Umeclidinium Ellipta

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

2 DOSAGE AND ADMINISTRATION The recommended dosage of Umeclidinium ELLIPTA for maintenance treatment of COPD is 1 actuation (umeclidinium 62.5 mcg) once daily by oral inhalation. • Umeclidinium ELLIPTA should be used at the same time every day. Do not use Umeclidinium 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 Umeclidinium ELLIPTA once daily administered by oral inhalation. ( 2 )

5 WARNINGS AND PRECAUTIONS • Do not initiate in acutely deteriorating COPD. Do not use to treat acute symptoms. ( 5.1 ) • If paradoxical bronchospasm occurs, discontinue Umeclidinium ELLIPTA and institute alternative therapy. ( 5.2 ) • Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a healthcare provider immediately if symptoms occur. ( 5.4 ) • Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a healthcare provider immediately if symptoms occur. ( 5.5 ) 5.1 Deterioration of Disease and Acute Episodes Umeclidinium ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. Umeclidinium ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of Umeclidinium ELLIPTA in this setting is not appropriate. Umeclidinium ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Umeclidinium 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 beta 2 -agonist. If Umeclidinium ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting re-evaluate the patient and the COPD treatment regimen at once. Increasing the daily dose of Umeclidinium ELLIPTA beyond the recommended dose is not appropriate in this situation. 5.2 Paradoxical Bronchospasm As with other inhaled therapies, Umeclidinium ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Umeclidinium ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; Umeclidinium ELLIPTA should be discontinued immediately; and alternative therapy should be instituted. 5.3 Hypersensitivity Reactions, including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, pruritus, rash, and urticaria may occur after administration of Umeclidinium ELLIPTA. Discontinue Umeclidinium 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 Umeclidinium ELLIPTA [see Contraindications (4), Adverse Reactions ( 6.2 )] . 5.4 Worsening of Narrow-Angle Glaucoma Umeclidinium ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should also be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop. 5.5 Worsening of Urinary Retention Umeclidinium ELLIPTA, like all therapies containing an anticholinergic, should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develop.

4 CONTRAINDICATIONS Umeclidinium 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 )

7 DRUG INTERACTIONS Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of Umeclidinium 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 Umeclidinium 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 )] .

8.1 Pregnancy Risk Summary There are insufficient data on the use of umeclidinium in pregnant women to inform a drug‑associated risk. Umeclidinium administered via inhalation or subcutaneously to pregnant rats and rabbits was not associated with adverse effect on embryofetal development at exposures approximately 50 and 200 times, respectively, the human exposure at the maximum recommended human daily inhaled dose (MRHDID). (See Data.) The estimated risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data: In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the MRHDID, respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species. In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day).

6 ADVERSE REACTIONS 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 Prasco Laboratories at 1-866-525-0688 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 Umeclidinium 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 umeclidinium 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 Umeclidinium ELLIPTA with ≥1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease Adverse Reaction Umeclidinium 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 umeclidinium 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 umeclidinium 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 umeclidinium ELLIPTA (62.5 mcg) or placebo administered once daily in addition to background ICS/LABA …