Valproic Acid and Fatalities in Children: A Review of Individual Case Safety Reports in VigiBase

Abstract

IntroductionValproic acid is an effective first line drug for the treatment of epilepsy. Hepatotoxicity is a rare and potentially fatal adverse reaction for this medicine.ObjectiveFirstly to characterise valproic acid reports on children with fatal outcome and secondly to determine reporting over time of hepatotoxicity with fatal outcome.MethodsIndividual 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.ResultsThere 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%).ConclusionHepatotoxicity 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.

Adverse Drug Reactions Across the Age Continuum: Epidemiology, Diagnostic Challenges, Prevention, and Treatments

“…51,52 Similarly, younger age has been identified as 1 of the major risk factors for valproic acid-induced hepatotoxicity. 53,54 A similar pattern has been demonstrated for ifosfamide, in that young children are at increased risk for ifosfamideinduced nephrotoxicity that we believe to be due to increased ability to produce the toxin chloroacetaldehyde by side-chain oxidation of ifosfamide versus oxidative metabolism of ifosfamide to isophosphoramide mustard, the desired antitumor metabolite. 55 When contemplating therapy for toddlers and early school age children-notably in the context of complex chronic care-ADR risk needs to be factored into care planning.…”

“…Young age has been identified as an independent risk factor for serious cutaneous ADRs to lamotrigine, an anticonvulsant known to be associated with a 1% risk for cutaneous ADRs . Similarly, younger age has been identified as 1 of the major risk factors for valproic acid–induced hepatotoxicity . A similar pattern has been demonstrated for ifosfamide, in that young children are at increased risk for ifosfamide‐induced nephrotoxicity that we believe to be due to increased ability to produce the toxin chloroacetaldehyde by side‐chain oxidation of ifosfamide versus oxidative metabolism of ifosfamide to isophosphoramide mustard, the desired antitumor metabolite .…”

Utilization of Antiepileptic Medicines in Swedish Children and Adolescents with Different Diagnoses

“…Overall, valproic acid and lamotrigine were the most commonly initiated AEDs in our cohort. There has been concern about the use of valproic acid in young children due to the risk of hepatotoxicity, a rare but potentially fatal adverse event . The risk of adverse events from valproic acid has been shown to be higher in female than male users, particularly after puberty when the risk of weight gain and hair loss is increased in girls .…”

Nodding Syndrome, Western Uganda, 1994

“…26 However, only limited data on the use of VPA in NS are available 7,27 and these do not indicate the greater efficacy of VPA over the alternative AEDs already mentioned. In view of the possibly severe adverse effects of VPA, [28][29][30] the high cost and its difficult availability in rural Africa, it might be reconsidered to abide by the general WHO recommendation to use PHB as the first-line drug, 31,32 especially in patients with coexisting head nodding and convulsive seizures. Controlled comparative studies of different candidate AEDs should be undertaken to improve therapeutic efficiency.…”