Fluticasone furoate with vilanterol

What it is

This is a fixed-dose combination inhaler containing fluticasone furoate, a synthetic trifluorinated corticosteroid, and vilanterol, a long-acting beta2-adrenergic agonist. It is a dry powder taken by mouth as one inhalation once daily from an Ellipta device, in strengths of 50/25, 100/25 and 200/25 micrograms. In the United States the 100/25 strength is approved for maintenance treatment of COPD, and for asthma from age five the label gives 100/25 or 200/25 for adults, 100/25 for ages 12 to 17 and 50/25 for ages 5 to 11. It is not a rescue inhaler and the label says so explicitly.

What the research says

For COPD with a history of exacerbations the pragmatic Salford Lung Study found an 8.4% lower exacerbation rate than continuing usual care over a year, with no difference in healthcare contacts and no difference in time to first exacerbation. IMPACT puts the absolute rate on this combination at 1.07 moderate or severe exacerbations per year, higher than the 0.91 on single-inhaler triple therapy. SUMMIT, the largest trial, found no effect on all-cause mortality or cardiovascular events in 16,485 people with moderate COPD and raised cardiovascular risk. For asthma, the Salford asthma trial found 71% of starters reached the control target against 56% on usual care, while a Cochrane review of 14 trials concluded the evidence was too sparse to draw firm conclusions or to compare it with twice-daily fluticasone propionate-salmeterol. The main documented harms are pneumonia in COPD, fractures, oropharyngeal candidiasis, and the systemic corticosteroid risks of adrenal suppression and reduced bone mineral density.

Evidence grade: Well established.

How it works

Drug class: Fixed-dose combination of an inhaled corticosteroid (fluticasone furoate) and a long-acting beta2-agonist (vilanterol)

Two medicines working on different problems in the same airway. Fluticasone furoate is a corticosteroid that reduces inflammation by acting on many immune cell types and inflammatory messengers; the label says the precise mechanism in COPD and asthma is not known. Vilanterol stimulates beta2 receptors on airway muscle, raising cyclic AMP inside the cell, which relaxes the muscle and widens the airway, and also blocks the release of mediators from mast cells. (Source 1)

What it is used for

• The pragmatic Salford Lung Study found an 8.4% lower rate of moderate or severe exacerbations than usual care in patients with prior exacerbations, while secondary outcomes including healthcare contacts and time to first exacerbation were null. IMPACT showed the dual combination performs worse on exacerbations than single-inhaler triple therapy, 1.07 versus 0.91 per year. Evidence: established. (Source 2)
• The Salford asthma trial found 71% of patients who started it reached the asthma-control responder definition at 24 weeks versus 56% on usual care, odds ratio 2.00. A Cochrane review of 6,641 participants - 14 included studies by its own Main results section, 13 by its conclusions - found the data too sparse to draw robust conclusions and insufficient to compare it against twice-daily fluticasone propionate-salmeterol. Evidence: established. (Source 3)
• SUMMIT tested exactly this in 16,485 people and missed its primary endpoint: all-cause mortality hazard ratio 0.88 (95% CI 0.74-1.04, p=0.137), with no effect on composite cardiovascular events. The trialists stated that secondary outcomes should therefore be interpreted with caution. Evidence: not-supported. (Source 4)
• Only the 100/25 strength is approved for COPD, yet the 200/25 strength was studied in the 12-month COPD trials, where pneumonia occurred in 7% of patients and fatal pneumonia in 7 patients, compared with 1 fatal pneumonia on 100/25. There is no approved COPD benefit to set against that. Evidence: limited. (Source 5)

Interactions

• Ketoconazole and other strong CYP3A4 inhibitors (including ritonavir and clarithromycin as drugs of that class) (pharmacokinetic study): Both ingredients are broken down by CYP3A4, so a strong inhibitor of that enzyme raises blood levels of both the steroid and the bronchodilator, which can bring on systemic steroid effects and cardiovascular effects. (Source 6)
• Loop and thiazide diuretics, and anything else that lowers potassium (label): Beta2-agonists can shift potassium into cells and so lower blood potassium; combined with a potassium-wasting diuretic this can be acutely worsened, with ECG changes. The label notes the potassium fall is usually transient and that BREO trials showed no treatment effect on serum potassium, so this is a caution rather than a demonstrated clinical event with this inhaler. (Source 7)
• Monoamine oxidase inhibitors, tricyclic antidepressants and QT-prolonging drugs (label): These can amplify the cardiovascular effects of the beta2-agonist component, and QT-prolonging drugs carry an increased risk of ventricular arrhythmia. (Source 8)
• Beta-blockers (label): Beta-blockers cancel out the bronchodilator effect of vilanterol and can themselves cause severe airway narrowing in people with asthma or COPD. (Source 9)
• Grapefruit and other dietary CYP3A4 inhibitors (theoretical): Both ingredients are CYP3A4 substrates, which is the mechanism by which grapefruit could in theory raise exposure, but the label names only strong CYP3A4 inhibitor drugs and we found no study of grapefruit or any other food with this inhaler. Treat this as theoretical, not demonstrated. (Source 6)
• Potassium supplements (label): No interaction with potassium supplements is documented. The relevant background is that beta2-agonists can transiently lower blood potassium, but in the trials of this inhaler in COPD and asthma there was no evidence of any treatment effect on serum potassium. (Source 10)

Stopping it

• There is no withdrawal syndrome described for this inhaler, but the label warns against abrupt dose reduction where systemic steroid effects have appeared: the dose should be reduced slowly, in line with how systemic corticosteroids are tapered. (Source 11)
• The label treats loss of control as a reason to reassess rather than to add doses: increasing use of a short-acting reliever is a marker of deteriorating asthma and calls for immediate reevaluation, and the COPD dose is not to be increased. (Source 12)
• The meta-analysis of adrenal insufficiency after corticosteroid use found that it occurs frequently after glucocorticoids are discontinued and recommends a low threshold for testing people with vague symptoms after stopping, which applies to inhaled steroids as well as tablets. (Source 13)

What goes wrong

In IMPACT the arms containing an inhaled corticosteroid, one of which was fluticasone furoate-vilanterol, had more pneumonia than the arm without one; the hazard ratio of 1.53 that the trial reports is for triple therapy against umeclidinium-vilanterol, not for fluticasone furoate-vilanterol on its own. (Source 14)

• Randomized trial, High certainty.
• Size: 10,355 patients.
• Who: Adults with COPD and a history of exacerbations.
• How long: 52 weeks.
• Result: Higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group; clinician-diagnosed pneumonia hazard ratio 1.53 (95% CI 1.22 to 1.92), P<0.001, for triple therapy versus umeclidinium-vilanterol.
• Funding: Industry-funded (GlaxoSmithKline)

Limit of this finding: The trial reports the pneumonia excess for the inhaled-corticosteroid groups together, and gives a hazard ratio (1.53, 95% CI 1.22 to 1.92) only for triple therapy against the steroid-free arm. IMPACT publishes no separate pneumonia hazard ratio for fluticasone furoate-vilanterol, so 1.53 must not be quoted as this inhaler's own risk.

There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001).

A Cochrane meta-analysis of inhaled steroids in COPD found that fluticasone - overwhelmingly fluticasone propionate in the trials it pooled - increased serious pneumonia needing hospital admission, an absolute excess of about 18 cases per 1,000 people treated over 18 months, with no sign that combining it with salmeterol or vilanterol reduced that. (Source 15)

• Meta-analysis, High certainty.
• Size: 43 studies; 26 fluticasone studies with 21,247 participants and 17 budesonide studies with 10,150.
• Who: Adults with COPD, mostly male, mean age around 63, mean over 40 pack-years, mean predicted FEV1 under 50%.
• How long: At least 12 weeks; the fluticasone estimate is expressed over 18 months.
• Result: Non-fatal serious pneumonia events odds ratio 1.78 (95% CI 1.50 to 2.12), 18 more per 1,000 treated over 18 months, graded high quality; no evidence that combining with salmeterol or vilanterol reduced this.
• Funding: Independent (Cochrane systematic review); high or uneven dropout rated a high risk of bias in almost 40% of trials.

Limit of this finding: This review pooled fluticasone trials without separating fluticasone propionate from the newer fluticasone furoate that is in this inhaler, and its own conclusions say that for fluticasone furoate 'little evidence of the associated pneumonia risk is currently available'. The odds ratio of 1.78 is therefore a fluticasone-class figure, not a measurement of this product. The same passage also describes budesonide as having 'increased' serious pneumonia events on an odds ratio of 1.62 with a 95% confidence interval of 1.00 to 2.62 - an interval that reaches 1, so by the usual convention that is not a clear increase; Cochrane itself hedges it as 'less precise' and grades it moderate rather than high quality.

Fluticasone increased non-fatal serious adverse pneumonia events (requiring hospital admission) (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.50 to 2.12; 18 more per 1000 treated over 18 months; high quality), and no evidence suggested that this outcome was reduced by delivering it in combination with salmeterol or vilanterol (subgroup differences: I(2) = 0%, P value 0.51), or that different doses, trial duration or baseline severity significantly affected the estimate.

The FDA label records the pneumonia rates directly: in two 12-month COPD trials, 6% of patients on BREO ELLIPTA 100/25 developed pneumonia versus 3% on vilanterol alone, with fatal pneumonia in 1 patient on 100/25 and 7 on 200/25. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 3,255 patients across replicate 12-month trials (820, 806, 811 and 818 per arm)
• Who: Patients with moderate to severe COPD who had had an exacerbation in the previous year.
• How long: 12 months.
• Result: Pneumonia 6% (51 of 806) on BREO ELLIPTA 100/25 mcg, 6% (48 of 820) on fluticasone furoate/vilanterol 50/25, 7% (55 of 811) on 200/25, versus 3% (27 of 818) on vilanterol 25 mcg alone; fatal pneumonia in 1 patient on 100/25 and 7 patients on 200/25.
• Funding: Industry (sponsor-generated data in the FDA label)

In replicate 12-month trials in 3,255 patients with moderate to severe COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in patients receiving fluticasone furoate/vilanterol 50/25 mcg: 6% (48 of 820 patients); BREO ELLIPTA 100/25 mcg: 6% (51 of 806 patients); or BREO ELLIPTA 200/25 mcg: 7% (55 of 811 patients) than in patients receiving vilanterol 25 mcg: 3% (27 of 818 patients).

In the same 12-month COPD trials, bone fractures were reported by 2% of patients on fluticasone furoate/vilanterol versus under 1% on vilanterol alone. (Source 16)

• Randomized trial, Moderate certainty.
• Size: 3,255 patients across replicate 12-month trials.
• Who: Patients with moderate to severe COPD.
• How long: 12 months.
• Result: Fractures 2% on each fluticasone furoate/vilanterol strength (50/25: 14 of 820; 100/25: 19 of 806; 200/25: 14 of 811) versus <1% (8 of 818) on vilanterol 25 mcg alone.
• Funding: Industry (sponsor-generated data in the FDA label)

In replicate 12-month trials in 3,255 patients with moderate to severe COPD, bone fractures were reported by 2% of patients receiving the fluticasone furoate/vilanterol combination (50/25 mcg: 2% [14 of 820 patients]; 100/25 mcg: 2% [19 of 806 patients]; or 200/25 mcg: 2% [14 of 811 patients]) compared with <1% of patients receiving vilanterol 25 mcg alone (8 of 818 patients).

Long-acting beta2-agonists used alone without an inhaled steroid increase asthma deaths, which is why vilanterol is only sold combined with a corticosteroid; in the SMART trial salmeterol alone was associated with 13 asthma deaths versus 3 on placebo. (Source 17)

• Randomized trial, Moderate certainty.
• Size: 26,355 patients in SMART (13,176 salmeterol, 13,179 placebo)
• Who: US patients with asthma on their usual therapy, with background inhaled corticosteroid not required.
• How long: 28 weeks.
• Result: Asthma-related deaths 13 of 13,176 on salmeterol versus 3 of 13,179 on placebo; relative risk 4.37 (95% CI 1.25 to 15.34); the label calls the increased risk a class effect of LABA monotherapy.
• Funding: Industry (sponsor trial reported in the FDA label)

A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy.

A meta-analysis of adrenal insufficiency after corticosteroid use found it in 6.8% of asthma patients treated with inhaled corticosteroids only, rising to 27.4% among those treated for more than a year. (Source 18)

• Meta-analysis, Moderate certainty.
• Size: 74 articles, 3,753 participants overall.
• Who: Adults treated with corticosteroids by various routes, including an asthma-with-inhaled-steroid-only stratum.
• How long: Varied; duration strata ranged from under 28 days to over a year.
• Result: Adrenal insufficiency 6.8% for asthma with inhalation corticosteroids only (95% CI 3.8-12.0); by duration in asthma patients, 1.4% under 28 days (95% CI 0.3-7.4) to 27.4% over 1 year (95% CI 17.7-39.8)
• Funding: Independent academic meta-analysis.

Stratified by disease, percentages ranged from 6.8% for asthma with inhalation corticosteroids only (95% CI, 3.8-12.0) to 60.0% for hematological malignancies (95% CI, 38.0-78.6).

In a four-year mortality trial in 16,568 people with moderate COPD, of whom 4,140 received BREO ELLIPTA 100/25, the adverse reactions the label records at 3% or more and more often than placebo were pneumonia, back pain, hypertension and influenza. (Source 19)

• Randomized trial, Moderate certainty.
• Size: 16,568 patients, 4,140 of them on BREO ELLIPTA 100/25 mcg.
• Who: Patients with moderate COPD (>=50% and <=70% predicted FEV1) who had a history of, or were at risk of, cardiovascular disease.
• How long: Treated for up to 4 years, median treatment duration 1.5 years.
• Result: Adverse reactions occurring in >=3% of patients on BREO ELLIPTA 100/25 mcg and more common than placebo: pneumonia, back pain, hypertension, influenza.
• Funding: Not stated (manufacturer's label)

In addition to the events in COPD trials shown in Table 2, adverse reactions occurring in ≥3% of the patients treated with BREO ELLIPTA 100/25 mcg and more common than placebo included pneumonia, back pain, hypertension, and influenza.

What the evidence supports

The Salford Lung Study, a pragmatic randomised trial in ordinary general practice, found starting fluticasone furoate-vilanterol lowered the rate of moderate or severe COPD exacerbations by 8.4% compared with continuing usual care. (Source 2)

• Randomized trial, Moderate certainty.
• Size: 2,799 patients with COPD across 75 general practices.
• Who: Patients with COPD and an exacerbation in the previous year, recruited in UK primary care with few exclusions.
• How long: 12 months.
• Result: Rate of moderate or severe exacerbations 8.4% lower (95% CI 1.1 to 15.2), P=0.02; no significant difference in COPD-related primary or secondary care contacts; no significant difference in time to first moderate, severe or first severe exacerbation.
• Funding: Industry-funded (GlaxoSmithKline; Salford Lung Study, NCT01551758)

The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with usual care (P=0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care.

The Salford Lung Study in asthma found that 71% of patients who started fluticasone furoate-vilanterol met the asthma-control responder definition at 24 weeks versus 56% on usual care, an absolute difference of 15 percentage points. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 4,233 randomised; 2,772 in the primary effectiveness analysis population.
• Who: Adults aged 18 and over with a GP diagnosis of symptomatic asthma already on maintenance inhaler therapy, in 74 UK general practices.
• How long: 12 months, primary endpoint at 24 weeks.
• Result: Responders 977 of 1,373 (71%) with fluticasone furoate-vilanterol vs 784 of 1,399 (56%) with usual care; odds ratio 2.00 (95% CI 1.70-2.34), p<0.0001; adjusted mean ACT score rose 4.4 vs 2.8 points, difference 1.6 (95% CI 1.3-2.0)
• Funding: Industry-funded (GlaxoSmithKline; NCT01706198); open-label design.

At week 24, the odds of being a responder were higher for patients who initiated treatment with fluticasone furoate and vilanterol than for those on usual care (977 [71%] of 1373 in the fluticasone furoate and vilanterol group vs 784 [56%] of 1399 in the usual care group; odds ratio [OR] 2·00 [95% CI 1·70-2·34], p<0·0001).

Four large dedicated safety trials in 35,089 patients aged 12 and over found no significant increase in serious asthma-related events when a long-acting beta2-agonist was combined with an inhaled steroid rather than used alone, though the trials were not designed to rule out all risk. (Source 17)

• Randomized trial, High certainty.
• Size: 17,537 on ICS/LABA and 17,552 on ICS alone in the pooled meta-analysis of three adult/paediatric trials, plus 6,208 children aged 4-11.
• Who: Patients with asthma aged 12 and over, and a separate trial in children aged 4 to 11.
• How long: 26 weeks each.
• Result: Serious asthma-related events 116 on ICS/LABA versus 105 on ICS alone, hazard ratio 1.10 (95% CI 0.85, 1.44); in children 27 of 3,107 (0.9%) versus 21 of 3,101 (0.7%), hazard ratio 1.29 (95% CI 0.73, 2.27)
• Funding: Industry (FDA-mandated sponsor safety trials, reported in the label)

A meta-analysis of the 3 adult and pediatric trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

What the evidence does not support

In the same trial several secondary outcomes were null: no difference in healthcare contacts and no difference in the time-to-event analyses of first exacerbation. (Source 2)

• Randomized trial, Moderate certainty.
• Size: 2,799 patients.
• Who: UK primary care patients with COPD and prior exacerbation.
• How long: 12 months.
• Result: No significant difference in annual rate of COPD-related contacts to primary or secondary care; no significant between-group differences in rates of the first moderate or severe exacerbation or the first severe exacerbation.
• Funding: Industry-funded (GlaxoSmithKline)

There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate-vilanterol group.

SUMMIT, a 16,485-patient mortality trial, found fluticasone furoate-vilanterol did not reduce all-cause mortality or cardiovascular events in people with moderate COPD and heightened cardiovascular risk. (Source 4)

• Randomized trial, High certainty.
• Size: 16,485 patients in the intention-to-treat efficacy population (4,111 placebo, 4,135 fluticasone furoate, 4,118 vilanterol, 4,121 combination); 23,835 screened and 16,590 randomised.
• Who: Adults with moderate COPD and heightened cardiovascular risk. The passages recorded here do not state the age range, lung-function range or smoking history the trial required.
• How long: Recruitment ran from 24 January 2011 to 12 March 2014. The passages recorded here do not state the treatment duration.
• Result: All-cause mortality hazard ratio 0.88 (95% CI 0.74-1.04), a 12% relative reduction, p=0.137; composite cardiovascular events HR 0.93 (95% CI 0.75-1.14); FEV1 decline 38 vs 46 mL per year, difference 8 mL per year (95% CI 1-15)
• Funding: Industry-funded (GlaxoSmithKline)

Limit of this finding: The Lancet abstract has a printing slip in this passage: the adverse-cardiac-event list reads '...18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group', with a duplicated 'and'. No figure is missing or altered; the stray word is reproduced because quotations are kept as printed. SUMMIT also missed its primary endpoint, so its own authors say the secondary results should be read with caution.

Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0·88 [95% CI 0·74-1·04]; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 [0·77-1·08]; p=0·284; vilanterol, 0·96 [0·81-1·14]; p=0·655), and therefore secondary outcomes should be interpreted with caution.

A follow-up interview substudy of the Salford asthma trial found that most patients reported no change in overall quality of life or in the daily-life domains, despite the improvement in the asthma control score. (Source 20)

• Survey study, Low certainty.
• Size: 400 patients interviewed from the Salford Lung Study in Asthma population.
• Who: Subgroup of adults with symptomatic asthma who had taken part in the trial.
• How long: Interviews after the 12-month trial.
• Result: No change in overall quality of life reported by 57.5%; no change in functioning 66.3%, activities 68.3%, relationships 86.8%, psychological 68.5%; breathlessness the symptom most likely to improve at 47.8%.
• Funding: Industry-funded (Research Support, Non-U.S. Gov't per the record; the parent trial was GlaxoSmithKline funded)

Most patients reported 'no change' in overall QoL (57.5%) and daily life domains (functioning 66.3%, activities 68.3%, relationships 86.8%, psychological 68.5%).

A Cochrane review of vilanterol plus fluticasone furoate for asthma concluded the evidence was too sparse and varied to draw firm conclusions, and that there was not enough information to say whether the once-daily combination was better or worse than twice-daily fluticasone propionate-salmeterol. (Source 21)

• Systematic review, Moderate certainty.
• Size: 14 studies and 6,641 randomised participants per the Main results section; the same abstract's conclusions section says 13 included studies.
• Who: Adults and children with chronic asthma.
• How long: Studies lasted between 2 and 78 weeks.
• Result: Main results report one study of health-related quality of life versus placebo, mean difference 0.30 (95% CI 0.14 to 0.46), 329 participants, rated moderate-quality evidence, while the conclusions section says five studies provided quality-of-life data; two studies comparing against placebo reported no exacerbations in either arm; five reported no serious adverse events in either arm.
• Funding: Independent (Cochrane systematic review)

Limit of this finding: This Cochrane abstract contradicts itself. Its Main results section says 14 studies were included and that only one of them looked at health-related quality of life; its Authors' conclusions section says 13 studies were included and that five of them provided quality-of-life data. Both passages are quoted here as published. Take the count as roughly 13 to 14 trials and do not rely on either quality-of-life figure; what both halves of the abstract agree on is that there were too few studies per comparison to draw firm conclusions.

In particular, we found insufficient information to assess whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety.

The same Cochrane review stated that the small number of studies per comparison prevented robust conclusions for practice and that the trials were too short to assess long-term side effects. (Source 21)

• Systematic review, Moderate certainty.
• Size: 14 studies and 6,641 participants per the Main results section; 13 included studies per the conclusions section of the same abstract.
• Who: Adults and children with chronic asthma.
• How long: 2 to 78 weeks.
• Result: No meta-analysable data for most primary outcomes; the Main results section says only one of the studies reported quality of life for the 100/25 mcg versus placebo comparison while the conclusions section says five provided quality-of-life data; only one study was in children.
• Funding: Independent (Cochrane systematic review)

Limit of this finding: This Cochrane abstract contradicts itself. Its Main results section says 14 studies were included and that only one of them looked at health-related quality of life; its Authors' conclusions section says 13 studies were included and that five of them provided quality-of-life data. Both passages are quoted here as published. Take the count as roughly 13 to 14 trials and do not rely on either quality-of-life figure; what both halves of the abstract agree on is that there were too few studies per comparison to draw firm conclusions.

The small number of studies contributing to each comparison precludes the opportunity to draw robust conclusions for clinical practice. These studies were not of sufficient duration to allow conclusions about long-term side effects.

IMPACT's authors stated their conclusion in terms of triple therapy rather than of this inhaler: triple therapy gave a lower rate of moderate or severe exacerbations than fluticasone furoate-vilanterol, and the trial was funded by the manufacturer of all three inhalers. (Source 22)

• Randomized trial, High certainty.
• Size: 10,355 patients with COPD.
• Who: Adults with COPD and a history of exacerbations.
• How long: 52 weeks.
• Result: Triple therapy lower than fluticasone furoate-vilanterol on the primary outcome of annual moderate or severe exacerbations; triple therapy also lower than umeclidinium-vilanterol for COPD hospitalisation.
• Funding: Industry-funded (GlaxoSmithKline; IMPACT, NCT02164513)

Limit of this finding: This is the trial's own summary of its result, and it is stated the other way round from how this inhaler is usually discussed: fluticasone furoate-vilanterol is the arm that did worse, not the arm being recommended. It applies to people with COPD who were already having exacerbations, which is who IMPACT enrolled, and the trial was paid for by the company that sells all three regimens compared.

Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population.

Where the evidence is mixed

IMPACT was a trial of once-daily single-inhaler triple therapy in which fluticasone furoate-vilanterol was one of the two comparator arms; it gives the absolute exacerbation rate on fluticasone furoate-vilanterol itself, 1.07 moderate or severe exacerbations per year, against 0.91 on triple therapy and 1.21 on the LAMA-LABA combination. (Source 14)

• Randomized trial, High certainty.
• Size: 10,355 patients with COPD.
• Who: Adults with COPD and a history of exacerbations.
• How long: 52 weeks.
• Result: Moderate or severe exacerbations per year: 0.91 triple, 1.07 fluticasone furoate-vilanterol, 1.21 umeclidinium-vilanterol; triple vs fluticasone furoate-vilanterol rate ratio 0.85 (95% CI 0.80 to 0.90), P<0.001.
• Funding: Industry-funded (GlaxoSmithKline; IMPACT, NCT02164513)

Limit of this finding: Fluticasone furoate-vilanterol was not the treatment IMPACT set out to test - it was a comparator against which triple therapy was measured, and it came out worse on the trial's primary outcome. The 1.07 exacerbations per year is a sound reading of how this inhaler performed in 10,355 people with COPD and prior exacerbations, but nothing here makes it the better of the three regimens, and the trial was funded by the manufacturer of all three.

The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001)

SUMMIT also found no excess pneumonia or cardiac events in this moderate-COPD population, which cuts against the pneumonia signal seen in trials of patients with more severe disease and prior exacerbations. (Source 4)

• Randomized trial, High certainty.
• Size: 16,485 patients in the intention-to-treat efficacy population (4,111 placebo, 4,135 fluticasone furoate, 4,118 vilanterol, 4,121 combination); 23,835 screened and 16,590 randomised.
• Who: Adults with moderate COPD and heightened cardiovascular risk. The passages recorded here do not state the age range, lung-function range or smoking history the trial required.
• How long: Recruitment ran from 24 January 2011 to 12 March 2014. The passages recorded here do not state the treatment duration.
• Result: Pneumonia 5% placebo, 6% combination, 5% fluticasone furoate, 4% vilanterol; adverse cardiac events 17% placebo, 18% combination, 17% fluticasone furoate, 17% vilanterol.
• Funding: Industry-funded (GlaxoSmithKline)

Limit of this finding: The Lancet abstract has a printing slip in this passage: the adverse-cardiac-event list reads '...18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group', with a duplicated 'and'. No figure is missing or altered; the stray word is reproduced because quotations are kept as printed. SUMMIT also missed its primary endpoint, so its own authors say the secondary results should be read with caution.

No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups.

The same Cochrane review found that although inhaled steroids as a class raised serious pneumonia events, they did not significantly affect overall mortality, and that pneumonia-related deaths were too rare to analyse. (Source 15)

• Meta-analysis, High certainty.
• Size: 43 studies.
• Who: Adults with COPD.
• How long: At least 12 weeks.
• Result: No significant difference in overall mortality between either inhaled steroid and controls, both rated high-quality evidence; pneumonia-related deaths too rare to permit conclusions.
• Funding: Independent (Cochrane systematic review)

Limit of this finding: The mortality result is for inhaled steroids as a class - budesonide and fluticasone propionate carry almost all of the data - not for this product; the review says little evidence exists for fluticasone furoate specifically. The same passage also describes budesonide as having 'increased' serious pneumonia events on an odds ratio of 1.62 with a 95% confidence interval of 1.00 to 2.62, which reaches 1 and so is not a conventionally significant increase.

No significant difference in overall mortality rates was observed between either of the inhaled steroids and the control interventions (both high-quality evidence), and pneumonia-related deaths were too rare to permit conclusions to be drawn.

The Salford COPD trial's authors summarised their result as a lower exacerbation rate than usual care with no greater risk of serious adverse events; the trial was funded by the inhaler's manufacturer. (Source 23)

• Randomized trial, Moderate certainty.
• Size: 2,799 patients in 75 general practices.
• Who: Patients with COPD and a history of exacerbations, managed in ordinary UK general practice.
• How long: 12 months.
• Result: Lower rate of moderate or severe exacerbations than usual care, 8.4% (95% CI 1.1 to 15.2), P=0.02, without a greater risk of serious adverse events.
• Funding: Industry-funded (GlaxoSmithKline; Salford Lung Study, NCT01551758)

Limit of this finding: This was an open-label effectiveness trial against usual care, not a blinded comparison against placebo or against another inhaler, so part of the difference may come from starting a new treatment and being watched rather than from the drug. The authors word it as an association, and the trial was funded by the manufacturer. 'Without a greater risk of serious adverse events' is the finding of this one 12-month trial and does not override the pneumonia signal in the longer-term evidence.

In patients with COPD and a history of exacerbations, a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than usual care, without a greater risk of serious adverse events.

Where the research disagrees

How much pneumonia risk inhaled fluticasone adds in COPD

• Kew and Seniukovich, Cochrane meta-analysis of 43 trials (2014), meta-analysis of 43 randomised trials, graded high quality: Fluticasone increased non-fatal serious adverse pneumonia events (requiring hospital admission) (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.50 to 2.12; 18 more per 1000 treated over 18 months; high quality) (Source 15)
• SUMMIT investigators, 16,485-patient randomised trial in moderate COPD (2016), single large randomised controlled trial in a population with moderate airflow limitation, not selected for prior exacerbations: No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups. (Source 4)

Whether the once-daily combination is better than established twice-daily inhaled steroid plus LABA combinations

• Salford Lung Study in Asthma investigators (2017), open-label pragmatic randomised trial against optimised usual care, industry funded: initiation of a once-daily treatment regimen of combined fluticasone furoate and vilanterol improved asthma control without increasing the risk of serious adverse events when compared with optimised usual care. (Source 24)
• Cochrane review of vilanterol and fluticasone furoate for asthma (2016), systematic review of 14 randomised trials with 6,641 participants: Information was insufficient for assessment of whether once-daily VI/FF was better or worse than twice-daily FP/SAL in terms of efficacy or safety. It is clear that more research is required to reduce the uncertainties that surround interpretation of these studies. (Source 25)

How much

• Reference intake: Dosing is set by the prescriber. As a position, the FDA label (BREO ELLIPTA, GlaxoSmithKline, SPL version 29, published Jun 08 2026) gives one actuation of the 100/25 mcg strength once daily by oral inhalation for COPD maintenance. (Source 26)
• Upper limit: As a position, the same label states the maximum recommended dosage for asthma is one inhalation of the 200/25 mcg strength once daily, and that for COPD the daily dose of 100/25 mcg should not be increased; patients should not use more than one inhalation once daily. (Source 27)
• Studied: The Salford Lung Study in COPD randomised patients to once-daily fluticasone furoate 100 micrograms with vilanterol 25 micrograms or to usual care. (Source 2)
• Studied: IMPACT compared fluticasone furoate 100 mcg with vilanterol 25 mcg against triple therapy adding umeclidinium 62.5 mcg and against umeclidinium-vilanterol, all once daily in a single Ellipta inhaler for 52 weeks. (Source 14)
• Studied: The replicate 12-month COPD trials in the label studied once-daily fluticasone furoate/vilanterol at 50/25, 100/25 and 200/25 mcg against vilanterol 25 mcg alone in 3,255 patients. (Source 5)
• Studied: As a position, the same label states a different strength for each age band in asthma: 200/25 mcg or 100/25 mcg once daily for adults 18 and over, 100/25 mcg once daily for ages 12 to 17, and 50/25 mcg once daily for ages 5 to 11. (Source 28)

A common belief, and what the research shows

The belief: This inhaler still carries the old black-box warning that long-acting bronchodilators cause asthma deaths.

What the research shows: The current FDA label for BREO ELLIPTA has no boxed warning at all; the asthma-death issue is now a Warning and Precaution, and it rests on a distinction between a LABA used alone and a LABA combined with a steroid. The label states: Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. It also records that the trials were not designed to rule out all risk, and that LABA monotherapy does increase asthma deaths.

Questions and answers

What is it?

This is a single dry-powder inhaler holding two different medicines: fluticasone furoate, a corticosteroid, and vilanterol, a long-acting beta2-agonist bronchodilator. It is taken once a day. It is licensed for the maintenance treatment of COPD and of asthma from the age of five, and explicitly not for relieving a sudden attack. (Source 29)

What does it do in the body?

The steroid component damps down airway inflammation and the bronchodilator relaxes airway muscle, so the airways stay more open day to day. The label is candid that the precise mechanism by which fluticasone furoate affects COPD and asthma symptoms is not known, and that the clinical relevance of its high receptor-binding affinity is unknown. (Source 30)

Is it good or bad for you?

It is useful for some people and carries a real cost. In COPD with prior exacerbations the Salford pragmatic trial found 8.4% fewer exacerbations than usual care, and in asthma 71% of starters met the control target versus 56% on usual care. Against that, a Cochrane meta-analysis graded high quality linked inhaled fluticasone - almost entirely the older propionate form in those trials - with about 18 extra hospital-treated pneumonias per 1,000 people over 18 months, and said little evidence yet exists for the furoate form used here; SUMMIT found no mortality or cardiovascular benefit in moderate COPD. (Source 31)

How do you get more of it?

This is not something to get more of; it is a prescribed inhaler, there is one inhalation a day, and the label states that extra doses must not be used for acute symptoms. For reference only, the COPD dose in the label is one actuation of the 100/25 strength once daily, with a separate short-acting rescue inhaler for breathlessness between doses. (Source 26)

If it is harmful, what reduces it?

If the systemic steroid effect becomes a problem, the label's instruction is to reduce the dose slowly rather than stop abruptly, in the same way systemic steroids are tapered, and to consider other treatments. Both components are broken down by the liver enzyme CYP3A4, so avoiding strong inhibitors of that enzyme reduces how much drug builds up in the body. (Source 11)

Why might someone be low in it or missing it?

Not applicable as a deficiency. The nearest equivalent question is why someone would not be on it, and the evidence gives reasons: SUMMIT showed no survival or cardiovascular benefit in moderate COPD, IMPACT showed higher exacerbation rates on this dual combination than on triple therapy, and the pneumonia risk is real, so an inhaled steroid is not automatically indicated for every person with airway disease. (Source 32)

Which whole foods contain it or feed it?

No food contains either ingredient. Both are CYP3A4 substrates, and the only dietary-type interaction that follows in principle is with strong inhibitors of that enzyme; the label names drugs such as ketoconazole rather than any food, and we found no study of grapefruit or any other food with this inhaler. (Source 6)

What happens if you do not have it?

Without maintenance treatment, exacerbations are more frequent in people who have had them before: the usual-care arm of the Salford COPD trial had 8.4% more moderate or severe exacerbations over a year, and in asthma 56% rather than 71% of patients reached the control target. In the interview substudy, however, most patients reported no change in overall quality of life either way, so the difference is measurable rather than transformative. (Source 20)

How can you test for it?

There is no blood test for the inhaler itself. What is measured is effect and harm: spirometry (FEV1), symptom scores such as the Asthma Control Test, and exacerbation counts for benefit; and for the steroid's systemic effects the label advises watching for signs of hypercorticism, taking particular care after surgery or during stress, and assessing bone mineral density before starting and periodically afterwards in COPD. (Source 16)

References

1. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 12.1 Mechanism of Action, Vilanterol subsection. 2026. Read the source
2. The New England journal of medicine. Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice. [Results section of the abstract]. 2016. PMID 27593504, DOI 10.1056/nejmoa1608033. Read the source
3. Lancet (London, England). Effectiveness of fluticasone furoate plus vilanterol on asthma control in clinical practice: an open-label, parallel group, randomised controlled trial. [Findings section of the abstract]. 2017. PMID 28903864, DOI 10.1016/s0140-6736(17)32397-8. Read the source
4. Lancet (London, England). Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. [Findings section of the abstract]. 2016. PMID 27203508, DOI 10.1016/s0140-6736(16)30069-1. Read the source
5. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 5.5 Pneumonia. 2026. Read the source
6. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 7.1 Inhibitors of Cytochrome P450 3A4. 2026. Read the source
7. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 7.4 Non-Potassium-Sparing Diuretics. 2026. Read the source
8. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 7.2 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and QTc Prolonging Drugs. 2026. Read the source
9. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 7.3 Beta-Adrenergic Receptor Blocking Agents. 2026. Read the source
10. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 5.17 Hyperglycemia and Hypokalemia. 2026. Read the source
11. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 5.8 Hypercorticism and Adrenal Suppression. 2026. Read the source
12. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 5.2 Deterioration of Disease and Acute Episodes. 2026. Read the source
13. The Journal of clinical endocrinology and metabolism. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. [Conclusions section of the abstract]. 2015. PMID 25844620, DOI 10.1210/jc.2015-1218. Read the source
14. The New England journal of medicine. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. [Results section of the abstract]. 2018. PMID 29668352, DOI 10.1056/nejmoa1713901. Read the source
15. The Cochrane database of systematic reviews. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. [Main results section of the abstract]. 2014. PMID 24615270, DOI 10.1002/14651858.cd010115.pub2. Read the source
16. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 5.13 Reduction in Bone Mineral Density. 2026. Read the source
17. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 5.1 Serious Asthma-Related Events, ICS/LABA safety trials and SMART. 2026. Read the source
18. The Journal of clinical endocrinology and metabolism. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. [Results section of the abstract]. 2015. PMID 25844620, DOI 10.1210/jc.2015-1218. Read the source
19. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 6.1 Clinical Trials Experience in COPD, 12-month trials and mortality trial narrative. 2026. Read the source
20. NPJ primary care respiratory medicine. A descriptive follow-up interview study assessing patient-centred outcomes: Salford Lung Study in Asthma (SLS Asthma). [Abstract section of the abstract]. 2019. PMID 31417102, DOI 10.1038/s41533-019-0142-x. Read the source
21. The Cochrane database of systematic reviews. Vilanterol and fluticasone furoate for asthma. [Main results section of the abstract]. 2016. PMID 27582089, DOI 10.1002/14651858.cd010758.pub2. Read the source
22. The New England journal of medicine. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. [Conclusions section of the abstract]. 2018. PMID 29668352, DOI 10.1056/nejmoa1713901. Read the source
23. The New England journal of medicine. Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice. [Conclusions section of the abstract]. 2016. PMID 27593504, DOI 10.1056/nejmoa1608033. Read the source
24. Lancet (London, England). Effectiveness of fluticasone furoate plus vilanterol on asthma control in clinical practice: an open-label, parallel group, randomised controlled trial. [Interpretation section of the abstract]. 2017. PMID 28903864, DOI 10.1016/s0140-6736(17)32397-8. Read the source
25. The Cochrane database of systematic reviews. Vilanterol and fluticasone furoate for asthma. [Authors' conclusions section of the abstract]. 2016. PMID 27582089, DOI 10.1002/14651858.cd010758.pub2. Read the source
26. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 2.1 Recommended Dosage for Maintenance Treatment of COPD. 2026. Read the source
27. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 2.2 Recommended Dosage for Maintenance Treatment of Asthma (Adult Patients Aged 18 Years and Older subsection). 2026. Read the source
28. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 2.2 Recommended Dosage for Maintenance Treatment of Asthma (Pediatric Patients subsections). 2026. Read the source
29. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - Highlights, Indications and Usage excerpt. 2026. Read the source
30. DailyMed / US FDA Structured Product Label. BREO ELLIPTA (fluticasone furoate and vilanterol trifenatate) inhalation powder - FDA prescribing information (GlaxoSmithKline LLC, SPL version 29, published Jun 08, 2026) - section 12.1 Mechanism of Action. 2026. Read the source
31. The Cochrane database of systematic reviews. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. [Authors' conclusions section of the abstract]. 2014. PMID 24615270, DOI 10.1002/14651858.cd010115.pub2. Read the source
32. Lancet (London, England). Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. [Interpretation section of the abstract]. 2016. PMID 27203508, DOI 10.1016/s0140-6736(16)30069-1. Read the source