Relvar Ellipta

Relvar Ellipta

Manufacturer:

GlaxoSmithKline

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Fluticasone furoate, vilanterol trifenatate.
Description
Each pre-dispensed dose contains either 100/25 micrograms or 200/25 micrograms of fluticasone furoate/vilanterol (as trifenatate).
Each single inhalation of fluticasone furoate/vilanterol provides a delivered dose of 92/22 micrograms of fluticasone furoate/vilanterol or 184/22 micrograms of fluticasone furoate/vilanterol.
Excipients/Inactive Ingredients: Lactose monohydrate (which contains milk protein); (12.5 milligram lactose monohydrate per blister); Magnesium stearate.
Action
Pharmacology: Pharmacodynamics: Mechanism of action: Fluticasone furoate and vilanterol represent two classes of medications (a synthetic corticosteroid and a selective, long-acting beta2-receptor agonist).
Pharmacodynamic effects: 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.
Clinical Studies: 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%).
RELVAR ELLIPTA 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%.
RELVAR ELLIPTA 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.
RELVAR ELLIPTA 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.
RELVAR ELLIPTA 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.
Pharmacokinetics: Absorption: 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.
Distribution: 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.
Metabolism: 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-and β2-agonist activity.
Elimination: 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.
Race: 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.
Children: 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.
Elderly: 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.
Renal impairment: 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.
Hepatic Impairment: 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.
Indications/Uses
Asthma: RELVAR ELLIPTA is indicated for the regular treatment of asthma in adults and adolescents aged 12 years and older where use of a combination medicinal product (long-acting beta2-agonist and inhaled corticosteroid) is appropriate: patients not adequately controlled with inhaled corticosteroids and "as needed" inhaled short-acting beta2-agonists; Patients already adequately controlled on both inhaled corticosteroid and long-acting beta2-agonist.
COPD: RELVAR ELLIPTA is indicated for the symptomatic treatment of adults with COPD with a FEV1<70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy.
Dosage/Direction for Use
RELVAR ELLIPTA is for inhalation only.
RELVAR ELLIPTA should be administered once daily either morning or evening but at the same time every day. If a dose is missed, the next dose should be taken at the usual time the next day.
After inhalation, the patient should rinse their mouth with water without swallowing.
ASTHMA: Patients should be made aware that RELVAR ELLIPTA must be used regularly, even when asymptomatic.
If symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
Patients should be regularly reassessed by a healthcare professional so that the strength of fluticasone furoate/vilanterol they are receiving remains optimal and is only changed on medical advice.
Populations: Adults and adolescents aged 12 years and over: The recommended dose of RELVAR ELLIPTA is: One inhalation of RELVAR ELLIPTA 100/25 micrograms once daily or One inhalation of RELVAR ELLIPTA 200/25 micrograms once daily.
A starting dose of RELVAR ELLIPTA 100/25 micrograms should be considered for patients who require a low to mid dose of inhaled corticosteroid in combination with a long-acting beta2-agonist.
RELVAR ELLIPTA 200/25 micrograms should be considered for patients who require a higher dose of inhaled corticosteroid in combination with a long-acting beta2-agonist.
If patients are inadequately controlled on RELVAR ELLIPTA 100/25 micrograms, consider increasing the dose to 200/25 micrograms, which may provide additional improvement in asthma control.
Children: The safety and efficacy of RELVAR ELLIPTA has not been established in children less than 12 years of age.
COPD: Populations: Adults: The recommended dose of RELVAR ELLIPTA is: One inhalation of RELVAR ELLIPTA 100/25 micrograms once daily.
RELVAR ELLIPTA 200/25 micrograms is not indicated for patients with COPD. There is no additional benefit of the 200/25 micrograms dose compared to the 100/25 micrograms dose and there is a potential increased risk of pneumonia and systemic corticosteroid-related adverse reactions.
Children: The use in children is not relevant for COPD indication for this product.
Special population: Asthma and COPD: Elderly: No dosage adjustment is required in patients over 65 years (see Pharmacology: Pharmacokinetics: Special Patient Populations under Actions).
Renal impairment: No dose adjustment is required for patients with renal impairment (see Pharmacology: Pharmacokinetics: Special Populations under Actions).
Hepatic Impairment: A clinical pharmacology study in subjects with mild, moderate and severe hepatic impairment showed up to 3-fold increase in systemic exposure to fluticasone furoate (AUC) (see Pharmacology: Pharmacokinetics under Actions).
Caution should be exercised when dosing patients with hepatic impairment who may be more at risk of systemic adverse reactions associated with corticosteroids. For patients with moderate or severe hepatic impairment the maximum dose is 100/25 micrograms (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
Symptoms and signs: There are no data available from clinical trials on overdose with RELVAR ELLIPTA.
An overdose of RELVAR ELLIPTA may produce signs and symptoms due to the individual components' actions, including those seen with overdose of other beta2-agonists and consistent with the known inhaled corticosteroid class effects (see Precautions).
Treatment: There is no specific treatment for an overdose with RELVAR ELLIPTA. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
Cardioselective beta-blockade should only be considered for profound vilanterol overdose effects that are clinically concerning and unresponsive to supportive measures.
Cardioselective beta-blocking drugs should be used with caution in patients with a history of bronchospasm.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Contraindications
RELVAR ELLIPTA is contraindicated in patients with severe milk-protein allergy or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol or any of the excipients.
Special Precautions
Exacerbations: RELVAR ELLIPTA should not be used to treat acute asthma symptoms or an acute exacerbation in COPD, for which a short-acting bronchodilator is required. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.
Patients should not stop therapy with RELVAR ELLIPTA, in asthma or COPD, without physician supervision since symptoms may recur after discontinuation.
Asthma-related adverse events and exacerbations may occur during treatment with RELVAR ELLIPTA. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of RELVAR ELLIPTA.
Paradoxical bronchospasm: As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a short-acting inhaled bronchodilator. RELVAR ELLIPTA should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Cardiovascular effects: Cardiovascular effects, such as cardiac arrhythmias e.g. supraventricular tachycardia and extrasystoles may be seen with sympathomimetic drugs, including RELVAR ELLIPTA. In a placebo-controlled study in subjects with history of, or an increased risk of, cardiovascular disease, there was no increase in the risk of, cardiovascular events, serious cardiovascular events, or adjudicated cardiovascular deaths in patients receiving fluticasone/vilanterol, compared with placebo (see Adverse Reactions). However, RELVAR ELLIPTA should be used with caution in patients with severe cardiovascular disease.
Patients with hepatic impairment: For patients with moderate to severe hepatic impairment, the 100/25 micrograms dose should be used and patients should be monitored for systemic corticosteroid-related adverse reactions (see Pharmacology: Pharmacokinetics under Actions).
Systemic corticosteroid effects: Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).
As with all medication containing corticosteroids, RELVAR ELLIPTA should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections.
Visual disturbance: Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Hyperglycaemia: There have been reports of increases in blood glucose levels with fluticasone furoate/vilanterol. This should be considered in patients with a history of, or with risk factors for, diabetes mellitus (see Adverse Reactions).
Pneumonia: An increase in pneumonia has been observed in patients with COPD receiving RELVAR ELLIPTA. There was also an increased incidence of pneumonias resulting in hospitalisation. In some incidences these pneumonia events were fatal (see Pharmacodynamics: Clinical studies under Actions and Adverse Reactions). Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. Risk factors for pneumonia in patients with COPD receiving RELVAR ELLIPTA include current smokers, patients with a history of prior pneumonia, patients with a body mass index <25 kg/m2 and patients with a (forced expiratory volume) FEV1<50% predicted. These factors should be considered when fluticasone furoate/vilanterol is prescribed and treatment should be re-evaluated if pneumonia occurs.
The incidence of pneumonia in patients with asthma was common at the higher dose. Patients with asthma taking fluticasone furoate/vilanterol 200/25 micrograms may be at an increased risk of pneumonia compared with those receiving fluticasone furoate/vilanterol 100/25 or placebo (see Adverse Reactions). No risk factors were identified.
Long-acting beta2-adrenergic agonists: Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in RELVAR ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABA, including vilanterol. Current available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-acting asthma control drugs mitigates the increase risk of asthma-related death from LABA.
Immunosuppression: Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration or corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chicken pox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral or parasitic infections; or ocular herpes simplex.
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of RELVAR ELLIPTA on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of fluticasone furoate or vilanterol.
Use In Pregnancy & Lactation
Fertility: There are no fertility data in humans. Animal studies showed no effect of vilanterol or fluticasone furoate on fertility (see Pharmacology: Toxicology: Pre-clinical Safety Data under Actions).
Pregnancy: There has been limited pregnancy exposure in humans.
Animal studies have shown reproductive toxicity after administration of beta2-agonists and corticosteroids (see Pharmacology: Toxicology: Pre-clinical Safety Data under Actions).
Administration of fluticasone furoate/vilanterol to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
Lactation: There is limited information on the excretion of fluticasone furoate or vilanterol or their metabolites in human milk. However, other corticosteroids and beta2-agonists are detected in human milk (see Pharmacology: Toxicology: Pre-clinical Safety Data under Actions). A risk to breastfed newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue RELVAR ELLIPTA therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Adverse Reactions
Clinical trial data: Data from large asthma and COPD clinical trials were used to determine the frequency of adverse reactions associated with RELVAR ELLIPTA. In the asthma clinical development program a total of 7,034 patients were included in an integrated assessment of adverse reactions. In the COPD clinical development program a total of 6,237 subjects were included in an integrated assessment of adverse reactions.
The most commonly reported adverse reactions with fluticasone furoate and vilanterol were headache and nasopharyngitis.
With the exception of pneumonia and fractures, the safety profile was similar in patients with asthma and COPD. During clinical studies, pneumonia and fractures were more frequently observed in patients with COPD.
These adverse reactions are listed by system organ class and frequency. The following convention has been used for the classification of adverse reactions: Very common: ≥1/10; Common: ≥1/100 to <1/10; Uncommon: ≥1/1000 to <1/100; Rare: ≥1/10000 to <1/1000; Very rare : <1/10000. (See Table 3.)

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Description of selected adverse reactions: *Pneumonia (see Precautions): In two replicate 12-month studies in a total of 3,255 patients with COPD (mean post-bronchodilator screening FEV1 45% of predicted, standard deviation (SF) 13%) who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia (6%-7%) reported in patients receiving the fluticasone furoate (at strengths of 50, 100, and 200 micrograms)/vilanterol 25 micrograms combination than in those receiving vilanterol 25 micrograms alone (3%). Pneumonia which required hospitalisation occurred in 3% of patients receiving RELVAR ELLIPTA (all strengths) and in <1% of patients receiving vilanterol. In these studies, nine fatal cases of pneumonia were reported. Of these, seven were reported during treatment with RELVAR ELLIPTA 200/25 micrograms, one during treatment with RELVAR ELLIPTA 100/25 micrograms and one post-treatment with vilanterol monotherapy. The number of pneumonia events per 1000 patient years was 97.9 with FF/VI 200/25, 85.7 in the FF/VI 100/25 and 42.3 in the VI 25 group. For severe pneumonia, the corresponding numbers of events per 1000 patient years were 33.6, 35.5, and 7.6 respectively, while for serious pneumonia, the corresponding events per 1000 patient years were 35.1 for FF/VI 200/25, 42.9 with FF/VI 100/25, 12.1 with VI 25. Finally, the exposure-adjusted cases of fatal pneumonia were 8.8 for FF/VI 200/25 versus 1.5 for FF/VI 100/25 and 0 for VI 25.
In SUMMIT, a multi-centre, randomised study (HZC113782), 16,568 subjects received fluticaseone furoate/vilanterol 100/25 micrograms, fluticasone furoate 100 micrograms, vilanterol 25 micrograms, or placebo for a mean of 1.7 years. Subjects had moderate COPD (mean pot-bronchodilator screening FEV1 60% of predicted, SF 6%) and a history of, or an increased risk of, cardiovascular disease. The adverse events of pneumonia are noted in table 4. (See Table 4.)

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In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of pneumonia (adjusted for exposure, due to low numbers and limited number of patients on placebo) seen with RELVAR ELLIPTA 100/25 microgram strength (9.6/1000 patient years) was similar to placebo (8.0/1000 patient years). There was a higher incidence of pneumonia in the 200/25 microgram strength (18.4/1000 patient years) compared to the 100/25 microgram strength. Few of the serious pneumonia events led to hospitalisation with either strength.
**Cardiovascular events (see Precautions): For the SUMMIT study (see description in previous text), cardiovascular adverse events are noted in Table 5. (See Table 5.)

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***Fractures: In two replicate 12-month studies in a total of 3,255 patients with COPD the incidence of bone fractures overall was low in all treatment groups, with a higher incidence in all RELVAR ELLIPTA groups (2%) compared with the vilanterol 25 micrograms group (<1%). Although there were more fractures in the RELVAR ELLIPTA groups compared with the vilanterol 25 micrograms group, fractures typically associated with corticosteroid use (e.g., spinal compression/thoracolumbar vertebral fractures, hip and acetabular fractures) occurred in <1% of the RELVAR ELLIPTA and vilanterol treatment arms.
For the SUMMIT study, (see description in previous text), fractures are noted in Table 6. (See Table 6.)

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In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of fractures was <1%, and usually associated with trauma.
Post-marketing data: (See Table 7.)

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Drug Interactions
Clinically significant drug interactions mediated by fluticasone furoate or vilanterol at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.
Interaction with beta-blockers: Beta-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists. Concurrent use of both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use.
Interaction with CYP3A4 inhibitors: Fluticasone furoate and vilanterol are both rapidly cleared by extensive first-pass metabolism mediated by the liver enzyme CYP3A4.
Care is advised when co-administering with strong CYP 3A4 inhibitors (e.g. ketoconazole, ritonavir) as there is potential for an increased systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions and concomitant use should be avoided. A repeat dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (200/25 micrograms) and the strong CYP3A4 inhibitor ketoconazole (400 mg). Co-administration increased mean fluticasone furoate AUC(0-24) and Cmax by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serum cortisol. Co-administration increased mean vilanterol AUC(0-t) and Cmax 65% and 22% respectively. The increase in vilanterol exposure was not associated with an increase in beta2-agonist related systemic effects on heart rate, blood potassium or QTcF interval.
Interaction with P-glycoprotein inhibitors: Fluticasone furoate and vilanterol are both substrates of P-glycoprotein (P-gp). A clinical pharmacology study in healthy subjects with co-administered vilanterol and the potent P-gp and moderate CYP3A4 inhibitor verapamil did not show any significant effect on the pharmacokinetics of vilanterol. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not been conducted.
Sympathomimetic medicinal products: Concomitant administration of other sympathomimetic medicinal products (alone or as a part of combination therapy) may potentiate the adverse reactions of fluticasone furoate/vilanterol. RELVAR ELLIPTA should not be used in conjunction with other long-acting beta2-adrenergic agonists.
Caution For Usage
Instructions for Use/Handling: When using Ellipta inhaler for the first time, there is no need to check that it is working properly or prepare it for use in any special way. The step-by-step instructions should be followed.
The inhaler is packaged in a tray. Do not open the tray until ready to inhale a dose of the medicine. When patient is ready to use the inhaler, peel back the lid to open the tray. The tray contains a desiccant sachet, to reduce moisture. Throw this dessicant sachet away. Do not open, eat or inhale it.
When taking the inhaler out of its box, it will be in the 'closed' position. Do not open the inhaler until ready to inhale a dose of medicine. Write the "Discard by" date on the inhaler label in the space provided.
The "Discard by" date is 1 month from the date the patient first open the tray. After this date, the inhaler should no longer be used.
The step-by-step instructions shown below for the 30-dose (30 day supply) Ellipta inhaler also apply to the 14-dose Ellipta (14 day supply) inhaler.
a) Read instructions before starting: If the patient opens and closes the cover without inhaling the medicine, the patient will lose the dose.
The lost dose will be securely held inside the inhaler, but it will no longer be available.
It is not possible to accidentally take extra medicine or a double dose in one inhalation.
b) How to prepare a dose: Open the cover when ready to take the dose.
Do not shake the inhaler.
Slide the cover down until hearing a "click".
The medicine is now ready to be inhaled.
The dose counter counts down by 1 to confirm.
If the dose counter does not count down when the "click" is heard, the inhaler will not deliver medicine. Take it back to the pharmacist for advice.
Do not shake the inhaler at any time.
c) Inhale medication: While holding the inhaler away from the mouth, breathe out as far as is comfortable.
Do not breathe out into the inhaler.
Put the mouthpiece between the lips, and close lips firmly around it. Do not block the air vent with fingers.
Take one long, steady, deep breath in. Hold this breath for as long as possible (at least 3-4 seconds).
Remove the inhaler from mouth.
Breathe out slowly and gently.
The patient may not be able to taste or feel the medicine, even when the patient is using the inhaler correctly.
In cleaning the mouthpiece, use a dry tissue, before closing the cover.
d) Close the inhaler and rinse mouth if possible: Slide the cover upwards as far as it will go, to cover the mouthpiece.
Rinse mouth with water after using the inhaler.
This will make it less likely that the patient will develop a sore mouth or throat as side effects.
Incompatibilities: None.
Storage
Storage condition depends on local registration requirements.
Store below 30°C.
If stored in the refrigerator, allow the inhaler to return to room temperature for at least an hour before use.
Shelf-Life: In-use shelf-life: The in-use shelf-life depends on the regularly registered storage conditions.
Following removal from the tray, the product may be stored for a maximum period of 1 month: below 30°C.
Write the date the inhaler should be discarded on the label in the space provided.
The date should be added as soon as the inhaler has been removed from the tray.
ATC Classification
R03AK10 - vilanterol and fluticasone furoate ; Belongs to the class of adrenergics in combination with corticosteroids or other drugs, excluding anticholinergics. Used in the treatment of obstructive airway diseases.
Presentation/Packing
100/25 mcg inhalation powd 30's. 200/25 mcg inhalation powd 30's.
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