Trelegy Ellipta Drug Interactions

Clinically significant drug interactions mediated by fluticasone furoate/umeclidinium/vilanterol at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.
Interaction with beta-blockers: Beta₂-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists, such as vilanterol. If beta-blockers are required, cardioselective beta-blockers should be considered, however, caution should be exercised during concurrent use of both non-selective and selective beta-blockers.
Interaction with CYP3A4 inhibitor: Fluticasone furoate and vilanterol are rapidly cleared by extensive first pass metabolism mediated by enzyme CYP3A4.
Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products) as there is potential for increased systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increased potential for adverse reactions. Co administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions, in which case patients should be monitored for systemic corticosteroid adverse reactions. A repeat dose study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (184/22 micrograms) and ketoconazole (400 milligrams, a strong CYP3A4 inhibitor). Co-administration increased mean fluticasone furoate AUC_(0-24) and C_max by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 hours weighted mean serum cortisol. Co-administration increased mean vilanterol AUC_(0-t) and C_max by 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta₂-agonist related systemic effects on heart rate or blood potassium.
Interaction with CYP2D6 inhibitors/CYP2D6 polymorphism: Umeclidinium is a substrate of cytochrome P450 2D6 (CYP2D6). The steady-state pharmacokinetics of umeclidinium was assessed in healthy volunteers lacking CYP2D6 (poor metabolisers). No effect on umeclidinium AUC or C_max was observed at a dose 8-fold higher than the therapeutic dose. An approximately 1.3-fold increase in umeclidinium AUC was observed at 16-fold higher dose with no effect on umeclidinium C_max. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when fluticasone furoate/umeclidinium/vilanterol is co-administered with CYP2D6 inhibitors or when administered to patients who are genetically deficient in CYP2D6 activity (poor metabolisers).
Interaction with P-glycoprotein inhibitors: Fluticasone furoate, umeclidinium and vilanterol are substrates of the P-glycoprotein transporter (P-gp). The effect of the moderate P-gp inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium and vilanterol was assessed in healthy volunteers. No effect of verapamil was observed on umeclidinium or vilanterol C_max. An approximately 1.4-fold increase in umeclidinium AUC was observed with no effect on vilanterol AUC. Based on the magnitude of these changes, no clinically relevant drug interaction is expected when fluticasone furoate/umeclidinium/vilanterol is co-administered with P-gp inhibitors. Clinical pharmacology studies with a specific P-gp inhibitor and fluticasone furoate have not been conducted.
Other long acting antimuscarinics and long acting beta₂-adrenergic agonists: Co-administration of TRELEGY ELLIPTA with other long-acting muscarinic antagonists or long-acting beta₂-adrenergic agonists has not been studied and is not recommended as it may potentiate the adverse reactions (see Adverse Reactions and Overdosage).
Hypokalaemia: Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta₂-adrenergic agonists, therefore caution should be exercised (see Precautions).