Domperidone
Peripheral dopamine D2 antagonist for nausea and delayed gastric emptying
Domperidone is a dopamine D2 receptor antagonist with antiemetic and prokinetic properties. Janssen launched the compound in 1978 under the brand name Motilium. In Germany, Motilium and numerous generics are available as tablets and suspension. In 2014, after an extensive benefit risk review, the EMA substantially restricted use because domperidone was associated with an increased risk of cardiac arrhythmia and sudden cardiac death.
The current indication is limited to the short term treatment of nausea and vomiting in adults and children from 12 years with a body weight of at least 35 kg. All earlier indications such as chronic dyspepsia, heartburn or stimulation of lactation are no longer approved. The maximum duration of use is 1 week and the daily dose is limited to 30 mg. These restrictions apply to all oral domperidone preparations in the European Union.
Mechanism of Action
Domperidone acts as an antagonist at dopamine D2 receptors with preference for peripheral receptors in the gastrointestinal tract and in the chemoreceptor trigger zone at the floor of the fourth ventricle. The chemoreceptor trigger zone lies outside the blood brain barrier, which is why domperidone can act there without penetrating the central nervous system. As a result, the central extrapyramidal side effects typical of metoclopramide are absent.
In the upper gastrointestinal tract domperidone acts as a prokinetic. Dopamine normally inhibits acetylcholine release from myenteric neurons, which slows peristalsis. By blocking this inhibitory mechanism the motility of the gastric antrum, coordination of antrum duodenum motility and gastric emptying increase. The tone of the lower oesophageal sphincter rises and reflux is reduced.
The half life is 7 to 9 hours and the oral bioavailability is about 15 percent because of pronounced first pass metabolism. Metabolism takes place in the liver predominantly via CYP3A4, and excretion is approximately equal between hepatic and renal routes. Polymorphisms in CYP3A4 or concomitant use of CYP3A4 inhibitors may raise plasma levels and thereby the QT risk.
Indications
- Short term treatment of nausea and vomiting in adults and children from 12 years with a body weight of at least 35 kg
The historical indications no longer approved since 2014 include chronic dyspepsia, heartburn, reflux, bloating and stimulation of lactation. In a few countries outside Europe broader indications still exist, for example in the treatment of diabetic gastroparesis or in Parkinson's patients with nausea from dopaminergic therapy. In Germany and the EU use is strictly limited to acute therapy.
Dosage and Administration
Adults and adolescents from 12 years and 35 kg: 10 mg three times daily, 15 to 30 minutes before meals. For nocturnal complaints an additional 10 mg at bedtime, maximum 30 mg per day. Treatment duration must not exceed 7 days.
Intake before meals is important because bioavailability is higher on an empty stomach. Swallow tablets with a glass of water, shake suspensions before use. In case of inadequate response the dose should not be increased; instead medical reassessment and if necessary a switch to another antiemetic.
Renal impairment: in severe impairment (creatinine clearance below 30 ml/min) 10 mg once or twice daily, not three times. Hepatic impairment: moderate to severe impairment contraindicated, mild impairment with caution. Children under 12 years or under 35 kg: not used in the EU since 2014. Elderly patients: use with caution because of the elevated QT risk, consider ECG check before starting therapy.
Side Effects
Common: dry mouth, headache, diarrhoea, hyperprolactinaemia with resulting galactorrhoea, gynaecomastia, menstrual disturbance, sexual dysfunction.
Uncommon: anxiety, drowsiness, nervousness, decreased libido, skin rash, pruritus.
Rare: extrapyramidal reactions (especially when the recommended dose is exceeded), seizures, agitation, QT prolongation, torsade de pointes, ventricular arrhythmia, sudden cardiac death.
Main reason for the 2014 restriction: observational studies and pharmacovigilance signals indicated an elevated risk of serious cardiac arrhythmia and sudden cardiac death, particularly in elderly patients, at high doses and with concomitant CYP3A4 inhibition. The lower recommended dose and the short treatment duration reduce this risk.
Interactions
- QT prolonging drugs (amiodarone, sotalol, quinidine, macrolides, quinolones, antidepressants, methadone, ondansetron): additive QT prolongation, avoid combination or perform strict ECG monitoring
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, ritonavir): marked elevation of plasma levels, combination contraindicated
- Moderate CYP3A4 inhibitors (fluconazole, amiodarone, diltiazem, verapamil, grapefruit juice): use with caution, choose the lowest dose
- Anticholinergics: antagonistic effect on the prokinetic component
- Levodopa, apomorphine (Parkinson therapy): blockade of peripheral dopamine receptors reduces nausea under these substances without cancelling the antiparkinson effect in the CNS
- Antacids, proton pump inhibitors, H2 blockers: may theoretically alter absorption, clinical relevance is low
Special Notes
ECG before therapy: in at risk patients (age above 60 years, known heart disease, electrolyte disturbance, concomitant QT prolonging medication) an ECG with QTc measurement before starting therapy is advisable. QTc above 450 ms in men or 470 ms in women are warning signs.
Contraindications: known hypersensitivity, significant QT prolongation, electrolyte disturbance such as hypokalaemia or hypomagnesaemia, bradyarrhythmia, heart failure, concomitant use of strong CYP3A4 inhibitors, prolactinoma, gastrointestinal bleeding, mechanical obstruction or perforation, moderate to severe hepatic impairment.
Pregnancy: data are limited, use only on vital indication. Breastfeeding: passes into breast milk, signals of risk to the infant, breastfeeding under therapy not recommended. The former indication of stimulating milk production is no longer approved.
Elderly patients and cardiovascular risk: combining domperidone with concomitant QT prolonging medication substantially raises the arrhythmia risk. In elderly patients a careful medication review is necessary before every domperidone prescription. The short duration of use of a maximum of 7 days must be strictly observed.
Monitoring: in at risk patients ECG and electrolytes before starting therapy. In case of hyperprolactinaemia symptoms (galactorrhoea, menstrual disturbance) consider ending therapy and measure prolactin. After end of treatment plasma levels normalise rapidly within 1 to 2 days.
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Frequently Asked Questions
Why can I take domperidone only for a short time?
In 2014 the EMA found that domperidone increases the risk of serious cardiac arrhythmia and sudden cardiac death with longer use or at higher doses. The indication was therefore restricted to the short term treatment of nausea and vomiting in adults and older children, with a maximum daily dose of 30 mg and a treatment duration of no more than 7 days.
What is the difference from metoclopramide?
Metoclopramide crosses the blood brain barrier and can cause central side effects such as extrapyramidal disturbances, drowsiness and tardive dyskinesia. Domperidone acts almost exclusively peripherally, which reduces central effects. On the other hand, domperidone has a higher risk of QT prolongation and cardiac arrhythmia. The choice depends on the individual risk profile.
Why does domperidone work in Parkinson's patients?
Dopaminergic therapies such as levodopa or apomorphine often cause nausea because they act on the chemoreceptor trigger zone in the brain. Domperidone blocks the dopamine receptor there without impairing the antiparkinson effect in the central nervous system, because it barely crosses the blood brain barrier. In Germany this use is off label; in some countries it is approved.
May I take domperidone to stimulate milk production?
No. The indication for stimulation of lactation was removed from the approved labelling in 2014. The evidence base was weak and the cardiovascular risk with longer therapy not acceptable. In case of insufficient milk production, other non medicinal measures such as frequent latching, breastfeeding counselling or alternative methods under gynaecological or midwifery support should be preferred.
Sources
- EMA, European Medicines Agency
- AWMF, guidelines on nausea and vomiting
- Gelbe Liste, domperidone active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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