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O-22 Safe excipient exposure in neonates and small children – the seen project
  1. Svinning,
  2. Valeur1,
  3. Hertel2,
  4. Engell Lundstrøm3,
  5. Holst1
  1. 1Bispebjerg and Frederiksberg University Hospitals, COPENHAGEN, Denmark
  2. 2Department of Neonatology, Rigshospitalet, COPENHAGEN, Denmark
  3. 3Department of Paediatric and Adolescent Medicine, Rigshospitalet, COPENHAGEN, Denmark


Background Several medicines frequently used in neonates and infants contain potentially harmful excip-ients like ethanol, propylene glycol (PG), methyl-and propyl-parabens. Especially preterm neonates may bechronically exposed as a result of being poly-medicated for extended periods. Hence, safeties of such excipients in relation to age and developmental-status have be-come a hot topic. Adverse drug events (ADEs) due to the content of excipients may be difficult to detect. The preservative methyl-paraben has been shown to displace bilirubin-binding to albumin and may cause hyperbiliru-binemia in concentrations as low as 1.2 mg/kg. Likewise, ethanol and PG are known to be neurotoxic and may re-sult in delayed neurological development after early-life exposure. The European Medicines Agency (EMA) has proposed tolerance limits of daily exposure rates (mg/kg/day) for some of these excipients in each drug prepa-ration. Tolerance limits of parabens only exist for meth-yl-paraben (10 mg/kg/day) and is based on data obtained after oral administrations -although commonly found in parenteral solutions. However, neonates may be more susceptible to excipient–excipient and/or drug–excip-ient pharmacokinetic-interactions compared to adults because of their reduced metabolic activity in the elim-ination pathways.

Aim To quantify the cumulative daily exposure level of benzyl alcohol, ethanol, PG, methyl-paraben and pro-pyl-paraben (in mg/kg/day) administered to poly-medi-cated neonates and infants.

Methods The study was conducted at the national hospital, Rigshospitalet, Denmark. All preparations ad-ministered to neonates receiving more than two drugs and infants receiving more than three drugs per day were registered. Levels were calculated based on quantities ob-tained from manufacturers or databases. Excipient levels were compared to tolerance limits outlined by the EMA.

Results In total, 470 neonates and 160 infants were in-cluded covering 4207 prescriptions and 316 preparations. Ethanol was administrated to 38%, PG to 23%, and benzyl alcohol to 2% of the neonates and infants, respectively. Methyl-paraben was administered 31% and propyl-para-ben to 24% of the neonates and infants. In patients re-ceiving drugs containing ethanol, the cumulative level exceeded the daily tolerance limits in 53% (n=81) of neo-nates and 62% (n=53) of infants, respectively. In patients receiving PG, the cumulative level was exceeded in 40% (n=36) of the neonates and 57% (n=32) of the infants. Few infants (n=14) were exposed to benzyl alcohol. The cumulative level of methyl-paraben exceeded the tol-erance limits in less than one percent of both neonates (n=5) and infants (n=5). No tolerance limit for propyl-par-aben was available for comparison.

Conclusion Tolerance limits for ethanol and PG pro-posed by the EMA are exceeded in more than 50% of poly-medicated neonates and infants due to the cumu-lative effect of these excipients. A constant awareness of potential pharmacokinetics, pharmacodynamics and, excipient–excipient-interactions, especially in NICU neo-nates taking multiple medications cannot be highlighted enough. Further, EMA might propose a tolerance limit for methyl-paraben based on safety-data obtained from in-travenous administrations.

References 1 Souza A et al. Eur J Pediatr. 2014

2 Nellis G et al. Arch Dis Child. 2015; Rasmussen LF et al. J Pediatr. 1976

3 Marek E et al. Curr Ther Res Clin Exp. 2014; European Medical Agency. 2003

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