 120). In Trial 9, the change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (108 mL; 95% CI: 45, 171; P <0.001) at Week 12 ( Table 9 ). In a descriptive analysis, the change from baseline in weighted mean FEV 1 (0 to 24 hours) for BREO ELLIPTA 200/25 mcg was numerically greater than BREO ELLIPTA 100/25 mcg (24 mL; 95% CI: -37, 86) at Week 12. The change from baseline in trough FEV 1 was significantly greater for BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (77 mL, 95% CI: 16, 138; P = 0.014) at Week 12 ( Table 9 ). In a descriptive analysis, the change from baseline in trough FEV 1 for BREO ELLIPTA 200/25 mcg was numerically greater than BREO ELLIPTA 100/25 mcg (16 mL; 95% CI: -46, 77) at Week 12. In Trial 10, the change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 200/25 mcg compared with fluticasone furoate 200 mcg (136 mL; 95% CI: 1, 270; P = 0.048) at Week 24 ( Table 9 ). The change from baseline in trough FEV 1 was significantly greater for BREO ELLIPTA 200/25 mcg compared with fluticasone furoate 200 mcg (193 mL, 95% CI: 108, 277; P <0.001) at Week 24. Lung function improvements were demonstrated through weighted mean FEV 1 (0 to 24 hours) over the 24-hour period following the final dose of BREO ELLIPTA in Trials 9 and 10. Serial FEV 1 measurements were taken within 30 minutes prior to dosing and postdose assessments at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours in Trials 1, 2, and 3. A representative figure is shown from Trial 9 in Figure 4 . Figure 4. Least Squares (LS) Mean Change from Baseline in Individual Serial FEV 1 (mL) Assessments over 24 Hours after 12 Weeks of Treatment (Trial 9) a a Although these trials included pediatric patients 12 to 17 years of age, the data only support the efficacy in adult patients. Patients receiving BREO ELLIPTA 100/25 mcg (Trial 9) or BREO ELLIPTA 200/25 mcg (Trial 10) had significantly greater improvements from baseline in percentage of 24-hour periods without need of beta 2 -agonist rescue medication use and percentage of 24-hour periods without asthma symptoms compared with patients receiving fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, respectively. In a descriptive analysis (Trial 9), patients receiving BREO ELLIPTA 200/25 mcg had numerical improvements from baseline in percentage of 24-hour periods without need of beta 2 -agonist rescue medication use and percentage of 24-hour periods without asthma symptoms compared with patients receiving BREO ELLIPTA 100/25 mcg. Trial 12 was a 24- to 76-week event-driven exacerbation trial that evaluated whether BREO ELLIPTA 100/25 mcg significantly decreased the risk of asthma exacerbations as measured by time to first asthma exacerbation when compared with fluticasone furoate 100 mcg in patients with asthma. Patients receiving low- to high-dose ICS (fluticasone propionate 100 mcg to 500 mcg twice daily or equivalent) or low- to mid-dose ICS plus a LABA (fluticasone propionate/salmeterol 100/50 mcg to 250/50 mcg twice daily or equivalent) and a history of 1 or more asthma exacerbations that required treatment with oral/systemic corticosteroid or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry, entered a 2-week run-in period during which LABA treatment was stopped. Patients reporting symptoms and/or rescue beta 2 -agonist medication use during the run-in period were continued in the trial. The primary endpoint was time to first asthma exacerbation. Asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroid for at least 3 days or an in‑patient hospitalization or emergency department visit due to asthma that required systemic corticosteroid. Rate of asthma exacerbation was a secondary endpoint. The hazard ratio from the Cox Model for the analysis of time to first asthma exacerbation for BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg was 0.795 (95% CI: 0.642, 0.985). This represents a 20% reduction in the risk of experiencing an asthma exacerbation for patients treated with BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg ( P = 0.036). Mean yearly rates of asthma exacerbations of 0.14 and 0.19 in patients treated with BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg, respectively, were observed (25% reduction in rate; 95% CI: 5%, 40%). Comparator Trial Trial 13 was a 24-week trial that compared the efficacy of BREO ELLIPTA 100/25 mcg once daily with fluticasone propionate/salmeterol 250/50 mcg twice daily (N = 806). Patients receiving mid-dose ICS (fluticasone propionate 250 mcg twice daily or equivalent) entered a 4-week run-in period during which all patients received fluticasone propionate 250 mcg twice daily. The primary endpoint was change from baseline in weighted mean FEV 1 (0 to 24 hours) at Week 24. The mean change (SE) from baseline in weighted mean FEV 1 (0 to 24 hours) for BREO ELLIPTA 100/25 mcg was 341 (18.4) mL compared with 377 (18.5) mL for fluticasone propionate/salmeterol 250/50 mcg (treatment difference -37 mL; 95% CI: -88, 15; P = 0.162). Pediatric Patients Aged 5 to 17 Years The efficacy of BREO ELLIPTA for the maintenance treatment of asthma in pediatric patients aged 5 to 17 years of age was based on Trial 14 (NCT03248128), a 24-week, randomized, double-blind, stratified, parallel-group clinical trial. This trial evaluated the efficacy of BREO ELLIPTA compared with fluticasone furoate in 902 pediatric patients with asthma aged 5 to 17 years who were uncontrolled on their current ICS treatment. All inhalations were administered once daily in the morning. At trial entry patients had at least a 6-month history of asthma and had been receiving stable asthma therapy for at least 4 weeks prior to screening. Patients had to have a pre-bronchodilator FEV 1 >50% to ≤100% of predicted normal and demonstrate a ≥12% reversibility of FEV 1 within 15 to 40 minutes following 2 to 4 inhalations of albuterol inhalation aerosol (or 1 nebulized treatment with albuterol solution). Exclusion criteria included a history of life-threatening asthma or any asthma exacerbation requiring the use of oral corticosteroids, systemic or depot corticosteroids, emergency department visit, or hospitalization within 6 weeks, 3 months, 3 months, or 6 months of screening, respectively. Patients entered a 4-week open-label run-in period during which all patients received fluticasone propionate 100 mcg twice daily. Patients reporting symptoms and/or rescue beta 2 -agonist medication use during the last week of the run-in period were continued in the trial and were stratified by age. Pediatric patients aged 12 to 17 years (n = 229) were randomized 1:1 to BREO ELLIPTA 100/25 mcg once daily (n = 117) or fluticasone furoate 100 mcg once daily (n = 112). Pediatric patients aged 5 to 11 years (n = 673) were randomized 1:1 to BREO ELLIPTA 50/25 mcg once daily (n = 337) or fluticasone furoate 50 mcg once daily (n = 336). The primary endpoint was weighted mean FEV 1 (0 to 4 hours) at Week 12. Of the 902 patients, the mean age was 10.0 years, 61% were male, and 73% were White, 8% African American, 6% American Indian or Alaska Native, 6% Asian, and 7% Other. Lung function improvements based on the primary endpoint of weighted mean FEV 1 (0 to 4 hours) are presented in Table 10 . Table 10. Weighted Mean FEV1 (0-4 h) (mL) at Week 12 in Patients Aged 5 to 17 Years (Intent to Treat Population) FEV 1 = Forced Expiratory Volume in 1 second, LS = Least squares, SE = standard error. Primary Endpoint Fluticasone Furoate a (N = 448) BREO ELLIPTA b (N = 454) Weighted Mean FEV 1 (0-4 h) (mL) n = 397 n = 394 LS mean 1999 2081 LS mean change (SE) 323 (16.4) 406 (16.5) Difference vs fluticasone furoate 83 (95% CI) (37, 129) a The dose of fluticasone furoate was 100 mcg once daily for pediatric patients aged 12 to 17 years and 50 mcg once daily for pediatric patients aged 5 to 11 years. b The dose of BREO ELLIPTA was 100/25 mcg once daily for pediatric patients aged 12 to 17 years and 50/25 mcg once daily for pediatric patients aged 5 to 11 years. Difference in LS mean change from baseline at Week 12 for BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg was 106 mL (95% CI: -8, 220) in pediatric patients 12 to 17 years of age, and difference in LS mean change from baseline at Week 12 for BREO ELLIPTA 50/25 mcg compared with fluticasone furoate 50 mcg was 73 mL (95% CI: 28, 118) in pediatric patients 5 to 11 years of age. Figure 4

8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of BREO ELLIPTA for COPD included 4,820 subjects aged 65 years and older and 1,118 subjects aged 75 years and older. Clinical trials of BREO ELLIPTA for asthma included 854 subjects aged 65 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.4 Pediatric Use The safety and effectiveness of BREO ELLIPTA for the maintenance treatment of asthma in pediatric patients 5 years of age and older have been established. This indication is based on Trial 14, an adequate and well-controlled trial in pediatric patients aged 5 to 17 years [see Adverse Reactions ( 6.2 ) and Clinical Studies ( 14.2 )] . The recommended dosage for pediatric patients is different than the adult dosage [see Dosage and Administration ( 2.2 )] . The safety and efficacy of BREO ELLIPTA in pediatric patients aged younger than 5 years have not been established. In Trial 12, an exacerbation trial [see Clinical Studies ( 14.2 )] , pediatric patients aged 12 to 17 years (n = 281) were treated with BREO ELLIPTA 100/25 mcg (n = 151) or treated with fluticasone furoate 100 mcg (n = 130). Among these patients, 10% of patients treated with BREO ELLIPTA 100/25 mcg reported an asthma exacerbation compared with 7% for patients treated with fluticasone furoate 100 mcg. Asthma-related hospitalizations occurred in 4 patients (2.6%) treated with BREO ELLIPTA 100/25 mcg compared with 0 patients treated with fluticasone furoate 100 mcg. Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in pediatric patients may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects of long-term treatment of pediatric patients with ICS, including fluticasone furoate, on final adult height are not known. Controlled clinical trials have shown that ICS may cause a reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids, including BREO ELLIPTA, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including BREO ELLIPTA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. A randomized, double-blind, parallel-group, multicenter, 1-year, placebo-controlled trial evaluated the effect of once-daily treatment with orally inhaled fluticasone furoate 50 mcg on growth velocity assessed by stadiometry. The patients were 457 prepubertal children (girls aged 5 to <8 years and boys aged 5 to <9 years). Mean growth velocity over the 52-week treatment period was lower in the patients receiving orally inhaled fluticasone furoate (5.905 cm/year) compared with placebo (6.065 cm/year). The mean reduction in growth velocity was 0.16 cm/year (95% CI: -0.14, 0.46) [see Warnings and Precautions ( 5.14 )] .

8.1 Pregnancy Risk Summary There are insufficient data on the use of BREO ELLIPTA or its individual components, fluticasone furoate and vilanterol, in pregnant women to inform a drug-associated risk. (See Clinical Considerations.) In an animal reproduction study, fluticasone furoate and vilanterol administered by inhalation alone or in combination to pregnant rats during the period of organogenesis produced no fetal structural abnormalities. The highest fluticasone furoate and vilanterol doses in this study were approximately 5 and 40 times the maximum recommended human daily inhalation doses (MRHDID) of 200 and 25 mcg, respectively. (See Data.) The estimated risk of major birth defects and miscarriage for the indicated populations 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 Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored, and medication adjusted as necessary to maintain optimal control of asthma. Labor or Delivery: BREO ELLIPTA should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility. Data Animal Data: Fluticasone Furoate and Vilanterol: In an embryofetal developmental study, pregnant rats received fluticasone furoate and vilanterol during the period of organogenesis at doses up to approximately 5 and 40 times the MRHDID of 200 and 25 mcg, respectively, alone or in combination (on a mcg/m 2 basis at inhalation doses up to approximately 95 mcg/kg/day). No evidence of structural abnormalities was observed. Fluticasone Furoate: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received fluticasone furoate during the period of organogenesis at doses up to approximately 4 and 1 times, respectively, the MRHDID of 200 mcg (on a mcg/m 2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day, respectively). No evidence of structural abnormalities in fetuses was observed in either species. In a perinatal and postnatal developmental study in rats, dams received fluticasone furoate during late gestation and lactation periods at doses up to approximately 1 time the MRHDID of 200 mcg (on a mcg/m 2 basis at maternal inhalation doses up to 27 mcg/kg/day). No evidence of effects on offspring development was observed. Vilanterol: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 1,000 times, respectively, the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 160 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on a mcg/m 2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects in offspring development was observed.

8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Fluticasone furoate systemic exposure may increase in patients with moderate or severe impairment. Monitor for systemic corticosteroid effects. ( 8.6 , 12.3 ) 8.1 Pregnancy Risk Summary There are insufficient data on the use of BREO ELLIPTA or its individual components, fluticasone furoate and vilanterol, in pregnant women to inform a drug-associated risk. (See Clinical Considerations.) In an animal reproduction study, fluticasone furoate and vilanterol administered by inhalation alone or in combination to pregnant rats during the period of organogenesis produced no fetal structural abnormalities. The highest fluticasone furoate and vilanterol doses in this study were approximately 5 and 40 times the maximum recommended human daily inhalation doses (MRHDID) of 200 and 25 mcg, respectively. (See Data.) The estimated risk of major birth defects and miscarriage for the indicated populations 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 Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored, and medication adjusted as necessary to maintain optimal control of asthma. Labor or Delivery: BREO ELLIPTA should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility. Data Animal Data: Fluticasone Furoate and Vilanterol: In an embryofetal developmental study, pregnant rats received fluticasone furoate and vilanterol during the period of organogenesis at doses up to approximately 5 and 40 times the MRHDID of 200 and 25 mcg, respectively, alone or in combination (on a mcg/m 2 basis at inhalation doses up to approximately 95 mcg/kg/day). No evidence of structural abnormalities was observed. Fluticasone Furoate: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received fluticasone furoate during the period of organogenesis at doses up to approximately 4 and 1 times, respectively, the MRHDID of 200 mcg (on a mcg/m 2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day, respectively). No evidence of structural abnormalities in fetuses was observed in either species. In a perinatal and postnatal developmental study in rats, dams received fluticasone furoate during late gestation and lactation periods at doses up to approximately 1 time the MRHDID of 200 mcg (on a mcg/m 2 basis at maternal inhalation doses up to 27 mcg/kg/day). No evidence of effects on offspring development was observed. Vilanterol: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 1,000 times, respectively, the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 160 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on a mcg/m 2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects in offspring development was observed. 8.2 Lactation Risk Summary There is no information available on the presence of fluticasone furoate or vilanterol in human milk, the effects on the breastfed child, or the effects on milk production. Low concentrations of other ICS have been detected in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BREO ELLIPTA and any potential adverse effects on the breastfed child from fluticasone furoate or vilanterol or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of BREO ELLIPTA for the maintenance treatment of asthma in pediatric patients 5 years of age and older have been established. This indication is based on Trial 14, an adequate and well-controlled trial in pediatric patients aged 5 to 17 years [see Adverse Reactions ( 6.2 ) and Clinical Studies ( 14.2 )] . The recommended dosage for pediatric patients is different than the adult dosage [see Dosage and Administration ( 2.2 )] . The safety and efficacy of BREO ELLIPTA in pediatric patients aged younger than 5 years have not been established. In Trial 12, an exacerbation trial [see Clinical Studies ( 14.2 )] , pediatric patients aged 12 to 17 years (n = 281) were treated with BREO ELLIPTA 100/25 mcg (n = 151) or treated with fluticasone furoate 100 mcg (n = 130). Among these patients, 10% of patients treated with BREO ELLIPTA 100/25 mcg reported an asthma exacerbation compared with 7% for patients treated with fluticasone furoate 100 mcg. Asthma-related hospitalizations occurred in 4 patients (2.6%) treated with BREO ELLIPTA 100/25 mcg compared with 0 patients treated with fluticasone furoate 100 mcg. Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. A reduction of growth velocity in pediatric patients may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects of long-term treatment of pediatric patients with ICS, including fluticasone furoate, on final adult height are not known. Controlled clinical trials have shown that ICS may cause a reduction in growth in children. In these trials, the mean reduction in growth velocity was approximately 1 cm/year (range: 0.3 to 1.8 cm/year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving orally inhaled corticosteroids, including BREO ELLIPTA, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including BREO ELLIPTA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms. A randomized, double-blind, parallel-group, multicenter, 1-year, placebo-controlled trial evaluated the effect of once-daily treatment with orally inhaled fluticasone furoate 50 mcg on growth velocity assessed by stadiometry. The patients were 457 prepubertal children (girls aged 5 to <8 years and boys aged 5 to <9 years). Mean growth velocity over the 52-week treatment period was lower in the patients receiving orally inhaled fluticasone furoate (5.905 cm/year) compared with placebo (6.065 cm/year). The mean reduction in growth velocity was 0.16 cm/year (95% CI: -0.14, 0.46) [see Warnings and Precautions ( 5.14 )] . 8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of BREO ELLIPTA for COPD included 4,820 subjects aged 65 years and older and 1,118 subjects aged 75 years and older. Clinical trials of BREO ELLIPTA for asthma included 854 subjects aged 65 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. 8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in adult patients with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects. The effect of hepatic impairment on fluticasone furoate and vilanterol systemic exposure in patients aged younger than 18 years has not been evaluated [see Clinical Pharmacology ( 12.3 )] . 8.7 Renal Impairment There were no significant increases in either fluticasone furoate or vilanterol exposure in patients with severe renal impairment (CrCl <30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING BREO ELLIPTA is supplied as a disposable light grey and pale blue plastic inhaler containing 2 foil strips, each with 30 blisters (or 14 blisters for the institutional pack). One strip contains fluticasone furoate (50, 100 or 200 mcg per blister), and the other strip contains vilanterol (25 mcg per blister). A blister from each strip is used to create 1 dose. The inhaler is packaged within a moisture-protective foil tray with a desiccant and a peelable lid in the following packs: NDC 0173-0916-10 BREO ELLIPTA 50/25 mcg 30 inhalations (60 blisters) NDC 0173-0859-10 BREO ELLIPTA 100/25 mcg 30 inhalations (60 blisters) NDC 0173-0859-14 BREO ELLIPTA 100/25 mcg 14 inhalations (28 blisters), institutional pack NDC 0173-0882-10 BREO ELLIPTA 200/25 mcg 30 inhalations (60 blisters) NDC 0173-0882-14 BREO ELLIPTA 200/25 mcg 14 inhalations (28 blisters), institutional pack 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 in a dry place away from direct heat or sunlight. Keep out of reach of children. BREO ELLIPTA should be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. Discard BREO ELLIPTA 6 weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.