Safe excipient exposure in neonates and small children

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–excipient 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 cumulative 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.