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Janssen-Cilag Pty Ltd Facts Sheet (New Zealand)
April 2000

MOTILIUM®

Domperidone

Presentation

MOTILIUM 10 mg tablets are white, circular, film-coated, biconvex tablets with m/10 imprinted on one side and JANSSEN on the other.

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Uses

Actions: Domperidone is a dopamine antagonist with antiemetic properties similar to those of metoclopramide and certain neuroleptic medicines. Unlike these medicines, however, domperidone does not readily cross the blood-brain barrier. It seldom causes extrapyramidal side effects, but does cause a rise in prolactin levels. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of central dopamine receptors in the chemoreceptor trigger zone which lies in the area postrema and is regarded as being outside the blood-brain barrier. Animal studies have shown that domperidone has no effect on plasma concentrations of homovanillic acid, a metabolite of dopamine.

It also antagonises the behavioural effects of dopamine much more effectively when administered intracerebrally than when given systemically. These findings, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.

Studies in humans have shown intravenous and oral domperidone to increase the duration of antral and duodenal contractions, to increase the gastric emptying of liquids and semi-solids in healthy subjects and in patients in whom it was delayed, and to increase lower oesophageal sphincter pressure in healthy subjects. Domperidone has no effect on gastric secretion. Intravenous domperidone 10, 20 and 40 mg had no effect on cardiac output, cardiac electric conduction, heart rate or blood pressure in healthy volunteers up to one hour after administration.

Pharmacokinetics

Absorption: Domperidone is rapidly absorbed following intramuscular and oral administration with peak plasma concentrations occurring at approximately 10 and 30 minutes, respectively. Systemic bioavailability of intramuscular domperidone is about 83% whereas that of oral domperidone is 13% to 17%.

The low oral bioavailability is probably due to first pass metabolism in the liver and gut wall. Oral bioavailability is decreased by prior administration of cimetidine or sodium bicarbonate (see Interactions ). The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral medicine is taken after a meal.

Metabolism: Oral domperidone does not appear to accumulate or induce its own metabolism: a peak plasma level after 90 minutes of 21 ng/mL after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/mL after the first dose.

Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.

Distribution: Domperidone is 91% to 93% bound to plasma proteins. Distribution studies with radio-labelled medicine in animals have shown wide tissue distribution with low brain concentration. Small amounts of medicine cross the placenta in rats and the medicine is excreted in the breast milk of this species.

Elimination: Urinary and faecal excretion amounts to 31 and 66%, respectively, of the oral dose. The proportion of the medicine excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.

Indications

Symptomatic treatment of the dyspeptic symptom complex which is often associated with delayed gastric emptying or gastro-oesophageal reflux and oesophagitis: epigastric sense of fullness, feeling of abdominal distension, upper abdominal pain, eructation, flatulence, heartburn.

Treatment of nausea and vomiting of various origins including functional, organic, infectious, dietetic, radiotherapy, medicine therapy.

As a diagnostic agent administered in radiology before a barium meal to increase the rate of passage of barium through the gastrointestinal tract.

Further notes:

Because of its side effect of raising Prolactin levels in the blood, Domperidone is often used as an aid to inducing lactation. Although Domperidone can induce lactation, it should be used as an aid, rather than a solution. Its effectiveness is limited as a galactagogue.

Dosage:

• General: Domeridone/Motilium should be taken 15-30 minutes before meals and, if necessary, before retiring.
• Adults: One, 10 mg, three to four times daily. If necessary this dose may be doubled after two weeks if an adequate therapeutic response is not attained. For acute and subacute conditions (e.g. nausea and vomiting) 20 mg three to four times daily.
• When used as a galactagogue: Up to two, 10 mg tablets, four times daily. Increasing beyond 80 mg per day does not seem to increase lactation accordingly. If headaches are encountered, reducing the dosage usually eliminates the headache.

Side Effects:

• The most frequent reactions to Domperidone/Motilium are those related to elevated Prolactin levels including breast tenderness, galactorrhoea, gynaecomastia and amenorrhoea. These effects are dose-related and gradually resolve after lowering the dose or discontinuing treatment.
• Other rarely reported adverse reactions include headache, diarrhoea, dizziness, mild and transient abdominal cramps, dry mouth and drowsiness. Rare allergic reactions, such as rash and urticaria (itching, burning, stinging), have also been reported.
• Extrapyramidal reactions, (loss of motor control), occur rarely in young children, very rarely in adults and usually resolve completely and spontaneously after cessation of treatment.