PRODUCT MONOGRAPHPrBREO ELLIPTAfluticasone furoate/vilanterol (as trifenatate) dry powder for oral inhalation100 mcg/25 mcg200 mcg/25 mcgInhaled Corticosteroid (ICS) and Bronchodilator(Long-Acting Beta2-Adrenergic Agonist (LABA)) Combination for Oral InhalationGlaxoSmithKline Inc.7333 Mississauga RoadMississauga, OntarioL5N 6L4Date of Revision:January 7, 2019Submission Control No: 213290 2018GSK group of companies or its licensorTrademarks are owned by or licensed to the GSK group of companiesPage 1 of 74


PrBREOELLIPTAfluticasone furoate/vilanterol dry powder for oral inhalationPART I: HEALTH PROFESSIONAL INFORMATIONSUMMARY PRODUCT INFORMATIONRoute ofDosage Form/StrengthAdministrationOral Inhalation Dry powder for oralinhalation/100 and 200 mcgfluticasone furoate/25 mcg vilanterolNonmedicinal IngredientsLactose monohydrate (which contains milkprotein) and magnesium stearateINDICATIONS AND CLINICAL USECOPDBREO ELLIPTA (fluticasone furoate/vilanterol) 100/25 mcg is a combination of aninhaled corticosteroid (ICS) and a long-acting beta2-adrenergic agonist (LABA),indicated for the long-term once-daily maintenance treatment of airflow obstruction inpatients with chronic obstructive pulmonary disease (COPD), including chronicbronchitis and/or emphysema, and to reduce exacerbations of COPD in patients with ahistory of exacerbations.BREO ELLIPTA 100/25 mcg once daily is the only strength indicated for the treatment ofCOPD. BREO ELLIPTA 200/25 mcg is not indicated for patients with COPD. There isno additional benefit of the 200/25 mcg dose compared to the 100/25 mcg dose and thereis a potential increased risk of pneumonia and systemic corticosteroid-related adversereactions.BREO ELLIPTA is not indicated for the relief of acute bronchospasm (see WARNINGSAND PRECAUTIONS, General).Page 3 of 74

AsthmaBREO ELLIPTA 100/25 mcg and BREO ELLIPTA 200/25 mcg are indicated for theonce-daily maintenance treatment of asthma in patients aged 18 years and older withreversible obstructive airways disease.BREO ELLIPTA, an ICS/LABA combination, should be prescribed for patients notadequately controlled on a long-term asthma control medication, such as an ICS, orwhose disease severity clearly warrants treatment with both an ICS and a LABA.BREO ELLIPTA is not indicated for patients whose asthma can be managed byoccasional use of a rapid onset, short duration, inhaled beta2-agonist or for patients whoseasthma can be successfully managed by ICS along with occasional use of a rapid onset,short duration, inhaled beta2-agonist.BREO ELLIPTA is not indicated for the relief of acute bronchospasm (see WARNINGSAND PRECAUTIONS, General).Geriatrics:No dosage adjustment is required in patients 65 years of age and older.Pediatrics:The safety and efficacy in pediatric patients younger than 18 years have not beenestablished.CONTRAINDICATIONS Patients who are hypersensitive to fluticasone furoate, vilanterol, or any ingredient inthe formulation or component of the container (see DOSAGE FORMS,COMPOSITION AND PACKAGING).Patients with severe hypersensitivity to milk proteins (see WARNINGS ANDPRECAUTIONS, Hypersensitivity).In the primary treatment of status asthmaticus or other acute episodes of asthma.Page 4 of 74

WARNINGS AND PRECAUTIONSGeneralSerious Asthma-Related Events – Hospitalizations, Intubations, DeathUse of LABA as monotherapy (without ICS) for asthma is associated with an increasedrisk of asthma-related death (see Salmeterol Multicenter Asthma Research Trial(SMART)). Available data from controlled clinical trials also suggest that use of LABAas monotherapy increases the risk of asthma-related hospitalization in pediatric andadolescent patients. These findings are considered a class effect of LABA monotherapy.When LABA are used in fixed-dose combination with ICS, data from large clinical trialsdo not show a significant increase in the risk of serious asthma-related events(hospitalizations, intubations, death) compared with ICS alone (see Serious AsthmaRelated Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic AgonistCombination Products).Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2adrenergic Agonist Combination ProductsFour (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trialswere conducted to evaluate the risk of serious asthma-related events when LABA wereused in fixed-dose combination with ICS compared with ICS alone in subjects withasthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1trial compared budesonide/formoterol with budesonide, 1 trial compared fluticasonepropionate/salmeterol with fluticasone propionate, and 1 trial compared mometasonefuroate/formoterol with mometasone furoate. The fourth trial included pediatric subjectsaged 4 to 11 years and compared fluticasone propionate/salmeterol with fluticasonepropionate. No safety study was conducted with BREO ELLIPTA. The primary safetyendpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations,death). A single, blinded, independent, joint adjudication committee determined whetherevents were asthma related.The 3 adult and adolescent trials were designed to rule out a 2.0-fold increase in relativerisk for ICS/LABA compared with ICS, and the pediatric trial was designed to rule out a2.7-fold increase in this relative risk. Each individual trial met its pre-specified objectiveand demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3adult and adolescent trials did not show a significant increase in risk of a serious asthmarelated event with ICS/LABA fixed-dose combination compared with ICS alone (Table1). These trials were not designed to rule out all risk for serious asthma-related eventswith ICS/LABA compared with ICS.Page 5 of 74

Table 1Meta-analysis of Serious Asthma-Related Events in Subjects withAsthma Aged 12 Years and OlderSerious asthma-related eventcAsthma-related deathAsthma-related intubation(endotracheal)Asthma-related hospitalization( 24-hour stay)ICS/LABA(n 17,537)aICS(n 17,552)a1162110502115105ICS/LABA vs. ICSHazard Ratio(95% CI)b1.10 (0.85, 1.44)ICS Inhaled Corticosteroid; LABA Long-acting Beta2-adrenergic Agonist.aRandomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis.bEstimated using a Cox proportional hazards model for time to first event with baseline hazards stratifiedby each of the 3 trials.cNumber of subjects with an event that occurred within 6 months after the first use of study drug or 7 daysafter the last date of study drug, whichever date was later. Subjects may have had one or more events, butonly the first event was counted for analysis. A single, blinded, independent, joint adjudicationcommittee determined whether events were asthma related.The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years whoreceived ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS(fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjectsrandomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienceda serious asthma-related event. There were no asthma-related deaths or intubations.ICS/LABA did not show a significant increase in risk of serious asthma-related eventscompared with ICS based on the pre-specified risk margin (2.7), with an estimated hazardratio of time to first event of 1.29 (95% CI: 0.73, 2.27). BREO ELLIPTA is not indicatedin children or adolescents younger than 18 years of age.Salmeterol Multicenter Asthma Research Trial (SMART)A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol withplacebo, each added to usual asthma therapy, showed an increase in asthma-relateddeaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterolversus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25,15.34]). Use of background ICS was not required in SMART. The increased risk ofasthma-related death is considered a class effect of LABA monotherapy.Not for Acute UseIt is crucial to inform patients that BREO ELLIPTA should not be used for the relief ofacute symptoms of asthma or COPD (i.e., as rescue therapy for the treatment of acuteepisodes of bronchospasm). Patients should be prescribed a rapid onset, short durationinhaled bronchodilator (e.g., salbutamol) to relieve acute symptoms such as shortness ofbreath, and advised to have this available for use at all times.When beginning treatment with BREO ELLIPTA, patients who have been taking a rapidonset, short duration, inhaled bronchodilator on a regular basis (e.g., q.i.d.) should bePage 6 of 74

instructed to discontinue the regular use of these drugs and use them only forsymptomatic relief if they develop acute symptoms while taking BREO ELLIPTA.Deterioration of Disease and Acute EpisodesBREO ELLIPTA should not be initiated in patients with acutely deteriorating COPD orasthma, which may be a life-threatening condition. The use of BREO ELLIPTA in thissetting is inappropriate.COPD or asthma may deteriorate acutely over a period of hours or chronically overseveral days or longer. If the patient’s inhaled, short-acting bronchodilator becomes lesseffective or the patient needs more inhalation of a short-acting bronchodilator than usual,these may be markers of deterioration of disease. In this setting, a re-evaluation of thepatient and the treatment regimen should be undertaken at once. Increasing the dailydosage of BREO ELLIPTA beyond the recommended dose is not appropriate in thissituation.Asthma-related adverse events and asthma or COPD exacerbations may occur duringtreatment with BREO ELLIPTA. Patients should be advised to continue treatment andseek medical advice if symptoms remain uncontrolled or worsen after initiation oftherapy with BREO ELLIPTA.Patients should not stop therapy with BREO ELLIPTA, in asthma or COPD, withoutphysician supervision since symptoms may recur after discontinuation.Excessive Use and Use with Other LABA ProductsBREO ELLIPTA should not be used more often than recommended, at higher doses thanrecommended, or in conjunction with other medicines containing LABA, as an overdosemay result. Clinically significant cardiovascular effects and fatalities have been reportedin association with excessive use of inhaled sympathomimetic drugs. Patients usingBREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol,formoterol fumarate, indacaterol, olodaterol) for any reason.CardiovascularClinically significant cardiovascular effects and fatalities have been reported inassociation with excessive use of inhaled sympathomimetic drugs. Cardiovascular effectssuch as tachycardia, arrhythmia, palpitations, myocardial ischemia, angina pectoris,hypertension or hypotension have been associated with use of beta-adrenergic agonists.In addition, beta-agonists have been reported to produce electrocardiographic changes,such as flattening of the T wave, prolongation of the QTc interval, and ST segmentdepression. Like all products containing sympathomimetic agents, BREO ELLIPTAshould therefore be used with caution in patients with severe cardiovascular disease,especially coronary insufficiency, cardiac arrhythmias (including tachyarrhythmias), orhypertension (see ADVERSE REACTIONS, Mortality Trial).Page 7 of 74

HemodynamicsLike other beta2-agonists, vilanterol can produce clinically significant cardiovasculareffects in some patients as measured by an increase in pulse rate, systolic or diastolicblood pressure, or cardiac arrhythm