title: Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase.
abstract: BACKGROUND
  Valproic acid is an effective first line drug for the treatment of epilepsy. Hepatotoxicity is a rare and potentially fatal adverse reaction for this medicine.
  
  
  OBJECTIVE
  Firstly to characterise valproic acid reports on children with fatal outcome and secondly to determine reporting over time of hepatotoxicity with fatal outcome.
  
  
  METHODS
  Individual case safety reports (ICSRs) for children ≤ 17 years with valproic acid and fatal outcome were retrieved from the WHO Global ICSR database, VigiBase, in June 2013. Reports were classified into hepatotoxic reactions or other reactions. Shrinkage observed-to-expected ratios were used to explore the relative reporting trend over time and for patient age. The frequency of polytherapy, i.e. reports with more than one antiepileptic medicine, was investigated.
  
  
  RESULTS
  There have been 268 ICSRs with valproic acid and fatal outcome in children, reported from 25 countries since 1977. A total of 156 fatalities were reported with hepatotoxicity, which has been continuously and disproportionally reported over time. There were 31 fatalities with pancreatitis. Other frequently reported events were coma/encephalopathy, seizures, respiratory disorders and coagulopathy. Hepatotoxicity was disproportionally and most commonly reported in children aged 6 years and under (104/156 reports) but affected children of all ages. Polytherapy was significantly more frequently reported for valproic acid with fatal outcome (58%) compared with non-fatal outcome (34%).
  
  
  CONCLUSIONS
  Hepatotoxicity remains a considerable problem. The risk appears to be greatest in young children (6 years and below) but can occur at any age. Polytherapy is commonly reported and seems to be a risk factor for hepatotoxicity, pancreatitis and other serious adverse drug reactions with valproic acid.
authors.affiliation: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Star
authors.affiliation: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
authors.forename: I Ralph
authors.initials: IR
authors.lastname: Edwards
authors.affiliation: Academic Division of Child Health, University of Nottingham, Derbyshire Children's Hospital, Nottingham, United Kingdom.
authors.forename: Imti
authors.initials: I
authors.lastname: Choonara
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology*; D002648:Child; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D008099:Liver / Q000187:drug effects; D014635:Valproic Acid / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid