Umeclidinium Bromide and Vilanterol Trifenatate

5 WARNINGS AND PRECAUTIONS

• LABA monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 )
• Do not initiate in acutely deteriorating COPD. Do not use to treat acute symptoms. ( 5.2 )
• Do not use in combination with additional therapy containing a LABA because of risk of overdose. ( 5.3 )
• If paradoxical bronchospasm occurs, discontinue Umeclidinium and Vilanterol ELLIPTA and institute alternative therapy. ( 5.5 )
• Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.7 )
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.8 )
• 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. ( 5.9 )
• 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. ( 5.10 )
• Be alert to hypokalemia and hyperglycemia. ( 5.11 )

5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death The safety and effectiveness of Umeclidinium and Vilanterol ELLIPTA in patients with asthma have not been established. Umeclidinium and Vilanterol ELLIPTA is not indicated for the treatment of asthma [see Contraindications ( 4 )] . Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone. Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled, U.S. 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 LABAs, including vilanterol, one of the active ingredients in Umeclidinium and Vilanterol ELLIPTA. No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with Umeclidinium and Vilanterol ELLIPTA has been conducted. Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes Umeclidinium and Vilanterol ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. Umeclidinium and Vilanterol ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of Umeclidinium and Vilanterol ELLIPTA in this setting is not appropriate. If Umeclidinium and Vilanterol 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. The daily dose of Umeclidinium and Vilanterol ELLIPTA should not be increased. Increasing use of inhaled, short-acting beta 2 -agonists is a signal of deteriorating disease. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the need for additional therapeutic options. Patients should not use more than 1 inhalation of Umeclidinium and Vilanterol ELLIPTA once daily. Umeclidinium and Vilanterol 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 and Vilanterol 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. When beginning treatment with Umeclidinium and Vilanterol ELLIPTA, patients who have been taking oral or inhaled, short-acting beta 2 -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 Umeclidinium and Vilanterol ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist and instruct the patient on how it should be used.

5.3 Avoid Excessive Use of Umeclidinium and Vilanterol ELLIPTA and Avoid Use with Other Long-Acting Beta 2 -Agonists Umeclidinium and Vilanterol ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other therapies containing LABAs, 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 Umeclidinium and Vilanterol ELLIPTA should not use another therapy containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of Umeclidinium and Vilanterol ELLIPTA with ketoconazole and other known strong cytochrome P450 3A4 (CYP3A4) inhibitors (including, but not limited to, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased cardiovascular adverse effects may occur [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )] .

5.5 Paradoxical Bronchospasm As with other inhaled therapies, Umeclidinium and Vilanterol ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Umeclidinium and Vilanterol ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; Umeclidinium and Vilanterol ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

5.6 Hypersensitivity Reactions, including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of Umeclidinium and Vilanterol ELLIPTA. Discontinue Umeclidinium and Vilanterol 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 and Vilanterol ELLIPTA [see Contraindications ( 4 ), Adverse Reactions ( 6.2 )] .

5.7 Cardiovascular Effects Vilanterol, like other beta 2 -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, Umeclidinium and Vilanterol 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 [see Clinical Pharmacology ( 12.2 )] . Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Umeclidinium and Vilanterol ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. In a 52-week trial of subjects with COPD, the exposure-adjusted rates for any on-treatment major adverse cardiac event, including non-fatal central nervous system hemorrhages and cerebrovascular conditions, non-fatal myocardial infarction, non-fatal acute myocardial infarction, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 mcg (n = 4,151), 1.9 per 100 patient-years for fluticasone furoate/vilanterol 100/25 mcg (n = 4,134), and 2.2 per 100 patient-years for umeclidinium and vilanterol ELLIPTA (n = 2,070). Adjudicated on‑treatment deaths due to cardiovascular events occurred in 20 of 4,151 patients (0.54 per 100 patient-years) receiving fluticasone furoate/umeclidinium/vilanterol, 27 of 4,134 patients (0.78 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 16 of 2,070 patients (0.94 per 100 patient-years) receiving umeclidinium and vilanterol ELLIPTA.

5.8 Coexisting Conditions Umeclidinium and Vilanterol ELLIPTA, like all therapies 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 beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.9 Worsening of Narrow-Angle Glaucoma Umeclidinium and Vilanterol 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.

5.10 Worsening of Urinary Retention Umeclidinium and Vilanterol 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.

5.11 Hypokalemia and Hyperglycemia Beta-adrenergic agonist therapies 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 therapies may produce transient hyperglycemia in some patients. In 4 clinical trials of 6-month duration evaluating umeclidinium and vilanterol ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

The following clinically significant adverse reactions are described elsewhere in labeling:

• Serious asthma-related events–hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )]
• Paradoxical bronchospasm [see Warnings and Precautions ( 5.5 )]
• Cardiovascular effects [see Warnings and Precautions ( 5.7 )]
• Worsening of narrow-angle glaucoma [see Warnings and Precautions ( 5.9 )]
• Worsening of urinary retention [see Warnings and Precautions ( 5.10 )] Most common adverse reactions (incidence ≥1% and more common than placebo) are pharyngitis, sinusitis, lower respiratory tract infection, constipation, diarrhea, pain in extremity, muscle spasms, neck pain, and chest pain. ( 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. The clinical program for umeclidinium and vilanterol ELLIPTA included 8,138 subjects with COPD in four 6‑month lung function trials, one 12-month long-term safety study, and 9 other trials of shorter duration. A total of 1,124 subjects have received at least 1 dose of umeclidinium and vilanterol ELLIPTA (umeclidinium/vilanterol 62.5/25 mcg), and 1,330 subjects have received a higher dose of umeclidinium/vilanterol (125/25 mcg). The safety data described below are based on the four 6-month and one 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials. 6-Month Trials The incidence of adverse reactions associated with umeclidinium and vilanterol ELLIPTA in Table 1 is based on four 6-month trials: 2 placebo-controlled trials (Trial 1 and Trial 2); N = 1,532 and N = 1,489, respectively) and 2 active-controlled trials (Trial 3 and Trial 4); N = 843 and N = 869, respectively). Of the 4,733 subjects, 68% were male and 84% were white. They had a mean age of 63 years and an average smoking history of 45 pack-years, with 50% identified as current smokers. At screening, the mean postbronchodilator percent predicted forced expiratory volume in 1 second (FEV 1 ) was 48% (range: 13% to 76%), the mean postbronchodilator FEV 1 /forced vital capacity (FVC) ratio was 0.47 (range: 0.13 to 0.78), and the mean percent reversibility was 14% (range: -45% to 109%). Subjects received 1 dose once daily of the following: umeclidinium and vilanterol ELLIPTA, umeclidinium/vilanterol 125/25 mcg, umeclidinium 62.5 mcg, umeclidinium 125 mcg, vilanterol 25 mcg, active control, or placebo. Table 1. Adverse Reactions with Umeclidinium and Vilanterol ELLIPTA with ≥1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease Adverse Reaction Umeclidinium and Vilanterol ELLIPTA (n = 842) % Umeclidinium 62.5 mcg (n = 418) % Vilanterol 25 mcg (n = 1,034) % Placebo (n = 555) % Infections and infestations Pharyngitis 2 1 2 <1 Sinusitis 1 <1 1 <1 Lower respiratory tract infection 1 <1 <1 <1 Gastrointestinal disorders Constipation 1 <1 <1 <1 Diarrhea 2 <1 2 1 Musculoskeletal and connective tissue disorders Pain in extremity 2 <1 2 1 Muscle spasms 1 <1 <1 <1 Neck pain 1 <1 <1 <1 General disorders and administration site conditions Chest pain 1 <1 <1 <1 Other adverse reactions with umeclidinium and vilanterol ELLIPTA observed with an incidence <1% but more common than placebo included the following: productive cough, dry mouth, dyspepsia, abdominal pain, gastroesophageal reflux disease, vomiting, musculoskeletal chest pain, chest discomfort, asthenia, atrial fibrillation, ventricular extrasystoles, supraventricular extrasystoles, myocardial infarction, pruritus, rash, and conjunctivitis. 12-Month Trial In a long-term safety trial (Trial 5), 335 subjects were treated for up to 12 months with umeclidinium/vilanterol 125/25 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo‑controlled efficacy trials described above. Adverse reactions observed with a frequency of ≥1% in the group receiving umeclidinium/vilanterol 125/25 mcg that exceeded that in placebo in this trial were: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, viral respiratory tract infection, toothache, and diabetes mellitus.

6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of umeclidinium and vilanterol 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 umeclidinium and vilanterol ELLIPTA or a combination of these factors. Cardiac Disorders Palpitations. Eye Disorders Blurred vision, eye pain, glaucoma, increased intraocular pressure. Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria. Nervous System Disorders Dysgeusia, tremor. Psychiatric Disorders Anxiety. Renal and Urinary Disorders Dysuria, urinary retention. Respiratory, Thoracic, and Mediastinal Disorders Dysphonia, paradoxical bronchospasm.

8.1 Pregnancy Risk Summary There are insufficient data on the use of umeclidinium and vilanterol ELLIPTA or its individual components, umeclidinium and vilanterol, in pregnant women to inform a drug-associated risk. (See Clinical Considerations.) In animal reproduction studies, umeclidinium administered via inhalation or subcutaneously to pregnant rats and rabbits was not associated with adverse effects on embryofetal development at exposures approximately 50 and 200 times, respectively, the human exposure at the maximum recommended human daily inhaled dose (MRHDID). Vilanterol administered via inhalation to pregnant rats and rabbits produced no fetal structural abnormalities at exposures approximately 70 times the 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. Clinical Considerations Labor or Delivery: Umeclidinium and Vilanterol ELLIPTA should be used during late gestation and labor only if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility. Data Animal Data: The combination of umeclidinium and vilanterol has not been studied in pregnant animals. Studies in pregnant animals have been conducted with umeclidinium and vilanterol individually. Umeclidinium: 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). Vilanterol: In separate embryofetal developmental studies, pregnant rats and rabbits received vilanterol during the period of organogenesis at doses up to approximately 13,000 and 450 times, respectively, the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 5,740 mcg/kg/day in rabbits). No evidence of structural abnormalities was observed at any dose in rats or in rabbits up to approximately 70 times the MRHDID (on an AUC basis at maternal doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. In a perinatal and postnatal developmental study in rats, dams received vilanterol during late gestation and the lactation periods at doses up to approximately 3,900 times the MRHDID (on a mcg/m 2 basis at maternal oral doses up to 10,000 mcg/kg/day). No evidence of effects in offspring development was observed.

8.2 Lactation Risk Summary There is no information available on the presence of umeclidinium or vilanterol in human milk, the effects on the breastfed child, or the effects on milk production. Umeclidinium was detected in the plasma of offspring of lactating rats treated with umeclidinium suggesting its presence in maternal milk. (See Data.) The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Umeclidinium and Vilanterol ELLIPTA and any potential adverse effects on the breastfed child from umeclidinium or vilanterol or from the underlying maternal condition. Data Subcutaneous administration of umeclidinium to lactating rats at greater than or equal to 60 mcg/kg/day resulted in a quantifiable level of umeclidinium in 2 of 54 pups, which may indicate transfer of umeclidinium in rat milk.

8.4 Pediatric Use The safety and effectiveness of Umeclidinium and Vilanterol ELLIPTA have not been established in pediatric patients. Umeclidinium and Vilanterol ELLIPTA is not indicated for use in pediatric patients.

8.5 Geriatric Use Based on available data, no adjustment of the dosage of Umeclidinium and Vilanterol ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of umeclidinium and vilanterol ELLIPTA for COPD included 2,143 subjects aged 65 years and older and 478 subjects aged 75 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.

8.6 Hepatic Impairment Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in C max or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed [see Clinical Pharmacology ( 12.3 )] .

8.7 Renal Impairment There were no significant increases in either umeclidinium or vilanterol exposure in subjects with severe renal impairment (CrCl <30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology ( 12.3 )] .

12.1 Mechanism of Action Umeclidinium and Vilanterol ELLIPTA Umeclidinium and Vilanterol ELLIPTA contains both umeclidinium and vilanterol. The mechanisms of action described below for the individual components apply to Umeclidinium and Vilanterol ELLIPTA. These drugs represent 2 different classes of medications (an anticholinergic and a LABA) each having different effects on clinical and physiological indices. Umeclidinium Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect. Vilanterol Vilanterol is a LABA. In vitro tests have shown the functional selectivity of vilanterol was similar to salmeterol. The clinical relevance of this in vitro finding is unknown. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenergic agonist drugs, including vilanterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

12.2 Pharmacodynamics Cardiac Electrophysiology Healthy Subjects: QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled crossover study in 86 healthy subjects. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 4.6 (7.1) milliseconds and 8.2 (10.7) milliseconds for umeclidinium/vilanterol 125/25 mcg and umeclidinium/vilanterol 500/100 mcg (8/4 times the recommended dosage), respectively. A dose-dependent increase in heart rate was also observed. The maximum mean (95% upper confidence bound) difference in heart rate from placebo after baseline correction was 8.8 (10.5) beats/min and 20.5 (22.3) beats/min seen 10 minutes after dosing for umeclidinium/vilanterol 125/25 mcg and umeclidinium/vilanterol 500/100 mcg, respectively. Subjects with Chronic Obstructive Pulmonary Disease: The effect of Umeclidinium and Vilanterol ELLIPTA on cardiac rhythm in subjects diagnosed with COPD was assessed using 24-hour Holter monitoring in 6- and 12‑month trials: 53 subjects received umeclidinium and vilanterol ELLIPTA, 281 subjects received umeclidinium/vilanterol 125/25 mcg, and 182 subjects received placebo. No clinically meaningful effects on cardiac rhythm were observed.

12.3 Pharmacokinetics Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg) and vilanterol (25 to 100 mcg). Absorption Umeclidinium: Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C max occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium and vilanterol ELLIPTA, steady state was achieved within 14 days with up to 1.8-fold accumulation. Vilanterol: Vilanterol plasma levels may not predict therapeutic effect. Following inhaled administration of vilanterol in healthy subjects, C max occurred at 5 to 15 minutes. Vilanterol is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium and vilanterol ELLIPTA, steady state was achieved within 14 days with up to 1.7-fold accumulation. Distribution Umeclidinium: Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%. Vilanterol: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. In vitro plasma protein binding in human plasma was on average 94%. Elimination Metabolism: Umeclidinium: In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. Vilanterol: In vitro data showed that vilanterol is metabolized principally by CYP3A4 and is a substrate for the P-gp transporter. Vilanterol is metabolized to a range of metabolites with significantly reduced β 1 - and β 2 -agonist activity. Excretion: Umeclidinium: The effective half-life after once-daily oral dosing is 11 hours. Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption. Vilanterol: The effective half-life for vilanterol, as determined from inhalation administration of multiple doses, is 11 hours. Following oral administration of radiolabeled vilanterol, mass balance showed 70% of the radiolabel in the urine and 30% in the feces. Specific Populations The effects of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of umeclidinium and vilanterol are shown in Figure 1 . Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 93 years) ( Figure 1 ), gender (69% male) ( Figure 1 ), inhaled corticosteroid use (48%), or weight (34 to 161 kg) on systemic exposure of either umeclidinium or vilanterol. In addition, there was no evidence of a clinically significant effect of race. Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI) Patients with Hepatic Impairment: The impact of hepatic impairment on the pharmacokinetics of umeclidinium and vilanterol ELLIPTA has been evaluated in subjects with moderate hepatic impairment (Child‑Pugh score of 7-9). There was no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (C max and AUC) ( Figure 1 ). There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. Umeclidinium and vilanterol ELLIPTA has not been evaluated in subjects with severe hepatic impairment. Patients with Renal Impairment: The pharmacokinetics of umeclidinium and vilanterol ELLIPTA has been evaluated in subjects with severe renal impairment (CrCl <30 mL/min). Umeclidinium systemic exposure was not increased and vilanterol systemic exposure (AUC (0-24) ) was 56% higher in subjects with severe renal impairment compared with healthy subjects ( Figure 1 ). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects. Drug Interaction Studies When umeclidinium and vilanterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately. Inhibitors of Cytochrome P450 3A4: Vilanterol is a substrate of CYP3A4. A double-blind, repeat-dose, 2-way crossover drug interaction trial was conducted in healthy subjects to investigate the pharmacokinetic and pharmacodynamic effects of vilanterol 25 mcg as an inhalation powder with ketoconazole 400 mg. The plasma concentrations of vilanterol were higher after single and repeated doses when coadministered with ketoconazole than with placebo ( Figure 2 ). The increase in vilanterol exposure was not associated with an increase in beta‑agonist–related systemic effects on heart rate or blood potassium. Inhibitors of Cytochrome P450 2D6: In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing in CYP2D6 normal (ultrarapid, extensive, and intermediate metabolizers) and poor metabolizer subjects ( Figure 1 ). Inhibitors of P-glycoprotein: Umeclidinium and vilanterol are both substrates of P‑gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium and vilanterol was assessed in healthy subjects. No effect on umeclidinium or vilanterol C max was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed with no effect on vilanterol AUC ( Figure 2 ). Figure 2. Impact of Extrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI) Figure 1 Figure 2

Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg) and vilanterol (25 to 100 mcg). Absorption Umeclidinium: Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C max occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium and vilanterol ELLIPTA, steady state was achieved within 14 days with up to 1.8-fold accumulation. Vilanterol: Vilanterol plasma levels may not predict therapeutic effect. Following inhaled administration of vilanterol in healthy subjects, C max occurred at 5 to 15 minutes. Vilanterol is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium and vilanterol ELLIPTA, steady state was achieved within 14 days with up to 1.7-fold accumulation. Distribution Umeclidinium: Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%. Vilanterol: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. In vitro plasma protein binding in human plasma was on average 94%. Elimination Metabolism: Umeclidinium: In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. Vilanterol: In vitro data showed that vilanterol is metabolized principally by CYP3A4 and is a substrate for the P-gp transporter. Vilanterol is metabolized to a range of metabolites with significantly reduced β 1 - and β 2 -agonist activity. Excretion: Umeclidinium: The effective half-life after once-daily oral dosing is 11 hours. Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption. Vilanterol: The effective half-life for vilanterol, as determined from inhalation administration of multiple doses, is 11 hours. Following oral administration of radiolabeled vilanterol, mass balance showed 70% of the radiolabel in the urine and 30% in the feces. Specific Populations The effects of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of umeclidinium and vilanterol are shown in Figure 1 . Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 93 years) ( Figure 1 ), gender (69% male) ( Figure 1 ), inhaled corticosteroid use (48%), or weight (34 to 161 kg) on systemic exposure of either umeclidinium or vilanterol. In addition, there was no evidence of a clinically significant effect of race. Figure 1. Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI) Patients with Hepatic Impairment: The impact of hepatic impairment on the pharmacokinetics of umeclidinium and vilanterol ELLIPTA has been evaluated in subjects with moderate hepatic impairment (Child‑Pugh score of 7-9). There was no evidence of an increase in systemic exposure to either umeclidinium or vilanterol (C max and AUC) ( Figure 1 ). There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. Umeclidinium and vilanterol ELLIPTA has not been evaluated in subjects with severe hepatic impairment. Patients with Renal Impairment: The pharmacokinetics of umeclidinium and vilanterol ELLIPTA has been evaluated in subjects with severe renal impairment (CrCl <30 mL/min). Umeclidinium systemic exposure was not increased and vilanterol systemic exposure (AUC (0-24) ) was 56% higher in subjects with severe renal impairment compared with healthy subjects ( Figure 1 ). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects. Drug Interaction Studies When umeclidinium and vilanterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately. Inhibitors of Cytochrome P450 3A4: Vilanterol is a substrate of CYP3A4. A double-blind, repeat-dose, 2-way crossover drug interaction trial was conducted in healthy subjects to investigate the pharmacokinetic and pharmacodynamic effects of vilanterol 25 mcg as an inhalation powder with ketoconazole 400 mg. The plasma concentrations of vilanterol were higher after single and repeated doses when coadministered with ketoconazole than with placebo ( Figure 2 ). The increase in vilanterol exposure was not associated with an increase in beta‑agonist–related systemic effects on heart rate or blood potassium. Inhibitors of Cytochrome P450 2D6: In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing in CYP2D6 normal (ultrarapid, extensive, and intermediate metabolizers) and poor metabolizer subjects ( Figure 1 ). Inhibitors of P-glycoprotein: Umeclidinium and vilanterol are both substrates of P‑gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium and vilanterol was assessed in healthy subjects. No effect on umeclidinium or vilanterol C max was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed with no effect on vilanterol AUC ( Figure 2 ). Figure 2. Impact of Extrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI) Figure 1 Figure 2