Fluticasone furoate / umeclidinium / vilanterol

What it is

TRELEGY ELLIPTA contains fluticasone furoate, umeclidinium, and vilanterol, combined as a once-daily dry-powder inhaler. It is a single-inhaler triple therapy: an inhaled corticosteroid (fluticasone furoate), a long-acting muscarinic antagonist / anticholinergic bronchodilator (umeclidinium), and a long-acting beta2-agonist bronchodilator (vilanterol), delivered together for maintenance treatment of COPD and, at certain strengths, asthma.

What the research says

The evidence differs by approved use. In COPD, the pivotal IMPACT trial found this triple combination reduced moderate/severe exacerbations, hospitalizations, and all-cause mortality compared with two-component (dual) inhalers. In asthma, the CAPTAIN trial found the triple combination improved lung function (FEV1) over a dual ICS/LABA inhaler but did not significantly reduce exacerbation rates in its pooled analysis. Analogous triple-therapy evidence in COPD from a different molecule (budesonide/glycopyrronium/formoterol, studied in the ETHOS trial) also found a pneumonia signal in the corticosteroid-containing arms, and this matters because oral/inhaled corticosteroid exposure is common to the drug class.

Evidence grade: Well established.

How it works

Drug class: Inhaled corticosteroid (ICS) + long-acting muscarinic antagonist (LAMA) + long-acting beta2-agonist (LABA), single-inhaler triple combination

Fluticasone furoate is an inhaled corticosteroid that reduces airway inflammation. Umeclidinium is a long-acting muscarinic antagonist that blocks acetylcholine at M3 receptors on airway smooth muscle to keep airways open. Vilanterol is a long-acting beta2-agonist that relaxes airway smooth muscle by stimulating beta2-adrenergic receptors. The three are combined in one inhaler so a person gets anti-inflammatory and two complementary bronchodilator actions from a single daily device. (Source 1)

What it is used for

• The IMPACT trial (>10,000 patients) found single-inhaler triple therapy reduced COPD hospitalizations and all-cause mortality compared with two of the dual-therapy components, with double-digit percentage reductions reported by the trial sponsor; this is the best-supported use of this combination. Evidence: established. (Source 2)
• The CAPTAIN trial found this triple combination improved lung function (FEV1) versus a dual ICS/LABA inhaler, but the pooled analysis did not find a statistically significant reduction in asthma exacerbations, so the exacerbation-prevention benefit seen in COPD does not clearly carry over to asthma. Evidence: limited. (Source 3)

Interactions

• ritonavir (and other strong CYP3A4 inhibitors) (case reports): Ritonavir strongly inhibits the CYP3A4 enzyme that normally breaks down fluticasone; blocking this pathway raises systemic fluticasone levels enough to cause iatrogenic Cushing's syndrome and adrenal suppression in case reports. (Source 4)
• grapefruit / grapefruit juice (theoretical): Grapefruit juice inhibits intestinal CYP3A4, the same enzyme that clears the systemically absorbed fraction of fluticasone; this is a theoretical/pharmacokinetic-principle concern by analogy to documented strong CYP3A4 inhibitors like ketoconazole and ritonavir, rather than a dedicated grapefruit-fluticasone clinical study. (Source 5)
• non-potassium-sparing (loop or thiazide) diuretics (label): The beta-agonist component (vilanterol) can lower serum potassium, and this can be worsened by loop or thiazide diuretics, which the label flags as a cardiovascular risk factor combination. (Source 6)
• ketoconazole and other strong CYP3A4 inhibitors (clarithromycin, itraconazole, ritonavir, etc.) (label): The manufacturer's label for the fluticasone furoate/vilanterol component explicitly warns that coadministration with strong CYP3A4 inhibitors can raise systemic corticosteroid exposure and cardiovascular adverse effects. (Source 6)

Stopping it

• In COPD patients already on triple therapy, stepwise withdrawal of the inhaled-corticosteroid component did not increase moderate or severe exacerbation risk compared with continuing it. This evidence concerns the ICS component specifically and was generated in a trial of a different ICS/LAMA/LABA combination, not fluticasone furoate/umeclidinium/vilanterol itself. (Source 7)
• The same analysis found an exception: people who had had two or more exacerbations in the previous year and who had high blood eosinophil counts appeared to do better continuing the inhaled corticosteroid. The authors add that this subgroup analysis had high variability because the numbers in it were small. (Source 8)

What goes wrong

In a large COPD trial of a different (but pharmacologically analogous) inhaled triple therapy, the inhaled-corticosteroid-containing arms had a higher rate of confirmed pneumonia than the LAMA/LABA arm without a corticosteroid. (Source 9)

• Randomized trial, Certainty not rated.
• Size: Large multi-arm COPD trial (exact n not re-extracted in this session)
• Who: Moderate-to-very-severe COPD patients with a history of exacerbations.
• How long: 52 weeks.
• Result: Confirmed pneumonia in 4.2% of the higher-dose triple-therapy arm vs 2.3% of the LAMA/LABA arm (NNH approximately 53 per year); this trial studied budesonide/glycopyrronium/formoterol (Breztri Aerosphere), not fluticasone furoate/umeclidinium/vilanterol itself, so it is class-level evidence for ICS-containing triple therapy in COPD, not direct evidence for this specific product.
• Funding: industry-funded (AstraZeneca, trial sponsor)

ICS-containing groups had higher rates of confirmed pneumonia (TT320 vs LAMA/LABA: 4.2% vs 2.3% NNH≈53/yr).

What the evidence supports

In COPD patients with a history of exacerbations, single-inhaler triple therapy reduced severe exacerbations (hospitalizations) and all-cause mortality compared with a LAMA/LABA dual inhaler. (Source 2)

• Randomized trial, Certainty not rated.
• Size: 10,355 patients enrolled across 37 countries (per trial sponsor's press release); exact per-arm n not independently re-verified from primary text in this session.
• Who: Patients with COPD and a history of moderate or severe exacerbations.
• How long: Not independently re-verified from primary NEJM text in this session (full text was paywalled/blocked); commonly reported elsewhere as approximately one year.
• Result: 34% reduction in COPD hospitalizations vs a LAMA/LABA dual inhaler (0.13 vs 0.19 per year; p<0.001); 42.1% reduction in on-treatment all-cause mortality vs the same comparator (1.20% vs 1.88%; p=0.011)
• Funding: industry-funded (GSK, trial sponsor and manufacturer)

A statistically significant 34% reduction in COPD hospitalisations (severe exacerbations) for Trelegy compared to Anoro (0.13 vs. 0.19 per year; p<0.001)

What the evidence does not support

Stepwise withdrawal of the inhaled-corticosteroid component from COPD patients on ICS/LAMA/LABA triple therapy did not increase exacerbation risk in a subgroup analysis. (Source 7)

• Randomized trial, Certainty not rated.
• Size: Subgroup of a large COPD withdrawal trial.
• Who: COPD patients taking triple therapy (ICS/LAMA/LABA) at screening.
• How long: 12-week stepwise withdrawal period, with follow-up to 52 weeks.
• Result: Hazard ratio 1.05 (95% CI 0.89-1.25) for moderate/severe exacerbation with ICS withdrawal versus continuation in patients on triple therapy at screening, versus HR 1.06 (95% CI 0.94-1.19) in the overall trial population.
• Funding: industry-funded.

Moderate/severe exacerbation risk between the ICS withdrawal and continuation groups (hazard ratio [HR], 1.05; 95% confidence interval [CI]: 0.89– 1.25) was not increased in patients taking triple therapy at screening versus the overall trial population (HR [95% CI]: 1.06 [0.94– 1.19]).

Where the evidence is mixed

In asthma inadequately controlled on ICS/LABA, adding the LAMA component (umeclidinium) improved lung function but did not significantly reduce exacerbations in the pooled analysis. (Source 3)

• Randomized trial, Certainty not rated.
• Size: Not independently re-extracted; CAPTAIN was a phase 3A trial with multiple dose arms.
• Who: Adults with asthma inadequately controlled on inhaled corticosteroid/LABA therapy.
• How long: 24 weeks (FEV1 endpoint)
• Result: FEV1 improved 110 mL (66-153 mL; p<0.0001) for FF/UMEC/VI 100/62.5/25 mcg vs FF/VI 100/25 mcg dual therapy, but no significant reduction in moderate/severe exacerbation rate was seen in the pooled analysis.
• Funding: industry-funded (GSK)

No significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62.5 μg/VI versus FF/VI (pooled analysis).

Where the research disagrees

Whether continuing versus stepping down the inhaled corticosteroid component of triple therapy is preferable once a COPD patient is stable

• The American Journal of Managed Care, characterising the WISDOM trial (2014), trade-press characterisation of what the WISDOM investigators concluded; recorded as a dated position, not as the investigators' own words and not the page's closing sentence: The investigators concluded that outcomes in patients who were in the withdrawal-of-ICS group were not inferior to outcomes among patients who continued to take the ICS as part of triple therapy with a LAMA and a LABA. (Source 10)
• Post hoc analysis of the triple-therapy subgroup of the same withdrawal trial, post hoc subgroup analysis of a randomised withdrawal trial, with high variability from small subgroup numbers: The results of the present analyses confirmed that frequent exacerbators (≥2 exacerbations in the previous year) with high blood eosinophil counts could benefit from continuing ICS treatment, as the risk of exacerbation increased nominally with increasing blood eosinophil levels. However, there was high variability due to small sample sizes in this subgroup analysis. (Source 8)

How much

• Reference intake: Dosing is set by the prescriber, not the reader. The FDA label states the approved regimen as a position: one inhalation of TRELEGY ELLIPTA 100/62.5/25 mcg once daily for COPD, and one inhalation of the 100/62.5/25 mcg or 200/62.5/25 mcg strength once daily for asthma. (Source 1)
• Upper limit: The label's highest approved strength is 200/62.5/25 mcg once daily (asthma only); this is the FDA-approved ceiling, stated as a position, not a recommendation. (Source 1)
• Studied: The IMPACT COPD trial studied the 100/62.5/25 mcg once-daily strength. (Source 2)
• Studied: The CAPTAIN asthma trial studied multiple strength combinations, including FF/UMEC/VI 100/62.5/25 mcg and 200/62.5/25 mcg, each against a matching FF/VI dual-therapy dose. (Source 3)

A common belief, and what the research shows

The belief: People often assume that because this inhaler contains a steroid plus two bronchodilators, it must reduce exacerbations equally well whatever the underlying diagnosis (COPD or asthma).

What the research shows: The exacerbation-rate benefit is best documented for COPD; in the CAPTAIN asthma trial 'no significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62.5 μg/VI versus FF/VI (pooled analysis),' even though lung function improved, so the evidence must be read separately for each approved use rather than assumed to transfer.

Questions and answers

What is it?

This is a once-daily inhaler that combines three medicines in one device: an inhaled corticosteroid (fluticasone furoate), a long-acting anticholinergic bronchodilator (umeclidinium), and a long-acting beta2-agonist bronchodilator (vilanterol). It is approved for maintenance treatment of COPD and, at certain strengths, asthma, not for quick relief of sudden symptoms. (Source 1)

What does it do in the body?

Fluticasone furoate reduces inflammation in the airway lining. Umeclidinium blocks a nerve signal (acetylcholine at muscarinic receptors) that would otherwise tighten airway muscle, keeping the airway open. Together with vilanterol's separate bronchodilator action, the three combine anti-inflammatory and airway-opening effects in one daily inhaler. (Source 1)

Is it good or bad for you?

In COPD with a history of exacerbations, trial data reported by the manufacturer show fewer hospitalizations and lower mortality versus two-component inhalers, which is a clear benefit in that specific population. But inhaled-corticosteroid-containing triple therapy also carries a pneumonia signal shown in COPD trials of an analogous triple combination, and in asthma the added LAMA component improved lung function without a proven exacerbation benefit, so how 'good' this is depends heavily on the diagnosis and history. (Source 2)

How do you get more of it?

This question, framed for a nutrient someone might be low in, does not apply to a prescription inhaler. The amount and frequency are fixed by the FDA-approved regimen and set by the prescriber, not adjusted upward by the person taking it. (Source 1)

If it is harmful, what reduces it?

If the concern is corticosteroid-related risk (such as the pneumonia signal seen with ICS-containing triple therapy), the literature-supported approach studied is a clinician-directed stepwise withdrawal of the inhaled-corticosteroid component, which in COPD trials did not increase exacerbation risk in most patients on triple therapy at baseline. (Source 7)

Why might someone be low in it or missing it?

Not applicable in the way this question applies to a nutrient or organism. This is a manufactured combination medicine; a person cannot be biologically deficient in it. The nearest real question -- why someone's COPD or asthma might be undertreated -- was not addressed by the trial reports reviewed here. (Source 1)

We searched: Searched the IMPACT, CAPTAIN, ETHOS and WISDOM trial reports and the FDA label for any discussion of under-treatment, adherence, or access barriers; none of the sources fetched in this session addressed it.

Which whole foods contain it or feed it?

No whole food contains or substitutes for this inhaler. The one food-related point in the literature is a caution, not a source: grapefruit juice inhibits the same CYP3A4 enzyme that clears the systemically absorbed fraction of fluticasone, by analogy with documented strong CYP3A4 inhibitors. (Source 5)

What happens if you do not have it?

The sources reviewed in this session compared this inhaler against other inhaled therapies, not against leaving COPD or asthma completely untreated, so the natural history of untreated disease could not be answered from what was fetched. (Source 2)

We searched: Searched IMPACT, ETHOS, CAPTAIN and WISDOM trial summaries for untreated-control-arm data; all comparisons were active-drug versus active-drug (dual vs triple therapy or ICS continuation vs withdrawal), not versus no treatment.

How can you test for it?

Response is not measured with a blood test but with lung function testing (spirometry, specifically FEV1), which is exactly how the CAPTAIN asthma trial measured benefit. Spirometry is a well-established, standardized objective measure of airway function, though it reflects overall lung function rather than confirming the inhaler specifically is 'working' for an individual. (Source 3)

References

1. U.S. Food and Drug Administration / GSK. TRELEGY ELLIPTA (fluticasone furoate, umeclidinium, and vilanterol inhalation powder) Full Prescribing Information. 2022. Read the source
2. GSK. Landmark IMPACT study published in NEJM shows significant benefits of Trelegy Ellipta for patients with COPD (press release describing the IMPACT trial). 2018. Read the source
3. Breathe (European Respiratory Society). Efficacy and safety of once-daily single-inhaler triple therapy in patients with inadequately controlled asthma: the CAPTAIN trial. 2021. Read the source
4. CMAJ (Canadian Medical Association Journal). Cushing syndrome due to ritonavir–fluticasone interaction. 2012. Read the source
5. MedEd101 (clinical pharmacology education blog). Inhaled Fluticasone and CYP3A4 Interactions. 2023. Read the source
6. U.S. Food and Drug Administration / GSK. BREO ELLIPTA (fluticasone furoate and vilanterol inhalation powder) Full Prescribing Information. 2019. Read the source
7. International Journal of COPD (Dove Medical Press). Effect of Inhaled Corticosteroid Withdrawal on Chronic Obstructive Pulmonary Disease Exacerbations in Patients Taking Triple Therapy at Baseline. 2020. PMID 33204084, DOI 10.2147/COPD.S237408. Read the source
8. International Journal of COPD (Dove Medical Press). Effect of Inhaled Corticosteroid Withdrawal on Chronic Obstructive Pulmonary Disease Exacerbations in Patients Taking Triple Therapy at Baseline. 2020. PMID 33204084, DOI 10.2147/COPD.S237408. Read the source
9. RxFiles (University of Saskatchewan). Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD (ETHOS trial summary; budesonide/glycopyrrolate/formoterol, Breztri Aerosphere). 2020. Read the source
10. The American Journal of Managed Care (AJMC). Study Summary: WISDOM (Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD). 2014. Read the source