Domperidone

Domperidone is a peripheral dopamine D2 antagonist used for nausea, vomiting and gastric stasis. It crosses the blood brain barrier poorly, so central adverse effects are uncommon, but it prolongs the QT interval and carries a risk of serious ventricular arrhythmia and sudden cardiac death.

Classification. Benzimidazole derivative; antiemetic; prokinetic.

Mechanism. Blocks D2 receptors in the gastrointestinal tract and in the chemoreceptor trigger zone (which lies outside the blood brain barrier). This increases lower oesophageal sphincter tone, gastric motility and antroduodenal coordination.

Pharmacodynamics. Raises serum prolactin because the pituitary lies outside the blood brain barrier. Prolongs the QT interval by blocking hERG potassium channels.

Pharmacokinetics. Oral bioavailability about 15% from extensive first-pass metabolism; absorption is reduced when gastric pH is raised. Protein binding 91% to 93%. Half-life about 7 to 9 hours, prolonged in severe kidney impairment.

Metabolism. Extensive hepatic metabolism through CYP3A4. Strong CYP3A4 inhibitors raise exposure markedly. About 30% is excreted in urine, mostly as metabolites, and 66% in faeces.

Adult and adolescent (12 years and over, weight 35 kg or more) oral doses. Use the lowest effective dose for the shortest time.

Nausea and vomiting. 10 mg up to three times daily, taken 15 to 30 minutes before meals. Maximum 30 mg daily. Usual duration up to 7 days without review.

Dyspepsia and gastric stasis (including diabetic gastroparesis). 10 mg up to three times daily before meals, with the last dose at bedtime if needed. Maximum 30 mg daily. Review need after 4 weeks.

Alternative regional dosing. Some labels allow 20 mg up to four times daily (maximum 80 mg daily). These doses exceed the limit linked to QT-related cardiac risk and are not advised.

Nausea and vomiting from levodopa or apomorphine in Parkinson disease. Domperidone is often preferred over metoclopramide, which worsens parkinsonism. Use 10 mg three times daily with ECG baseline.

Children and adults under 35 kg. Not advised under 12 years or under 35 kg because efficacy is unproven. Where used under regional labelling, the dose is 0.25 mg/kg up to three times daily for a maximum of 7 days.

Kidney and liver adjustment.

• CrCl 30 to 60 mL/min: no change for single use; reduce frequency for repeated dosing.

• CrCl under 30 mL/min: reduce to once or twice daily and monitor.

• Moderate or severe liver impairment: contraindicated.

Contraindications.

• Prolactinoma; gastrointestinal haemorrhage, obstruction or perforation.

• Moderate to severe liver impairment.

• Known QT prolongation, significant electrolyte disturbance (hypokalaemia, hypomagnesaemia), or underlying heart disease such as heart failure.

• Coadministration with QT prolonging drugs or strong CYP3A4 inhibitors.

Common adverse effects. Dry mouth, headache, diarrhoea, rash, and effects of raised prolactin (galactorrhoea, breast tenderness, amenorrhoea, gynaecomastia).

Serious adverse effects.

• QT prolongation, torsades de pointes, ventricular arrhythmia and sudden cardiac death; risk rises with doses over 30 mg daily, age over 60 and interacting drugs.

• Extrapyramidal reactions, uncommon in adults but seen in infants.

Major interactions.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, ritonavir and other protease inhibitors, diltiazem, verapamil): contraindicated.

• QT prolonging drugs: contraindicated. These include antimalarials such as artemether-lumefantrine, quinine and chloroquine, which are used widely in East Africa, as well as azithromycin, fluoroquinolones, citalopram, escitalopram, haloperidol, methadone, ondansetron, amiodarone and sotalol.

• Antacids and antisecretory drugs: reduce bioavailability; take domperidone before meals and antacids after.

• Anticholinergics and opioids: oppose the prokinetic effect.

• Dopamine agonists (bromocriptine, cabergoline, levodopa): opposed prolactin and motility effects.

Special groups.

• Pregnancy: limited data; avoid unless clearly needed.

• Breastfeeding: low milk transfer; QT risk to the mother is the concern; use only the lowest dose for the shortest time. Use as a galactagogue is unlicensed and not advised without ECG assessment.

• Children: not advised.

• Older adults: use the lowest dose; higher cardiac risk over 60 years.

• Kidney impairment: when CrCl is under 30 mL/min, reduce to once or twice daily.

• Liver impairment: contraindicated in moderate to severe impairment.

Formulations. Tablets 10 mg; oral suspension 5 mg in 5 mL; suppositories 30 mg (market dependent). Domperidone injection has been withdrawn in most countries.

Oral administration. Take 15 to 30 minutes before meals. If a dose is needed at bedtime, give it on an empty stomach.

Baseline. ECG with QTc in anyone with heart disease, electrolyte risk, interacting drugs or age over 60. Potassium and magnesium before starting. Review all medicines for QT effect and CYP3A4 inhibition.

Monitoring.

• Review need at 7 days for nausea and at 4 weeks for gastric stasis, and stop if no benefit.

• Repeat ECG if new interacting drugs are added or if palpitations, syncope or dizziness occur.

• Potassium and magnesium with diuretics, diarrhoea or vomiting.

• Prolactin effects: galactorrhoea, amenorrhoea.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop immediately for palpitations, syncope, QTc over 450 ms in men or 470 ms in women, or addition of a contraindicated drug.

Referral and escalation. Cardiology review for QTc prolongation or arrhythmia. Gastroenterology review for gastroparesis that fails to respond.