Published: 5 March 2015

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Domperidone - At the Heart of the Matter

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Prescriber Update 36(1): 10-11
March 2015

Domperidone is a peripheral dopamine (D₂) receptor antagonist. It acts as a gastroprokinetic agent by blocking gastrointestinal (GI) tract D₂-receptors and as an antiemetic by blocking D₂-receptors at the chemo-receptor trigger zone.^{1, 2} Domperidone is used to treat dyspeptic symptoms that may be associated with delayed gastric emptying and acute symptoms of nausea and vomiting.

Recent population-based studies and subsequent reviews have associated domperidone use with an increased risk of adverse cardiac effects such as QT interval prolongation, ventricular arrhythmias and sudden cardiac death.^{1, 3, 4} The Medicines Adverse Reactions Committee (MARC) reviewed the efficacy and safety data for domperidone due to these concerns. (www.medsafe.govt.nz/profs/adverse/Minutes158.htm).

The MARC concluded that there is a small increased risk of adverse cardiac effects. However, the balance of benefits and potential harms for domperidone remains favourable. The available data suggests that this small increased risk may be higher in patients older than 60 years or at total daily doses of more than 30mg.

As a result of the MARC review, several changes have been made to the domperidone data sheets (www.medsafe.govt.nz/Medicines/infoSearch.asp). The key changes are highlighted below.

Indications

Domperidone is indicated for the symptomatic treatment of the dyspeptic symptom complex that may be associated with delayed gastric emptying such as epigastric sense of fullness, abdominal distension or swelling, or epigastric pain or discomfort. Domperidone may also be used for the acute symptoms of nausea and vomiting.

The MARC considered that there was insufficient evidence to support the use of domperidone in childhood gastro-oesophageal reflux disease. It may not be suitable for chemotherapy- or radiotherapy-induced nausea and vomiting or post-operative nausea and vomiting.

Dosage and Administration

Janssen (manufacturer of the Motilium brand of domperidone) has concluded that the maximum recommended dose should be reduced from 80mg to 40mg daily. The dose of domperidone should be the lowest effective dose for the individual situation for the shortest possible duration. For children weighing ≥ 35kg, the dose is 0.25 mg/kg three or four times a day, up to a maximum daily dose of 1.0 mg/kg. The use in children under 2 years of age is contraindicated.⁵

Contraindications

Domperidone is predominantly metabolised by the cytochrome P450 enzyme 3A4 (CYP3A4)². When domperidone is co-administered with potent CYP3A4 inhibitors, domperidone plasma concentrations can increase. The risk of QT prolongation is increased when domperidone plasma concentrations are increased. Examples of potent CYP3A4 inhibitors include (but are not limited to) clarithromycin, diltiazem, erythromycin, itraconazole, verapamil and ritonavir. ⁶ Medicines that prolong the QTc interval are also contraindicated with concomitant domperidone use.

Warnings and Precautions

Studies suggest that the increased risk of arrhythmia and sudden cardiac death may be higher in patients older than 60 years or at total daily doses of more than 30mg. Caution should also be exercised in patients who have existing prolongation of cardiac conduction intervals, significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure. Other risk factors for sudden cardiac arrest include a family history of coronary artery disease, high blood pressure, high blood cholesterol, obesity, diabetes, smoking and excessive alcohol consumption.

Further information on the data reviewed is published in Medsafe's alert communication (www.medsafe.govt.nz/safety/EWS/2014/Domperidone.asp).

References

1. Doggrell SA, Hancox JC. 2014. Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine. Expert Opinion on Drug Safet. 13(1): 131-138.
2. Reddymasu SC, Soykan I, McCallum RW. 2007. Domperidone: review of pharmacology and clinical applications in gastroenterology. American Journal of Gastroenterology. 102(9): 2036-2045.
3. van Noord C, Dieleman JP, van Herpen G, et al. 2010. Domperidone and ventricular arrhythmia or sudden cardiac death: a population-based case-control study in the Netherlands. Drug Safety. 33(11): 1003-14.
4. Johannes CB, Varas-Lorenzo C, McQuay LJ, et al. 2010. Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: a nested case-control study. Pharmacoepidemiology and Drug Safety. 19: 881-88.
5. Janssen-Cilag (New Zealand) Ltd. 2014. Motilium data sheet. 24 December 2013. URL: www.medsafe.govt.nz/profs/datasheet/m/motiliumtab.pdf (accessed 20 December 2014).
6. Lynch T, Price A. 2007. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. American Family Physician. 76: 391-396.