The Cumulative Daily Tolerance Levels of Potentially Toxic Excipients Ethanol and Propylene Glycol Are Commonly Exceeded in Neonates and Infants

Abstract

Polymedicated neonates and young infants may be at risk of harmful cumulative exposure to toxic excipients like ethanol, propylene glycol and benzyl alcohol during routine clinical care. The aim of this study was to calculate the cumulative daily alcohol exposure (mg/kg/day) in polymedicated neonates and infants and compare these levels to the tolerance limits found in guidelines published by European Medicines Agency (EMA). As part of the SEEN study, all medicinal products administered to neonates and infants were recorded. All included neonates received ≥2 medicinal products/day and infants ≥3 medicinal products/day. Daily excipient levels were calculated based on quantities obtained from manufacturers or databases. Excipient levels were compared to tolerance limits proposed by the EMA. Altogether, 470 neonates and 160 infants were included, recording 4207 prescriptions and 316 products. In total, 45% (n = 288) of patients were exposed to an alcohol of interest; 2% (n = 14) were exposed to benzyl alcohol (BA), 38% (n = 237) to ethanol and 23% (n = 146) to propylene glycol (PG). Of the total number of prescriptions involving ethanol-containing medicinal products (n = 334), 51% would alone exceed tolerance limit of 6 mg/kg/day. Of the total number of prescriptions involving PG-containing medicinal products (n = 174), 70% would alone exceed a maximum tolerance limit of 50 mg/kg/day. Maximal daily exposure to ethanol (1563 mg/kg/day) or PG (954 mg/kg/day) exceeded the tolerance limits recommended by EMA 260.5 and 19.1 times, respectively. Tolerance limits for ethanol and PG as proposed by the EMA are frequently exceeded in polymedicated neonates and infants due to the cumulative effect of these alcohols. Alternative formulations may minimize excipient exposure.

A Focus Group Study about Oral Drug Administration Practices at Hospital Wards—Aspects to Consider in Drug Development of Age-Appropriate Formulations for Children

“…Further observations revealed that excipient amounts exceeded the recommendations for maximum daily intake for adults in 19% of oral medicines. Additionally, a Danish study showed that the exposure of benzyl alcohol, ethanol and propylene glycol in hospitalized neonates and infants less than 2 years of age was substantial and the cumulative daily exposure frequently exceeded the tolerance limits stated by EMA [14].…”

Design, Optimization, Manufacture and Characterization of Efavirenz-Loaded Flaxseed Oil Nanoemulsions

“…The dose size of EFV is 200 mg for pediatric patients and 600 mg for adults and as a nanoemulsion the dose unit is relatively small and is not expected to produce blood ethanol levels above regulated limits [ 38 ]. The European Medicines Agency (EMA) recommends a daily limit of 260.5 mg/kg/day of ethanol [ 39 ]. The levels for Span ® 20 (A), Tween ® 80 (B) and ethanol (C) used in the mixture fell in the range between the minimum and maximum levels listed in Table 2 with the sum of the components A, B and C always totaling 100%.…”

Benefits and Prerequisites Associated with the Adoption of Oral 3D-Printed Medicines for Pediatric Patients: A Focus Group Study among Healthcare Professionals

“…The participants in this study believed that, in case the printing method used does not enable printing of a QR code, other measures should be taken to ensure identification of the drug product and, thus, to prevent medication errors. In drug development of pediatric medicines, one must consider that the colorant as well as other excipients are safe for use in children, since investigations have shown that neonates and infants are extensively exposed to harmful excipients during oral administration of medicines [38][39][40]. Furthermore, this study shows that healthcare professionals prefer dosage forms containing excipients that enable the administration of the dosage form through enteral feeding tubes as well as after dissolving or dispersing the dosage form in liquid, e.g., water.…”