Umeclidinium and Vilanterol Ellipta umeclidinium bromide and vilanterol trifenatate 62.5 ug; 25 ug Powder — NDC 66993-134-97 (Billing 66993-0134-97)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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 inhal… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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 eviden… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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.

14 CLINICAL STUDIES The safety and effectiveness of umeclidinium and vilanterol ELLIPTA were evaluated in a clinical development program that included 6 dose-ranging trials, 4 lung function trials of 6 months’ duration (2 placebo controlled and 2 active controlled), two 12-week crossover trials, and a 12-month long‑term safety trial. The efficacy of umeclidinium and vilanterol ELLIPTA is based primarily on the dose-ranging trials in 1,908 subjects with COPD or asthma [see Clinical Studies ( 14.1 )] and the 2 placebo-controlled confirmatory trials, with additional support from the 2 active-controlled and 2 crossover trials in 5,388 subjects with COPD, including chronic bronchitis and/or emphysema [see Clinical Studies ( 14.2 )] .

Evidence of efficacy for umeclidinium and vilanterol 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 ( 14.2 )] .

14.1Dose-Ranging Trials Dose selection for umeclidinium and vilanterol ELLIPTA in COPD was based on dose-ranging trials for the individual components, vilanterol and umeclidinium. Based on the findings from these studies, once-daily doses of umeclidinium/vilanterol 62.5/25 mcg and umeclidinium/vilanterol 125/25 mcg were evaluated in the confirmatory COPD trials. Umeclidinium and Vilanterol ELLIPTA is not indicated for asthma.

Umeclidinium 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 3 ). 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 3. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV 1 (mL) on Days 1 and 7 Day 1 Day 7 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 FEV 1 at Day 1 and Day 28 ( Figure 4 ).

Figure 4. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV 1 (0 ‑ 24 h) (mL) on Days 1 and 28 Day 1 Day 28 The differences in trough FEV 1 after Day 28 from baseline for placebo and the 3-, 6.25-, 12.5-, 25-, and 50-mcg doses were 29 mL (95% CI: -8, 66), 120 mL (95% CI: 83, 158), 127 mL (95% CI: 90, 164), 138 mL (95% CI: 101, 176), 166 mL (95% CI: 129, 203), and 194 mL (95% CI: 156, 231), respectively. These results supported the evaluation of vilanterol 25 mcg in the confirmatory trials for COPD.

Dose-ranging trials in subjects with asthma evaluated doses from 3 to 50 mcg and 12.5 mcg once-daily versus 6.25 mcg twice-daily dosing frequency. The results supported the selection of the vilanterol 25 mcg once-daily dose for further evaluation in the confirmatory trials for COPD. Figure 3 Figure 3 Figure 4 Figure 4

14.2Confirmatory Trials Lung Function The clinical developm… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Umeclidinium and Vilanterol ELLIPTA No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with umeclidinium and vilanterol ELLIPTA; however, studies are available for the individual components, umeclidinium and vilanterol, as described below. Umeclidinium 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). Vilanterol In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhaled dose of 29,500 mcg/kg/day (approximately 7,800 times the MRHDID for adults on an AUC basis).

No increase in tumors was seen at an inhaled dose of 615 mcg/kg/day (approximately 210 times the MRHDID for adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhaled doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 20 times the MRHDID for adults on an AUC basis). No tumors were seen at an inhaled dose of 10.5 mcg/kg/day (approximately equal to the MRHDID for adults on an AUC basis).

These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay.

Vilanterol tested equivocal in the in vitro mouse lymphoma assay. No evidence of impairment of fertility was observed in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (both approximately 5,490 times the MRHDID based on AUC).