Motilium (Domperidone)

Motilium (Domperidone)

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Motilium (Domperidone)

MOTILIUM is an antiemetic and a prokinetic medicine. It works by blocking the action of a chemical messenger in the brain which causes the feeling of nausea and vomiting, as well as increasing the movement or contractions of the stomach and intestines, allowing food to move more easily through the stomach.

Therapeutic indications

  • Motilium is a medication that increases the movements or contractions of the stomach and intestine.
  • Domperidone is additionally used to treat nausea and emesis caused by other medicine.
  • Used to treat Parkinson’s Diseases such as levodopa, pramipexole, and apomorphine.
  • It is used in the management of Gastroesophageal reflux disease (GERD).
  • Epigastric Pain.
  • Dyspepsia
  • Heart Burn.

Mechanism of action

Domperidone is a dopamine antagonist with anti-emetic properties, Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially in adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.

Studies in man have shown oral domperidone to increase lower oesophaegeal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

Pharmacokinetic properties

Absorption

Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations occurring at approximately 1hr after dosing. The Cmax and AUC values of domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. A 2- to 3-fold accumulation of domperidone AUC was observed with repeated four times daily (every 5 hr) dosing of domperidone for 4 days.

The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone’s bioavailability is enhanced in normal subjects when taken after a meal, patients with gastro-intestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.

Distribution

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 is 91-93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug cross the placenta in rats.

Metabolism

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.

Excretion

Urinary and faecal excretions amount to 31 and 66% of the oral dose respectively. The proportion of the drug 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.

Posology and method of administration

Motilium should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting.

It is recommended to take oral Motilium before meals. If taken after meals, absorption of the drug is somewhat delayed.

Patients should try to take each dose at the scheduled time. If a scheduled dose is missed, the missed dose should be omitted and the usual dosing schedule resumed. The dose should not be doubled to make up for a missed dose.

Usually, the maximum treatment duration should not exceed one week.

Adults and adolescents (12 years of age and older and weighing 35 kg or more)

One 10mg tablet up to three times per day with a maximum dose of 30 mg per day.

Hepatic Impairment

Motilium is contraindicated in moderate or severe hepatic impairment. Dose modification in mild hepatic impairment is however not needed.

Renal Impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration, the dosing frequency of Motilium should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced. Such patients on prolonged therapy should be reviewed regularly

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Paediatric population

The efficacy of Motilium in children less than 12 years of age has not been established.

The efficacy of Motilium in adolescents 12 years of age and older and weighing less than 35 kg has not been established.

Contraindications

Motilium is contraindicated in the following situations:

  • Known hypersensitivity to domperidone or any of the excipients
  • Prolactin-releasing pituitary tumour (prolactinoma).
  • when stimulation of the gastric motility could be harmful e.g in patients with gastro-intestinal haemorrhage, mechanical obstruction or perforation.
  • in patients with moderate or severe hepatic impairment.
  • in patients who have known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure
  • co-administration with QT-prolonging drugs, at the exception of apomorphine
  • co-administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects)

Side effects

  • Abdominal cramps,
  • Dry mouth,
  • Diarrhea,
  • Nausea,
  • Rash,
  • Itching,
  • Hives,
  • Breast enlargement,
  • Galactorrhea,
  • Breast pain/tenderness,
  • Hypogonadism,
  • Gynecomastia, and
  • Menstrual irregularities)

Special warnings and precautions for use

Cardiovascular effects

Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking domperidone. These reports included patients with confounding risk factors, electrolyte abnormalities and concomitant treatment which may have been contributing factors.

Epidemiological studies showed that domperidone was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. A higher risk was observed in patients older than 60 years, patients taking daily doses greater than 30 mg, and patients concurrently taking QT-prolonging drugs or CYP3A4 inhibitors.

Domperidone should be used at the lowest effective dose in adults and adolescents 12 years of age and older.

Domperidone is contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with underlying cardiac diseases such as congestive heart failure due to increased risk of ventricular arrhythmia. Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) or bradycardia are known to be conditions increasing the proarrythmic risk.

Treatment with domperidone should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia, and the patients should consult their physician.

Patients should be advised to promptly report any cardiac symptoms.

Use with apomorphine

Domperidone is contra-indicated with QT prolonging drugs including apomorphine, unless the benefit of the co-administration with apomorphine outweighs the risks, and only if the recommended precautions for co-administration mentioned in the apomorphine SmPC are strictly fulfilled. Please refer to the apomorphine SmPC.

Renal impairment

The elimination half-life of domperidone is prolonged in severe renal impairment. For repeated administration, the dosing frequency of Motilium should be reduced to once or twice daily depending on the severity of the impairment. The dose may also need to be reduced.

Fertility, pregnancy and lactation

Pregnancy: There are limited post-marketing data on the use of domperidone in pregnant women. Studies in animals have shown reproductive toxicity at maternally toxic doses (see section 5.3). Motilium should only be used during pregnancy when justified by the anticipated therapeutic benefit.

Breast-feeding: Domperidone is excreted in human milk and breast-fed infants receive less than 0.1 % of the maternal weight-adjusted dose. Occurrence of adverse effects, in particular cardiac effects cannot be excluded after exposure via breast milk. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from domperidone therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Caution should be exercised in case of QTc prolongation risk factors in breast-fed infants.

Effects on ability to drive and use machines: Motilium has no or negligible influence on the ability to drive and use machines.

Overdose

Symptoms of over dosage may include agitation, altered consciousness, convulsions, disorientation, somnolence and extrapyramidal reactions.

There is no specific antidote to domperidone, but in the event of overdose, standard symptomatic treatment should be given immediately. Gastric lavage as well as the administration of activated charcoal, may be useful. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Close medical supervision and supportive therapy is recommended.

Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

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