Drug Use and Acute Liver Injury in Children: Signal Detection Using Multiple Healthcare Databases

Background: Drug-induced acute liver injury (ALI) is one of the leading causes of drug withdrawal from the market. There is, however, lack of data on ALI in the pediatric population. Combining multi-country electronic healthcare databases offers the opportunity to explore the risk of ALI in children and adolescents and facilitate detection of potential drug safety signals. Objectives: To identify drugs potentially associated with ALI in the pediatric population using the EU-ADR database network and to estimate the power of such a network for signal detection concerning ALI as a function of actual drug use, minimal detectable relative risk (RR) and Background incidence rate (IR) of ALI in children and adolescents. Methods: We extracted data on all potential cases of ALI and data concerning prescribed/dispensed drugs among individuals 0–15 years registered within eight European, population-based, electronicmedical record and claims databases of the EU-ADR network during the period 1995–2010. We estimated the Background IR of ALI in the pediatric population and assessed drug use according to number of person-years (PYs) of exposure by Anatomical Therapeutic and Chemical (ATC) classification, 5th level. Based on IR of ALI derived within EU-ADR, power = 80% and alpha = 5%, we estimated how much drug exposure would be necessary to allow for detection of a signal concerning ALI. Finally, among drugs with enough exposure, all potential signals were identified by measuring age- and sex-adjusted relative risks of ALI, with all other drugs as comparator. Results: Children 0–15 years of age contributed 20 088 726 PYs of follow-up to the EU-ADR database network. The incidence rate for ALI was estimated to be 4.3 per 100 000 PYs in this pediatric population. The total amount of drug exposure that would be required to detect a ‘weak’ association (RR= 2) with ALI, if present, was 186 490 PYs and 28 554 PYs to detect a ‘moderate’ association (RR = 4). The following drugs were identified to be potentially associated with ALI: amoxicillin (RR 4.3, 95% CI 2.6, 7.0); clarithromycin (3.7, 1.8, 7.5); cetirizine (3.1, 1.5, 6.5); flunisolide (2.5, 1.0, 6.8); budesonide (2.5, 1.1, 5.5); and amoxicillin plus clavulanic acid (2.3, 1.3, 4.1). Conclusions: Combining multiple electronic healthcare databases may facilitate identification of potentially drug-related cases of ALI and increase the power for drug safety signal detection in the pediatric population. Except for the anti-asthmatic medications, the signals detected are already known in adults.