Incruse Ellipta umeclidinium 62.5 ug Aerosol, Powder — NDC 0173-0873-10 (Billing 00173-0873-10)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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 receptors 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.

12.2Pharmacodynamics Cardiac Electrophysiology QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover study in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent.

12.3Pharmacokinetics Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg). Absorption 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 INCRUSE ELLIPTA, steady state was achieved within 14 days with up to 1.8-fold accumulation. Distribution 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%. Elimination Metabolism: 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. Excretion: The effective half-life after once-daily orally inhaled 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. Specific Populations 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 umeclidinium.

In addition, there was no evidence of a clinically significant effect of race. Patients with Hepatic Impairment: The impact of hepatic impairment on the pharmacokinetics of INCRUSE 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 umeclidinium (C max and AUC) (Figure 1).

There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. INCRUSE ELLIPTA has not been evaluated in subjects with severe hepatic impairment. Patients with Renal Impairment: The pharmacokinetics of INCRUSE ELLIPTA has been evaluated in subjects with severe renal impairment (CrCl <30 mL/min).

There was no evidence of a… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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 receptors 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.

12.3Pharmacokinetics Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg). Absorption 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 INCRUSE ELLIPTA, steady state was achieved within 14 days with up to 1.8-fold accumulation. Distribution 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%. Elimination Metabolism: 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. Excretion: The effective half-life after once-daily orally inhaled 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. Specific Populations 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 umeclidinium.

In addition, there was no evidence of a clinically significant effect of race. Patients with Hepatic Impairment: The impact of hepatic impairment on the pharmacokinetics of INCRUSE 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 umeclidinium (C max and AUC) (Figure 1).

There was no evidence of altered protein binding in subjects with moderate hepatic impairment compared with healthy subjects. INCRUSE ELLIPTA has not been evaluated in subjects with severe hepatic impairment. Patients with Renal Impairment: The pharmacokinetics of INCRUSE ELLIPTA has been evaluated in subjects with severe renal impairment (CrCl <30 mL/min).

There was no evidence of an increase in systemic exposure to umeclidinium (C max and AUC) (Figure 1). There was no evidence of altered protein binding in subjects with severe renal impairment compared with healthy subjects. Figure 1.

Impact of Intrinsic and Extrinsic Factors on the Systemic Exposure of Umeclidinium Drug Interaction Studies Umeclidinium and P-glycoprotein Transporter: Umeclidinium is a substrate of P-gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium was assessed in healthy subjects. No effect on umeclidinium C max was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed (Figure 1).

Umeclidinium and 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 to normal (ultrarapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects (Figure 1). Figure 1.

Impact of Intrinsic and Extrinsic Factors on the Systemic Exposure of Umeclidinium

12.2Pharmacodynamics Cardiac Electrophysiology QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover study in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent.

14 CLINICAL STUDIES The safety and efficacy of umeclidinium 62.5 mcg were evaluated in 3 dose-ranging trials, 2 placebo-controlled clinical trials (one 12-week trial and one 24-week trial), and a 12-month long‑term safety trial. The efficacy of INCRUSE ELLIPTA is based primarily on the dose‑ranging trials in 624 subjects and the 2 placebo-controlled confirmatory trials in 1,738 subjects with COPD, including chronic bronchitis and/or emphysema. [See Clinical Studies ( 14.1 , 14.2 ).] The safety and efficacy of INCRUSE ELLIPTA in combination with an ICS/LABA were also evaluated in four 12-week clinical trials.

The efficacy of INCRUSE ELLIPTA in combination with an ICS/LABA is based on 1,637 subjects with COPD. [See Clinical Studies ( 14.3 ).] Evidence of efficacy for INCRUSE ELLIPTA on COPD exacerbations was established by the efficacy of the umeclidinium component as part of a fixed-dose combination with an ICS/LABA, as assessed in a 12-month trial in 10,355 subjects. [See Clinical Studies ( 14.3 ).]

14.1Dose-Ranging Trials Dose selection for umeclidinium in COPD was supported by a 7-day, randomized, double-blind, placebo-controlled, crossover trial evaluating 4 doses of umeclidinium (15.6 to 125 mcg) or placebo dosed once daily in the morning in 163 subjects with COPD. A dose ordering was observed, with the 62.5- and 125-mcg doses demonstrating larger improvements in FEV 1 over 24 hours compared with the lower doses of 15.6 and 31.25 mcg (Figure 2). The differences in trough FEV 1 from baseline after 7 days for placebo and the 15.6-, 31.25-, 62.5-, and 125-mcg doses were -74 mL (95% CI: -118, -31), 38 mL (95% CI: -6, 83), 27 mL (95% CI: -18, 72), 49 mL (95% CI: 6, 93), and 109 mL (95% CI: 65, 152), respectively.

Two additional dose-ranging trials in subjects with COPD demonstrated minimal additional benefit at doses above 125 mcg. The dose-ranging results supported the evaluation of 2 doses of umeclidinium, 62.5 and 125 mcg, in the confirmatory COPD trials to further assess dose response. Evaluations of dosing interval by comparing once- and twice-daily dosing supported selection of a once-daily dosing interval for further evaluation in the confirmatory COPD trials.

Figure 2. Adjusted Mean Change from Baseline in Postdose Serial FEV 1 (mL) on Days 1 and 7 Day 1 Day 7 Figure 2. Adjusted Mean Change from Baseline in Postdose Serial FEV1 (mL) on Days 1 and 7, Day 1 Figure 2.

Adjusted Mean Change from Baseline in Postdose Serial FEV1 (mL) on Days 1 and 7, Day 7

14.2Maintenance Treatment: Confirmatory Trials Lung Function The clinical development program for INCRUSE ELLIPTA included 2 randomized, double‑blind, placebo-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy of INCRUSE ELLIPTA on lung function. Trial 1 (NCT01313650) was a 24-week placebo‑controlled trial, and Trial 2 (NCT01387230) was a 12-week placebo‑controlled trial. These trials treated subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking ≥10 pack-years, had a post-albuterol FEV 1 ≤70% of predicted normal values, had a ratio of FEV 1 /FVC of <0.7, and had a Modified Medical Research Council (mMRC) score ≥2.

Subjects in Trial 1 had a mean age of 63 years and an average smoking history of 46 pack-years, with 50% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 47% (range: 13% to 74%), the mean postbronchodilator FEV 1 /FVC ratio was 0.47 (range: 0.20 to 0.74), and the mean percent reversibility was 15% (range: -35% to 109%). The majority of subjects (72%) reported not having a COPD exacerbation in the prior 12 months.

Baseline demographics and lung function for subjects in Trial 2 were similar to those in Trial 1. Trial 1 evaluated umeclidinium 62.5 mcg and placebo. The primary endpoint was change from baseline in trough (predose) FEV 1 at Day 169 (defined as the mean of the FEV 1 values obtained at 23 and 24 hours after the pre… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times, respectively, the MRHDID for adults on an AUC basis). Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and at inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID for adults on an AUC basis).