Trelegy Ellipta
fluticasone furoate / umeclidinium / vilanterol
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| COPD — maintenance treatment | Adults | Triple combination (ICS + LAMA + LABA) | FDA Approved |
| Asthma — maintenance treatment | Adults ≥18 years | Triple combination (ICS + LAMA + LABA) | FDA Approved |
Fluticasone-umeclidinium-vilanterol is the first once-daily single-inhaler triple therapy approved for both COPD and asthma in the United States. For COPD, it is positioned for patients who require the addition of a LAMA to an existing ICS/LABA regimen, or who warrant initiation of all three controller classes. For asthma, it targets adults whose disease remains uncontrolled on an ICS/LABA dual combination. It is not a rescue inhaler and must never be used for acute bronchospasm relief.
Asthma-COPD overlap (ACO): Some clinicians use fluticasone-umeclidinium-vilanterol in patients exhibiting features of both conditions. Evidence quality: Low-Moderate. Dedicated ACO trials have not been conducted with this specific product, but GOLD and GINA documents acknowledge that patients with overlap features may benefit from triple therapy.
Dosing
COPD
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| COPD maintenance — step-up from ICS/LABA | 100/62.5/25 mcg, 1 inhalation once daily | 100/62.5/25 mcg, 1 inhalation once daily | 100/62.5/25 mcg once daily | Only the 100/62.5/25 strength is approved for COPD The 200/62.5/25 strength is NOT indicated for COPD |
| COPD maintenance — step-up from LAMA/LABA | 100/62.5/25 mcg, 1 inhalation once daily | 100/62.5/25 mcg, 1 inhalation once daily | 100/62.5/25 mcg once daily | For patients with exacerbation history or elevated eosinophils who benefit from ICS addition Discontinue separate LAMA and/or ICS/LABA inhalers when switching |
| Transition from oral corticosteroids | 100/62.5/25 mcg, 1 inhalation once daily | 100/62.5/25 mcg, 1 inhalation once daily | 100/62.5/25 mcg once daily | Taper prednisone by 2.5 mg/week (FDA PI) Monitor for adrenal insufficiency throughout taper |
Asthma (Adults ≥18 Years)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Persistent asthma — uncontrolled on medium-dose ICS/LABA | 100/62.5/25 mcg, 1 inhalation once daily | 100/62.5/25 mcg, 1 inhalation once daily | 200/62.5/25 mcg once daily | May step up to 200/62.5/25 if inadequate control Reassess after appropriate trial period |
| Persistent asthma — uncontrolled on high-dose ICS/LABA | 200/62.5/25 mcg, 1 inhalation once daily | 200/62.5/25 mcg, 1 inhalation once daily | 200/62.5/25 mcg once daily | Already at maximum approved strength If still inadequate, consider additional therapeutic options (biologics, etc.) |
| Step-down after achieving control | Current effective strength | 100/62.5/25 mcg, 1 inhalation once daily | N/A | Titrate to lowest effective dose Consider stepping down to ICS/LABA if LAMA can be withdrawn |
Trelegy Ellipta is administered as a single inhalation once daily at the same time each day. The Ellipta dry powder inhaler requires no shaking, no priming, and no coordination of actuation with breathing — the patient simply opens the cover (which loads the dose), breathes in steadily and deeply, then closes the cover. Clinical studies demonstrated that 97–98% of patients used the Ellipta inhaler correctly by Day 28. Patients should rinse their mouth with water and spit after each dose to prevent oral candidiasis. The inhaler contains a dose counter and should be discarded after 30 doses or 6 weeks after opening the foil tray, whichever comes first.
Pharmacology
Mechanism of Action
Trelegy Ellipta combines three pharmacologically distinct classes in a single inhaler. Fluticasone furoate is a synthetic trifluorinated corticosteroid with approximately 30-fold greater glucocorticoid receptor binding affinity than dexamethasone. It suppresses airway inflammation by inhibiting pro-inflammatory cytokine release, eosinophil recruitment, and mediator production, reducing bronchial hyperresponsiveness over sustained use.
Umeclidinium is a long-acting muscarinic antagonist (LAMA) with high affinity for M3 receptors on airway smooth muscle. By competitively and reversibly blocking acetylcholine-mediated bronchoconstriction, it provides sustained bronchodilation lasting more than 24 hours, complementing the LABA component through a distinct neural pathway.
Vilanterol is a selective, long-acting beta-2 adrenergic agonist (LABA) that activates adenylyl cyclase in airway smooth muscle, increasing intracellular cyclic AMP and producing sustained relaxation for at least 24 hours after a single dose. The combination of muscarinic blockade plus beta-2 stimulation provides greater bronchodilation than either mechanism alone, while the ICS addresses the underlying inflammatory pathology.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | FF: Tmax 0.5–1 h; absolute bioavailability ~15% (inhaled). UMEC: Tmax 5–15 min. VI: rapid absorption from lung | Once-daily dosing is supported by sustained receptor occupancy; bronchodilation from UMEC and VI begins within minutes |
| Distribution | FF: Vd 661 L, protein binding >99%. UMEC: Vd ~86 L (IV), protein binding ~89%. VI: Vd ~165 L, protein binding ~94% | All three components distribute beyond plasma volume; high protein binding of FF limits systemic free drug availability |
| Metabolism | FF: CYP3A4 to inactive metabolites. UMEC: CYP2D6 (primary), but CYP2D6 poor metaboliser status does not clinically alter exposure. VI: CYP3A4 (O-dealkylation) | Strong CYP3A4 inhibitors increase FF and VI systemic exposure; no clinically relevant impact of CYP2D6 polymorphisms on UMEC |
| Elimination | FF: t½ ~24 h; faecal/urinary. UMEC: t½ ~11 h (effective); faecal 58%, urinary 22%. VI: t½ ~11 h (effective); urinary 70%, faecal 30% | All three components support once-daily dosing; no dose adjustment needed for renal impairment |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Pharyngitis / nasopharyngitis | 17% | Most frequently reported event in asthma trials (vs 16% with FF/VI); generally mild upper respiratory symptoms |
| Adverse Effect | Incidence (COPD / Asthma) | Clinical Note |
|---|---|---|
| Headache | 4% (COPD) / 9% (asthma) | More frequent in asthma trials; usually self-limiting |
| Back pain | 4% (COPD) / ≥2% (asthma) | Occurred more frequently than placebo+FF/VI in COPD trials |
| Upper respiratory tract infection | ≥1% (COPD) / 8% (asthma) | Reported in both indications across multiple trials |
| Pneumonia (COPD) | 8% (52-week IMPACT trial) | ICS-class risk in COPD; higher than LAMA/LABA alone (5%); closely monitor sputum changes, fever, cough worsening |
| Bronchitis | ≥1% (COPD) / ≥2% (asthma) | Reported across all treatment groups including comparators |
| Sinusitis | ≥1% (COPD) / ≥2% (asthma) | Comparable incidence to ICS/LABA dual therapy |
| Oral candidiasis | ≥1% (COPD 52-week) | ICS-class effect; mouth rinsing after each dose is essential prevention |
| Dysgeusia | 2% (COPD) | Taste disturbance; related to the lactose carrier and/or umeclidinium; vs <1% placebo |
| Diarrhoea | 2% (COPD) | More frequent than placebo+FF/VI (<1%); usually mild |
| Urinary tract infection | ≥1% (COPD) / ≥2% (asthma) | Anticholinergic-related urinary stasis may contribute; monitor in elderly men |
| Dysphonia | ≥1% (COPD 52-week) | Local ICS effect on vocal cords; improves with technique optimisation |
| Cough | 1% (COPD) | Dry powder inhalation can trigger cough; vs <1% placebo |
| Oropharyngeal pain | 1% (COPD) | Local irritation from inhaled powder; rinse mouth after use |
| Gastroenteritis | 1% (COPD) | Occurred more frequently than placebo+FF/VI (0%); generally self-limiting GI symptoms |
| Constipation | ≥1% (COPD 52-week) | Anticholinergic class effect from umeclidinium; advise adequate hydration |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Pneumonia (COPD) | 8% annually (IMPACT trial); fatal: 0.35/100 patient-years | Any time; cumulative ICS exposure increases risk | Radiographic confirmation; treat with antibiotics; reassess need for ICS component in stable COPD patients |
| Paradoxical bronchospasm | Rare | Immediately after inhalation | Treat with rescue SABA; permanently discontinue Trelegy; switch to alternative |
| Anaphylaxis / angioedema | Very rare (postmarketing) | Minutes to hours after dose | Emergency treatment; permanent discontinuation; do not rechallenge |
| Adrenal suppression / adrenal crisis | Rare; higher risk with supratherapeutic doses or systemic steroid transition | Weeks to months (cumulative) | Taper Trelegy slowly; stress-dose hydrocortisone if crisis; endocrine referral |
| Acute narrow-angle glaucoma | Rare; LAMA class effect | Hours to days | Emergency ophthalmology referral; discontinue anticholinergic component |
| Urinary retention | Uncommon; LAMA class effect | Days to weeks | Discontinue if significant; urology referral; higher risk with prostatic hyperplasia |
| Cardiac arrhythmias | Rare | Variable | ECG monitoring; discontinue if clinically significant; cardiology referral |
| Reduced bone mineral density | Uncommon; cumulative ICS exposure | Months to years | DEXA scan in high-risk patients; calcium/vitamin D supplementation |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| COPD/asthma exacerbation | Most common reason across all arms | Not unique to triple therapy; comparable to dual-therapy controls |
| Pneumonia (COPD) | Contributory in the 52-week trial | Higher ICS-containing arms vs non-ICS arm (UMEC/VI) |
The IMPACT trial demonstrated an 8% pneumonia incidence with Trelegy (vs 5% with UMEC/VI without ICS) over 52 weeks. Clinicians should maintain a high index of suspicion for pneumonia in COPD patients using ICS-containing regimens. Key differentiators from exacerbation include new consolidation on imaging, fever, and purulent sputum. For COPD patients with infrequent exacerbations and low eosinophil counts, periodically reassess whether ICS withdrawal (stepping down to LAMA/LABA) is appropriate.
Drug Interactions
Fluticasone furoate and vilanterol are both CYP3A4 substrates, making strong CYP3A4 inhibitors the most clinically significant drug interaction. Umeclidinium interactions relate to its anticholinergic pharmacology. Vilanterol interactions include QTc prolongation risk, beta-blocker antagonism, and additive sympathomimetic effects.
Monitoring
- Lung Function (FEV1)Baseline, then every 3–6 months
RoutineAssess therapeutic response; FEV1 improvement from all three mechanisms should be evident within days to weeks. Declining function may warrant therapy reassessment. - Oral CavityEach visit
RoutineInspect for oropharyngeal candidiasis or dysphonia. Reinforce mouth rinsing technique. - Pneumonia Surveillance (COPD)Each visit; imaging if symptomatic
RoutineMaintain high index of suspicion in COPD patients. Distinguish exacerbation from pneumonia using chest imaging when clinical features overlap. - Bone Mineral DensityBaseline DEXA in high-risk patients
Trigger-basedParticularly important for postmenopausal women, prolonged ICS use, or concurrent systemic steroids. Consider calcium/vitamin D supplementation. - Ophthalmological ExamBaseline if risk factors, then periodically
Trigger-basedScreen for cataracts (ICS class) and narrow-angle glaucoma (LAMA class). Urgent referral if eye pain, visual halos, or blurred vision develop. - Urinary SymptomsEach visit in at-risk patients
Trigger-basedLAMA class effect: monitor for urinary retention symptoms in patients with prostatic hyperplasia or bladder-neck obstruction. - Serum PotassiumWhen concurrent diuretics or digoxin
Trigger-basedVilanterol can decrease serum potassium; check electrolytes if on potassium-lowering agents. - HPA Axis FunctionIf clinical suspicion of adrenal suppression
Trigger-basedMorning cortisol if features of adrenal insufficiency develop, especially during systemic steroid taper or with strong CYP3A4 inhibitors.
Contraindications & Cautions
Absolute Contraindications
- Status asthmaticus or acute COPD/asthma episodes requiring intensive measures. Trelegy is a maintenance controller, not a rescue medication.
- Severe hypersensitivity to milk proteins — the Ellipta inhaler contains lactose monohydrate with milk proteins as the carrier.
- Known hypersensitivity to fluticasone furoate, umeclidinium, vilanterol, or any excipient.
Relative Contraindications (Specialist Input Recommended)
- Narrow-angle glaucoma: Umeclidinium may precipitate or worsen acute narrow-angle glaucoma. Ophthalmology co-management is advisable.
- Prostatic hyperplasia or bladder-neck obstruction: Anticholinergic effects of umeclidinium may worsen urinary retention.
- Severe cardiovascular disease: Vilanterol’s beta-adrenergic stimulation may exacerbate coronary insufficiency, arrhythmias, or hypertension.
- Active or quiescent pulmonary tuberculosis: ICS component may reactivate latent infection.
Use with Caution
- Diabetes mellitus: Both ICS and LABA components can contribute to hyperglycaemia.
- Convulsive disorders: Beta-agonists can lower seizure threshold.
- Thyrotoxicosis: Vilanterol may exacerbate symptoms.
- Hepatic impairment: FF systemic exposure increases 34–83% with mild to severe impairment (FDA PI). Monitor for hypercorticism.
- Patients transitioning from systemic corticosteroids: Wean oral steroids slowly (prednisone by 2.5 mg/week per FDA PI); monitor for adrenal insufficiency.
LABA monotherapy (without ICS) is associated with increased asthma-related death (SMART trial: relative risk 4.37 for salmeterol monotherapy). This is a class effect of all LABAs. However, four large safety trials (including the AUSTRI trial for fluticasone furoate/vilanterol) confirmed that ICS/LABA fixed combinations do not significantly increase serious asthma-related events compared with ICS alone (HR 1.10; 95% CI: 0.85–1.44). Based on these results, the FDA removed the boxed warning for ICS/LABA combinations in 2017. Trelegy Ellipta contains vilanterol (a LABA) in fixed combination with an ICS and LAMA. The current PI retains detailed safety language regarding LABA use. Trelegy is not indicated in pediatric patients.
Patient Counselling
Purpose of Therapy
Trelegy Ellipta is a once-daily maintenance inhaler that combines three medicines to keep airways open, reduce inflammation, and prevent flare-ups in COPD or asthma. It is not a rescue inhaler. Patients must always carry a separate short-acting rescue inhaler (such as albuterol) for sudden breathing difficulty.
How to Take
Use Trelegy once daily at the same time each day. Open the cover of the Ellipta inhaler fully until you hear a click (this loads the dose). Breathe out gently away from the inhaler, then place the mouthpiece in your mouth and breathe in steadily and deeply. Hold breath for 3–4 seconds, then breathe out slowly. Close the cover. After each dose, rinse your mouth with water and spit it out. Never exhale into the inhaler. Discard the inhaler 6 weeks after opening the foil tray or when the dose counter reads 0, whichever comes first.
Sources
- Trelegy Ellipta (fluticasone furoate, umeclidinium, and vilanterol) Prescribing Information. GlaxoSmithKline. Revised June 2023. DailyMed / FDA SPLPrimary source for all dosing, contraindications, adverse reaction data, and pharmacokinetic parameters in this monograph.
- FDA Drug Safety Communication: FDA review finds no significant increase in risk of serious asthma outcomes with LABAs used in combination with ICS. December 2017. FDA.govRegulatory basis for the removal of the LABA boxed warning from ICS/LABA fixed-dose combination labels.
- FDA Approval Letter — NDA 209482/S-010 (asthma indication and 200/62.5/25 strength). September 2020. FDA.govDocuments the supplemental approval of Trelegy for asthma maintenance in adults and the additional 200/62.5/25 mcg strength.
- Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD (IMPACT). N Engl J Med. 2018;378(18):1671-1680. doi:10.1056/NEJMoa1713901Pivotal 52-week COPD trial (N=10,355) demonstrating superiority of FF/UMEC/VI over FF/VI and UMEC/VI for exacerbation reduction; source of pneumonia incidence data.
- Lee LA, Maltais F, Engel M, et al. Effect of fluticasone furoate/umeclidinium/vilanterol on exacerbations of COPD: the IMPACT trial lung function results. Eur Respir J. 2018;52(suppl 62):PA3890. doi:10.1183/13993003.congress-2018.PA3890Supplementary lung function analysis from the IMPACT trial confirming sustained FEV1 improvement with triple therapy.
- Lee LA, Bailes Z, Barnes N, et al. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a randomised, double-blind, phase 3A trial. Lancet Respir Med. 2021;9(1):69-84. doi:10.1016/S2213-2600(20)30389-1Primary asthma efficacy trial establishing superiority of triple therapy over FF/VI in trough FEV1 improvement; source of asthma-specific adverse reaction data.
- Vestbo J, Anderson JA, Brook RD, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT). Lancet. 2016;387(10030):1817-1826. doi:10.1016/S0140-6736(16)30069-1Large-scale mortality trial (N=16,568) with FF/VI in COPD; provided annualised pneumonia incidence data and cardiovascular safety reassurance.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Prevention, Diagnosis and Management of COPD, 2024 Report. goldcopd.orgInternational COPD guideline positioning ICS/LAMA/LABA triple therapy for patients with persistent exacerbations and elevated eosinophils despite dual therapy.
- Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2024. ginasthma.orgRecommends add-on LAMA (tiotropium) at Step 4–5 for asthma uncontrolled on ICS/LABA; Trelegy delivers this as a single-inhaler approach.
- Slack RJ, Barrett VJ, Morrison VS, et al. In vitro pharmacological characterization of vilanterol, a novel long-acting beta2-adrenoceptor agonist with 24-hour duration of action. J Pharmacol Exp Ther. 2013;344(1):218-230. doi:10.1124/jpet.112.198481Establishes vilanterol’s 24-hour duration of action and intrinsic efficacy at the beta-2 receptor, supporting once-daily dosing.
- Salmon M, Luttmann MA, Foley JJ, et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013;345(2):260-270. doi:10.1124/jpet.112.202051Characterises umeclidinium’s long duration of M3 receptor antagonism and bronchodilatory effect supporting once-daily use.
- Allen A, Bareille PJ, Rousell VM. Fluticasone furoate, a novel inhaled corticosteroid, demonstrates prolonged lung retention in healthy volunteers after inhaled administration. Br J Clin Pharmacol. 2013;75(6):1478-1487. doi:10.1111/bcp.12049Demonstrates the prolonged lung retention of fluticasone furoate that supports its once-daily ICS dosing and ~24-hour elimination half-life.
- Feldman GJ, Galkin DV, Patel P, et al. Correct use and ease of use of a placebo dry powder inhaler in subjects with asthma and chronic obstructive pulmonary disease. Chron Respir Dis. 2019;16:1-10. doi:10.1177/1479973119860916Demonstrates 97–98% correct use of the Ellipta inhaler by Day 28 in COPD and asthma patients, supporting ease-of-use counselling.