INCRUSE ELLIPTA

INCRUSE ELLIPTA is an inhalation powder drug product for delivery of umeclidinium (an anticholinergic) to patients by oral inhalation. Umeclidinium bromide has the chemical name 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azoniabicyclo[2.2.2]octane bromide and the following chemical structure: Umeclidinium bromide is a white powder with a molecular weight of 508.5, and the empirical formula is C 29 H 34 NO 2 •Br (as a quaternary ammonium bromide compound). It is slightly soluble in water. INCRUSE ELLIPTA is a light grey and light green plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder blend of micronized umeclidinium bromide (74.2 mcg equivalent to 62.5 mcg of umeclidinium), magnesium stearate (75 mcg), and lactose monohydrate (to 12.5 mg). The lactose monohydrate contains milk proteins. After the inhaler is activated, the powder within the blister is exposed and ready for dispersion into the airstream created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, INCRUSE ELLIPTA delivers 55 mcg of umeclidinium per dose 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 forced expiratory volume in 1 second/forced vital capacity [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 67.5 L/min (range: 41.6 to 83.3 L/min). The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. incruse-ellipta-spl-graphic-01.jpg

INCRUSE ELLIPTA is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). INCRUSE ELLIPTA is an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). ( 1 )

The recommended dosage of INCRUSE ELLIPTA for maintenance treatment of COPD is 1 actuation (umeclidinium 62.5 mcg) once daily by oral inhalation. • INCRUSE ELLIPTA should be used at the same time every day. Do not use INCRUSE ELLIPTA more than 1 time every 24 hours. • No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment [see Clinical Pharmacology ( 12.3 )] . • For oral inhalation only. ( 2 ) • Maintenance treatment of COPD: 1 actuation of INCRUSE ELLIPTA once daily administered by oral inhalation. ( 2 )

INCRUSE ELLIPTA is contraindicated in the following conditions: • Severe hypersensitivity to milk proteins [see Warnings and Precautions ( 5.3 )] • Hypersensitivity to umeclidinium or any of the excipients [see Warnings and Precautions ( 5.3 ), Description ( 11 )] • Severe hypersensitivity to milk proteins. ( 4 ) • Hypersensitivity to any ingredient. ( 4 )

The following adverse reactions are described in greater detail in other sections: • Paradoxical bronchospasm [see Warnings and Precautions ( 5.2 )] • Worsening of narrow-angle glaucoma [see Warnings and Precautions ( 5.4 )] • Worsening of urinary retention [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence ≥2% and more common than placebo) include nasopharyngitis, upper respiratory tract infection, cough, arthralgia. ( 6.1 ) 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 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. In the 8 clinical trials conducted to support initial approval of INCRUSE ELLIPTA, a total of 1,663 subjects with COPD (mean age: 62.7 years; 89% white; 65% male across all treatments, including placebo) received at least 1 inhalation dose of umeclidinium at doses of 62.5 or 125 mcg. In the 4 randomized, double-blind, placebo- or active-controlled, efficacy clinical trials, 1,185 subjects received umeclidinium for up to 24 weeks, of which 487 subjects received the recommended dose of umeclidinium 62.5 mcg. In a 12-month, randomized, double-blind, placebo-controlled, long-term safety trial, 227 subjects received umeclidinium 125 mcg for up to 52 weeks [see Clinical Studies ( 14 )] . The incidence of adverse reactions associated with INCRUSE ELLIPTA in Table 1 is based upon 2 placebo-controlled trials: one 24-week trial (Trial 1) and one 12-week trial (Trial 2) [ see Clinical Studies (14.2)]. Table 1. Adverse Reactions with INCRUSE ELLIPTA with ≥1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease Adverse Reaction INCRUSE ELLIPTA (n = 487) % Placebo (n = 348) % Infections and infestations Nasopharyngitis 8% 7% Upper respiratory tract infection 5% 4% Pharyngitis 1% <1% Viral upper respiratory tract infection 1% <1% Respiratory, thoracic, and mediastinal disorders Cough 3% 2% Musculoskeletal and connective tissue disorders Arthralgia 2% 1% Myalgia 1% <1% Gastrointestinal disorders Abdominal pain upper 1% <1% Toothache 1% <1% Injury, poisoning, and procedural complications Contusion 1% <1% Cardiac disorders Tachycardia 1% <1% Other adverse reactions with INCRUSE ELLIPTA observed with an incidence <1% but more common than placebo included atrial fibrillation. In a long-term safety trial (Trial 3), 336 subjects (n = 227 umeclidinium 125 mcg, n = 109 placebo) were treated for up to 52 weeks with umeclidinium 125 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the efficacy trials described above. Adverse reactions that occurred with a frequency ≥1% in subjects receiving umeclidinium 125 mcg that exceeded that in placebo in this trial were: nasopharyngitis, upper respiratory tract infection, urinary tract infection, pharyngitis, pneumonia, lower respiratory tract infection, rhinitis, supraventricular tachycardia, supraventricular extrasystoles, sinus tachycardia, idioventricular rhythm, headache, dizziness, sinus headache, cough, back pain, arthralgia, pain in extremity, neck pain, myalgia, nausea, dyspepsia, diarrhea, rash, depression, and vertigo. The safety and efficacy of INCRUSE ELLIPTA in combination with an inhaled corticosteroid/long-acting beta 2 -adrenergic agonist (ICS/LABA) were also evaluated in four 12‑week clinical trials (Trial 4, Trial 5, Trial 6, and Trial 7). A total of 1,637 subjects with COPD across four 12‑week, randomized, double-blind clinical trials received at least 1 dose of INCRUSE ELLIPTA (62.5 mcg) or placebo administered once daily in addition to background ICS/LABA (mean age: 64 years, 88% white, 65% male across all treatments). Two trials (Trials 4 and 5) evaluated INCRUSE ELLIPTA in combination with fluticasone furoate/vilanterol (FF/VI) 100 mcg/25mcg administered once daily, and 2 trials (Trials 6 and 7) evaluated INCRUSE ELLIPTA administered once daily in combination with fluticasone propionate/salmeterol (FP/SAL) 250 mcg/50 mcg administered twice daily [see Clinical Studies ( 14.3 )] . Adverse reactions that occurred with INCRUSE ELLIPTA in combination with an ICS/LABA were similar to those reported with INCRUSE ELLIPTA as monotherapy. In addition to the umeclidinium monotherapy adverse reactions reported above, adverse reactions occurring with INCRUSE ELLIPTA in combination with an ICS/LABA, at an incidence of ≥1% and exceeding ICS/LABA alone, were oropharyngeal pain and dysgeusia. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of INCRUSE ELLIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to INCRUSE ELLIPTA or a combination of these factors. Eye Disorders Eye pain, glaucoma, vision blurred. Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, and urticaria. Renal and Urinary Disorders Dysuria, urinary retention. Respiratory, Thoracic and Mediastinal Disorders Dysphonia, oropharyngeal pain.

Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of INCRUSE ELLIPTA with other anticholinergic-containing drugs. ( 7.1 ) 7.1 Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of INCRUSE ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions ( 5.4 , 5.5 )] .