| Combination of | |
|---|---|
| Fluticasone furoate | Corticosteroid |
| Umeclidinium bromide | Muscarinic antagonist |
| Vilanterol | Ultra-long-acting β2 agonist |
| Clinical data | |
| Trade names | Trelegy Ellipta, Elebrato Ellipta, Temybric Ellipta |
| Other names | FF/UMEC/VI |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a618017 |
| License data | |
| Pregnancy category | |
| Routes of administration | Inhalation |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| CAS Number | |
| KEGG | |
Fluticasone furoate/umeclidinium bromide/vilanterol, sold under the brand nameTrelegy Ellipta among others, is afixed-dose combination inhaledmedication that is used for the maintenance treatment ofchronic obstructive pulmonary disease (COPD).[6][7] The medications work in different ways:fluticasone furoate is an inhaledcorticosteroid (ICS),umeclidinium is a long-actingmuscarinic antagonist (LAMA), andvilanterol is along-acting beta-agonist (LABA).
In 2023, it was the 118th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[8][9]
The combination fluticasone furoate/umeclidinium bromide/vilanterol product is approved by the USFood and Drug Administration with an indication for the maintenance treatment of a chronic lung problem calledchronic obstructive pulmonary disease (COPD) in adults who (1) have already triedfluticasone furoate/vilanterol (brand name Breo Ellipta) but are still experiencing symptoms of airway obstruction or who want to reduce the risk for COPD exacerbations and (2) are already receiving umeclidinium and fluticasone furoate/vilanterol and would like to consolidate their inhaler therapy into a single product.[4] Similarly, in the European Union, FF/UMEC/VI is indicated for the maintenance treatment in adults with moderate to severe COPD who are not adequately treated by an inhaled corticosteroid (ICS) plus long-acting beta-agonist (LABA) combination or a LABA plus long-acting muscarinic antagonist (LAMA) combination.[5] Because FF/UMEC/VI is for maintenance (chronic prophylaxis) treatment, it is not used when people are experiencing acute symptoms consistent with worsening airway obstruction (i.e.COPD exacerbation or anasthma exacerbation).[4]
The 2018 National Institute for Health and Care Excellence (NICE) guidelines recommend consideration for ICS/LABA/LAMA triple therapy (like FF/UMEC/VI) provided that the person with COPD has received optimal non-pharmacologic management (e.g. smoking cessation), is experiencing acute COPD exacerbations (either 1 severe exacerbation leading to hospitalization or 2 moderate exacerbations within 1 year), and their COPD has worsened their quality of life.[10] The 2020Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend consideration for triple therapy for people with COPD that—despite ICS/LABA therapy—are persistently breathless, cannot exercise due to their symptoms, or develop further exacerbations.[11]
Fluticasone furoate/umeclidinium bromide/vilanterol is only available as an inhaler, which generally contains thirty doses (one-month supply) of medicated powder for inhalation (except in the case of, e.g.,sample products from the manufacturer or those produced specifically for hospitals [institutional formulations], which contain 14 doses).[4] FF/UMEC/VI exists as adry-powder inhaler, which means that the force of the user's breath causes the medicated powder to leave the device and enter the lungs[4] (unlike, e.g., ametered-dose inhaler which includes a propellant).[12]
Fluticasone furoate/umeclidinium bromide/vilanterol is contraindicated in people who are allergic to any of the individual medication components (i.e. an allergy to vilanterol precludes use of the combination product) or who are severely allergic to milk proteins.[4] This is because each dose of FF/UMEC/VI is formulated withlactose monohydrate (a sugar found in milk), a portion of which contains detectable milk proteins.[4]
The adverse effects of fluticasone furoate/umeclidinium bromide/vilanterol include those that are characteristic of its individual components. For example, there is a risk foranticholinergic side effects (e.g.difficulty urinating) due to umeclidinium. Effects on thecardiovascular system, such asincreased pulse,elevated blood pressure, andabnormal heart rhythms, can occur due to vilanterol. Fluticasone furoate, as an inhaled corticosteroid (ICS), can cause side effects that are characteristic of corticosteroids, such as decreasedbone mineral density,adrenal suppression (decreased production of corticosteroids in the body), and aweakened immune system.[4] There is an elevated risk ofpneumonia (a type of serious lung infection) with FF/UMEC/VI; inclinical trials, there was a 1.53-fold higher risk of pneumonia in people that received FF/UMEC/VI or FF/VI instead of UMEC/VI (which does not include fluticasone furoate, an ICS).[13]
Fluticasone furoate/umeclidinium bromide/vilanterol may havedrug–drug interactions (DDIs) that are bothpharmacokinetic (related to metabolism) andpharmacodynamic (related to the effect of medications) in nature. FF/UMEC/VI is susceptible to DDIs that would normally arise from any of the individual components of the medication.[citation needed]
All three components are substrates of the efflux transporterp-glycoprotein (p-gp),[4] a protein that causes drugs to be transported out of cells. The presence of p-gp inhibiting drugs did not appear to effect the pharmacokinetics of vilanterol, though thearea under the curve (a measure of systemic absorption) of umeclidinium increased 1.4-fold. The effect of p-gp inhibitors on fluticasone pharmacokinetics are unknown.[4]
Fluticasone furoate is metabolized bycytochrome P450 3A4 (CYP3A4).[4] Medications that are inhibitors of CYP3A4 (e.g.ketoconazole) may decrease fluticasone's metabolism in the body, causing levels to accumulate. Thebioavailability (the amount of a medication that reaches the blood after administration) of fluticasone in the FF/UMEC/VI product is low (15.2%),[4] decreasing the risk of acute toxicity in overdose/accumulation situations. However, if a person is exposed to high doses of fluticasone over time, it may increase their risk of experiencingCushing's syndrome[4] (a syndrome that occurs due to high levels ofglucocorticoids, like fluticasone, and includes muscular weakness, weight gain, andexcessive hairiness). In drug interaction studies of FF/UMEC/VI in the presence of the CYP3A4 inhibitor ketoconazole,adrenal insufficiency (as measured by serumcortisol levels was noted at 24 hours (27% decrease in cortisol).[4]
Umeclidinium is primarily metabolized byCYP2D6, in addition to a fewsecondary metabolism pathways (e.g.glucuronidation).[4] At doses of umeclidinium that are above the recommended doses, no clinically significant differences in blood levels of umeclidinium was found after repeated dosing in people with impaired CYP2D6 function (compared to people with normal CYP2D6 function).[4]
Vilanterol is also a CYP3A4 substrate.[4] Like fluticasone, CYP3A4 inhibitors may increase the levels of vilanterol in the body.[4] In drug interaction studies of FF/UMEC/VI in the presence of the CYP3A4 inhibitor ketoconazole, side effects that are characteristic of vilanterol overdose were not observed (i.e.elevated heart rate).[4]
Fluticasone furoate is a corticosteroid, a type of hormone that can suppress the function of theimmune system (which fights off infections).[4] This can increase the risk of infection, especially oral fungal infections when people do not rinse out their mouths with water after using fluticasone.[4] Combining fluticasone with other steroids (e.g. oralprednisone) may theoretically increase the risk of infections.[14]
Umeclidinium is a medication withanticholinergic properties. When combined with other medication that also antagonize cholinergic receptors, this may lead to a duplicate anticholinergic effect, increasing the risk for anticholinergic spectrum side effects (e.g.dry mouth,constipation).[4]
Vilanterol is abeta2-adrenergic receptor agonist. When combined with medications that have the opposite effect (i.e.beta blockers, likecarvedilol), this may theoretically prevent vilanterol from working as intended.[4]
Fluticasone furoate/umeclidinium bromide/vilanterol is a combination product made up of three medications:[4][15][16][5]
In the setting of chronic obstructive pulmonary disease (COPD), an inhaled corticosteroid (ICS) will reduce inflammation while a long-acting muscarinic antagonist (LAMA) and a long-acting beta-agonist (LABA) will causebronchodilation (widening and opening of thebronchi, the airways of the lungs).[4] Because LABAs and LAMAs are "long-acting", they are not used for acute problems with breathing.[4]
| Fluticasone furoate | Fluticasone propionate | Fluticasone | |
|---|---|---|---|
| Chemical structure |  |  |  |
Fluticasone furoate, likefluticasone propionate, is a synthetic corticosteroid that is derived fromfluticasone (another synthetic corticosteroid).[17][18]
| Umeclidinium bromide | |
|---|---|
| Chemical structure |  |
Umeclidinium bromide is thebromide (Br−) salt form of umeclidinium, which contains aquaternary ammonium compound.[19]
| Vilanterol | |
|---|---|
| Chemical structure |  |
Vilanterol is a 1,3-dichlorobenzene derivative.[20]
Fluticasone furoate/umeclidinium bromide/vilanterol was approved for medical use in the United States and in the European Union in 2017.[6][15][3][16] It was approved in the European Union with an additional indication in June 2019.[5]
Due to theCOVID-19 pandemic, a meeting of the Pulmonary-Allergy Drugs Advisory Committee (PADAC) of the U.S.Food and Drug Administration (FDA) scheduled for April 2020, on the subject of FF/UMEC/VI was postponed indefinitely.[21] The Advisory Committee had planned to discuss the manufacturer's claim that the medication reduces all-cause mortality in people with COPD.[21] FF/UMEC/VI was one of many medications whose regulatory status was affected by the pandemic.[22]
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