Promoting tolerance of enteral feeds in children and young people: domperidone

Evidence review: safety

The randomised crossover study by Gounaris et al. (2010) reported there were no side effects in the 22 neonates treated. However, the study was too small (n=22) and short term (48-hour treatment) to provide reliable information on safety or side effects.

The contraindications in the summary of product characteristics (SPC) for licensed 1 mg/ml domperidone oral suspension (the formulation most likely to be used off-label to promote tolerance of enteral feeds in children) indicate it should not be used when stimulation of gastric motility could be harmful, such as in people with gastrointestinal haemorrhage, mechanical obstruction or perforation. It is also contraindicated when there is a known hypersensitivity to domperidone or any of the excipients, and in the presence of a prolactin-releasing pituitary tumour (prolactinoma).

Precautions of using domperidone oral suspension in infants in the SPC include rare neurological side effects. It reports that since metabolic functions and the blood–brain barrier are not fully developed in the first months of life the risk of neurological side effects is higher in young children. Therefore, it recommends that the dose (for its licensed indications) be determined accurately and followed strictly in neonates, infants, toddlers and small children. The SPC also notes that overdosing may cause extrapyramidal symptoms in children.

The British national formulary for children states that prolactinaemia is a contraindication for use in children and that one of the rare side effects of domperidone may include hyperprolactinaemia.

The SPC also states in the precautions for use and undesirable effects sections that some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias (very rare, frequency of less than 1 in 10,000), QT_c interval prolongation (an alteration of the electrical activity in the heart; frequency unknown) or sudden cardiac death (frequency unknown). It states that domperidone should be used at the lowest effective dose in adults and children.

Caution needs to be exercised when using domperidone and other drugs that prolong QTc intervals in people who have existing prolongation of cardiac conduction intervals, particularly QT_c, and in people with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

The main metabolic pathway of domperidone is through the enzyme CYP3A4 and therefore co-administration with oral ketoconazole, erythromycin or other potent CYP3A4 inhibitors that prolong the QT_c interval should be avoided.

In 2011, the European Medicines Agency Pharmacovigilance Working Party evaluated concerns about domperidone-related adverse heart effects, including QT_c interval prolongation and arrhythmias (unstable heartbeats). They recommended that all product information for domperidone be updated to reflect the risk of these cardiac adverse events and that domperidone should be used with caution in people with certain heart conditions, including heart failure, a previous heart attack, angina (chest pains) and heart rhythm disorders.

In May 2012, the Medicines and Healthcare products Regulatory Agency issued a drug safety update, Domperidone: small risk of serious ventricular arrhythmia and sudden cardiac death. This stated that some epidemiological studies have shown that domperidone may be associated with a small increased risk of serious ventricular arrhythmia or sudden cardiac death. These risks may be higher in people older than 60 years and in people who receive daily oral doses of more than 30 mg. Non-prescription domperidone products are not recommended for use in people with underlying cardiac disease without medical supervision.

On 7 March 2013, the European Medicines Agency started a new safety review of domperidone-containing medicines in relation to continued concerns about its adverse effects on the heart. The European Medicines Agency will review all available data on the benefit–risk balance of domperidone-containing medicines, and issue an opinion on whether their marketing authorisations should be maintained, varied, suspended or withdrawn across the European Union. No expected date for the final decision has been given.

The European Medicines Agency advises that while the safety review is ongoing people should speak to their doctor or pharmacist if they have any questions or concerns.