Loading Dose of Fomepizole is Safe in Children with Presumed Toxic Alcohol Exposure – A Case Series

Abstract

Dear Editor, Fomepizole, a potent alcohol dehydrogenase inhibitor, was shown to be an effective and safe antidote for treating toxic alcohol poisoning in adults 1. However, evidence for its effectiveness and safety in children remains limited 2. We reviewed the records of children treated with fomepizole sulphate (Fomepizole AP-HP®), the only marketed product in France, manufactured and distributed by the state pharmaceutical agency for Paris hospitals (AGEPS). Data were prospectively collected from post-marketing questionnaires sent by AGEPS to the hospitals immediately after ordering fomepizole. If no answer was obtained, a reminder was sent about 21 days later. The questionnaires contained the expected specific adverse effects to look for, and an additional free text was possible. All the questionnaires were completed by the treating physicians from either the paediatric emergency department or the paediatric intensive care unit (recovery rate: 45%), and data were further checked and validated by the authors, using the patients’ medical records. From August 2002 to August 2013, 38 patients [12F/26M; median age: 3.9 years (interquartile range (IQR), 2.4–7.2); median weight: 18.1 kg (IQR, 13.3–31.4)] were treated with fomepizole in 28 different hospitals in France for presumed toxic alcohol exposure. Exposure was unintentional (36 cases) or related to suicidal attempts (two cases). The ingested products contained ethylene glycol (27 cases), glycol ethers (three cases), methanol (three cases), isopropyl alcohol (one case), propylene glycol (one case), polyoxyalkylene glycol (one case), nitromethane (one case) and nitromethane/methanol mixture (one case). Five patients (13%) were either symptomatic or exhibited blood concentrations of ethylene glycol or methanol ≥20 mg/dL (table 1). Falsely elevated serum creatinine concentrations were observed in the two patients who ingested nitromethane, in relation to laboratory interference with the Jaffé reaction, as previously reported 3. All the patients received an intravenous loading dose of 15 mg/kg fomepizole. Delay from ingestion to fomepizole infusion was a median of 3.5 hr (IQR, 2.0–5.3). In five patients, 2 (IQR, 1–3) additional median maintenance doses of 10 mg/kg fomepizole were infused. The total administered dose of fomepizole was a median of 25 mg/kg (IQR, 25–35). No patient was haemodialyzed, and none received ethanol, folinic acid, thiamine or pyridoxine. Outcome was favourable in all the cases without sequelae. No significant adverse event, including headache, vomiting, dizziness, nystagmus, intolerance to pain at the infusion site, eosinophilia and transient elevation in serum aminotransferase, was reported in the 38 patients after fomepizole administration and during the hospital stay. Accidental, suicidal or malicious ingestion of toxic alcohols can be life-threatening, even fatal or result in serious sequelae 1. When there is a recent history of ingesting significant amounts of toxic alcohols or it is strongly suspected in children, the challenging diagnosis and limited availability of blood concentration measurements in the majority of care centres require administering a safe antidote prior to analytical confirmation of exposure 2, 4. Despite limitations related to the fact that our data were from questionnaires completed by the treating physicians and follow-up restricted to hospital stay, our study provides additional evidence to support the safe prescription of a loading dose of fomepizole in the paediatric population with suspicion of toxic alcohol poisoning, using the same dosage regimen as in adults. Additionally, despite a possible underpowered study to pick up a rare adverse event of <1–2% incidence, a relatively low recovery rate (45%) resulting in possible biases with missed cases, our series represents one of the largest multi-centre fomepizole-treated children cohort study. We also acknowledge that possible subjective adverse effects such as headache cannot be definitively ruled out in the pre-verbal or minimally verbal children included in our series, but paediatricians in charge did not report any behaviour suggestive of pain. As the last review published by Brent in 2010 reporting 14 paediatric poisonings treated with fomepizole, due to ethylene glycol (n = 10), methanol (n = 2), diethylene glycol (n = 1) and butoxyethanol (n = 1) 2, five additional cases of paediatric methanol (n = 4) and ethylene glycol (n = 1) poisonings treated with fomepizole have been published 4-6. As with our five patients, all these children recovered fully, without any significant side effect attributable to fomepizole. Our series supports the recent proposal based on the adult experience for inclusion of fomepizole in the World Health Organization model list of essential medicines 7. Dimitri Frémont and Marie-Pierre Berleur work in the public institution (AGEPS) that manufactures fomepizole in France. Bruno Mégarbane has no conflict of interest to report. The authors alone are responsible for the content and writing the paper.