Breo Ellipta

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

2 DOSAGE AND ADMINISTRATION • For oral inhalation only. ( 2.3 ) • Maintenance treatment of COPD: 1 actuation of BREO ELLIPTA 100/25 mcg once daily administered by oral inhalation. ( 2.1 ) • Maintenance treatment of asthma in adult patients aged 18 years and older: 1 actuation of BREO ELLIPTA 100/25 mcg or BREO ELLIPTA 200/25 mcg once daily administered by oral inhalation. ( 2.2 ) • Maintenance treatment of asthma in pediatric patients aged 12 to 17 years: 1 actuation of BREO ELLIPTA 100/25 mcg once daily administered by oral inhalation. ( 2.2 ) • Maintenance treatment of asthma in pediatric patients aged 5 to 11 years: 1 actuation of BREO ELLIPTA 50/25 mcg once daily administered by oral inhalation. ( 2.2 ) 2.1 Recommended Dosage for Maintenance Treatment of Chronic Obstructive Pulmonary Disease The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation. If shortness of breath occurs in the period between doses, an inhaled, short-acting beta 2 -agonist (rescue medicine, e.g., albuterol) should be used for immediate relief. 2.2 Recommended Dosage for Maintenance Treatment of Asthma Adult Patients Aged 18 Years and Older The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation or BREO ELLIPTA 200/25 mcg (containing fluticasone furoate 200 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation. • When choosing the starting dosage strength of BREO ELLIPTA, consider the patients’ disease severity, their previous asthma therapy, including the inhaled corticosteroid (ICS) dosage, as well as the patients’ current control of asthma symptoms and risk of future exacerbation. • The median time to onset, defined as a 100-mL increase from baseline in mean forced expiratory volume in 1 second (FEV1), was approximately 15 minutes after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief. • For patients who do not respond adequately to BREO ELLIPTA 100/25 mcg once daily, increasing the dose to BREO ELLIPTA 200/25 mcg once daily may provide additional improvement in asthma control. For patients who do not respond adequately to BREO ELLIPTA 200/25 mcg once daily, re-evaluate and consider other therapeutic regimens and additional therapeutic options. • The maximum recommended dosage is 1 inhalation of BREO ELLIPTA 200/25 mcg once daily. • If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be used for immediate relief. Pediatric Patients Aged 12 to 17 Years The recommended dosage of BREO ELLIPTA 100/25 mcg (containing fluticasone furoate 100 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation [see Warnings and Precautions ( 5.14 )] . Pediatric Patients Aged 5 to 11 Years The recommended dosage of BREO ELLIPTA 50/25 mcg (containing fluticasone furoate 50 mcg and vilanterol 25 mcg) is 1 actuation once daily by oral inhalation [see Warnings and Precautions ( 5.14 )] . 2.3 Administration Information • After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis [see Warnings and Precautions ( 5.4)] . • BREO ELLIPTA should be used at the same time every day. Do not use BREO ELLIPTA more than 1 time every 24 hours. • More frequent administration or a greater number of inhalations (more than 1 inhalation daily) of the prescribed strength of BREO ELLIPTA is not recommended as some patients are more likely to experience adverse effects with higher doses.

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

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

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Serious Asthma-Related Events – Hospitalizations, Intubations, Death [see Warnings and Precautions ( 5.1 )] • Oropharyngeal Candidiasis [see Warnings and Precautions ( 5.4 )] • Pneumonia [see Warnings and Precautions ( 5.5 )] • Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.6 )] • Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.8 )] • Paradoxical Bronchospasm [see Warnings and Precautions ( 5.10 )] • Cardiovascular Effects [see Warnings and Precautions ( 5.12 )] • Reduction in Bone Mineral Density [see Warnings and Precautions ( 5.13 )] • Growth Effects [see Warnings and Precautions ( 5.14 )] • Glaucoma and Cataracts [see Warnings and Precautions ( 5.15 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. • COPD: Most common adverse reactions (incidence ≥3%) are nasopharyngitis, upper respiratory tract infection, headache, oral candidiasis, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, and pyrexia. ( 6.1 ) • Asthma: Most common adverse reactions (incidence ≥2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease The safety data described below are based on two 6-month and two 12-month trials and one long-term mortality trial. In these studies, 5,356 patients with COPD received at least 1 dose of BREO ELLIPTA 100/25 mcg. Adverse reactions observed in other studies of BREO ELLIPTA in COPD patients were similar to those observed in these 5 trials. 6-Month Trials The incidence of adverse reactions associated with BREO ELLIPTA 100/25 mcg in Table 2 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 patients, 70% were male and 84% were White. They had a mean age of 62 years and an average smoking history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV 1 /forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Patients received 1 inhalation once daily of the following: BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo. Table 2. Adverse Reactions with BREO ELLIPTA 100/25 mcg with ≥3% Incidence and More Common than Placebo in Patients with Chronic Obstructive Pulmonary Disease a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis. Adverse Reaction BREO ELLIPTA 100/25 mcg (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % Infections and infestations Nasopharyngitis 9 10 8 8 Upper respiratory tract infection 7 5 4 3 Oropharyngeal candidiasis a 5 2 3 2 Nervous system disorders Headache 7 9 7 5 12-Month Trials Long-term safety data are based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 patients, of which 57% were male and 85% were White. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicte …

7 DRUG INTERACTIONS • Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. May cause systemic corticosteroid and cardiovascular effects. ( 7.1 ) • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of vilanterol on cardiovascular system. ( 7.2 ) • Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 ) • Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.4 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol are both substrates of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of BREO ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.3 )] . 7.2 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and QTc Prolonging Drugs Vilanterol, like other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. 7.3 Beta-Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, but may also produce severe bronchospasm in patients with COPD or asthma. Therefore, patients with COPD or asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution. 7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/or hypokalemia that may result from the administration of non–potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics.

8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Fluticasone furoate systemic exposure may increase in patients with moderate or severe impairment. Monitor for systemic corticosteroid effects. ( 8.6 , 12.3 ) 8.1 Pregnancy Risk Summary There are insufficient data on the use of BREO ELLIPTA or its individual components, fluticasone furoate and vilanterol, in pregnant women to inform a drug-associated risk. (See Clinical Considerations.) In an animal reproduction study, fluticasone furoate and vilanterol administered by inhalation alone or in combination to pregnant rats during the period of organogenesis produced no fetal structural abnormalities. The highest fluticasone furoate and vilanterol doses in this study were approximately 5 and 40 times the maximum recommended human daily inhalation doses (MRHDID) of 200 and 25 mcg, respectively. (See Data.) The estimated risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored, and medication adjusted as necessary to maintain optimal control of asthma. Labor or Delivery: BREO ELLIPTA should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility. Data Animal Data: Fluticasone Furoate and Vilanterol: In an embryofetal developmental study, pregnant rats received fluticasone furoate and vilanterol during the period of organogenesis at doses up to approximately 5 and 40 times the MRHDID of 200 and 25 mcg, respectively, alone or in combination (on a mcg/m 2 basis at inhalation doses up to approximately 95 mcg/kg/day). No evidence of structural abnormalities was observed. Fluticasone Furoate: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received fluticasone furoate during the period of organogenesis at doses up to approximately 4 and 1 times, respectively, the MRHDID of 200 mcg (on a mcg/m 2 basis at maternal inhalation doses up to 91 and 8 mcg/kg/day, respectively). No evidence of structural abnormalities in fetuses was observed in either species. In a perinatal and postnatal developmental study in rats, dams received fluticasone furoate during late gestation and lactation periods at doses up to approximately 1 time the MRHDID of 200 mcg (on a mcg/m 2 basis at maternal inhalation doses up to 27 mcg/kg/day). No evidence of effects on offspring development was observed. Vilanterol: In 2 separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 1,000 times, respectively, the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 160 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID …

12.1 Mechanism of Action BREO ELLIPTA BREO ELLIPTA contains both fluticasone furoate and vilanterol. The mechanisms of action described below for the individual components apply to BREO ELLIPTA. These drugs represent 2 different classes of medications (an ICS and a LABA), each having different effects on clinical and physiological indices. Fluticasone Furoate Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone furoate affects COPD and asthma symptoms is not known. Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. Vilanterol Vilanterol is a LABA. In vitro tests have shown the functional selectivity of vilanterol was similar to salmeterol. The clinical relevance of this in vitro finding is unknown. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenergic agonist drugs, including vilanterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

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

10 OVERDOSAGE BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA. Treatment of overdosage consists of discontinuation of BREO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage. Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions ( 5.8 )] . Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.

16 HOW SUPPLIED/STORAGE AND HANDLING BREO ELLIPTA is supplied as a disposable light grey and pale blue plastic inhaler containing 2 foil strips, each with 30 blisters (or 14 blisters for the institutional pack). One strip contains fluticasone furoate (50, 100 or 200 mcg per blister), and the other strip contains vilanterol (25 mcg per blister). A blister from each strip is used to create 1 dose. The inhaler is packaged within a moisture-protective foil tray with a desiccant and a peelable lid in the following packs: NDC 0173-0916-10 BREO ELLIPTA 50/25 mcg 30 inhalations (60 blisters) NDC 0173-0859-10 BREO ELLIPTA 100/25 mcg 30 inhalations (60 blisters) NDC 0173-0859-14 BREO ELLIPTA 100/25 mcg 14 inhalations (28 blisters), institutional pack NDC 0173-0882-10 BREO ELLIPTA 200/25 mcg 30 inhalations (60 blisters) NDC 0173-0882-14 BREO ELLIPTA 200/25 mcg 14 inhalations (28 blisters), institutional pack Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. Keep out of reach of children. BREO ELLIPTA should be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. Discard BREO ELLIPTA 6 weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.