"The U.S. Food and Drug Administration today approved Breo Ellipta (fluticasone furoate and vilanterol inhalation powder) for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary di"...
Mechanism Of Action
Since 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 (a synthetic corticosteroid and a LABA) that have different effects on clinical and physiological indices.
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 in vitro findings is unknown. The precise mechanism through which fluticasone furoate affects COPD symptoms is not known. 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.
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 beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-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 beta2-agonists may have cardiac effects.
The pharmacologic effects of beta2-adrenoceptor 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.
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 200mcg/25 mcg and fluticasone furoate/vilanterol 800 mcg/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 mcg/25 mcg and fluticasone furoate/vilanterol 800 mcg/100 mcg, respectively.
Chronic Obstructive Pulmonary Disease: In 4 clinical trials of 6- and 12-month duration, there was no evidence of a treatment effect on heart rate, QTcF, or blood pressure in subjects with COPD given combination doses of fluticasone furoate (50, 100, or 200 mcg)/vilanterol 25 mcg, the individual components of fluticasone furoate or vilanterol alone, or placebo [see Clinical Studies].
HPA 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.
Chronic Obstructive Pulmonary Disease: In a trial with subjects with COPD, treatment with fluticasone furoate/vilanterol (50 mcg/25 mcg, 100 mcg/25 mcg, and 200 mcg/25 mcg), vilanterol 25 mcg, and fluticasone furoate (100 and 200 mcg) for 6 months did not affect 24-hour urinary cortisol excretion. A separate trial with subjects with COPD demonstrated no effects on serum cortisol after 28 days of treatment with fluticasone furoate/vilanterol (50 mcg/25 mcg, 100 mcg/25 mcg, and 200 mcg/25 mcg).
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.
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 administrated 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 subjects with COPD was 46% lower 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 administrated 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 (less than 2%) due to extensive first-pass metabolism. Systemic exposure in subjects with COPD was 24% higher than observed in healthy subjects.
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 (99.6%).
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 93.9%.
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 p1- and p2-agonist activity.
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 dose, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered doses, respectively. Following repeatdose 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% of the recovered radioactive dose, respectively). The effective half-life for accumulation of vilanterol, as determined from inhalation administration of multiple doses of vilanterol 25 mcg, is 21.3 hours in subjects with COPD.
The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of fluticasone furoate and vilanterol is shown in Figure 1.
Figure 1: Impact of Intrinsic Factors on the
Pharmacokinetics (PK) of Fluticasone Furoate and Vilanterol Following
Administration as Fluticasone Furoate/Vilanterol Combination
a Age, gender, and ethnicity comparison for BREO ELLIPTA (fluticasone furoate/vilanterol 100 mcg/25 mcg) in subjects with COPD.
b Renal groups (fluticasone furoate/vilanterol 200 mcg/25 mcg) and hepatic groups (fluticasone furoate/vilanterol 200 mcg/25 mcg or fluticasone furoate/vilanterol 100 mcg/12.5 mcg) compared with healthy control group.
Race: Systemic exposure (AUC(0-24)) to inhaled fluticasone furoate 200 mcg was 27% to 49% higher in healthy subjects of Japanese, Korean, and Chinese heritage compared with Caucasian subjects. Similar differences were observed for subjects with COPD (Figure 1). However, there is no evidence that this higher exposure to fluticasone furoate results in clinically relevant effects on urinary cortisol excretion or on efficacy in these racial groups.
There was no effect of race on the pharmacokinetics of vilanterol in subjects with COPD.
Hepatic Impairment: Fluticasone Furoate: Following repeat dosing of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 7 days, there was an increase of 34%, 83%, and 75% in fluticasone furoate systemic exposure (AUC) in subjects with mild, moderate, and severe hepatic impairment, respectively, compared with healthy subjects (see Figure 1).
In subjects with moderate hepatic impairment receiving fluticasone furoate/vilanterol 200 mcg/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (95% CI: 11%, 51%) compared with healthy subjects. In subjects with severe hepatic impairment receiving fluticasone furoate/vilanterol 100 mcg/12.5 mcg, mean serum cortisol (0 to 24 hours) was increased by 14% (95% CI: -16%, 55%) compared with healthy subjects. Patients with moderate to severe hepatic disease should be closely monitored.
Vilanterol: Hepatic impairment had no effect on vilanterol systemic exposure (Cmax and AUC(0-24) on Day 7) following repeat-dose administration of fluticasone furoate/vilanterol 200 mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 7 days (see Figure 1).
There were no additional clinically relevant effects of the fluticasone furoate/vilanterol combinations on heart rate or serum potassium in subjects with mild or moderate hepatic impairment (vilanterol 25 mcg combination) or with severe hepatic impairment (vilanterol 12.5 mcg combination) compared with healthy subjects.
Renal Impairment: Fluticasone furoate 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 (see Figure 1). There was no evidence of greater corticosteroid or beta-agonist class-related systemic effects (assessed by serum cortisol, heart rate, and serum potassium) in subjects with severe renal impairment compared with healthy subjects.
There were no clinically relevant differences in the pharmacokinetics or pharmacodynamics of either fluticasone furoate or vilanterol when administered in combination compared with administration alone. The potential for fluticasone furoate and vilanterol to inhibit or induce metabolic enzymes and transporter systems is negligible at low inhalation doses.
Inhibitors of Cytochrome P450 3A4: The exposure (AUC) of fluticasone furoate and vilanterol were 36% and 65% higher, respectively, when coadministered with ketoconazole 400 mg compared with placebo (see Figure 2). The increase in fluticasone furoate exposure was associated with a 27% reduction in weighted mean serum cortisol (0 to 24 hours). The increase in vilanterol exposure was not associated with an increase in beta-agonist-related systemic effects on heart rate or blood potassium.
Figure 2: Impact of Coadministered Drugsa on the
Pharmacokinetics (PK) of Fluticasone Furoate and Vilanterol Following
Administration as Fluticasone Furoate/Vilanterol Combination or Vilanterol
Coadministered With a Long-Acting Muscarinic Antagonist
a Compared with placebo group.
Inhibitors of P-glycoprotein: Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). Coadministration of repeat-dose (240 mg once daily) verapamil (a potent P-gp inhibitor and moderate CYP3A4 inhibitor) did not affect the vilanterol Cmax or AUC in healthy subjects (see Figure 2). Drug interaction trials with a specific P-gp inhibitor and fluticasone furoate have not been conducted.
The safety and efficacy of BREO ELLIPTA were evaluated in 7,700 subjects with COPD. The development program included 4 confirmatory trials of 6- and 12-months' duration, three 12-week active comparator trials, and dose-ranging trials of shorter duration. The efficacy of BREO ELLIPTA is based primarily on the dose-ranging trials and the 4 confirmatory trials described below.
Dose selection for BREO ELLIPTA for COPD was based on dose-ranging trials for the individual components, vilanterol and fluticasone furoate, in patients with COPD and asthma. BREO ELLIPTA 100 mcg/25 mcg is not indicated for asthma.
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 patients with COPD. Results demonstrated dose-related increases in FEV1 compared with placebo at Day 1 and Day 28 (Figure 3).
Figure 3: Least Squares (LS) Mean Difference From
Placebo in Post-Dose Serial FEV1 (024 h, mL) on Days 1 and 28
The differences in trough FEV1 on Day 28 from placebo for the 3-, 6.25-, 12.5-, 25-, and 50-mcg doses were 92 mL (95% CI: 39, 144), 98 mL (95% CI: 46, 150), 110 mL (95% CI: 57, 162), 137 mL (95% CI: 85, 190), and 165 mL (95% CI: 112, 217), respectively. These results supported the evaluation of vilanterol 25 mcg in the confirmatory COPD trials.
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 COPD trials.
Eight doses of fluticasone furoate ranging from 25 to 800 mcg once daily were evaluated in 3 randomized, double-blind, placebo-controlled, 8-week trials in subjects with asthma. A dose-related increase in trough FEV1 at Week 8 was seen for doses from 25 to 200 mcg with no consistent additional benefit for doses above 200 mcg. To evaluate dosing frequency, a separate trial compared fluticasone furoate 200 mcg once-daily, fluticasone furoate 100 mcg twice-daily, fluticasone propionate 100 mcg twice-daily, and fluticasone propionate 200 mcg once-daily. The results supported the selection of the once-daily dosing frequency. Based on the dose-ranging trials in asthma and COPD, once-daily doses of fluticasone furoate/vilanterol 50 mcg/25 mcg, 100 mcg/25 mcg, and 200 mcg/25 mcg were evaluated in the confirmatory COPD trials.
The clinical development program for BREO ELLIPTA included 4 confirmatory trials in subjects with COPD designed to evaluate the efficacy of BREO ELLIPTA on lung function (Trials 1 and 2) and exacerbations (Trials 3 and 4).
Trials 1 and 2 were 24-week, randomized, double-blind, placebocontrolled trials designed to evaluate the efficacy of BREO ELLIPTA on lung function in subjects with COPD. In Trial 1, subjects were randomized to BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, and placebo. In Trial 2, subjects were randomized to BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/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 Caucasian. 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 FEV1 was 48% (range: 14% to 87%), mean postbronchodilator FEV1/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 FEV1 (0 to 4 hours) postdose on Day 168 and change from baseline in trough FEV1 on Day 169 (the mean of the FEV1 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 FEV1 comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA.
BREO ELLIPTA 100 mcg/25 mcg demonstrated a larger increase in the weighted mean FEV1 (0 to 4 hours) relative to placebo and fluticasone furoate 100 mcg at Day 168 (Table 2).
Table 2: Least Squares Mean Change From Baseline in
Weighted Mean FEV1 (0-4 h) and Trough FEV1 at 6 Months
|Treatment||N||Weighted Mean FEV1 (0-4 h)a (mL)||Trough FEV1b (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)|
|BREO ELLIPTA 100 mcg/25 mcg||204||214 (161, 266)||168 (116, 220)||—||144 (91, 197)||45 (-8, 97)|
|Fluticasone furoate/vilanterol 200 mcg/25 mcg||205||209 (157, 261)||—||168 (117, 219)||131 (80, 183)||32 (-19, 83)|
|BREO ELLIPTA 100 mcg/25 mcg||206||173 (123, 224)||120 (70, 170)||—||115 (60, 169)||48 (-6, 102)|
|a At Day 168.
b At Day 169.
Serial spirometric evaluations were performed pre-dose and up to 4 hours after dosing. Results from Trial 1 at Day 1 and Day 168 are shown in Figure 4. Similar results were seen in Trial 2 (not shown).
Figure 4: Raw Mean Change From Baseline in Post-Dose
Serial FEV1 (0-4 h, mL) on Days 1 and 168
The second co-primary variable was change from baseline in trough FEV1 following the final treatment day. At Day 169, both Trials 1 and 2 demonstrated significant increases in trough FEV1 for all strengths of the fluticasone furoate/vilanterol combination compared with placebo (Table 2). The comparison of BREO ELLIPTA 100 mcg/25 mcg with vilanterol did not achieve statistical significance (Table 2).
Trials 1 and 2 evaluated FEV1 as a secondary endpoint. Peak FEV1 was defined as the maximum postdose FEV1 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 FEV1 were observed for the groups receiving fluticasone furoate/vilanterol 100 mcg/25 mcg compared with placebo (152 and 139 mL, respectively). The median time to onset, defined as a 100-mL increase from baseline in FEV1, was 16 minutes in subjects receiving fluticasone furoate/vilanterol 100 mcg/25 mcg.
Trials 3 and 4 were randomized, double-blind, 52-week trials designed to evaluate the effect of BREO ELLIPTA on the rate of moderate and severe COPD exacerbations. All patients were treated with fluticasone propionate/salmeterol 250 mcg/50 mcg twice daily during a 4-week run-in period prior to being randomly assigned to 1 of the following treatment groups: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg.
The primary efficacy variable in both trials was the annual rate of moderate/severe exacerbations. The comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA. In these 2 trials, exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days. COPD exacerbations were considered to be of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if hospitalization was required.
Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 45% (range: 12% to 91%), and mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. The mean percent reversibility was 15% (range: -65% to 313%).
Patients treated with BREO ELLIPTA 100 mcg/25 mcg had a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol in both trials (Table 3).
Table 3: Moderate and Severe Chronic Obstructive
Pulmonary Disease Exacerbations
|Treatment||N||Mean Annual Rate (exacerbations/ year)||Ratio vs Vilanterol||95% CI|
|Fluticasone furoate/vilanterol 200 mcg/25 mcg||409||0.79||0.69||(0.56, 0.85)|
|BREO ELLIPTA 100 mcg/ 25 mcg||403||0.90||0.79||(0.64, 0.97)|
|Fluticasone furoate/vilanterol 50 mcg/25 mcg||412||0.92||0.81||(0.66, 0.99)|
|Vilanterol 25 mcg||409||1.14||—||—|
|Fluticasone furoate/vilanterol 200 mcg/25 mcg||402||0.90||0.85||(0.70, 1.04)|
|BREO ELLIPTA 100 mcg/ 25 mcg||403||0.70||0.66||(0.54, 0.81)|
|Fluticasone furoate/vilanterol 50 mcg/25 mcg||408||0.92||0.87||(0.72, 1.06)|
|Vilanterol 25 mcg||409||1.05||—||—|
Last reviewed on RxList: 3/20/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Breo Ellipta Information
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