Characterization of agomelatine-induced liver injury, incidence and risk factors: A pooled analysis of 7605 treated patients

Abstract : Introduction/objective The hepatic safety of agomelatine was assessed in 49 phase II and III studies. The aim was to analyze the characteristics of patients who developed an increase in transaminases whilst taking agomelatine. Method A retrospective pooled analysis of changes in serum transaminase in 7605 patients treated with agomelatine (25 mg or 50 mg/day) from 49 completed studies was undertaken. A significant increase in serum transaminase was defined as > 3-fold the upper limit of normal (> 3 ULN). Final causality was determined in a case-by-case review by five academic experts. Results Transaminase increased to > 3 ULN in 1.3% and 2.5% of patients treated with 25 mg and 50 mg of agomelatine respectively, compared to 0.5% for placebo. The onset of increased transaminases occurred at < 12 weeks in 64% of patients. The median time to recovery (to ≤ 2ULN) was 14 days following treatment withdrawal. Liver function tests recovered in 36.1% patients despite the continuation of agomelatine, suggesting the presence of a liver adaptive mechanism. Patients with elevated transaminases at baseline, secondary to obesity and fatty liver disease (NAFLD), had an equally increased risk of developing further elevations of transaminases with agomelatine and placebo. This reflects the widespread fluctuations of serum transaminases in patients with NAFLD. Conclusions The overall incidence of abnormal transaminases was low and dose dependent. No specific population was identified regarding potential risk factors. Withdrawal of agomelatine led to rapid recovery, and some patients exhibited an adaptive phenomenon. The liver profile of agomelatine seems safe when serum transaminases are monitored