Fluticasone Furoate and Vilanterol

6 ADVERSE REACTIONS Use of LABA may result in the following: • Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )] • Cardiovascular effects [see Warnings and Precautions ( 5.12 )] Systemic and local corticosteroid use may result in the following: • Candida albicans infection [see Warnings and Precautions ( 5.4 )] • Increased risk of pneumonia in COPD [see Warnings and Precautions ( 5.5 )] • Immunosuppression [see Warnings and Precautions ( 5.6 )] • Hypercorticism and adrenal suppression [see Warnings and Precautions ( 5.8 )] • Reduction in bone mineral density [see Warnings and Precautions ( 5.13 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. • COPD: Most common adverse reactions (incidence ≥3%) are nasopharyngitis, upper respiratory tract infection, headache, oral candidiasis, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, and pyrexia. ( 6.1 ) • Asthma: Most common adverse reactions (incidence ≥2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease The clinical program for fluticasone furoate/vilanterol ELLIPTA included more than 24,000 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, 1 mortality trial, and 6 other trials of shorter duration. A total of 6,174 subjects with COPD received at least 1 dose of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, and 1,087 subjects received a higher strength of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6- and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials. 6-Month Trials The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in Table 2 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 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%). Subjects received 1 inhalation once daily of the following: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50 /25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo. Table 2. Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg with ≥3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis. Adverse Reaction Fluticasone Furoate/ Vilanterol ELLIPTA 100/25 mcg (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % Infections and infestations Nasopharyngitis 9 10 8 8 Upper respiratory tract infection 7 5 4 3 Oropharyngeal candidiasis a 5 2 3 2 Nervous system disorders Headache 7 9 7 5 12-Month Trials Long-term safety data are based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, 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 subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 2 , adverse reactions occurring in ≥3% of the subjects treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions ( 5.5 )] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia. Mortality Trial Safety data are available from a mortality trial in subjects 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 subjects, 4,140 of whom received fluticasone furoate/vilanterol ELLIPTA 100/25 mcg. In addition to the events in COPD trials shown in Table 2 , adverse reactions occurring in ≥3% of the subjects treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg and more common than placebo included pneumonia, back pain, hypertension, and influenza. 6.2 Clinical Trials Experience in Asthma Fluticasone furoate/vilanterol ELLIPTA for the treatment of asthma was studied in 18 double-blind, parallel-group, controlled trials (11 with placebo) of 4 to 76 weeks’ duration, which enrolled 9,969 subjects with asthma. Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg was studied in 2,369 subjects and fluticasone furoate/vilanterol ELLIPTA 200/25 mcg was studied in 956 subjects. While subjects aged 12 to 17 years were included in these trials, fluticasone furoate/vilanterol ELLIPTA is not approved for use in this age group [see Use in Specific Populations ( 8.4 )] . The safety data described below are based on two 12-week efficacy trials, one 24-week efficacy trial, and 2 long-term trials. 12-Week Trials Trial 1 was a 12-week trial that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg in adult and adolescent subjects with asthma compared with fluticasone furoate 100 mcg and placebo. Of the 609 subjects, 58% were female and 84% were white; the mean age was 40 years. The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg is shown in Table 3 . Table 3. Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg with ≥2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1) a Includes oral candidiasis and oropharyngeal candidiasis. Adverse Reaction Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % Infections and infestations Nasopharyngitis 10 7 7 Oral candidiasis a 2 2 0 Nervous system disorders Headache 5 4 4 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 2 2 1 Dysphonia 2 1 0 Trial 2 was a 12-week trial that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, and fluticasone furoate 100 mcg in adult and adolescent subjects with asthma. This trial did not have a placebo arm. Of the 1,039 subjects, 60% were female and 88% were white; the mean age was 46 years. The incidence of adverse reactions associated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg and fluticasone furoate/vilanterol ELLIPTA 200/25 mcg is shown in Table 4 . Table 4. Adverse Reactions with Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg and Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg with ≥2% Incidence in Subjects with Asthma (Trial 2) Adverse Reaction Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg (n = 346) % Fluticasone Furoate/Vilanterol 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 3 was a 24-week trial that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA 200/25 mcg once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in adult and adolescent subjects with asthma. Of the 586 subjects, 59% were female and 84% were white; the mean age was 46 years. 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 subjects treated with fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg once daily (n = 201), fluticasone furoate/vilanterol ELLIPTA 200/25 mcg once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in adult and adolescent subjects with asthma (Trial 4). Overall, 63% were female and 67% were white. The mean age was 39 years; adolescents (aged 12 to 17 years) made up 16% of the population. In addition to the reactions shown in Tables 3 and 4 , adverse reactions occurring in ≥2% of the subjects treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg or fluticasone furoate/vilanterol 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. Exacerbation Trial In a 24- to 76-week trial, subjects received fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010) (Trial 5). Subjects 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. Overall, 67% were female and 73% were white; the mean age was 42 years (adolescents aged 12 to 17 years made up 14% of the population). While subjects aged 12 to 17 years were included in this trial, fluticasone furoate/vilanterol ELLIPTA is not approved for use in this age group [see Use in Specific Populations ( 8.4 )] . Asthma-related hospitalizations occurred in 10 subjects (1%) treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with 7 subjects (0.7%) treated with fluticasone furoate 100 mcg. Among subjects aged 12 to 17 years, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 151) compared with 0 subjects treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial. 6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 The use of Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg and Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg are inhalation powders for oral inhalation that contain a combination of fluticasone furoate (an ICS) and vilanterol (a LABA). One active component of Fluticasone Furoate/Vilanterol ELLIPTA is fluticasone furoate, a synthetic trifluorinated corticosteroid having 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. The other active component of Fluticasone Furoate/Vilanterol ELLIPTA is vilanterol trifenatate, a LABA with 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. Fluticasone Furoate/Vilanterol ELLIPTA is a light grey and pale blue plastic inhaler containing 2 foil blister strips. Each blister on one strip contains a white powder mix of micronized fluticasone furoate (100 or 200 mcg) and lactose monohydrate (12.4 or 12.3 mg), and each blister on the other strip contains a white powder mix 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, fluticasone furoate/vilanterol ELLIPTA delivers 92 and 184 mcg of fluticasone furoate and 22 mcg of vilanterol per blister when tested at a flow rate of 60 L/min for 4 seconds. In adult subjects 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 subjects with severe asthma, mean peak inspiratory flow through the ELLIPTA inhaler was 96.6 L/min (range: 72.4 to 124.6 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 chemical structure

2 DOSAGE AND ADMINISTRATION Fluticasone Furoate/Vilanterol ELLIPTA should be administered as 1 inhalation once daily by the orally inhaled route only. Fluticasone Furoate/Vilanterol ELLIPTA should be used at the same time every day. Do not use Fluticasone Furoate/Vilanterol ELLIPTA more than 1 time every 24 hours. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis. More frequent administration or a greater number of inhalations (more than 1 inhalation daily) of the prescribed strength of Fluticasone Furoate/Vilanterol ELLIPTA is not recommended as some patients are more likely to experience adverse effects with higher doses. Patients using Fluticasone Furoate/Vilanterol ELLIPTA should not use additional LABA for any reason. [See Warnings and Precautions ( 5.3 , 5.5 , 5.8 , 5.12 ).] • For oral inhalation only. ( 2 ) • Maintenance treatment of COPD: 1 inhalation of Fluticasone Furoate/Vilanterol ELLIPTA inhalation powder 100/25 mcg once daily. ( 2.1 ) • Asthma: 1 inhalation of Fluticasone Furoate/Vilanterol ELLIPTA inhalation powder 100/25 mcg or Fluticasone Furoate/Vilanterol ELLIPTA inhalation powder 200/25 mcg once daily. ( 2.2 ) 2.1 Chronic Obstructive Pulmonary Disease Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg should be administered as 1 inhalation once daily. The maximum recommended dosage is 1 inhalation of Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg once daily, the only strength indicated for the treatment of COPD. If shortness of breath occurs in the period between doses, an inhaled, short-acting beta 2 -agonist (rescue medicine, e.g., albuterol) should be taken for immediate relief. 2.2 Asthma The recommended starting dosage is Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg or Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg administered as 1 inhalation once daily. When choosing the starting dosage strength of Fluticasone Furoate/Vilanterol ELLIPTA, consider the patients’ disease severity, based on their previous asthma therapy, including the ICS dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation. The maximum recommended dosage is 1 inhalation of Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg once daily. The median time to onset, defined as a 100-mL increase from baseline in mean forced expiratory volume in 1 second (FEV 1 ), was approximately 15 minutes after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately to Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg, increasing the dose to Fluticasone Furoate/Vilanterol ELLIPTA 200/25 mcg may provide additional improvement in asthma control. If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist (rescue medicine, e.g., albuterol) should be taken for immediate relief. If a previously effective dosage regimen of Fluticasone Furoate/Vilanterol ELLIPTA fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of Fluticasone Furoate/Vilanterol ELLIPTA with a higher strength, adding additional ICS, initiating oral corticosteroids) should be considered.

1 INDICATIONS AND USAGE Fluticasone Furoate/Vilanterol ELLIPTA is a combination of fluticasone furoate, an inhaled corticosteroid (ICS), and vilanterol, a long‑acting beta 2 -adrenergic agonist (LABA), indicated for: • Long-term, once-daily, maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD). ( 1.1 ) • Once-daily treatment of asthma in patients aged 18 years and older. ( 1.2 ) Important limitation of use: Not indicated for relief of acute bronchospasm. ( 1.1 , 1.2 , 5.2 ) 1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg is indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Fluticasone Furoate/Vilanterol ELLIPTA 100/25 mcg once daily is the only strength indicated for the treatment of COPD. Important Limitation of Use Fluticasone Furoate/Vilanterol ELLIPTA is NOT indicated for the relief of acute bronchospasm 1.2 Treatment of Asthma Fluticasone Furoate/Vilanterol ELLIPTA is indicated for the once-daily treatment of asthma in patients aged 18 years and older. Fluticasone Furoate/Vilanterol ELLIPTA should be used for patients not adequately controlled on a long-term asthma control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta 2 -adrenergic agonist (LABA). Important Limitation of Use Fluticasone Furoate/Vilanterol ELLIPTA is NOT indicated for the relief of acute bronchospasm.

10 OVERDOSAGE No human overdosage data has been reported for fluticasone furoate/vilanterol ELLIPTA. Fluticasone Furoate/Vilanterol ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to Fluticasone Furoate/Vilanterol ELLIPTA. Treatment of overdosage consists of discontinuation of Fluticasone Furoate/Vilanterol 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. 10.1 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 )] . Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days. 10.2 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 vascular system. ( 7.2 ) • Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 ) • Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.4 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol, the individual components of Fluticasone Furoate/Vilanterol ELLIPTA, are both substrates of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of Fluticasone Furoate/Vilanterol ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.3 )] . 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants 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, a component of Fluticasone Furoate/Vilanterol ELLIPTA, 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 Fluticasone Furoate/Vilanterol ELLIPTA Since Fluticasone Furoate/Vilanterol ELLIPTA contains both fluticasone furoate and vilanterol, the mechanisms of action described below for the individual components apply to Fluticasone Furoate/Vilanterol ELLIPTA. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have 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 -adrenoceptor 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 mcg/25 mcg and fluticasone furoate/vilanterol 800 mcg/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 mcg/25 mcg and fluticasone furoate/vilanterol 800 mcg/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. Subjects with Chronic Obstructive Pulmonary Disease: In a trial with subjects with COPD, treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg, vilanterol 25 mcg, and fluticasone furoate (100 or 200 mcg) for 6 months did not affect 24-hour urinary cortisol excretion. A separate trial with subjects with COPD demonstrated no effects on serum cortisol after 28 days of treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg. Subjects with Asthma: A randomized, double-blind, parallel-group trial in 185 subjects with asthma showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100 mcg/25 mcg or fluticasone furoate/vilanterol 200 mcg/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 administrated 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 subjects 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 administrated 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 subjects with COPD was 24% higher than observed in healthy subjects. Systemic exposure (AUC) in subjects 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 (99.6%). 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 93.9%. 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. Elimination 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% of the recovered radioactive dose, respectively). The plasma elimination half-life of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in subjects with COPD and 16.0 hours in subjects with asthma. Specific Populations The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate and vilanterol is 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 Racial or Ethnic Groups: 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 subjects 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. There was no effect of race on the pharmacokinetics of vilanterol in subjects with COPD. In subjects with asthma, vilanterol C max is estimated to be higher (3-fold) and AUC (0-24) comparable for those subjects from an Asian heritage compared with subjects 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 mcg/25 mcg (100 mcg/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 subjects with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects ( Figure 1 ). In subjects with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200 mcg/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (90% CI: 11%, 51%) compared with healthy subjects. In subjects with severe hepatic impairment receiving fluticasone furoate/vilanterol 100 mcg/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 mcg/25 mcg (100 mcg/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 subjects 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 subjects 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 subjects 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 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 potent P-gp inhibitor and moderate CYP3A4 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 Figure 2

12.1 Mechanism of Action Fluticasone Furoate/Vilanterol ELLIPTA Since Fluticasone Furoate/Vilanterol ELLIPTA contains both fluticasone furoate and vilanterol, the mechanisms of action described below for the individual components apply to Fluticasone Furoate/Vilanterol ELLIPTA. These drugs represent 2 different classes of medications (a synthetic corticosteroid and a LABA) that have 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 -adrenoceptor 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 mcg/25 mcg and fluticasone furoate/vilanterol 800 mcg/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 mcg/25 mcg and fluticasone furoate/vilanterol 800 mcg/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. Subjects with Chronic Obstructive Pulmonary Disease: In a trial with subjects with COPD, treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg, vilanterol 25 mcg, and fluticasone furoate (100 or 200 mcg) for 6 months did not affect 24-hour urinary cortisol excretion. A separate trial with subjects with COPD demonstrated no effects on serum cortisol after 28 days of treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg. Subjects with Asthma: A randomized, double-blind, parallel-group trial in 185 subjects with asthma showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100 mcg/25 mcg or fluticasone furoate/vilanterol 200 mcg/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 administrated 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 subjects 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 administrated 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 subjects with COPD was 24% higher than observed in healthy subjects. Systemic exposure (AUC) in subjects 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 (99.6%). 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 93.9%. 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. Elimination 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% of the recovered radioactive dose, respectively). The plasma elimination half-life of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in subjects with COPD and 16.0 hours in subjects with asthma. Specific Populations The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate and vilanterol is 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 Racial or Ethnic Groups: 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 subjects 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. There was no effect of race on the pharmacokinetics of vilanterol in subjects with COPD. In subjects with asthma, vilanterol C max is estimated to be higher (3-fold) and AUC (0-24) comparable for those subjects from an Asian heritage compared with subjects 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 mcg/25 mcg (100 mcg/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 subjects with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects ( Figure 1 ). In subjects with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200 mcg/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (90% CI: 11%, 51%) compared with healthy subjects. In subjects with severe hepatic impairment receiving fluticasone furoate/vilanterol 100 mcg/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 mcg/25 mcg (100 mcg/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 subjects 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 subjects 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 subjects 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 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 potent P-gp inhibitor and moderate CYP3A4 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 Figure 2

20220224

3

3 DOSAGE FORMS AND STRENGTHS Inhalation powder: Disposable light grey and pale blue plastic inhaler containing 2 foil blister strips of powder intended for oral inhalation only. One strip contains fluticasone furoate (100 or 200 mcg per blister), and the other strip contains vilanterol (25 mcg per blister). Inhalation powder: Inhaler containing 2 foil blister strips of powder formulation for oral inhalation. One strip contains fluticasone furoate 100 or 200 mcg per blister and the other contains vilanterol 25 mcg per blister. ( 3 )

Fluticasone Furoate and Vilanterol fluticasone furoate and vilanterol FLUTICASONE FUROATE FLUTICASONE VILANTEROL TRIFENATATE VILANTEROL LACTOSE MONOHYDRATE MAGNESIUM STEARATE Fluticasone Furoate and Vilanterol fluticasone furoate and vilanterol FLUTICASONE FUROATE FLUTICASONE VILANTEROL TRIFENATATE VILANTEROL LACTOSE MONOHYDRATE MAGNESIUM STEARATE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fluticasone Furoate/Vilanterol ELLIPTA No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with fluticasone furoate/vilanterol 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 (approximately 0.5 times the MRHDID in adults 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 based on AUC) [see Use in Specific Populations ( 8.1 )] . Vilanterol In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/day (approximately 530 times the MRHDID in adults 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 inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults 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 (approximately 5,490 times the MRHDID based on AUC).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fluticasone Furoate/Vilanterol ELLIPTA No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with fluticasone furoate/vilanterol 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 (approximately 0.5 times the MRHDID in adults 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 based on AUC) [see Use in Specific Populations ( 8.1 )] . Vilanterol In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/day (approximately 530 times the MRHDID in adults 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 inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults 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 (approximately 5,490 times the MRHDID based on AUC).

NDA204275

Fluticasone Furoate and Vilanterol

fluticasone furoate and vilanterol

66993-135

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

Principal Display Panel NDC 66993-135-97 Fluticasone Furoate/Vilanterol ELLIPTA Inhalation Powder 100 mcg/25 mcg PRASCO FOR ORAL INHALATION ONLY Fluticasone Furoate/Vilanterol ELLIPTA Inhalation Powder contains 2 foil strips of 30 blisters each. Each blister on one strip contains 100 mcg of fluticasone furoate and lactose monohydrate. Each blister on the other strip contains 25 mcg of vilanterol, magnesium stearate, and lactose monohydrate. Rx Only 1 ELLIPTA Inhaler containing 30 doses (60 blisters total) 62000000074871 Fluticasone Furoate-Vilanterol Ellipta 100 mcg-25mcg carton

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 Fluticasone Furoate/Vilanterol ELLIPTA, there is not a significant increase in the risk of these events. Not for Acute Symptoms Inform patients that Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation. Do Not Use Additional Long-acting Beta 2 -agonists Instruct patients not to use other LABA for COPD and asthma. Local Effects Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with Fluticasone Furoate/Vilanterol ELLIPTA, but at times therapy with Fluticasone Furoate/Vilanterol 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. Pneumonia Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia. Immunosuppression Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Hypercorticism and Adrenal Suppression Advise patients that Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol ELLIPTA. 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. 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. 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. Hypersensitivity Reactions, Including Anaphylaxis Advise patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, rash, urticaria) may occur after administration of Fluticasone Furoate/Vilanterol ELLIPTA. Instruct patients to discontinue Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol ELLIPTA. ELLIPTA is a registered trademark of the GSK group of companies. Manufactured for: Prasco Laboratories Mason, OH 45040 USA Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709 BRE-PS:1PI

14 CLINICAL STUDIES 14.1 Chronic Obstructive Pulmonary Disease The safety and efficacy of fluticasone furoate/vilanterol ELLIPTA were evaluated in more than 24,000 subjects with COPD. The development program included 4 confirmatory trials of 6 and 12 months’ duration, three 12-week active comparator trials with fluticasone propionate/salmeterol 250/50 mcg, 1 long-term trial, and dose-ranging trials of shorter duration. The efficacy of fluticasone furoate/vilanterol ELLIPTA is based primarily on the dose-ranging trials and the 4 confirmatory trials described below. Dose Selection for Vilanterol Dose selection for vilanterol in COPD was supported by a 28-day, randomized, double-blind, placebo-controlled, parallel-group trial evaluating 5 doses of vilanterol (3 to 50 mcg) or placebo dosed in the morning in 602 subjects with COPD. Results demonstrated dose-related increases from baseline in FEV 1 at Day 1 and Day 28 ( Figure 3 ). Figure 3. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV 1 (0-24 h) (mL) on Days 1 and 28 Day 1 Day 28 The differences in trough FEV 1 on Day 28 from placebo for the 3-, 6.25-, 12.5-, 25-, and 50-mcg doses were 92 mL (95% CI: 39, 144), 98 mL (95% CI: 46, 150), 110 mL (95% CI: 57, 162), 137 mL (95% CI: 85, 190), and 165 mL (95% CI: 112, 217), respectively. These results supported the evaluation of vilanterol 25 mcg once daily in the confirmatory trials for COPD. Dose Selection for Fluticasone Furoate Dose selection of fluticasone furoate for Phase 3 trials in subjects with COPD was based on dose-ranging trials conducted in subjects with asthma; these trials are described in detail below [see Clinical Studies ( 14.2 )] . Confirmatory Trials The 4 confirmatory trials evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA on lung function (Trials 1 and 2) and exacerbations (Trials 3 and 4). Lung Function: Trials 1 and 2 were 24-week, randomized, double-blind, placebo-controlled trials designed to evaluate the efficacy of fluticasone furoate/vilanterol ELLIPTA on lung function in subjects with COPD. In Trial 1, subjects were randomized to fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, and placebo. In Trial 2, subjects were randomized to fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA. The trough FEV 1 comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to fluticasone furoate/vilanterol ELLIPTA. Fluticasone furoate/vilanterol 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 5 ). Table 5. Least Squares Mean Change from Baseline in Weighted Mean FEV 1 (0-4 h) and Trough FEV 1 at 6 Months 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 Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg 204 214 (161, 266) 168 (116, 220) –– 144 (91, 197) 45 (-8, 97) Fluticasone furoate/vilanterol ELLIPTA 200/25 mcg 205 209 (157, 261) –– 168 (117, 219) 131 (80, 183) 32 (-19, 83) Trial 2 Fluticasone furoate/vilanterol 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 4 . Similar results were seen in Trial 2 (not shown). Figure 4. 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 5 ). The comparison of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg with vilanterol did not achieve statistical significance ( Table 5 ). 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 fluticasone furoate/vilanterol 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 subjects receiving fluticasone furoate/vilanterol ELLIPTA 100/25 mcg. Exacerbations: Trials 3 and 4 were randomized, double-blind, 52-week trials designed to evaluate the effect of fluticasone furoate/vilanterol ELLIPTA on the rate of moderate and severe COPD exacerbations. All subjects 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: fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 subjects, 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 subject population had moderate to very severely impaired airflow obstruction. The mean percent reversibility was 15% (range: -65% to 313%). Subjects treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg had a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol in both trials ( Table 6 ). Table 6. Moderate and Severe Chronic Obstructive Pulmonary Disease Exacerbations Treatment n Mean Annual Rate (exacerbations/year) Ratio vs. Vilanterol 95% CI Trial 3 Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg 403 0.90 0.79 0.64, 0.97 Fluticasone furoate/vilanterol 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 Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg 403 0.70 0.66 0.54, 0.81 Fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg once daily versus fluticasone propionate/salmeterol 250/50 mcg twice daily to evaluate the efficacy of serial lung function of fluticasone furoate/vilanterol ELLIPTA in subjects with COPD. The primary endpoint of each study was change from baseline in weighted mean FEV 1 (0 to 24 hours) on Day 84. Of the 519 patients in Trial 5, 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 fluticasone furoate/vilanterol ELLIPTA 100/25mcg, 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, 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 fluticasone furoate/vilanterol 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, 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 prospectively evaluated the efficacy of fluticasone furoate/vilanterol 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 subjects aged 40 to 80 years received fluticasone furoate/vilanterol 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). Subjects 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 subjects 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, 0.35 for placebo, 0.31 for fluticasone furoate, and 0.31 for vilanterol. Treatment with fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol 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 subjects, the on-treatment SGRQ responder rates at 1 year (defined as a change in score of 4 or more as threshold) were 49% for fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with placebo). Figure 3 Figure 3 Figure 4 Day 1 Figure 4 Day 168 14.2 Asthma The safety and efficacy of fluticasone furoate/vilanterol ELLIPTA were evaluated in 9,969 subjects with asthma. The development program included 4 confirmatory trials (2 of 12 weeks’ duration, 1 of 24 weeks’ duration, 1 exacerbation trial of 24 to 76 weeks’ duration), one 24-week active comparator trial with fluticasone propionate/salmeterol 250/50 mcg, and dose‑ranging trials of shorter duration. The efficacy of fluticasone furoate/vilanterol ELLIPTA is based primarily on the dose-ranging trials and the 4 confirmatory trials described below. Dose Selection for Vilanterol Dose selection for vilanterol in asthma was supported by a 28-day, randomized, double-blind, placebo-controlled, parallel-group trial evaluating 5 doses of vilanterol (3 to 50 mcg) or placebo dosed in the evening in 607 subjects with asthma. Results demonstrated dose-related increases from baseline in FEV 1 at Day 1 and Day 28 ( Figure 5 ). Figure 5. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV 1 (0-24 h) (mL) on Days 1 and 28 Day 1 Day 28 The differences in trough FEV 1 on Day 28 from placebo for the 3-, 6.25-, 12.5-, 25-, and 50-mcg doses were 64 mL (95% CI: -36, 164), 69 mL (95% CI: -29, 168), 130 mL (95% CI: 30, 230), 121 mL (95% CI: 23, 220), and 162 mL (95% CI: 62, 261), respectively. These results and results of the secondary endpoints supported the evaluation of vilanterol 25 mcg once daily in the confirmatory trials for asthma. Dose Selection for Fluticasone Furoate Eight doses of fluticasone furoate ranging from 25 to 800 mcg once daily were evaluated in 3 randomized, double-blind, placebo-controlled, 8-week trials in subjects with asthma. A dose‑related increase in trough FEV 1 at Week 8 was seen for doses from 25 to 200 mcg with no consistent additional benefit for doses above 200 mcg. To evaluate dosing frequency, a separate trial compared fluticasone furoate 200 mcg once daily and fluticasone furoate 100 mcg twice daily. The results supported the selection of the once-daily dosing frequency ( Figure 6 ). Figure 6. Fluticasone Furoate Dose-Ranging and Dose-Frequency Trials Confirmatory Trials The efficacy of fluticasone furoate/vilanterol ELLIPTA was evaluated in 4 randomized, double‑blind, parallel-group clinical trials in adult and adolescent subjects with asthma. Three (3) trials were designed to evaluate the safety and efficacy of fluticasone furoate/vilanterol ELLIPTA given once daily in subjects who were not controlled on their current treatments of ICS or combination therapy consisting of an ICS plus a LABA (Trials 1, 2, and 3). A 24- to 76‑week exacerbation trial was designed to demonstrate that treatment with fluticasone furoate/vilanterol 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 (Trial 5). This trial enrolled subjects 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 6) are provided in Table 7 . While subjects aged 12 to 17 years were included in these trials, fluticasone furoate/vilanterol ELLIPTA is not approved for use in this age group [see Indications ( 1.2 ), Adverse Reactions ( 6.2 ), Use in Specific Populations ( 8.4 )] . Table 7. Demography of Asthma Trials 1, 2, 3, 5, and 6 N/A = Data not collected. a Trials did not include current smokers; past smokers had fewer than 10 packs per year history. Parameter Trial 1 n = 609 Trial 2 n = 1,039 Trial 3 n = 586 Trial 5 n = 2,019 Trial 6 n = 806 Mean age (years) (range) 40 (12, 84) 46 (12, 82) 46 (12, 76) 42 (12, 82) 43 (12, 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 1, 2, and 3 were 12- or 24-week trials that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA on lung function in subjects with asthma. In Trial 1, subjects were randomized to fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate 100 mcg, or placebo. In Trial 2, subjects were randomized to fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, or fluticasone furoate 100 mcg. In Trial 3, subjects were randomized to fluticasone furoate/vilanterol 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. Subjects 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. Subjects reporting symptoms and/or rescue beta 2 ‑agonist medication use during the run‑in period were continued in the trial. In Trials 1 and 3, 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 2, 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. (See Table 8 .) Weighted mean FEV 1 (0 to 24 hours) was derived from serial measurements 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 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 8. Change from Baseline in Weighted Mean FEV 1 (0-24 h) (mL) and Trough FEV 1 (mL) at Study Endpoint (Trials 1, 2, and 3) ICS = inhaled corticosteroid, LABA = long-acting beta 2 -adrenergic agonist. Study (Duration) Background Treatment n Weighted Mean FEV 1 (0-24 h) (mL) Difference from Treatment Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Trial 1 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg 108 302 (178, 426) 116 (-5, 236) –– Trial 2 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg 312 –– 108 (45, 171) –– Trial 3 (24 Weeks) High-dose ICS or mid-dose ICS + LABA Fluticasone furoate/vilanterol ELLIPTA 200/25 mcg 89 –– –– 136 (1, 270) Study (Duration) Background Treatment n Trough FEV 1 (mL) Difference from Treatment Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Trial 1 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg 200 172 (87, 258) 36 (-48, 120) –– Trial 2 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg 334 –– 77 (16, 138) –– Trial 3 (24 Weeks) High-dose ICS or mid-dose ICS + LABA Fluticasone furoate/vilanterol ELLIPTA 200/25 mcg 187 –– –– 193 (108, 277) In Trial 1, weighted mean FEV 1 (0 to 24 hours) was assessed in a subset of subjects (n = 309). At Week 12, change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with placebo (302 mL; 95% CI: 178, 426; P <0.001) ( Table 8 ); change from baseline in weighted mean FEV 1 (0 to 24 hours) for fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with placebo (172 mL; 95% CI: 87, 258; P <0.001) ( Table 8 ); change from baseline in trough FEV 1 for fluticasone furoate/vilanterol ELLIPTA 100/25 mcg was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (36 mL; 95% CI: -48, 120). In Trial 2, the change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (108 mL; 95% CI: 45, 171; P <0.001) at Week 12 ( Table 8 ). In a descriptive analysis, the change from baseline in weighted mean FEV 1 (0 to 24 hours) for fluticasone furoate/vilanterol ELLIPTA 200/25 mcg was numerically greater than fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (77 mL, 95% CI: 16, 138; P = 0.014) at Week 12 ( Table 8 ). In a descriptive analysis, the change from baseline in trough FEV 1 for fluticasone furoate/vilanterol ELLIPTA 200/25 mcg was numerically greater than fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (16 mL; 95% CI: -46, 77) at Week 12. In Trial 3, the change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for fluticasone furoate/vilanterol ELLIPTA 200/25 mcg compared with fluticasone furoate 200 mcg (136 mL; 95% CI: 1, 270; P = 0.048) at Week 24 ( Table 8 ). The change from baseline in trough FEV 1 was significantly greater for fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA in Trials 2 and 3. 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 2 in Figure 7 . Figure 7. Least Squares (LS) Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments over 24 Hours after 12 Weeks of Treatment (Trial 2) Subjects receiving fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (Trial 2) or fluticasone furoate/vilanterol ELLIPTA 200/25 mcg (Trial 3) 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 subjects receiving fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, respectively. In a descriptive analysis (Trial 2), subjects receiving fluticasone furoate/vilanterol 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 subjects receiving fluticasone furoate/vilanterol ELLIPTA 100/25 mcg. Trial 5 was a 24- to 76-week event-driven exacerbation trial that evaluated whether fluticasone furoate/vilanterol 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 subjects with asthma. Subjects 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. Subjects 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 fluticasone furoate/vilanterol 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 subjects treated with fluticasone furoate/vilanterol 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 subjects treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg, respectively, were observed (25% reduction in rate; 95% CI: 5%, 40%). Comparator Trial Trial 6 was a 24-week trial that compared the efficacy of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg once daily with fluticasone propionate/salmeterol 250/50 mcg twice daily (N = 806). Subjects receiving mid-dose ICS (fluticasone propionate 250 mcg twice daily or equivalent) entered a 4‑week run-in period during which all subjects 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 fluticasone furoate/vilanterol 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). Figure 5 Day 1 Figure 5 Day 28 Figure 6 Figure 7

8.5 Geriatric Use Based on available data, no adjustment of the dosage of Fluticasone Furoate/Vilanterol ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of fluticasone furoate/vilanterol ELLIPTA for COPD included 4,820 subjects aged 65 and older and 1,118 subjects aged 75 and older. Clinical trials of fluticasone furoate/vilanterol 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 subjects.

8.4 Pediatric Use Fluticasone Furoate/Vilanterol ELLIPTA is not indicated for use in children and adolescents. The safety and efficacy in pediatric patients (aged 17 years and younger) have not been established. In a 24- to 76-week exacerbation trial, subjects received fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010). Subjects had a mean age of 42 years and 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 study entry. [See Clinical Studies ( 14.2 ).] Adolescents aged 12 to 17 years made up 14% of the study population (n = 281), with a mean exposure of 352 days for subjects in this age group treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 151) and 355 days for subjects in this age group treated with fluticasone furoate 100 mcg (n = 130). In this age group, 10% of subjects treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg reported an asthma exacerbation compared with 7% for subjects treated with fluticasone furoate 100 mcg. Among the adolescents, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with 0 subjects treated with fluticasone furoate 100 mcg. There were no asthma‑related deaths or asthma-related intubations observed in the adolescent age group. Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. A reduction of growth velocity in children and adolescents may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects of long-term treatment of children and adolescents 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 children and adolescents receiving orally inhaled corticosteroids, including Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol 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 110 mcg of fluticasone furoate in the nasal spray formulation on growth velocity assessed by stadiometry. The subjects were 474 prepubescent children (girls aged 5 to 7.5 years and boys aged 5 to 8.5 years). Mean growth velocity over the 52-week treatment period was lower in the subjects receiving fluticasone furoate nasal spray (5.19 cm/year) compared with placebo (5.46 cm/year). The mean reduction in growth velocity was 0.27 cm/year (95% CI: 0.06, 0.48) [see Warnings and Precautions ( 5.17 )] .

8.1 Pregnancy Risk Summary There are insufficient data on the use of fluticasone furoate/vilanterol ELLIPTA, fluticasone furoate, or vilanterol in pregnant women. There are clinical considerations with use of fluticasone furoate/vilanterol ELLIPTA in pregnant women. (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 in adults, 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 and Delivery: There are no human studies evaluating the effects of fluticasone furoate/vilanterol ELLIPTA during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of Fluticasone Furoate/Vilanterol ELLIPTA during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. 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, 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 the MRHDID, respectively (on a mcg/m 2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day). 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 (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 fluticasone furoate/vilanterol ELLIPTA, fluticasone furoate, or vilanterol in pregnant women. There are clinical considerations with use of fluticasone furoate/vilanterol ELLIPTA in pregnant women. (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 in adults, 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 and Delivery: There are no human studies evaluating the effects of fluticasone furoate/vilanterol ELLIPTA during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of Fluticasone Furoate/Vilanterol ELLIPTA during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. 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, 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 the MRHDID, respectively (on a mcg/m 2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day). 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 (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 Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol ELLIPTA is not indicated for use in children and adolescents. The safety and efficacy in pediatric patients (aged 17 years and younger) have not been established. In a 24- to 76-week exacerbation trial, subjects received fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010). Subjects had a mean age of 42 years and 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 study entry. [See Clinical Studies ( 14.2 ).] Adolescents aged 12 to 17 years made up 14% of the study population (n = 281), with a mean exposure of 352 days for subjects in this age group treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (n = 151) and 355 days for subjects in this age group treated with fluticasone furoate 100 mcg (n = 130). In this age group, 10% of subjects treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg reported an asthma exacerbation compared with 7% for subjects treated with fluticasone furoate 100 mcg. Among the adolescents, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with 0 subjects treated with fluticasone furoate 100 mcg. There were no asthma‑related deaths or asthma-related intubations observed in the adolescent age group. Effects on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. A reduction of growth velocity in children and adolescents may occur as a result of poorly controlled asthma or from use of corticosteroids, including ICS. The effects of long-term treatment of children and adolescents 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 children and adolescents receiving orally inhaled corticosteroids, including Fluticasone Furoate/Vilanterol 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 Fluticasone Furoate/Vilanterol 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 110 mcg of fluticasone furoate in the nasal spray formulation on growth velocity assessed by stadiometry. The subjects were 474 prepubescent children (girls aged 5 to 7.5 years and boys aged 5 to 8.5 years). Mean growth velocity over the 52-week treatment period was lower in the subjects receiving fluticasone furoate nasal spray (5.19 cm/year) compared with placebo (5.46 cm/year). The mean reduction in growth velocity was 0.27 cm/year (95% CI: 0.06, 0.48) [see Warnings and Precautions ( 5.17 )] . 8.5 Geriatric Use Based on available data, no adjustment of the dosage of Fluticasone Furoate/Vilanterol ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of fluticasone furoate/vilanterol ELLIPTA for COPD included 4,820 subjects aged 65 and older and 1,118 subjects aged 75 and older. Clinical trials of fluticasone furoate/vilanterol 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 subjects. 8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3‑fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use Fluticasone Furoate/Vilanterol ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology ( 12.3 )] . 8.7 Renal Impairment There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects 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 Fluticasone Furoate/Vilanterol ELLIPTA inhalation powder is supplied as a disposable light grey and pale blue plastic inhaler containing 2 foil strips, each with 30 blisters. One strip contains fluticasone furoate (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 66993-135-97 100/25 mcg 30 inhalations (60 blisters) NDC 66993-136-97 200/25 mcg 30 inhalations (60 blisters) 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. Fluticasone Furoate/Vilanterol ELLIPTA should be stored inside the unopened moisture‑protective foil tray and only removed from the tray immediately before initial use. Discard Fluticasone Furoate/Vilanterol 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.