Motilium (Domperidone)

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Domperidon; Domperidona; Domperidonas; Domperidone; Domperidoni; Domperidonum; R-33812.

C₂₂H₂₄CIN₅0₂ = 425.9.

CAS — 57808-66-9.

ATC — A03FA03.

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Domperidone). A white or almost white powder. Practically insoluble in water slightly soluble in alcohol and in methyl alcohol soluble in dimethylformamide. Protect from light.

Domperidone Maleate

Drug Approvals

(British Approved Name Modified, rINNM)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Domperidone, maleate de; Domperidoni maleas; Domperidon-imaleaatti; Domperidonmaleat; Domperidon-maleat; Domperidon-maleinat; Domperidono maleatas; Maleato de domperidona.

C₂₂H₂₄CIN₅O₂C₄H₄O₄ = 542.0.

CAS — 99497-03-7.

ATC — A03FA03.

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Domperidone Maleate). A white or almost white powder it exhibits polymorphism. Very slightly soluble in water and in alcohol sparingly soluble in dimethylformamide slightly soluble in methyl alcohol. Protect from light.

Appearance

White tablet containing 10mg Domperidone

Why this Medication is Used

Domperidone is used to speed up the time it takes for food to move through your stomach and intestines after eating. It may also be used to prevent nausea and vomiting.

Adverse Effects

Plasma-prolactin concentrations may be increased, which may lead to galactorrhoea or gynaecomastia. There have been reports of reduced libido, and rashes and other allergic reactions. Domperidone does not readily cross the blood-brain barrier and the incidence of central effects such as extrapyramidal reactions or drowsiness may be lower than with metoclopramide however, there have been reports of dystonic reactions.

Domperidone by injection has been associated with convulsions, arrhythmias, and cardiac arrest. Fatalities have restricted use by this route.

Effects on the cardiovascular system

Sudden death has occurred in cancer patients given domperidone intravenously in high doses. Four cancer patients experienced cardiac arrest after high intravenous doses and 2 of 4 similar patients had ventricular arrhythmias. After such reports the injection has been withdrawn from general use in many countries, including the UK.

Prolongation of the QT interval has been reported in an infant given oral domperidone, with normalisation after the drug was stopped.

Effects on the endocrine system

There have been reports of galactorrhoea with gynaecomastia or mastalgia’ generally associated with raised serum-prolactin concentrations. Gynaecomastia without galactorrhoea has also been reported

Extrapyramidal effects

There are reports of extrapyramidal symptoms, including acute dystonic reactions and neuroleptic malignant syndrome in individual patients given domperidone.

Precautions

Domperidone is not recommended for chronic use or for the routine prophylaxis of postoperative nausea and vomiting. Domperidone should be used with great caution if given intravenously, because of the risk of arrhythmias, especially in patients predisposed to cardiac arrhythmias or hypokalaemia.

Breast feeding

No adverse effects have been seen in breastfed infants whose mothers were given domperidone, and the American Academy of Pediatrics considers that it is therefore usually compatible with breast feeding. However, the FDA in the USA has issued a warning against the use of domperidone to increase milk production because of the possibility of serious adverse effects. Others have commented that these warnings were based on data from patients with malignant disease receiving high doses of intravenous domperidone, and that if the mother were taking smaller oral doses, the total amount of drug ingested by an infant would be extremely small.

They recommend that low-dose domperidone should still be considered for lactating women with decreased milk supply who are unresponsive to non-pharmacological measures to enhance lactation. However, patients should be warned of the risk of arrhythmias at high doses, and women with known cardiac disease should not take domperidone.

Interactions

As with other dopamine antagonists (see Metoclopramide), there is a theoretical potential that domperidone may antagonise the hypoprolactinaemic effect of drugs such as bromocriptine. In addition, the prokinetic effects of domperidone may alter the absorption of some drugs. Opioid analgesics and antimuscarinics may antagonise the prokinetic effects of domperidone.

Domperidone is metabolised via the cytochrome P450 isoenzyme CYP3A4 use with ketoconazole has been reported to produce a threefold increase in plasma concentrations of domperidone, and an associated slight prolongation in QT interval. Similar increases in domperidone concentrations might theoretically be seen with other potent inhibitors of CYP3A4 such as erythromycin or ritonavir, and such combinations may be best avoided.

Pharmacokinetics

Although absorption is rapid, the systemic bioavaila-bility of domperidone is only about 15% in fasting subjects given an oral dose this is increased when domperidone is given after food. The low bioavailability is thought to be due to first-pass hepatic and intestinal metabolism. The bioavailability of rectal domperidone is similar to that after oral doses, although peak plasma concentrations are only about one-third that of an oral dose and are achieved after about an hour, compared with 30 minutes after an oral dose.

Domperidone is more than 90% bound to plasma proteins, and has a terminal elimination half-life of about 7.5 hours. It undergoes rapid and extensive hepatic metabolism. The main metabolic pathways are Afdealkylafion by cytochrome P450 isoenzyme CYP3A4, and aromatic hydroxylation by CYP3A4, CYP1A2, and CYP2E1. About 30% of an oral dose is excreted in urine within 24 hours, almost entirely as metabolites the remainder of a dose is excreted in faeces over several days, about 10% as unchanged drug. It does not readily cross the blood-brain barrier.

Small amounts of domperidone are distributed into breast milk concentrations are 10 to 50% of those in maternal serum.

Uses and Administration

Domperidone is a dopamine antagonist with actions and uses similar to those of metoclopramide. It is used as an antiemetic for the short-term treatment ofnausea and vomiting ofvarious aetiologies. It is not considered suitable for chronic nausea and vomiting, nor for the routine prophylaxis of postoperative vomiting.

Domperidone is also used for its prokinetic actions in dyspepsia and has been tried in diabetic gastroparesis (see Diabetic Complications). It has been given with paracetamol in the symptomatic treatment of migraine.

Domperidone is used as the maleate in tablet preparations and as the base in suppositories and the oral suspension doses are expressed in terms of the base. Domperidone maleate 12.73 mg is equivalent to about 10 mg of domperidone. Domperidone has been given parenterally, but this route has been associated with severe adverse effects (see above). For the treatment of nausea and vomiting domperidone may be given in oral doses of 10 to 20 mg three or four times daily up to a maximum daily dose of 80 mg or it may be given rectally in a dose of 60 mg twice daily. For doses in children see below.

For the symptomatic management of non-ulcer dyspepsia similar oral doses of 10 mg taken up to four times daily (the last dose to be taken at night) have been recommended if necessary, an increase in the dose to 20 mg may be prescribed. An initial course of treatment should not normally exceed 2 to 4 weeks. In migraine, a dose of 20 mg has been given orally up to every 4 hours, with paracetamol, as required, up to a maximum of 4 doses in 24 hours.

Administration in children

UK licensed product information states that children may be given domperidone in oral doses equivalent to 250 to 500 micrograms/kg three or four times daily a total daily dose of 2.4 mg/kg or 80 mg, whichever is less, should not be exceeded. Alternatively, children weighing more than 15 kg may be given a rectal dose of 30 mg twice daily. The BNFC gives similar doses, but specifies use in children over 2 years in those children over 35 kg, it allows an oral dose of 10 to 20 mg three or four times daily (maximum 80 mg daily) or a rectal dose of 60 mg twice daily.

Gastro-oesophageal reflux disease

A systematic review of the use of domperidone in infants and young children with gastro-oesophageal reflux, which identified 4 randomised controlled studies of such use, considered that there was very little evidence of its efficacy in reducing symptoms. Some suggest that it has been overused because of the lack of a suitable alternative after withdrawal of cisapride in many countries.

Parkinsonism

Domperidone is used to control gastrointestinal effects of dopaminergic drugs given in the management of parkinsonism. It may be of use in those patients who experience peripheral effects with levodopa despite the use of peripheral dopa-decarboxylase inhibitors and for patients using dopamine agonists such as bromocriptine or apomorphine since peripheral dopa-decarboxylase inhibitors are ineffective for preventing the peripheral effects of these drugs. Although domperidone does not readily cross the blood-brain barrier there have been isolated reports of extrapyramidal effects associated with its use (see above).

Consequently there has been concern over its potential to produce central effects and some consider that domperidone should only be used in patients with parkinsonism when safer antiemetic measures have failed. However, this view has been contested both by the manufacturers and other authors. In a subsequent review of the use of domperidone in Parkinson’s disease it was considered that domperidone might produce central blockade of the therapeutic effects of levodopa if given at a high oral dosage such as 120 mg daily for prolonged periods but also noted that such high doses were rarely required to control levodopa-induced vomiting.

Domperidone was found to significantly improve anorexia, nausea, vomiting, abdominal bloating, and regurgitation in patients taking levodopa. Dysphagia and constipation were unaffected these are thought to be more likely a reflection of the disease process. Doses ranged from 50 to 120 mg daily, with most patients responding to 80 mg daily. No central effects were noted.

Preparations

British Pharmacopoeia 2008: Domperidone Tablets.

Proprietary Preparations

Argentina: Ecuamon Euciton Moperidona Motilium Peridon

Australia:: Motilium

Austria: Motilium

Belgium: Docdomperi Domperitop Motilium Zilium

Brazil: Domperol Motilium Peridal

Canada: Motiliumf

Chile: Donegal Dosin Gasdol Idon Restol Siligaz

Czech Republic: Motilium

Denmark: Motilium

France: Biperidys Motilium Motilyo Peridys

Germany: Domidon Motilium

Greece: Giroton

Hong Kong: Costi Dompeon Doridone Motilium Qualidom Rabugen

Hungary: Motilium

India: Domperi Domperon Domstal Nautigo Stopvom Vomistop

Indonesia: Costil DOM Domedon Domet Dometa Dometic Gafflux Gerdilium Monell Motilium Novotil Regit Tilidon Vometa Vomidone Vomistop Vomitas Vosedon

Ireland: Domerid Motilium

Israel: Motilium

Italy: Digestivo Giuliani Fobidon Gastronorm Motilium Peridon Permod Permotil Riges Stalcare

Japan: Nauzelin

Malaysia: Domper Motilium Rabugen

Mexico: Biolix Emiken Motilium Seronex

The Netherlands: Gastrocure Motilium

New Zealand: Motilium

Philippines: Dompenyl Gilax Motilium

Portugal: Cinet Mogasinte Motilium Nausidone Nefius Nordonil Remotil

Russia: Motilak Motilium Motonium Passagix

South Africa: Motilium Vomiclon

Singapore: Dompel Dompenyl Domper Doridone Mirax Motilium

Spain: Motilium

Switzerland: Motilium

Thailand: Dany Dolium Domerdon Domidone Domper-M Domperdone Donum Mirax Mocydone Modomed Molax Moticon Motidom Motilium Movelium Ninlium Peptomet Peridom-M Pondperdone Rabugen-M

Turkey: Motilium

UK: Motilium Vivadone

Venezuela: Agilam Tilium Tonun.

Multi-ingredient

Argentina: Alplax Net Ansielix Digest Bigetric Bilagol Dom-Polienzim Euciton Complex Euciton Reflux Euciton Stress Faradil Novo Megalex Moperidona AF Moperidona Enzimatica Praxis Sidomal Tensium Gastric Tetralgin Novo Vegestabil Digest

Belgium: Touristil

Brazil: Lansodom

India: Aciloc RD Domcet Esoz-D Nogacid D Okacid D Okalan D Pantosec D Praize-D Vertigil

UK: Domperamol.