5.3 Excipients:

The use of excipients in paediatric medicines is driven by functional requirements and should be justified through a risk-based assessment, taking into account factors such as the paediatric age group, frequency of dosing and duration of treatment.

The added challenge for paediatric medicines compared to adult medicines is that excipients may lead to adverse reactions in children that are not experienced by adults or are not seen to the same extent. Reviews of the literature on adverse reactions attributed to excipients show that the available data on excipient safety are limited in quantity and variable in quality.

Major problems with excipients in paediatric medicines, especially when used to treat infants and neonates, have been reported (21), e.g. medicines with benzyl alcohol, azo-dyes, propylene glycol, ethanol and propyl paraben. A study on the exposure to benzyl alcohol and propylene glycol of neonates receiving parenteral medication demonstrated a potential risk of toxic doses, especially for neonates receiving continuous infusion (22). The toxicity of excipients to newborns and infants can be explained by factors related to their physiological and metabolic development (2). Information
on the safety of some excipients may be found, for example, in reviews published by the American Academy of Pediatrics (23). Alternative sources of information should also be consulted, e.g. the WHO Technical Report Series on Evaluation of certain food additives (24).

In the development of paediatric medicines, the number of excipients and their quantity in a formulation should be the minimum required to ensure an appropriate product with respect to performance, stability, palatability, microbial control, dose uniformity and other considerations necessary to support product quality. Risks for adverse reactions are mostly associated with excipients used for liquid dosage forms.

In the choice of excipients consideration should be given to:

■ The safety profile of the excipient for children of the target age groups;

■ The route of administration;

■ The single and daily dose of the excipient;

■ Duration of the treatment;

■ Acceptability for the intended paediatric population;

■ Potential alternatives;

■ Regulatory status in the intended market.

Potential alternatives to excipients which pose a significant risk to children should always be considered. Another dosage form or even a different route of administration might be necessary to avoid significant risk. Although well-known excipients with well-defined safety profiles are preferred, new excipients cannot be excluded. Novel excipients should only be used when their safety, quality and appropriateness for use in children have been established. It may also be necessary to look at alternative excipients because of different cultural attitudes or for religious reasons, e.g. the use of gelatin may not be acceptable for all patients.

Development of Paediatric Medicines: points to consider in formulation, 
(Annex 5, WHO Technical Report Series 970, 2012)

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