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Safety of “inert” additives or excipients in paediatric medicines
  1. Milap C Nahata
  1. Correspondence to Milap C Nahata, College of Pharmacy, Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA; nahata.1{at}osu.edu

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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.

Role and potential adverse effects of excipients

Benzyl alcohol has antimicrobial properties and thus is often used as a preservative in medicines including parenteral dexamethasone, methylprednisolone, enoxaparin, midazolam and multivitamins. In adults, it is metabolised to benzoic acid, followed by the conjugation with glycine to form hippuric acid which is excreted in the urine.5 The conversion of benzoic acid to hippuric acid, however, was substantially decreased in neonates.6 Due to the serious toxicities including metabolic acidosis, respiratory and central nervous system (CNS) depression and death associated with the use of benzyl alcohol in medicines, intravenous fluids and heparin flush solutions,7 8 the US Food and Drug Administration (FDA) has recommended exclusion of this excipient for newborns.9 The World Health Organization (WHO) has set an acceptable daily intake of up to 5 mg/kg/day in adults,5 but specific acceptable daily intake in the paediatric population is unknown.

Ethanol is used as a pharmaceutical solvent; it is also a preservative. Unlike in the past, it is found as an excipient in fewer oral medicines for infants in the USA (eg, iron, ranitidine and phenobarbital). It is rapidly absorbed from the gastrointestinal tract and metabolised to acetaldehyde, which is then oxidised to acetate.10 Its pharmacokinetics in preterm and term infants is not well understood. Ethanol is a CNS depressant and can also cause respiratory and cardiovascular toxicities at high concentrations. In the USA, the maximum amount of alcohol allowed in OTC medicines is 0.5% v/v for products used in children <6 years age, 5% v/v for 6–12 years of age and 10% v/v for those >12 years of age.10

The American Academy of Pediatrics recommended removal of ethanol from more than 700 liquid preparations for children in 1984.11 This recommendation seems to have been adopted by many manufacturers in the USA – the commonly used oral medicines including furosemide listed no ethanol as an excipient, unlike in the UK.

Propylene glycol is a solvent used in a variety of pharmaceutical products including those for oral and parenteral use, for example, acetaminophen, diphenhydramine, furosemide, ibuprofen, prednisone and pseudoephedrine liquids and lorazepam injection. It is metabolised to lactic and pyruvic acid and also excreted unchanged in the urine12; however, the pharmacokinetics is not clearly known in premature and term neonates at various stages of development. Although it is considered one-third as intoxicating as ethanol, the toxicities of propylene glycol involve CNS and hyperosmolality.13 14 15 The WHO has set an acceptable daily limit of propylene glycol intake of up to 25 mg/kg/day in adults,12 although the acceptable limit in neonates is unknown.

Sorbitol is frequently used as a diluent in tablets, as a plasticiser for gelatine in capsules, and as a vehicle and stabiliser in oral liquid formulations, for example, diphenhydramine, ferrous sulphate, furosemide, ondansetron, prednisolone and pseudoephedrine. It is absorbed from the gastrointestinal tract more slowly than sucrose, and is metabolised to fructose and glucose. The common adverse effect associated with sorbitol is osmotic diarrhoea.16 Thus, ingestion of amount >20 g/day should be avoided in adults; the recommendation for acceptable intake of sorbitol in infants and children is not available.

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

REFERENCES

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Footnotes

  • Competing interests None.

  • Provenance and Peer review Commissioned; not externally peer reviewed.

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