Pladevall M, Hallas J, Schink T, Morros R, Poblador-Plou B, Forns J, Hellfritzsch M, Reinders T, Giner-Soriano M, Prados-Torres A, Cainzos-Achirica M, Pottegard A, Kollhorst B, Cortes J, Aguado J, Perlemuter G, Castellsague J, Jacquot E, Deltour N, Perez-Gutthann S. Agomelatine and risk of hospitalization for acute liver injury: nested case-control study in Spain, Germany, and Denmark. Poster presented at the 33rd ICPE International Conference on Pharmacoepidemiology & Therapeutic Risk Management; August 29, 2017. Montreal, Canada. [abstract] Pharmacoepidemiol Drug Saf. 2017 Aug; 26(Suppl 2):389. doi: 10.1002/pds

BACKGROND: Agomelatine is a melatonergic agonist and 5-HT2C antagonist indicated for major depressive episodes in adults. Hepatotoxicity is an identified risk in the risk management plan.

OBJECTIVES: To evaluate the risk of acute liver injury (ALI) associated with agomelatine and other antidepressant drugs.

METHODS: Multinational, multi-data source, nested case-control (incidence density sampled controls) study of new users of agomelatine (main exposure of interest), citalopram (common reference group), fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline (2009-2014). Population-based data sources were SIDIAP (Catalonia, Spain) and EpiChron Cohort (Aragon, Spain), GePaRD (Germany), and the Danish national registers. The primary endpoint required a specific hospital discharge diagnosis code (ICD-9/ICD- 10) for ALI. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) for ALI were estimated at each data source with conditional logistic regression and combined estimates with meta-analysis.

RESULTS: In total, 61,035 new users of agomelatine were included, with one case of ALI each in EpiChron and GePaRD, less than five in Denmark, and none in SIDIAP. Among all studied antidepressants, 370 cases of ALI with hospitalization and 7,462 controls were included. The multivariable-adjusted OR (95% CI) for current use of agomelatine compared with current use of citalopram was 0.61 (0.05-7.87) in EpiChron, 0.56 (0.06-5.15) in  GePaRD, and 0.21 (0.03-1.56) in Denmark. The OR could not be calculated in SIDIAP. The combined OR (95% CI) from the meta-analysis was 0.39 (0.11-1.39). Pooled ORs for other study antidepressants were imprecise, with 95% CIs that included the null value in most cases, and were below unity for all antidepressants but venlafaxine (1.19; 0.77-1.84), fluoxetine (1.31; 0.64-2.71), and paroxetine (1.92; 1.04-3.56).

CONCLUSIONS: These interim results suggest that current use of agomelatine was not associated with higher risk of ALI hospitalisation compared with current use of citalopram. Final study results will include additional endpoints and may provide more precise risk estimates.