Most, if not all, medicines contain both the pharmacologically active and inactive ingredients. The therapeutically inactive components of a medicine are considered excipients. The excipients demonstrate many critical functions including: being diluents, wetting agents, solvents, fillers, binders, emulsifiers, absorption enhancers, sustained release matrices, preservatives, sweeteners, and stabilising, colouring or flavouring agents.1 These excipients serve an important purpose of converting a medicinal compound to an elegant pharmaceutical product with improved delivery for clinical use. It is generally assumed that because the excipients are inert and pharmacologically inactive, they are safe in patients. This assumption, however, may not always be accurate.

A recent study by Whittaker et al2 in this journal documented exposure to over 20 excipients including ethanol, propylene glycol and sorbitol in 36 preterm infants. Further, some infants were exposed to amounts higher than those recommended for adults per kilogramme of body weight. This was not surprising that the infants received these excipients since without excipients they would have been deprived of essential medicines. The question is: are patients at risk of developing undesirable health effects and adverse outcomes from excipients? As the authors stated, this question could not be answered in their study as the clinical effects of excipients were not studied in infants.

A policy statement by the American Academy of Pediatrics on inactive ingredients in pharmaceutical products raised questions about the safety of excipients including antioxidants, propylene glycol, sorbitol, lactose, artificial sweeteners, benzyl alcohol, benzalkonium chloride, and colouring agents. The evidence came largely from small uncontrolled and observational studies or case reports. A mandatory labelling of inactive ingredients was recommended for both prescription and over-the-counter (OTC) products.3

As one may expect, the exposure to excipients from continuous infusions of parenteral medicines may be higher than that from intermittent injections. Shehab et al4 have recently reported that critically ill neonates on continuous infusions received a median cumulative dose of benzyl alcohol, 106 mg/kg/day (21 times the “acceptable daily intake” of 5 mg/kg/day), and propylene glycol, 4555 mg/kg/day (182 times the acceptable daily intake of 25 mg/kg/day). These investigators also did not evaluate clinical consequences of the excessive exposures.

The purpose of this article is to raise the awareness of the role excipients (eg, benzyl alcohol, ethanol, propylene glycol and sorbitol) play in making medicines, describe potential adverse effects associated with these excipients, and discuss what needs to be done to minimise adverse health outcomes from the use of excipients in medicines for use in infants.

Summary and suggestions to minimise potential adverse health outcomes associated with excipients in infants and children

• Preterm or term infants, and children are exposed to a variety of excipients present in the medicines essential for the treatment of both acute and chronic illnesses.

• Excipients can elicit pharmacological response depending on dose, patient’s susceptibility to adverse effects and organ systems development for metabolism and elimination. Thus, use of excipients should be avoided if possible.

• Daily intake of certain excipients among infants and children may exceed the proposed maximum acceptable daily intake per kilogramme of body weight for adults; however, the clinical consequences of this exposure in paediatric patients are unknown.

• The acceptable daily and cumulative intake of excipients needs to be defined for preterm and term infants, and children.

• Excipients are listed by name on the medicine label but the amounts of most excipients are not. The amounts of all excipients should be listed on the label of all medicines so that practitioners can consider their potential safety in patients.

• There is a need to determine the safety of excipients in paediatric patients especially in preterm and term infants whose metabolic and elimination pathways may not be fully developed or who may be more susceptible to adverse effects during the first few weeks and months after birth.

• Critically ill infants receiving continuous infusions of medicines are likely to be exposed to the highest amounts of excipients per day. Thus, excipient-free medicines should be made available for these patients when possible, for example, midazolam is now available preservative-free in the USA. Lack of preservative, however, can decrease medicine shelf-life and thus increase medicine cost.

• Manufacturers should adopt best practices about the safe and effective use of excipients at the global level, for example, if ethanol can be removed from certain oral liquid medicines in one country, it should be carried out globally.

• Healthcare providers should be educated about the role, benefits and potential adverse effects of excipients, especially among preterm and term infants, and young children.

• Regulatory agencies should enforce standards for the safe and effective use of excipients in the paediatric population. The FDA provides guidance for industry on non-clinical studies for the safety evaluation of pharmaceutical excipients but this document does not define safe levels of excipients in the paediatric population.17