Pharmacology: Pharmacodynamics: Mechanism of action:
Fluticasone furoate and vilanterol represent two classes of medications (a synthetic corticosteroid and a selective, long-acting beta2
Fluticasone furoate: Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects asthma and COPD symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) and mediators (e.g. cytokines and chemokines involved in inflammation).
Vilanterol trifenatate: Vilanterol trifenatate is a selective long-acting, beta2
-adrenergic agonist (LABA).
The pharmacologic effects of beta2
-adrenoceptor agonist drugs, including vilanterol trifenatate, are at least in part attributable to stimulation of intracellular adenylate 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.
In peripheral blood mononuclear cells from subjects with COPD, a larger anti-inflammatory effect was seen in the presence of the combination of fluticasone furoate/vilanterol compared with fluticasone furoate alone at concentrations achieved with clinical doses.
RELVAR ELLIPTA clinical studies: Asthma: The safety and efficacy of fluticasone furoate (FF) and vilanterol (VI) in the treatment of asthma has been evaluated in 3 randomised, double-blinded clinical trials of between 12 to 76 weeks in duration (HZA106827, HZA106829 and HZA106837) involving 3,210 patients 12 years of age and older with persistent asthma.
All subjects were using an ICS (Inhaled Corticosteroid) with or without LABA for at least 12 weeks prior to Visit 1. In HZA106837 all patients had at least one exacerbation that required treatment with oral corticosteroids in the year prior to Visit 1. Results for HZA106827 and HZA106829 are shown in the table as follows: (See Table 1.)
Click on icon to see table/diagram/image
HZA106837 was of variable treatment duration (from a minimum of 24 weeks to a maximum of 76 weeks with the majority of patients treated for at least 52 weeks) and compared RELVAR ELLIPTA
100/25 micrograms [N=1009] and FF 100 micrograms [N=1010] both administered once daily. The primary endpoint was the time to first severe asthma exacerbation (a severe asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids).
The risk of experiencing a severe asthma exacerbation in patients receiving RELVAR ELLIPTA
100/25 was reduced by 20% compared with FF 100 alone (hazard ratio 0.795, p=0.036 95% CI (0.642, 0.985)). The rate of severe asthma exacerbations per patient per year was 0.19 in the FF 100 group and 0.14 in the RELVAR ELLIPTA
100/25 group. The ratio of the exacerbation rate for RELVAR ELLIPTA
100/25 versus FF 100 was 0.755 (95% CI 0.603, 0.945). This represents a 25% reduction in the rate of severe asthma exacerbations for subjects treated with RELVAR ELLIPTA
100/25 compared with FF 100 (p=0.014). The 24-hour bronchodilator effect of RELVAR ELLIPTA
was maintained throughout a one-year treatment period with no evidence of loss in efficacy (no tachyphylaxis). RELVAR ELLIPTA
100/25 micrograms consistently demonstrated 83 mL to 95 mL improvements in trough FEV1
at Weeks 12, 36 and 52 and Endpoint compared with FF 100 (p<0.001 95% CI 52, 126 mL at Endpoint). Forty four percent of patients in the RELVAR ELLIPTA
100/25 group were well controlled (ACQ7 ≤0.75) at end of treatment compared to 36% of subjects in the FF 100 group (p<0.001 95% CI 1.23, 1.82).
Studies versus salmeterol/fluticasone propionate combinations: In a 24-week study (HZA113091) in adult and adolescent patients with uncontrolled persistent asthma, both fluticasone furoate/vilanterol 100/25 micrograms given once daily in the evening and salmeterol/FP 50/250 micrograms given twice daily demonstrated improvements from baseline in lung function. Adjusted mean treatment increases from baseline in weighted mean 0-24 hours FEV1
of 341 mL (fluticasone furoate/vilanterol) and 377 mL (salmeterol/FP) demonstrated an overall improvement in lung function over 24 hours for both treatments. The adjusted mean treatment difference of -37 mL between the groups was not statistically significant (p=0.162). For trough FEV1
subjects in the fluticasone furoate/vilanterol group achieved a LS mean change from baseline of 281 mL and subjects in the salmeterol/FP group a change of 300 mL; the difference in adjusted mean of -19 mL (95% CI: -0.073, 0.034) was not statistically significant (p=0.485).
A randomised, double-blind, parallel group, 24-week study (201378) was conducted to demonstrate non-inferiority (using a margin of -100mL for trough FEV1
) of fluticasone furoate/vilanterol 100/25 once daily to salmeterol/FP 50/250 twice daily in adults and adolescents whose asthma was well controlled following 4 weeks of treatment with open-label salmeterol/FP 50/250 twice daily (N=1504). Subjects randomised to once-daily FF/VI maintained lung function comparable with those randomised to twice-daily salmeterol/FP [difference in trough FEV1
of +19mL (95% CI: -11, 49)].
No comparative studies versus salmeterol/FP or versus other ICS/LABA combinations have been conducted to appropriately compare the effects on asthma exacerbations.
Chronic Obstructive Pulmonary Disease: The efficacy of fluticasone furoate and vilanterol in the treatment of patients with COPD has been evaluated in two 6-month (HZC112206, HZC112207), two one-year randomised controlled studies (HZC102970, HZC102871), and one long-term study (SUMMIT) in patients with a clinical diagnosis of COPD.
Six-month studies: HZC112206 and HZC112207 were 24 week randomised, double-blind, placebo controlled, parallel group studies comparing the effect of the combination to vilanterol and FF alone and placebo. HZC112206 evaluated the efficacy of RELVAR ELLIPTA
50/25 micrograms [n=206] and RELVAR ELLIPTA
100/25 micrograms [n=206]) compared with FF (100 micrograms [n=206]) and vilanterol (25 micrograms [n=205]) and placebo (n=207), all administered once daily.
HZC112207 evaluated the efficacy of RELVAR ELLIPTA
100/25 micrograms [n=204] and RELVAR ELLIPTA
200/25 [n=205]) compared with FF (100 micrograms [n=204] and 200 micrograms [n=203]) and vilanterol (25 micrograms [n=203]) and placebo (n=205), all administered once daily.
All patients were required to have a smoking history of at least 10 pack years; a post-salbutamol FEV1
/FVC ratio of less than or equal to 0.70; post-salbutamol FEV1
less than or equal to 70% predicted and have a Modified Medica Research Council (mMRC) dyspnea score ≥ (scale 0-4) at screening. At screening, the mean pre-bronchodilator FEV1
was 42.6% and 43.6% of predicted, and the mean reversibility was 15.9% and 12.0% in HZC112206 and HZC112207, respectively. The co-primary endpoints in both studies were the weighted mean FEV1
from zero to 4 hours post-dose and change from baseline in pre-dose trough FEV1
at the end of the study.
In an integrated analysis of both studies, RELVAR ELLIPTA
100/25 micrograms showed clinically meaningful improvements in lung function. At Day 169 RELVAR ELLIPTA
100/25 micrograms and vilanterol increased trough FEV1
by 129 mL (95% CI 91, 167 mL, p<0.001) and 83mL (95% CI 46, 121mL, p<0.001) respectively compared with placebo. RELVAR ELLIPTA
100/25 micrograms increased trough FEV1
by 46 ml compared with vilanterol (95% CI 8, 83 mL, p=0.017).
At Day 168 RELVAR ELLIPTA
100/25 micrograms and vilanterol had a higher weighted mean FEV1
over 0-4 hours of 193 mL (95% CI 156, 230 mL, p<0.001) and 145 mL (95% CI 108, 181 mL, p<0.001) respectively compared with placebo. The difference in weighted mean FEV1
over 0-4 hours between the fluticasone furoate/vilanterol 100/25 and vilanterol groups was 48 mL (95% CI 12, 84 mL, p=0.009).
12 months studies: Studies HZC102970 and HZC102871 were 52 week randomised, double-blind, parallel-group, studies comparing the effect of RELVAR ELLIPTA
200/25 micrograms, RELVAR ELLIPTA
100/25 micrograms, fluticasone furoate/vilanterol 50/25 micrograms and vilanterol 25 micrograms, all administered once daily, on the annual rate of moderate/severe exacerbations in subjects with COPD with a smoking history of at least 10 pack years and a post-salbutamol FEV1
/FVC ratio less than or equal to 0.70 and post-salbutamol FEV1
less than or equal to 70% predicted and documented history of ≥1 COPD exacerbation that required antibiotics and/or oral corticosteroids or hospitalisation in the 12 months prior to visit 1. The primary endpoint was the annual rate of moderate and severe exacerbations in subjects with COPD. Moderate/severe exacerb ations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. Both studies had a 4 week run-in during which all subjects received open-label salmeterol/FP 50/250 twice daily to standardise COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2
-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2
-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies.
The results of both studies showed that treatment with RELVAR ELLIPTA
100/25 micrograms once daily resulted in a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol (see Table 2).
Click on icon to see table/diagram/image
In an integrated analysis of HZC102970 and HZC102871 at Week 52, an improvement was seen when comparing the RELVAR ELLIPTA
100/25 micrograms versus vilanterol 25 microgram in adjusted mean trough FEV1
(42 mL 95% CI: 19, 64 mL, p<0.001). The 24-hour bronchodilator effect of fluticasone furoate/vilanterol was maintained from the first dose through a one-year treatment period with no evidence of loss in efficacy (no tachyphylaxis).
Overall, across the two studies combined 2009 (62%) patients had cardiovascular history/risk factors at screening. The incidence of cardiovascular history/risk factors was similar across the treatment groups with patients most commonly suffering from hypertension (46%), followed by hypercholesterolemia (29%) and diabetes mellitus (12%). Similar effects in reduction of moderate and severe exacerbations were observed in this subgroup as compared with the overall population. In patients with a cardiovascular history/risk factors, RELVAR ELLIPTA
100/25 micrograms resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with vilanterol (adjusted mean annual rates of 0.83 and 1.18 respectively, 30% reduction (95% CI 16, 42%, p<0.001)). Improvements were also seen in this subgroup at week 52 when comparing the RELVAR ELLIPTA
100/25 micrograms versus vilanterol 25 micrograms in adjusted mean trough FEV1
(44 mL 95% CI: 15, 73 mL, (p=0.003)).
Long-term study: SUMMIT was a multi-centre, randomised, double-blind study evaluating the effects on survival of RELVAR ELLIPTA
100/25 micrograms compared with placebo in 16,568 subjects. Subjects were treated for up to 4 years (mean 1.7 years) with either RELVAR ELLIPTA
100/25 micrograms, fluticasone furoate 100 micrograms, vilanterol 25 micrograms, or placebo. All subjects had COPD with moderate airflow limitation (≥50% and ≤70% predicted FEV1
) and history of, or an increased risk of, cardiovascular disease.
Survival with RELVAR ELLIPTA
was not significantly improved compared with placebo (HR 0/878; 95% CI: 0.739, 1.042; p=0.137), FF (HR 0.964; 95% CI: 0.808, 1.149, p=0.681) or VI (HR 0.912; 95% CI: 0.767, 1.085; p=0.299). All-cause mortality was: fluticasone furoate/vilanterol, 6.0%; placebo, 6.7%; fluticasone furoate, 6.1%; vilanterol, 6.4%).
slowed the rate of decline in lung function as measured by FEV1
by 8 mL/year compared with placebo (95% CI: 1, 15; p=0.019). There was no impact (0 mL/year; 95% CI: -6, 7; p=0.913) on the rate of decline for RELVAR ELLIPTA
compared with fluticasone furoate; there was a difference of 10 mL/year for RELVAR ELLIPTA
compared with vilanterol (95% CI: 3, 16; p=0.004). The mean rate of decline in FEV1
was: RELVAR ELLIPTA
, 38 mL/year; placebo, 46 mL/year; fluticasone furoate, 38 mL/year; vilanterol, 47 mL/year.
The risk of a cardiovascular composite event (on-treatment cardiovascular death, myocardial infarction, stroke, unstable angina, or transient ischaemic attack) with RELVAR ELLIPTA
was not significantly lower than placebo (HR 0.926; 95% CI: 0.750, 1.143; p=0.475), FF (HR 1.033; 95% CI: 0.834, 1.281; p=0.763) or VI (HR 0.938; 95% CI: 0.761, 1.155; p=0.545). The incidence of cardiovascular composite events was RELVAR ELLIPTA
, 4.2%; placebo, 4.2%; fluticasone furoate, 3.9%; vilanterol 4.4%.
demonstrated a larger mean change from baseline in post-bronchodilator FEV1
at Day 360 compared with placebo (89 mL; 95% CI: 76, 102; p<0.001), FF (40 mL; 95% CI: 27, 53; p<0.001), and VI (26 mL; 95% CI: 13, 39; p<0.001). The adjusted mean change from baseline was RELVAR ELLITA
50 mL, placebo, -39 mL; fluticaseone furoate, 9 mL; vilanterol, 24 mL.
reduced the annual rate of moderate or severe exacerbations by 29% (95% CI: 22, 35; p<0.001) compared with placebo, by 19% compared with FF (95% CI: 12, 26; p<0.001), and by 21% compared with VI (95% CI: 14, 28; p<0.001). The annual rate of moderate or severe exacerbations was 0.25 for RELVAR ELLIPTA
, 0.35 for placebo, 0.31 for fluticasone furoate, and 0.31 for vilanterol.
reduced the annual rate of severe exacerbations (i.e. requiring hospitalisation) by 27% (95% CI: 13, 39; p<0.001) compared with placebo, by 11% compared with FF (95% CI: -6, 25; p=0.204) and by 9% compared with VI (95% CI: -8, 24; p=0.282). The annual rate of exacerbations requiring hospitalisation was 0.05 for RELVAR ELLIPTA,
0.07 for placebo, 0.06 for fluticasone furoate, and 0.06 for vilanterol.
Studies versus salmeterol/fluticasone propionate combinations: In a 12-week study (HZA113107) in COPD patients both RELVAR ELLIPTA
100/25 micrograms given once daily in the morning and salmeterol/FP 50/500 micrograms given twice daily, demonstrated improvements from baseline in lung function. Adjusted mean treatment increases from baseline in weighted mean 0-24 hours FEV1
of 130 mL (fluticasone furoate/vilanterol) and 108 mL (salmeterol/FP) demonstrated an overall improvement in lung function over 24 hours for both treatments. The adjusted mean treatment difference of 22 mL (95% CI: -18, 63 mL) between the groups was not statistically significant (p=0.282). The adjusted mean change from baseline in trough FEV1
on Day 85 was 111 mL in the fluticasone furoate/vilanterol group and 88 mL in the salmeterol/FP group; the 23 mL (95% CI: -20, 66) difference between the treatment groups was not clinically meaningful or statistically significant (p=0.294). No comparative studies versus salmeterol or versus other established bronchodilators have been conducted to appropriately compare the effect on COPD exacerbations.
The absolute bioavailability for fluticasone furoate and vilanterol when administered by inhalation as RELVAR ELLIPTA
was on average 15.2% and 27.3%, respectively. The oral bioavailability of both fluticasone furoate and vilanterol was low, on average 1.26% and <2%, respectively. Given this low oral bioavailability, systemic exposure for fluticasone furoate and vilanterol following inhaled administration is primarily due to absorption of the inhaled portion of the dose delivered to the lung.
Following intravenous dosing, both fluticasone furoate and vilanterol are extensively distributed with average volumes of distribution at steady state of 661 L and 165 L, respectively.
Both fluticasone furoate and vilanterol have a low association with red blood cells. In vitro
plasma protein binding in human plasma of fluticasone furoate and vilanterol was high, on average >99.6% and 93.9%, respectively. There was no decrease in the extent of in vitro
plasma protein binding in subjects with renal or hepatic impairment.
Fluticasone furoate and vilanterol are substrates for P-gp, however, concomitant administration of fluticasone furoate/vilanterol with P-gp inhibitors is considered unlikely to alter fluticasone furoate or vilanterol systemic exposure since they are both well absorbed molecules.
Based on in vitro
data, the major routes of metabolism of both fluticasone furoate and vilanterol in human are mediated primarily by CYP3A4.
Fluticasone furoate is primarily metabolised through hydrolysis of the S-fluoromethyl carbothioate group to metabolites with significantly reduced corticosteroid activity.
Vilanterol is primarily metabolised by O-dealkylation to a range of metabolites with significantly reduced β1
Following oral administration, fluticasone furoate was eliminated in humans mainly by metabolism with metabolites being excreted almost exclusively in faeces, with <1% of the recovered radioactive dose eliminated in the urine. The apparent plasma elimination half-life of fluticasone furoate following inhaled administration of fluticasone furoate/vilanterol was, on average, 24 hours.
Following oral administration, vilanterol was eliminated in humans mainly by metabolism followed by excretion of metabolites in urine and faeces approximately 70% and 30% of the radioactive dose respectively. The apparent plasma elimination half-life of vilanterol following inhaled administration of fluticasone furoate/vilanterol was, on average, 2.5 hours. The effective half-life for accumulation of vilanterol, as determined from inhalation administration of repeat doses of vilanterol 25 micrograms, is 16.0 hours in subjects with asthma and 21.3 hours in subjects with COPD.
Special Patient Populations:
Population PK meta-analyses for fluticasone furoate and vilanterol were conducted in phase III studies in subjects with asthma or COPD. The impact of demographic covariates (age, gender, weight, BMI, racial group, ethnicity) on the pharmacokinetics of fluticasone furoate and vilanterol were evaluated as part of the population pharmacokinetic analysis.
In subjects with asthma or COPD, estimates of fluticasone furoate AUC(0-24)
for East Asian, Japanese and South East Asian subjects (12-14% subjects) were up to 53% higher on average compared with Caucasian subjects. However, there was no evidence for the higher systemic exposure in these populations to be associated with greater effect on 24 hour urinary cortisol excretion. There was no effect of race on pharmacokinetic parameter estimates of vilanterol in subjects with COPD.
On average, vilanterol Cmax
is estimated to be 220 to 287% higher and AUC(0-24)
comparable for those subjects from an Asian heritage compared with subjects from other racial groups. However, there was no evidence that this higher vilanterol Cmax
resulted in clinically significant effects on heart rate.
In adolescents (12 years or older), there are no recommended dose modifications.
The pharmacokinetics of fluticasone furoate/vilanterol in patients less than 12 years of age has not been studied. The safety and efficacy of fluticasone furoate/vilanterol in children under the age of 12 years has not yet been established.
The effects of age on the pharmacokinetics of fluticasone furoate and vilanterol were determined in phase III studies in COPD and asthma.
There was no evidence for age (12-84) to affect the PK of fluticasone furoate and vilanterol in subjects with asthma.
There was no evidence for age to affect the PK of fluticasone furoate in subjects with COPD while there was an increase (37%) in AUC(0-24)
of vilanterol over the observed age range of 41 to 84 years. For an elderly subject (aged 84 years) with low bodyweight (35 kg), vilanterol AUC(0-24)
is predicted to be 35% higher than the population estimate (subject with COPD aged 60 years and bodyweight of 70 kg), whilst Cmax
was unchanged. These differences are unlikely to be of clinical relevance.
A clinical pharmacology study of fluticasone furoate/vilanterol showed that severe renal impairment (creatinine clearance <30 mL/min) did not result in significantly greater exposure to fluticasone furoate or vilanterol or more marked corticosteroid or beta2
-agonist systemic effects compared with healthy subjects. No dose adjustment is required for patients with renal impairment.
The effects of haemodialysis have not been studied.
Following repeat dosing of fluticasone furoate/vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure (up to three-fold as measured by AUC(0–24)
) in subjects with hepatic impairment (Child-Pugh A, B or C) compared with healthy subjects. The increase in fluticasone furoate systemic exposure (fluticasone furoate/vilanterol 200/25 micrograms) in subjects with moderate hepatic impairment (Child-Pugh B) was associated with an average 34% reduction in serum cortisol compared with healthy subjects. In subjects with severe hepatic impairment (Child Pugh C) that received a lower dose of 100/12.5 micrograms, there was no reduction in serum cortisol. For patients with moderate or severe hepatic impairment the maximum dose is 100/25 micrograms (see Dosage & Administration
Following repeat dosing of fluticasone furoate/vilanterol for 7 days, there was no significant increase in systemic exposure to vilanterol (Cmax
and AUC) in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh A, B or C).
There were no clinically relevant effects of the fluticasone furoate/vilanterol combination on beta-adrenergic systemic effects (heart rate or serum potassium) in subjects with mild or moderate hepatic impairment (vilanterol, 25 micrograms) or with severe hepatic impairment (vilanterol, 12.5 micrograms) compared with healthy subjects.
Gender, Weight and BMI:
There was no evidence for gender, weight or BMI to influence the pharmacokinetics of fluticasone furoate based on a population pharmacokinetic analysis of phase III data in 1213 subjects with asthma (712 females) and 1225 subjects with COPD (392 females).
There was no evidence for gender, weight or BMI to influence the pharmacokinetics of vilanterol based on a population pharmacokinetic analysis in 856 subjects with asthma (500 females) and 1091 subjects with COPD (340 females).
No dosage adjustment is necessary based on gender, weight or body mass index (BMI).
Toxicology: Pre-clinical Safety Data:
Pharmacological and toxicological effects seen with fluticasone furoate or vilanterol in nonclinical studies were those typically associated with either glucocorticoids or beta2
-agonists. Administration of fluticasone furoate combined with vilanterol did not result in any significant new toxicity.
Carcinogenesis/mutagenesis: Fluticasone furoate was not genotoxic in a standard battery of studies and was not carcinogenic in lifetime inhalation studies in rats or mice at exposures similar to those at the maximum recommended human dose, based on AUC.
Genetic toxicity studies indicate vilanterol does not represent a genotoxic hazard to humans. Consistent with findings for other beta2
-agonists, in lifetime inhalation studies vilanterol caused proliferative effects in the female rat and mouse reproductive tract and rat pituitary gland. There was no increase in tumour incidence in rats or mice at exposures 2-or 30-fold, respectively, those at the maximum recommended human dose, based on AUC.
Reproductive Toxicology: Effects seen following inhalation administration of fluticasone furoate in combination with vilanterol in rats were similar to those seen with fluticasone furoate alone.
Fluticasone furoate was not teratogenic in rats or rabbits, but delayed development in rats and caused abortion in rabbits at maternally toxic doses. There were no effects on development in rats at exposures approximately 3-times greater than those at the maximum recommended human dose, based on AUC.
Vilanterol was not teratogenic in rats. In inhalation studies in rabbits, vilanterol caused effects similar to those seen with other beta2
-agonists (cleft palate, open eyelids, sternebral fusion and limb flexure/malrotation). When given subcutaneously there were no effects at exposures 84-times greater than those at the maximum recommended human dose, based on AUC.
Neither fluticasone furoate nor vilanterol had any adverse effects on fertility or pre-and post-natal development in rats.