Aim To evaluate oral liquid formulations of propranolol and to select the optimal preparation for use in Infantile Haemangioma.
Method Four oral liquid preparations of propranolol were considered:
A – an alcohol-free suspension prepared as a ‘special’ (the current treatment of choice)
B and C – generic solutions available in four different strengths
D – a French solution not marketed in the United Kingdom (UK)
Preparations were evaluated against six criteria:
Ease of purchase
Ease of dosing
Results Licensing status: Preparation A is unlicensed and should not be used if a licensed product is suitable. Preparations B and C are licensed in children but not for Infantile Haemangioma. Preparation D has a European license for Infantile Haemangioma.
Ease of purchase: Preparation A is made to order but has a short lead time. Preparations B and C are available from wholesalers. No current importer for Preparation D was found.
Shelf life: The licensed preparations have 2–3 years shelf life. Preparation A has a 1 month shelf life.
Excipients: All excipients were considered. Aspartame, ethanol, maltitol, methylhydroxybenzoate, propylhydroxybenzoate, propylene glycol, saccharin sodium and Sunset Yellow can all cause adverse effects. The excipient most likely to cause problems was propylene glycol. This is eliminated by both renal excretion and liver metabolism but, in infants, these processes are immature and accumulation occurs with resultant toxicity. Preparation A contains no propylene glycol and can be used in children of all ages. Levels in Preparations B and C are safe for use in children over 1 month.1 The propylene glycol content of Preparation D could not be ascertained. Preparation B contained ethanol. Levels were below safety limits2 but ethanol competes with propylene glycol for metabolism via alcohol dehydrogenase increasing the risk of propylene glycol toxicity.
Ease of dosing: Dose volumes were calculated for a neonate (3.5 kg), a 6 month-old (7.6 kg) and a 1 year-old (9 kg). All preparations with strengths between 1 mg/ml and 3.75 mg/ml gave suitable dose volumes. Doses for Preparation D are expressed as propranolol base. In the UK, doses are expressed as propranolol hydrochloride. This could be confusing and lead to prescribing or dispensing errors.
Cost: Preparation A was more expensive than B or C. The cost of Preparation D could not be established.
Conclusions Although Preparation D is licensed for Infantile Haemangioma, its use would be complicated by difficulties in obtaining supplies, likely cost and the risk of confusion between propranolol base and hydrochloride when prescribing and dispensing. Preparations B and C are suitable for use in children over 1 month of age. Preparation C is recommended because it contains less propylene glycol and no alcohol. Preparation A should only be used in children under 28 days. Using Preparation C instead of Preparation A gives the benefits that a licensed preparation is used, dispensing delays are reduced and costs are reduced.
European Medicines Agency Committee for Human Medicinal Products (CHMP). Background review for the excipient propylene glycol, EMA/CHMP/334655/2013. [Internet]. 2014 [cited 30.3.19.]. Available from: https://www.ema.europa.eu/en/documents/report/background-review-excipient-propylene-glycol-context-revision-guideline-excipients-label-package_en.pdf
European Medicines Agency Committee for Human Medicinal Products (CHMP). Questions and Answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00), EMA/CHMP/507988/2013. [Internet]. 2014 [cited 30.3.19.]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-ethanol-context-revision-guideline-excipients-label-package-leaflet-medicinal_en.pdf
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