Vilanterol and Umeclidinium bromide

Co-administration of umeclidinium/vilanterol with other long-acting muscarinic antagonists, long-acting beta₂-adrenergic agonists or medicinal products containing either of these agents has not been studied and is not recommended as it may potentiate known inhaled muscarinic antagonist or beta₂-adrenergic agonist adverse reactions.

Vilanterol is a substrate of cytochrome P450 3A4 (CYP3A4). Concomitant administration of strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, itraconazole, ritonavir, telithromycin) may inhibit the metabolism of, and increase the systemic exposure to, vilanterol. Co-administration with ketoconazole (400 mg) in healthy volunteers increased mean vilanterol AUC_(0-t) and C_max, 65% and 22% respectively. The increase in vilanterol exposure was not associated with an increase in beta-adrenergic agonist related systemic effects on heart rate, blood potassium or QT interval (corrected using the Fridericia method). Care is advised when co-administering umeclidinium/vilanterol with ketoconazole and other known strong CYP3A4 inhibitors as there is potential for an increased systemic exposure to vilanterol, which could lead to an increase in the potential for adverse reactions. Verapamil, a moderate CYP3A4 inhibitor, did not significantly affect the pharmacokinetics of vilanterol.

The use of umeclidinium/vilanterol has not been studied in patients with severe hepatic impairment and should be used with caution.

Medicinal products containing beta-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists, such as vilanterol. Concurrent use of either non-selective or selective beta-adrenergic blockers should be avoided unless there are compelling reasons for their use.

Umeclidinium/vilanterol should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta₂-adrenergic agonists.

Upon initiation of treatment with umeclidinium/vilanterol plasma glucose should be monitored more closely in diabetic patients.

There are no data from the use of umeclidinium/vilanterol in pregnant women. Studies in animals have shown reproductive toxicity at exposures which are not clinically relevant after administration of vilanterol.

Umeclidinium/vilanterol should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the foetus.

It is unknown whether umeclidinium or vilanterol are excreted in human milk. However, other beta₂-adrenergic agonists are detected in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue umeclidinium/vilanterol therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of umeclidinium/vilanterol on human fertility. Animal studies indicate no effects of umeclidinium or vilanterol on fertility.

Umeclidinium/vilanterol has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequently reported adverse reaction with umeclidinium/vilanterol was nasopharyngitis (9%).

Tabulated summary of adverse reactions

The safety profile of umeclidinium/vilanterol is based on safety experience with umeclidinium/vilanterol combination and the individual components from the clinical development program comprising of 6,855 patients with COPD and from spontaneous reporting. The clinical development programme included 2,354 patients who received umeclidinium/vilanterol once daily in the Phase III clinical studies of 24 weeks or more, of whom 1,296 patients received the recommended dose of 55/22 micrograms in 24-week studies, 832 patients received a higher dose of 113/22 micrograms in 24-week studies and 226 patients received 113/22 micrograms in a 12-month study.

The frequencies assigned to the adverse reactions identified in the table below include crude incidence rates observed in the integration of five 24-week studies and in the 12-month safety study.

The frequency of adverse reactions is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from available data).