08/2021: Dovato, Kivexa, Triumeq, Trizivir, Combivir - Update of the last SmPC

Scope of the variation

Update of sections 4.2, 4.4 and 5.2 of the SmPC of the fixed-dose combination products Combivir, Dovato, Kivexa, Triumeq and Trizivir to include new information about use of the products in patients with renal impairment. Furthermore, minor editorial changes have been implemented throughout the Product Information and the lists of local representatives have been updated for all products.

Summary of the update

Patients with a creatinine clearance between 30 and 49 mL/min receiving Combivir/Dovato/ Kivexa/ Triumeq/ Trizivir may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing Combivir/Dovato/ Kivexa/Triumeq/ Trizivir to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse events (such as gastrointestinal and hepatic disorders) may occur.
The CHMP considered that, with the exception of Epivir, the previous recommendations to adjust the dose in patients with a sustained creatinine clearance between 30 and 49 mL/min can be removed. Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Combivir/Dovato/ Kivexa/ Triumeq/ Trizivir should be monitored for lamivudinerelated
adverse events, notably haematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with Combivir/Dovato/ Kivexa/ Triumeq/ Trizivir. Combivir/Dovato/ Kivexa/ Triumeq/ Trizivir should be discontinued and the individual components should be used
to construct the treatment regimen.
The existing dose recommendations for Epivir have been maintained. The CHMP considered the lack of impact on pill burden when the lamivudine dose is adjusted for a monocomponent product and the fact that dose adjustments may be still used for subjects initially treated with lamivudine-containing fixed dose combinations, but requiring dose-adjusted individual components

Source: European Medicines Agency, last visit 09/2021, https://www.ema.europa.eu/en/medicines/human/EPAR/dovato#authorisation-details-section,