Breo Ellipta (fluticasone furoate 200 MCG/ACTUAT / vilanterol 25 MCG/ACTUAT (as vilanterol trifenatate 40 MCG/ACTUAT)) Dry Powder Inhaler, 14 ACTUAT

Details

DRUG INTERACTIONS

7 •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 BREO 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 BREO ELLIPTA with long-term 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 beta2-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 BREO 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.

OVERDOSAGE

10 No human overdosage data has been reported for BREO ELLIPTA.

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.

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.

DESCRIPTION

11 BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 are inhalation powders for oral inhalation that contain a combination of fluticasone furoate (an ICS) and vilanterol (a LABA).

One active component of BREO 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 C27H29F3O6S.

It is practically insoluble in water.

The other active component of BREO ELLIPTA is vilanterol trifenatate, a LABA with the chemical name triphenylacetic acid-4-{(1R)-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 C24H33Cl2NO5•C20H16O2.

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 mix of micronized fluticasone furoate (100 or 200 mcg) and lactose monohydrate (12.4 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, BREO 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 FEV1/FVC less than 70% and FEV1 less than 30% predicted or FEV1 less than 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 trifenatate chemical structure

CLINICAL STUDIES

14 14.1 Chronic Obstructive Pulmonary Disease The safety and efficacy of BREO ELLIPTA were evaluated in 7,700 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 mcg/50 mcg, and dose-ranging trials of shorter duration.

The efficacy of BREO 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 FEV1 at Day 1 and Day 28 (Figure 3).

Figure 3.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28 Day 1 Day 28 The differences in trough FEV1 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 III 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 BREO 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 BREO ELLIPTA on lung function in subjects with COPD.

In Trial 1, subjects were randomized to BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, and placebo.

In Trial 2, subjects were randomized to BREO ELLIPTA 100/25, fluticasone furoate/vilanterol 50 mcg/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 FEV1 was 48% (range: 14% to 87%), mean postbronchodilator FEV1/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 FEV1 (0 to 4 hours) postdose on Day 168 and change from baseline in trough FEV1 on Day 169 (the mean of the FEV1 values obtained 23 and 24 hours after the final dose on Day 168).

The weighted mean comparison of the fluticasone furoate/vilanterol combination with fluticasone furoate was assessed to evaluate the contribution of vilanterol to BREO ELLIPTA.

The trough FEV1 comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA.

BREO ELLIPTA 100/25 demonstrated a larger increase in the weighted mean FEV1 (0 to 4 hours) relative to placebo and fluticasone furoate 100 mcg at Day 168 (Table 4).

Table 4.

Least Squares Mean Change from Baseline in Weighted Mean FEV1 (0-4 h) and Trough FEV1 at 6 Months Treatment n Weighted Mean FEV1 (0-4 h)a (mL) Trough FEV1 b (mL) Difference from Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Placebo (95% CI) Vilanterol 25 mcg (95% CI) Trial 1 BREO ELLIPTA 100/25 204 214 (161, 266) 168 (116, 220) –– 144 (91, 197) 45 (-8, 97) BREO ELLIPTA 200/25 205 209 (157, 261) –– 168 (117, 219) 131 (80, 183) 32 (-19, 83) Trial 2 BREO ELLIPTA 100/25 206 173 (123, 224) 120 (70, 170) –– 115 (60, 169) 48 (-6, 102) a At Day 168.

bAt Day 169.

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 FEV1 (0-4 h) (mL) on Days 1 and 168 Day 1 Day 168 The second co-primary variable was change from baseline in trough FEV1 following the final treatment day.

At Day 169, both Trials 1 and 2 demonstrated significant increases in trough FEV1 for all strengths of the fluticasone furoate/vilanterol combination compared with placebo (Table 4).

The comparison of BREO ELLIPTA 100/25 with vilanterol did not achieve statistical significance (Table 4).

Trials 1 and 2 evaluated FEV1 as a secondary endpoint.

Peak FEV1 was defined as the maximum postdose FEV1 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 FEV1 were observed for the groups receiving BREO ELLIPTA 100/25 compared with placebo (152 and 139 mL, respectively).

The median time to onset, defined as a 100-mL increase from baseline in FEV1, was 16 minutes in subjects receiving BREO ELLIPTA 100/25.

Exacerbations: Trials 3 and 4 were randomized, double-blind, 52-week trials designed to evaluate the effect of BREO ELLIPTA on the rate of moderate and severe COPD exacerbations.

All subjects were treated with fluticasone propionate/salmeterol 250 mcg/50 mcg twice daily during a 4-week run-in period prior to being randomly assigned to 1 of the following treatment groups: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, or vilanterol 25 mcg.

The primary efficacy variable in both trials was the annual rate of moderate/severe exacerbations.

The comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA.

In these 2 trials, exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days.

COPD exacerbations were considered to be of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if hospitalization was required.

Trials 3 and 4 included 3,255 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 FEV1 was 45% (range: 12% to 91%), and mean postbronchodilator FEV1/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 BREO ELLIPTA 100/25 had a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol in both trials (Table 5).

Table 5.

Moderate and Severe Chronic Obstructive Pulmonary Disease Exacerbations Treatment n Mean Annual Rate (exacerbations/year) Ratio vs.

Vilanterol 95% CI Trial 3 BREO ELLIPTA 100/25 403 0.90 0.79 0.64, 0.97 BREO ELLIPTA 200/25 409 0.79 0.69 0.56, 0.85 Fluticasone furoate/vilanterol 50 mcg/25 mcg 412 0.92 0.81 0.66, 0.99 Vilanterol 25 mcg 409 1.14 –– –– Trial 4 BREO ELLIPTA 100/25 403 0.70 0.66 0.54, 0.81 BREO ELLIPTA 200/25 402 0.90 0.85 0.70, 1.04 Fluticasone furoate/vilanterol 50 mcg/25 mcg 408 0.92 0.87 0.72, 1.06 Vilanterol 25 mcg 409 1.05 –– –– Comparator Trials Three 12-week, randomized, double-blind, double-dummy trials were conducted with BREO ELLIPTA 100/25 once daily versus fluticasone propionate/salmeterol 250 mcg/50 mcg twice daily to evaluate the efficacy of serial lung function of BREO ELLIPTA in subjects with COPD.

The primary endpoint of each study was change from baseline in weighted mean FEV1 (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 BREO ELLIPTA 100/25, the mean postbronchodilator percent predicted FEV1 was 48% (range: 19% to 70%), the mean (SD) FEV1/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 mcg/50 mcg, the mean postbronchodilator percent predicted FEV1 was 47% (range: 14% to 71%), the mean (SD) FEV1/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 BREO ELLIPTA 100/25, the mean postbronchodilator percent predicted FEV1 was 48% (range: 18% to 70%), the mean (SD) FEV1/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 mcg/50 mcg, the mean postbronchodilator percent predicted FEV1 was 49% (range: 15% to 70%), the mean (SD) FEV1/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 BREO ELLIPTA 100/25, the mean postbronchodilator percent predicted FEV1 was 48% (range: 18% to 70%), the mean (SD) FEV1/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 mcg/50 mcg, the mean postbronchodilator percent predicted FEV1 was 48% (range: 16% to 70%), the mean (SD) FEV1/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 FEV1 (0 to 24 hours) with BREO ELLIPTA 100/25 was 174 (15) mL compared with 94 (16) mL with fluticasone propionate/salmeterol 250 mcg/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 FEV1(0 to 24 hours)with BREO ELLIPTA 100/25 was 142 (18) mL and 168 (12) mL, respectively, compared with 114 (18) mL and 142 (12) mL, respectively, for fluticasone propionate/salmeterol 250 mcg/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).

Figure 3.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 1 Figure 3.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 28 Figure 4.

Raw Mean Change from Baseline in Postdose Serial FEV1 (0-4 h) (mL) on Days 1 and 168, Day 1 Figure 4.

Raw Mean Change from Baseline in Postdose Serial FEV1 (0-4 h) (mL) on Days 1 and 168, Day 168 14.2 Asthma The safety and efficacy of BREO 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 mcg/50 mcg, and dose-ranging trials of shorter duration.

The efficacy of BREO 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 FEV1 at Day 1 and Day 28 (Figure 5).

Figure 5.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28 Day 1 Day 28 The differences in trough FEV1 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 FEV1 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 FF = fluticasone furoate, FP = fluticasone propionate, QD = once daily, BID = twice daily.

Confirmatory Trials The efficacy of BREO ELLIPTA was evaluated in 4 randomized, double‑blind, parallel-group clinical trials in adolescent and adult subjects with asthma.

Three trials were designed to evaluate the safety and efficacy of BREO ELLIPTA given once daily in subjects who were not controlled on their current treatments of inhaled corticosteroid or combination therapy consisting of an inhaled corticosteroid plus a LABA (Trials 1, 2, and 3).

A 24- to 76-week exacerbation trial was designed to demonstrate that treatment with BREO ELLIPTA 100/25 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 one 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 6.

While subjects aged 12 to 17 years were included in these trials, BREO 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 6.

Demography of Asthma Trials 1, 2, 3, 5, and 6 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 smokeda (%) N/A 84 N/A 86 81 Predose FEV1 (L) at baseline 2.32 1.97 2.15 2.20 2.03 Mean percent predicted FEV1 at baseline (%) 70 62 67 72 68 % Reversibility 29 30 29 24 28 Absolute reversibility (mL) 614 563 571 500 512 N/A = Data not collected.

a Trials did not include current smokers; past smokers had less than 10 packs per year history.

Trials 1, 2, and 3 were 12- or 24-week trials that evaluated the efficacy of BREO ELLIPTA on lung function in subjects with asthma.

In Trial 1, subjects were randomized to BREO ELLIPTA 100/25, fluticasone furoate 100 mcg, or placebo.

In Trial 2, subjects were randomized to BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, or fluticasone furoate 100 mcg.

In Trial 3, subjects were randomized to BREO ELLIPTA 200/25, 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 inhaled corticosteroid or an inhaled corticosteroid plus a LABA (doses of inhaled corticosteroid 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 beta2-agonist medication use during the run-in period were continued in the trial.

In Trials 1 and 3, change from baseline in weighted mean FEV1 (0 to 24 hours) and change from baseline in trough FEV1 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 FEV1 (0 to 24 hours) at Week 12 was the primary efficacy endpoint; change from baseline in trough FEV1 at approximately 24 hours after the last dose at Week 12 was a secondary endpoint.

(See Table 7.) Weighted mean FEV1 (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 7.

Change from Baseline in Weighted Mean FEV1 (0-24 h) (mL) and Trough FEV1 (mL) at Study Endpoint (Trials 1, 2, and 3) Study (Duration) Background Treatment n Weighted Mean FEV1 (0-24 h) (mL) Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Treatment Trial 1 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA BREO ELLIPTA 100/25 108 302 (178, 426) 116 (-5, 236) –– Trial 2 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 100/25 312 –– 108 (45, 171) –– Trial 3 (24 Weeks) High-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 200/25 89 –– –– 136 (1, 270) Study (Duration) Background Treatment n Trough FEV1 (mL) Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Treatment Trial 1 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA BREO ELLIPTA 100/25 200 172 (87, 258) 36 (-48, 120) –– Trial 2 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 100/25 334 –– 77 (16, 138) –– Trial 3 (24 Weeks) High-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 200/25 187 –– –– 193 (108, 277) ICS = inhaled corticosteroid, LABA = long-acting beta2-adrenergic agonist.

In Trial 1, weighted mean FEV1 (0 to 24 hours) was assessed in a subset of subjects (n = 309).

At Week 12, change from baseline in weighted mean FEV1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 100/25 compared with placebo (302 mL; 95% CI: 178, 426; P<0.001) (Table 7); change from baseline in weighted mean FEV1 (0 to 24 hours) for BREO ELLIPTA 100/25 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 FEV1 was significantly greater for BREO ELLIPTA 100/25 compared with placebo (172 mL; 95% CI: 87, 258; P<0.001) (Table 7); change from baseline in trough FEV1 for BREO ELLIPTA 100/25 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 FEV1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 100/25 compared with fluticasone furoate 100 mcg (108 mL; 95% CI: 45, 171; P<0.001) at Week 12 (Table 7).

In a descriptive analysis, the change from baseline in weighted mean FEV1 (0 to 24 hours) for BREO ELLIPTA 200/25 was numerically greater than BREO ELLIPTA 100/25 (24 mL; 95% CI: -37, 86) at Week 12.

The change from baseline in trough FEV1 was significantly greater for BREO ELLIPTA 100/25 compared with fluticasone furoate 100 mcg (77 mL, 95% CI: 16, 138; P = 0.014) at Week 12 (Table 7).

In a descriptive analysis, the change from baseline in trough FEV1 for BREO ELLIPTA 200/25 was numerically greater than BREO ELLIPTA 100/25 (16 mL; 95% CI: -46, 77) at Week 12.

In Trial 3, the change from baseline in weighted mean FEV1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 200/25 compared with fluticasone furoate 200 mcg (136 mL; 95% CI: 1, 270; P = 0.048) at Week 24 (Table 7).

The change from baseline in trough FEV1 was significantly greater for BREO ELLIPTA 200/25 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 FEV1 (0 to 24 hours) over the 24-hour period following the final dose of BREO ELLIPTA in Trials 2 and 3.

Serial FEV1 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 BREO ELLIPTA 100/25 (Trial 2) or BREO ELLIPTA 200/25 (Trial 3) had significantly greater improvements from baseline in percentage of 24-hour periods without need of beta2-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 BREO ELLIPTA 200/25 had numerical improvements from baseline in percentage of 24-hour periods without need of beta2-agonist rescue medication use and percentage of 24-hour periods without asthma symptoms compared with subjects receiving BREO ELLIPTA 100/25.

Trial 5 was a 24- to 76-week event-driven exacerbation trial that evaluated whether BREO ELLIPTA 100/25 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 inhaled corticosteroid (fluticasone propionate 100 mcg to 500 mcg twice daily or equivalent) or low- to mid-dose inhaled corticosteroid plus a LABA (fluticasone propionate/salmeterol 100 mcg/50 mcg to 250 mcg/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 beta2-agonist medication use during the run-in period were continued in the trial.

The primary endpoint was time to first asthma exacerbation.

Asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroid for at least 3 days or an in‑patient hospitalization or emergency department visit due to asthma that required systemic corticosteroid.

Rate of asthma exacerbation was a secondary endpoint.

The hazard ratio from the Cox Model for the analysis of time to first asthma exacerbation for BREO ELLIPTA 100/25 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 BREO ELLIPTA 100/25 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 BREO ELLIPTA 100/25 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 BREO ELLIPTA 100/25 once daily with fluticasone propionate/salmeterol 250 mcg/50 mcg twice daily (N = 806).

Subjects receiving mid-dose inhaled corticosteroid (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 FEV1 (0 to 24 hours) at Week 24.

The mean change (SE) from baseline in weighted mean FEV1 (0 to 24 hours) for BREO ELLIPTA 100/25 was 341 (18.4) mL compared with 377 (18.5) mL for fluticasone propionate/salmeterol 250 mcg/50 mcg (treatment difference -37 mL; 95% CI: -88, 15; P = 0.162).

Figure 5.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 1 Figure 5.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 28 Figure 6: Fluticasone Furoate Dose-Ranging and Dose-Frequency Trials Figure 7.

Least Squares (LS) Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments over 24 Hours at Day 1 (Trial 1)

HOW SUPPLIED

16 /STORAGE AND HANDLING Product: 50090-2404 NDC: 50090-2404-0 1 POWDER in a TRAY

GERIATRIC USE

8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Clinical trials of BREO ELLIPTA for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 and older.

Clinical trials of BREO ELLIPTA for asthma included 854 subjects aged 65 years and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

DOSAGE FORMS AND STRENGTHS

3 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)

MECHANISM OF ACTION

12.1 Mechanism of Action BREO ELLIPTA Since 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 (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 beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-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 beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-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.

INDICATIONS AND USAGE

1 BREO ELLIPTA is a combination of fluticasone furoate, an inhaled corticosteroid (ICS), and vilanterol, a long-acting beta2‑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: Not indicated for relief of acute bronchospasm.

(1.1, 1.2, 5.2) 1.1 Maintenance Treatment of Chronic Obstructive Pulmonary Disease BREO® ELLIPTA® 100/25 is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) 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.

BREO ELLIPTA 100/25 is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

BREO ELLIPTA 100/25 once daily is the only strength indicated for the treatment of COPD.

Important Limitation of Use BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm.

1.2 Treatment of Asthma BREO ELLIPTA is a combination ICS/LABA indicated for the once-daily treatment of asthma in patients aged 18 years and older.

LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death.

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Use in Specific Populations (8.4)].

Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA.

Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid.

Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Important Limitation of Use BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm.

PEDIATRIC USE

8.4 Pediatric Use BREO 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 BREO ELLIPTA 100/25 (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010).

Subjects had a mean age of 42 years and a history of one 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 BREO ELLIPTA 100/25 (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 BREO ELLIPTA 100/25 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 BREO ELLIPTA 100/25 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 inhaled corticosteroids.

The effects of long-term treatment of children and adolescents with inhaled corticosteroids, including fluticasone furoate, on final adult height are not known.

Controlled clinical trials have shown that inhaled corticosteroids 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 BREO ELLIPTA, should be monitored routinely (e.g., via stadiometry).

The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies.

To minimize the systemic effects of orally inhaled corticosteroids, including BREO ELLIPTA, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

A randomized, double-blind, parallel-group, multicenter, 1-year, placebo-controlled trial evaluated the effect of once-daily treatment with 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 to 0.48) [see Warnings and Precautions (5.17)].

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy Category C.

There are no adequate and well-controlled trials with BREO ELLIPTA in pregnant women.

Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels.

Because animal reproduction studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women should be advised to contact their physicians if they become pregnant while taking BREO ELLIPTA.

Fluticasone Furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 5 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone furoate and vilanterol, alone or in combination, up to approximately 95 mcg/kg/day).

Fluticasone Furoate: There were no teratogenic effects in rats and rabbits at approximately 4 and 1 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively).

There were no effects on perinatal and postnatal development in rats at approximately 1 time the MRHDID in adults (on a mcg/m2 basis at maternal doses up to 27 mcg/kg/day).

Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits).

However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (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.

There were no effects on perinatal and postnatal development in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).

Nonteratogenic Effects Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy.

Such infants should be carefully monitored.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk.

However, other corticosteroids and beta2-agonists have been detected in human milk.

Since there are no data from controlled trials on the use of BREO ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman.

BOXED WARNING

WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death.

Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol.

This finding with salmeterol is considered a class effect of LABA.

Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids [see Warnings and Precautions (5.1)].

WARNING: ASTHMA-RELATED DEATH See full prescribing information for complete boxed warning.

• Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, increase the risk of asthma-related death.

A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths.

This finding with salmeterol is considered a class effect of all LABA.

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

(5.1) • When treating patients with asthma, only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an ICS, or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA.

Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose ICS.(1.2, 5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •LABA increase the risk of asthma-related death and asthma-related hospitalizations.

Prescribe only for recommended patient populations.

(5.1) •Do not initiate in acutely deteriorating COPD or asthma.

Do not use to treat acute symptoms.

(5.2) •Do not use in combination with an additional medicine containing a LABA because of risk of overdose.

(5.3) • Candida albicans infection of the mouth and pharynx may occur.

Monitor patients periodically.

Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk.

(5.4) •Increased risk of pneumonia in patients with COPD.

Monitor patients for signs and symptoms of pneumonia.

(5.5) •Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex).

Use with caution in patients with these infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

(5.6) •Risk of impaired adrenal function when transferring from systemic corticosteroids.

Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA.

(5.7) •Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue BREO ELLIPTA slowly.

(5.8) •If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy.

(5.10) •Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation.

(5.12) •Assess for decrease in bone mineral density initially and periodically thereafter.

(5.13) •Close monitoring for glaucoma and cataracts is warranted.

(5.14) •Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.

(5.15) •Be alert to hypokalemia and hyperglycemia.

(5.16) 5.1 Asthma-Related Death LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death.

Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs.

3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]).

The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA.

No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted.

Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.

5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma.

BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma.

The initiation of BREO ELLIPTA in this setting is not appropriate.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer.

If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease.

In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once.

For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation.

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma.

In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids.

Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.

BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm.

BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose.

Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms.

When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.

5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-acting Beta2-agonists BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result.

Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA.

When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted.

Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials.

There was also an increased incidence of pneumonias resulting in hospitalization.

In some incidences these pneumonia events were fatal.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 mcg/25 mcg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 mcg: 3% (27 of 818 subjects).

There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg.

There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (less than 1% for each treatment group).

5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.

In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.

How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.7 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.

Although BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.

These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA.

Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA.

Lung function (FEV1 or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active.

Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of BREO ELLIPTA.

However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)].

Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects.

Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects.

If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered.

5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening.

If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

5.11 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA.

Discontinue BREO ELLIPTA if such reactions occur.

There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications (4)].

5.12 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles.

If such effects occur, BREO ELLIPTA may need to be discontinued.

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 segment depression, although the clinical significance of these findings is unknown.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias.

Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids.

The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.

Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter.

If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.

5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of inhaled corticosteroids.

Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

5.15 Coexisting Conditions BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines.

Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects.

The decrease in serum potassium is usually transient, not requiring supplementation.

Beta-agonist medications may produce transient hyperglycemia in some patients.

In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum glucose or potassium.

5.17 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents.

[See Use in Specific Populations (8.4).]

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Asthma-Related Death Inform patients with asthma that LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Also inform them that currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Not for Acute Symptoms Inform patients that BREO ELLIPTA is not meant to relieve acute symptoms of COPD or asthma and extra doses should not be used for that purpose.

Advise patients to treat acute symptoms with an inhaled, short-acting beta2-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 beta2-agonists •Need for more inhalations than usual of inhaled, short-acting beta2-agonists •Significant decrease in lung function as outlined by the physician Tell patients they should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-acting Beta2-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, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with BREO ELLIPTA, but at times therapy with BREO ELLIPTA may need to be temporarily interrupted under close medical supervision.

Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

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 BREO ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.

Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Patients should taper slowly from systemic corticosteroids if transferring to BREO ELLIPTA.

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.

Ocular Effects Inform patients that long-term use of inhaled corticosteroids 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 beta2‑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 BREO ELLIPTA.

Instruct patients to discontinue BREO ELLIPTA if such reactions occur.

BREO and ELLIPTA are registered trademarks of the GSK group of companies.

BREO ELLIPTA was developed in collaboration with Theravance.

BRE:7PI

DOSAGE AND ADMINISTRATION

2 BREO ELLIPTA should be administered once daily every day by the orally inhaled route only.

BREO ELLIPTA should be taken at the same time every day.

Do not use BREO 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 BREO ELLIPTA is not recommended as some patients are more likely to experience adverse effects with higher doses.

Patients using BREO 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 BREO ELLIPTA 100/25 once daily.

(2.1) •Asthma: 1 inhalation of BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 once daily.

(2.2) 2.1 Chronic Obstructive Pulmonary Disease BREO ELLIPTA 100/25 should be administered as 1 inhalation once daily.

The maximum recommended dosage is 1 inhalation of BREO ELLIPTA 100/25 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 beta2-agonist (rescue medicine, e.g., albuterol) should be taken for immediate relief.

2.2 Asthma If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist (rescue medicine, e.g., albuterol) should be taken for immediate relief.

The recommended starting dosage is BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 administered as 1 inhalation once daily.

The maximum recommended dosage is 1 inhalation of BREO ELLIPTA 200/25 once daily.

The starting dosage is based on patients’ asthma severity.

For patients previously treated with low- to mid-dose corticosteroid–containing treatment, BREO ELLIPTA 100/25 should be considered.

For patients previously treated with mid- to high-dose corticosteroid–containing treatment, BREO ELLIPTA 200/25 should be considered.

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, increasing the dose to BREO ELLIPTA 200/25 may provide additional improvement in asthma control.

If a previously effective dosage regimen of BREO 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 BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be considered.