Commentary on ‘Prostaglandin E1 Infusions for Duct Dependent Congenital Heart Defects Can Cause Severe Ethanol Intoxication’

The report by Padari et al. [1] titled ‘Prostaglandin E1 Infusions for Duct Dependent Congenital Heart Defects Can Cause Severe Ethanol Intoxication’ describes symptomatic ethanol poisoning in a neonate secondary to continuous alprostadil therapeutic infusion, with a blood alcohol concentration (BAC) of 770 mg/dL measured on the fourth day of treatment. Ethanol is a potent neurotoxin in the paediatric population with no established safety threshold. The European Medicines Agency guidance for ethanol in pharmaceuticals offers the most conservative warning that BAC should not exceed 1 mg/dL in children younger than 6 years old as a result of exposure to ethanol-containing preparations [2-4]. The authors noted that only the 20 mcg/mL alprostadil preparation was available in their facility at the time, instead of the on-label 500 mcg/mL. Both alprostadil formulations contain ethanol as the primary excipient in similar concentrations (785 and 790 mg/mL, respectively). Thus, the ethanol:alprostadil (E:A) ratios are 39.25 and 1.58 mg/mcg, respectively. Administration of these preparations at the same alprostadil dose and rate (in mg/kg/h) results in ~25-fold higher exposure with the 20 mcg/mL formulation. Using the reported dosing range of alprostadil (0.05–0.10 mcg/kg/min) and the aforementioned E:A ratio, ethanol exposure is estimated as a constant infusion of 2–4 mg/kg/min or 120–240 mg/kg/h. Ethanol elimination in term newborns is largely unknown but is bound to be maturation-dependent, making predictions difficult and accumulation possible in a variety of scenarios [2, 4]. Alprostadil formulations can present higher risks than other pharmaceutical preparations in the neonatal intensive care unit (NICU), due to their high alcohol content and the requirement for uninterrupted administration from diagnosis to surgical correction and closure of the ductus arteriosus. The duration of alprostadil treatment can vary significantly, depending on clinical status, body weight and overall readiness for surgery. Thus, it is not unlikely that ethanol exposure via this treatment may be prolonged. Therefore, careful risk management strategies should be applied when an alternative formulation is considered. When no other option is available, the treating team should strive to procure and switch to the appropriate product as soon as possible. It is worth noting that prolonged infusion with the 500 mcg/mL formulation in neonates may also result in elevated ethanol concentrations, albeit at a lower rate. To the best of our knowledge, no clinical studies or reports have addressed this potential risk. This case highlights the potential pharmacological and toxicological effects of excipients (often wrongly dubbed ‘inactive’ ingredients) in pharmaceutical preparations administered in the NICU. When administered to neonates, excipients can have a significant impact on the safety of treatment [5]. Pharmaceutical products in the NICU should not be considered interchangeable based on the active ingredient only; careful verification of the adequacy of the entire formulation is necessary. In addition, drug manufacturers should be encouraged to seek alternative excipients with a better safety profile for neonates and children. Dotan Shaniv: conceptualization, writing – original draft, writing – review and editing. Ophir Lavon: writing – review and editing, supervision, writing – original draft. This article is linked to Padari et al. papers. To view this article, visit https://doi.org/10.1111/apa.70424. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.