Title:Safety and Tolerability of Agomelatine: Focus on Hepatotoxicity
Volume: 15
Issue: 7
Author(s): Maximilian Gahr, Wolfgang Kratzer, Michael Fuchs and Bernhard J. Connemann
Affiliation:
Keywords:
Adverse drug reaction, antidepressant, liver enzymes, liver injury, melatonin, pharmacovigilance, S20098.
Abstract: Hepatotoxicity related to antidepressive pharmacotherapy is a major safety concern, particularly considering that severe forms
of hepatic failure with fatal outcome have been reported. Severe hepatotoxic adverse drug reactions were also reported for agomelatine
(AGM), an antidepressive agent, which was approved for the treatment of major depressive disorder (MDD) in adults by the European
Medicines Agency (EMA) in February 2009. Its general safety and tolerability profile appears to be favourable or similar in comparison
to other antidepressants, particularly regarding metabolic aspects, sexual functioning, gastrointestinal side effects, and discontinuation
phenomena. Epidemiology and pathophysiology of AGM-related hepatotoxicity are currently poorly understood. Pooled data from clinical
trials indicate that patients treated with AGM demonstrate increased prevalence rates of elevated liver transaminases (> 3 x ULN;
1.34% on AGM 25 mg/day, 2.51% on AGM 50 mg/day) in comparison to placebo (0.5%). AGM-related hepatotoxic adverse drug reactions
are unpredictable and usually occur as asymptomatic increases of liver enzymes, which develop during the first months of treatment
and mostly recover after discontinuation of AGM-treatment or even on continued treatment. Liver injury due to AGM-related hepatotoxicity
is mostly hepatocellular. The underlying mechanism appears to be idiosyncratic. Cholestatic or hypersensitivity reactions have not
yet been reported. Some evidence suggests dose-dependence of AGM-related hepatotoxicity. In a recent post-authorisation opinion of the
EMA, hepatotoxic reactions related to AGM were declared as an important identified risk and new contraindications for treatment with
AGM were released (hypersensitivity to AGM, elevations of liver enzymes > 3 x ULN, hepatic impairment (not further specified), parallel
use of potent CYP1A2 inhibitors). Considering these aspects, treatment with AGM must only be performed under strict accordance
with the recently modified prescribing information. A final evaluation of AGM-related hepatotoxicity is currently not possible; further
studies are necessary.
