Jacquot E, Olivier V, Percheron C, Mazens F, Deltour N, Perez-Gutthann S. Agomelatine post-authorization safety studies program: comprehensive results. Poster presented at the 35th ICPE International Conference on Pharmacoepidemiology & Therapeutic Risk Management; August 27, 2019. Philadelphia, PA. [abstract] Pharmacoepidemiol Drug Saf. 2019 Aug 20; 28(S2):500. doi: 10.1002/pds.4864

BACKGROUND: Agomelatine, indicated from 2009 in Europe to treat major depressive episode, is covered by a risk management plan including hepatotoxic reaction as an important identified risk. Risk‐minimisation measures (RMMs) were implemented from marketing authorization, and consist of contraindications in patients with hepatic impairment and precautions of use in patients at risk of liver injury; liver testing at several time points, as well as a prescriber's guide and a patient booklet. Two information letters were distributed to prescribers in 2012 and 2013.

OBJECTIVES: Five post‐authorization safety studies were conducted in 9 countries overall allowing a diverse geographic representation of Europe, to further characterize agomelatine hepatic risk or measure effectiveness of these RMMs.

METHODS: A prospective observational cohort assessed the safety of agomelatine in current medical practice as the drug was launched, with focus on hepatic reactions. A pharmacogenomics study aimed at identifying genomic biomarkers associated with agomelatine‐induced liver injury. A prescription survey assessed prescribers' knowledge on the risk of hepatotoxicity. A chart review evaluated the adherence to the liver test requirements and compliance with contraindications and precautions of use, and a patient survey assessed reasons for non‐compliance with the liver testing. A case–control study nested in an antidepressant new users cohort quantified the risk of acute liver injury (ALI) comparing agomelatine to citalopram.

RESULTS: The incidence rate and type of hepatic events observed in the prospective cohort were comparable to what was observed in clinical trials. No genomic biomarkers were identified to be associated with agomelatine‐induced liver injury. The prescription survey suggested that physicians, with up to 80% of the psychiatrists and up to 51% of GPs, have a good knowledge of the safety concerns associated with agomelatine. The chart review showed that after the last RMMs were implemented 16% of patients treated with agomelatine had one test at initiation and during treatment (25% had a test at initiation and 61.5% during treatment) and 99% of patients were treated with respect to the contraindications. The nested case control study showed that, in the context of the current RMMs, the risk of ALI among agomelatine users is not higher than that for citalopram users.

CONCLUSIONS: These studies allowed to better characterize the agomelatine hepatotoxic risk and to assess the effectiveness of the RMMs, showing that altogether these RMMs with the current level of adherence are effective in preventing ALI among agomelatine users.

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