Star Kristina, Edwards I Ralph, Choonara Imti
Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
Academic Division of Child Health, University of Nottingham, Derbyshire Children's Hospital, Nottingham, United Kingdom.
PLoS One. 2014 Oct 10;9(10):e108970. doi: 10.1371/journal.pone.0108970. eCollection 2014.
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.
Firstly to characterise valproic acid reports on children with fatal outcome and secondly to determine reporting over time of hepatotoxicity with fatal outcome.
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.
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%).
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.
丙戊酸是治疗癫痫的一种有效的一线药物。肝毒性是该药物一种罕见但可能致命的不良反应。
首先描述丙戊酸治疗儿童导致致命后果的报告，其次确定肝毒性导致致命后果的报告随时间的变化情况。
2013年6月从世界卫生组织全球个案安全报告数据库VigiBase中检索年龄≤17岁使用丙戊酸且出现致命后果的儿童的个案安全报告（ICSR）。报告分为肝毒性反应或其他反应。使用观察到的与预期的收缩比来探讨随时间和患者年龄的相对报告趋势。调查了联合治疗的频率，即使用一种以上抗癫痫药物的报告。
自1977年以来，25个国家报告了268例儿童使用丙戊酸且出现致命后果的ICSR。共报告了156例肝毒性导致的死亡，随着时间的推移，该情况一直被不成比例地报告。有31例死于胰腺炎。其他经常报告的事件是昏迷/脑病、癫痫发作、呼吸系统疾病和凝血病。肝毒性在6岁及以下儿童中报告比例失调且最为常见（104/156份报告），但所有年龄段的儿童均受影响。与非致命后果（34%）相比，丙戊酸导致致命后果的联合治疗报告频率显著更高（58%）。
肝毒性仍然是一个相当严重的问题。风险似乎在幼儿（6岁及以下）中最大，但任何年龄都可能发生。联合治疗的报告很常见，似乎是丙戊酸导致肝毒性、胰腺炎和其他严重药物不良反应的一个风险因素。
