Breo Ellipta fluticasone furoate and vilanterol trifenatate 100 ug; 25 ug Powder — NDC 0173-0859-61 (Billing 00173-0859-61)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action BREO ELLIPTA BREO ELLIPTA contains both fluticasone furoate and vilanterol. The mechanisms of action described below for the individual components apply to BREO ELLIPTA. These drugs represent 2 different classes of medications (an ICS and a LABA), each having different effects on clinical and physiological indices.

Fluticasone Furoate Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown.

The precise mechanism through which fluticasone furoate affects COPD and asthma symptoms is not known. Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. 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 85 healthy volunteers. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 4.9 (7.5) milliseconds and 9.6 (12.2) milliseconds seen 30 minutes after dosing for fluticasone furoate/vilanterol 200/25 mcg and fluticasone furoate/vilanterol 800/100 mcg, 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 7.8 (9.4) beats/min and 17.1 (18.7) beats/min seen 10 minutes after dosing for fluticasone furoate/vilanterol 200/25 mcg and fluticasone furoate/vilanterol 800/100 mcg, respectively. Hypothalamic-Pituitary-Adrenal Axis Effects Healthy Subjects: Inhaled fluticasone furoate at repeat doses up to 400 mcg was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects.

Decreases in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose. Patients with Chronic Obstructive Pulmonary Disease: In a trial with patients with CO… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action BREO ELLIPTA BREO ELLIPTA contains both fluticasone furoate and vilanterol. The mechanisms of action described below for the individual components apply to BREO ELLIPTA. These drugs represent 2 different classes of medications (an ICS and a LABA), each having different effects on clinical and physiological indices.

Fluticasone Furoate Fluticasone furoate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. The clinical relevance of these findings is unknown.

The precise mechanism through which fluticasone furoate affects COPD and asthma symptoms is not known. Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation.

Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. 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 fluticasone furoate (200 to 800 mcg) and vilanterol (25 to 100 mcg). On repeated once-daily inhalation administration, steady state of fluticasone furoate and vilanterol plasma concentrations was achieved after 6 days, and the accumulation was up to 2.6-fold for fluticasone furoate and 2.4-fold for vilanterol as compared with single dose. Absorption Fluticasone Furoate: Fluticasone furoate plasma levels may not predict therapeutic effect.

Peak plasma concentrations are reached within 0.5 to 1 hour. Absolute bioavailability of fluticasone furoate when administered by inhalation was 15.2%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose is low (approximately 1.3%) due to extensive first-pass metabolism.

Systemic exposure (AUC) in patients with COPD or asthma was 46% or 7% lower, respectively, than observed in healthy subjects. Vilanterol: Vilanterol plasma levels may not predict therapeutic effect. Peak plasma concentrations are reached within 10 minutes following inhalation.

Absolute bioavailability of vilanterol when administered by inhalation was 27.3%, primarily due to absorption of the inhaled portion of the dose delivered to the lung. Oral bioavailability from the swallowed portion of the dose of vilanterol is low (<2%) due to extensive first-pass metabolism. Systemic exposure (AUC) in patients with COPD was 24% higher than observed in healthy subjects.

Systemic exposure (AUC) in patients with asthma was 21% lower than observed in healthy subjects. Distribution Fluticasone Furoate: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 661 L. Binding of fluticasone furoate to human plasma proteins was high (>99%).

Vilanterol: Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. Binding of vilanterol to human plasma proteins was on average 94%. Elimination Metabolism: Fluticasone Furoate: Fluticasone furoate is cleared from systemic circulation principally by hepatic metabolism via CYP3A4 to metabolites with significantly reduced corticosteroid activity.

There was no in vivo evidence for cleavage of the furoate moiety resulting in the formation of fluticasone. Vilanterol: Vilanterol is mainly metabolized, principally via CYP3A4, to a range of metabolites with significantly reduced β 1 - and β 2 -agonist activity. Excretion: Fluticasone Furoate: Fluticasone furoate and its metabolites are eliminated primarily in the feces, accounting for approximately 101% and 90% of the orally and intravenously administered doses, respectively.

Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered doses, respectively. Following repeat-dose inhaled administration, the plasma elimination phase half-life averaged 24 hours. Vilanterol: Following oral administration, vilanterol was eliminated mainly by metabolism followed by excretion of metabolites in urine and feces (approximately 70% and 30%, respectively, of the recovered radioactive dose).

The plasma elimination half-life of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in patients with COPD and 16.0 hours in patients with asthma. Specific Populations The effects of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate and vilanterol are shown in Figure 1 . Figure 1.

Impact of Intrinsic Factors on the Pharmacokinetics (PK) of Fluticasone Furoate (FF) and Vilanterol (VI) Following Administration as Fluticasone Furoate/Vilanterol Combination a Severe renal impairment (CrCl <30 mL/min) compared with healthy subjects; mild (Child‑Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared with healthy subjects. b For COPD and asthma,… [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 85 healthy volunteers. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 4.9 (7.5) milliseconds and 9.6 (12.2) milliseconds seen 30 minutes after dosing for fluticasone furoate/vilanterol 200/25 mcg and fluticasone furoate/vilanterol 800/100 mcg, 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 7.8 (9.4) beats/min and 17.1 (18.7) beats/min seen 10 minutes after dosing for fluticasone furoate/vilanterol 200/25 mcg and fluticasone furoate/vilanterol 800/100 mcg, respectively. Hypothalamic-Pituitary-Adrenal Axis Effects Healthy Subjects: Inhaled fluticasone furoate at repeat doses up to 400 mcg was not associated with statistically significant decreases in serum or urinary cortisol in healthy subjects.

Decreases in serum and urine cortisol levels were observed at fluticasone furoate exposures several-fold higher than exposures observed at the therapeutic dose. Patients with Chronic Obstructive Pulmonary Disease: In a trial with patients with COPD, treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg, vilanterol 25 mcg, or fluticasone furoate (100 or 200 mcg) for 6 months did not affect 24-hour urinary cortisol excretion. A separate trial with patients with COPD demonstrated no effects on serum cortisol after 28 days of treatment with fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg.

Patients with Asthma: A randomized, double-blind, parallel-group trial in 104 pediatric patients with asthma (aged 5 to 11 years) showed no difference between once-daily treatment with inhaled fluticasone furoate 50 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours) and serum cortisol AUC (0-24) following 6 weeks of treatment. A randomized, double-blind, parallel-group trial in 185 patients with asthma aged 12 to 65 years showed no difference between once-daily treatment with fluticasone furoate/vilanterol 100/25 mcg or fluticasone furoate/vilanterol 200/25 mcg compared with placebo on serum cortisol weighted mean (0 to 24 hours), serum cortisol AUC (0-24) , and 24-hour urinary cortisol after 6 weeks of treatment, whereas prednisolone 10 mg given once daily for 7 days resulted in significant cortisol suppression.

14 CLINICAL STUDIES

14.1Chronic Obstructive Pulmonary Disease Four trials evaluated the efficacy of BREO ELLIPTA on lung function (Trial 1, NCT01053988 and Trial 2, NCT01054885) and exacerbations (Trial 3, NCT01009463 and Trial 4, NCT01017952). Lung Function: Trials 1 and 2 were 24-week, randomized, double-blind, placebo-controlled trials designed to evaluate the efficacy of BREO ELLIPTA on lung function in patients with COPD. In Trial 1, patients were randomized to BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, and placebo.

In Trial 2, patients were randomized to BREO ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, fluticasone furoate 100 mcg, vilanterol 25 mcg, and placebo. All treatments were administered as 1 inhalation once daily. Of the 2,254 patients, 70% were male and 84% were White.

They had a mean age of 62 years and an average smoking history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 14% to 87%), mean postbronchodilator FEV 1 /FVC ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). The co-primary efficacy variables in both trials were weighted mean FEV 1 (0 to 4 hours) postdose on Day 168 and change from baseline in trough FEV 1 on Day 169 (the mean of the FEV 1 values obtained 23 and 24 hours after the final dose on Day 168).

The weighted mean comparison of the fluticasone furoate/vilanterol combination with fluticasone furoate was assessed to evaluate the contribution of vilanterol to BREO ELLIPTA. The trough FEV 1 comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA. BREO ELLIPTA 100/25 mcg demonstrated a larger increase in the weighted mean FEV 1 (0 to 4 hours) relative to placebo and fluticasone furoate 100 mcg at Day 168 ( Table 6 ).

Table 6. Least Squares Mean Change from Baseline in Weighted Mean FEV 1 (0-4 h) and Trough FEV 1 at 6 Months FEV 1 = Forced Expiratory Volume in 1 second. a At Day 168. b At Day 169. Treatment N Weighted Mean FEV 1 (0-4 h) a (mL) Trough FEV 1 b (mL) Difference from Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Placebo (95% CI) Vilanterol 25 mcg (95% CI) Trial 1 BREO ELLIPTA 100/25 mcg 204 214 (161, 266) 168 (116, 220) –– 144 (91, 197) 45 (-8, 97) BREO ELLIPTA 200/25 mcg 205 209 (157, 261) –– 168 (117, 219) 131 (80, 183) 32 (-19, 83) Trial 2 BREO ELLIPTA 100/25 mcg 206 173 (123, 224) 120 (70, 170) –– 115 (60, 169) 48 (-6, 102) Serial spirometric evaluations were performed predose and up to 4 hours after dosing.

Results from Trial 1 at Day 1 and Day 168 are shown in Figure 3 . Similar results were seen in Trial 2 (not shown). Figure 3.

Raw Mean Change from Baseline in Postdose Serial FEV 1 (0-4 h) (mL) on Days 1 and 168 Day 1 Day 168 The second co-primary variable was change from baseline in trough FEV 1 following the final treatment day. At Day 169, both Trials 1 and 2 demonstrated significant increases in trough FEV 1 for all strengths of the fluticasone furoate/vilanterol combination compared with placebo ( Table 7 ). The comparison of BREO ELLIPTA 100/25 mcg with vilanterol did not achieve statistical significance ( Table 7 ).

Trials 1 and 2 evaluated FEV 1 as a secondary endpoint. Peak FEV 1 was defined as the maximum postdose FEV 1 recorded within 4 hours after the first dose of trial medicine on Day 1 (measurements recorded at 5, 15, and 30 minutes and 1, 2, and 4 hours). In both trials, differences in mean change from baseline in peak FEV 1 were observed for the groups receiving BREO ELLIPTA 100/25 mcg compared with placebo (152 and 139 mL, respectively).

The median time to onset, defined as a 100-mL increase from baseline in FEV 1 , was 16 minutes in patients receiving BREO… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below. Fluticasone Furoate Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (both approximately 0.5 times the MRHDID of 200 mcg on a mcg/m 2 basis).

Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro . There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/day, respectively (approximately 3 and 8 times, respectively, the MRHDID of 200 mcg 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 8,750 times the MRHDID on an AUC basis). No increase in tumors was seen at an inhaled dose of 615 mcg/kg/day (approximately 530 times the MRHDID 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 45 times the MRHDID on an AUC basis).

No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID 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).