Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the level of prolactin in the human body.
may include headache, anxiety, dry mouth, , diarrhea, and elevated prolactin levels.
Domperidone was discovered in 1974 and was introduced for medical use in 1979.
Medical uses
Nausea and vomiting
There is some evidence that domperidone has
antiemetic activity.
It is recommended by the Canadian Headache Society for treatment of nausea associated with acute
migraine.
Gastroparesis
Gastroparesis is a medical condition characterised by delayed emptying of the stomach when there is
no mechanical gastric outlet obstruction. Its cause is most commonly
idiopathic, a
diabetes complication or a result of abdominal surgery. The condition causes nausea, vomiting,
postprandial, early satiety (feeling full before the meal is finished), abdominal pain, and bloating. Domperidone can be used to increase the transit of food through the stomach by increasing
gastrointestinal peristalsis and hence to treat gastroparesis.
It may be useful in idiopathic and diabetic gastroparesis.
However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate well with relief of symptoms.
Lactation
Domperidone is used
Off-label use in some countries to stimulate
lactation or enhance breast milk production, but, as of December 2023, it is not approved for that purpose in any country, and is not approved for use in humans in the United States.
[ ] Domperidone acts as a peripheral
dopamine antagonist and is hypothesized to stimulate
prolactin secretion, with a 2003 study supporting that hypothesis.
A 2018 meta-analysis of five randomized controlled trials found that domperidone resulted in a moderate increase of in breast milk volume for mothers of preterm infants with insufficient milk supply. The analysis also indicated that domperidone was well tolerated with no significant difference in maternal adverse events compared to placebo.
A 2021 case study showed that domperidone can be used to induce lactation in trans women wishing to breastfeed their children.
The US Food and Drug Administration (FDA) has expressed concerns about serious adverse side effects and concerns about its effectiveness.
A review by Health Canada also found a link between the sudden discontinuation or tapering of domperidone when used off-label for lactation, and psychiatric withdrawal events, particularly daily doses greater than the maximum recommended dose of 30 mg per day.
Other uses
Parkinson's disease
Parkinson's disease is a degenerative neurological condition where a decrease in
dopamine in the
brain leads to
muscle rigidity (stiffness of movement),
tremor, and other symptoms and signs. Poor
gastrointestinal function,
nausea, and
vomiting are major problems for people with Parkinson's disease because most medications used to treat Parkinson's disease are given by mouth. These
, such as
levodopa, can also cause nausea as a
side effect. Furthermore,
antiemetic, such as
metoclopramide, which do cross the blood–brain barrier, may worsen the extrapyramidal symptoms of Parkinson's disease. Domperidone can be used to relieve nausea and gastrointestinal symptoms in Parkinson's disease; it blocks peripheral D
2 receptors but minimally crosses the blood-brain barrier in normal doses, so has no effect on the extrapyramidal symptoms of the disease.
In addition, domperidone may be useful in the treatment of orthostatic hypotension caused by
dopaminergic therapy in people with Parkinson's disease.
Other gastrointestinal uses
Domperidone may be used in functional dyspepsia in both adults and children.
It has also been found effective in the treatment of reflux in children.
[ (Google Books)] However some specialists consider its risks prohibitory of the treatment of infantile reflux.
Available forms
Domperidone is available for use by oral administration in the form of tablets, orally disintegrating tablets (ODTs) and suspension, and by rectal administration in the form of
suppository.
The oral tablets are available in the strength of 10mg.
Domperidone has been studied for use by intramuscular injection and an intravenous formulation was previously available, but the medication is now only available in forms for oral and rectal administration.
Veterinary uses
Domperidone is used as immunotherapy to treat
leishmania in dogs.
Domperidone also has an FDA-approved formulation for the prevention of fescue toxicosis in periparturient mares.
Contraindications
Domperidone is
contraindication with QT-prolonging drugs like
amiodarone.
[Swannick G. (ed.) "MIMS Australia." December 2013]
Side effects
Side effects associated with domperidone include
dry mouth,
,
diarrhea,
nausea,
rash,
pruritus,
urticaria, and hyperprolactinemia (the symptoms of which may include
mammoplasia,
galactorrhea,
mastodynia,
gynecomastia,
hypogonadism, and menstrual irregularities).
Due to the blockade of D2 receptors in the central nervous system, D2 receptor antagonists like metoclopramide and can also produce a variety of additional side effects including drowsiness, akathisia, restlessness, insomnia, lassitude, fatigue, extrapyramidal symptoms, dystonia, parkinsonism, tardive dyskinesia, and depression.
Elevated prolactin levels
Due to D
2 receptor blockade, domperidone causes hyperprolactinemia.
Hyperprolactinemia can suppress the secretion of gonadotropin-releasing hormone (GnRH) from the
hypothalamus, in turn suppressing the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and resulting in
hypogonadism and low levels of the
estradiol and
testosterone.
Accordingly, 10 to 15% of females have been reported to experience
mammoplasia (breast enlargement),
mastodynia (breast pain/tenderness),
galactorrhea (inappropriate or excessive milk production/secretion), and
amenorrhea (cessation of
) with domperidone therapy.
Males may experience low
libido, erectile dysfunction, and impaired
spermatogenesis, as well as
galactorrhea and
gynecomastia.
D
2 receptor antagonists like
and domperidone may also increase the risk of
, but more research is needed to confirm this.
Rare reactions
Cardiac complications
Domperidone use is associated with an increased risk of sudden cardiac death (by 70%)
most likely through its prolonging effect of the cardiac
QT interval and ventricular arrhythmias.
The cause is thought to be
channel blocker of
hERG voltage-gated potassium channels.
The risks are dose-dependent, and appear to be greatest with high/very high doses via intravenous administration and in the elderly, as well as with drugs that interact with domperidone and increase its circulating concentrations (namely CYP3A4 inhibitors).
Conflicting reports exist, however.
In neonates and infants, QT prolongation is controversial and uncertain.
UK drug regulatory authorities (MHRA) have issued the following restriction on domperidone in 2014 due to increased risk of adverse cardiac effects:
However, a 2015 Australian review concluded the following:
Possible central toxicity in infants
In Britain, a legal case involved the death of two children of a mother whose three children had all had
hypernatraemia. She was charged with poisoning the children with salt. One of the children, who was born at 28 weeks gestation with
respiratory complications and had a
fundoplication for gastroesophageal reflux and failure to thrive was prescribed domperidone. An
advocate for the mother suggested the child may have had neuroleptic malignant syndrome as a side effect of domperidone due to the drug crossing the child's immature blood–brain barrier.
Interactions
In healthy volunteers, the CYP3A4
enzyme inhibitor ketoconazole increased the C
max and AUC concentrations of domperidone by 3- to 10-fold.
This was accompanied by a QT interval prolongation of about 10–20 milliseconds when domperidone 10 mg four times daily and ketoconazole 200 mg twice daily were administered, whereas domperidone by itself at the dosage assessed produced no such effect.
As such, domperidone with ketoconazole or other CYP3A4 inhibitors is a potentially dangerous combination.
Pharmacology
Pharmacodynamics
Domperidone is a peripherally selective
dopamine D
2 and D
3 receptor antagonist.
It has no clinically significant interaction with the D
1 receptor, unlike
metoclopramide.
The medication provides relief from nausea by blocking D
2 receptors in the chemoreceptor trigger zone and from gastrointestinal symptoms by blocking D
2 receptors in the gut.
It blocks D
2 receptors in the
of the anterior pituitary gland increasing release of
prolactin which in turn increases
lactation.
[Saeb-Parsy K. "Instant pharmacology." John Wiley & Sons, 1999 , 9780471976394 p216.] Domperidone may be more useful in some patients and cause harm in others by way of the
genotype of the person, such as polymorphisms in the drug transporter
gene ABCB1 (which encodes
P-glycoprotein), the voltage-gated potassium channel
KCNH2 gene (
hERG), and the α
1D-adrenergic receptor
ADRA1D gene.
Effects on prolactin levels
A single 20 mg oral dose of domperidone has been found to increase mean serum prolactin levels (measured 90 minutes post-administration) in non-lactating women from 8.1 ng/mL to 110.9 ng/mL (a 13.7-fold increase).
This was similar to the increase in prolactin levels produced by a single 20 mg oral dose of metoclopramide (7.4 ng/mL to 124.1 ng/mL; 16.7-fold increase).
After two weeks of repeated administration (30 mg/day in both cases), the increase in prolactin levels produced by domperidone was reduced (53.2 ng/mL; 6.6-fold above baseline), but the increase in prolactin levels produced by metoclopramide, conversely, was heightened (179.6 ng/mL; 24.3-fold above baseline).
This indicates that acute and continuous administration of both domperidone and metoclopramide is effective in increasing prolactin levels, but that there are different effects on the secretion of prolactin with repeated use.
The mechanism of the difference is unknown.
The increase in prolactin levels observed with the two drugs was much greater in women than in men.
This appears to be due to the higher
estrogen levels in women, as estrogen stimulates prolactin secretion from the
pituitary gland.
For comparison, normal prolactin levels in women are less than 20 ng/mL, prolactin levels peak at 100 to 300 ng/mL at parturition in pregnancy women, and in lactating women, prolactin levels have been found to be 90 ng/mL at 10 days postpartum and 44 ng/mL at 180 days postpartum.
Pharmacokinetics
Absorption
The absolute bioavailability of domperidone is low (13–17% or approximately 15%).
This is due to extensive first-pass metabolism in the
and
liver.
Conversely, its bioavailability is high via intramuscular injection (90%).
The onset of action of domperidone taken orally is about 30 to 60 minutes.
Peak levels of domperidone following an oral dose occur after about 60 minutes.
Domperidone exposure increases proportionally with doses in the 10 to 20 mg dose range.
There is a 2- to 3-fold accumulation in levels of domperidone with frequent repeated oral administration of domperidone (four times per day (every 5 hours) for 4 days).
The oral
bioavailability of domperidone is somewhat increased, and time to peak slightly increased when it is taken with food and bioavailability is decreased by prior concomitant administration of
cimetidine and sodium bicarbonate.
Distribution
The plasma protein binding of domperidone is 91 to 93%.
The tissue distribution of domperidone based on animal studies is wide, but concentrations are low in the brain.
The drug is a substrate for the
P-glycoprotein (ABCB1) transporter, and animal studies suggest that this is the reason for the low central nervous system penetration of domperidone.
Small amounts of domperidone cross the
placenta in animals.
Metabolism
Domperidone is extensively
metabolism in the
liver and
with oral administration.
This occurs via
hydroxylation and
N-dealkylation.
Domperidone is almost exclusively metabolized by CYP3A4/5, though minor contributions by CYP1A2, CYP2D6, and CYP2C8 have been reported.
CYP3A4 is the major enzyme involved in the N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 are involved in its aromatic hydroxylation.
All of the
of domperidone are inactive as D
2 receptor ligands.
Overall and peak levels of domperidone are increased by about 2.9- and 1.5-fold in moderate hepatic impairment, respectively.
Elimination
Domperidone is eliminated 31% in urine and 66% in feces.
The proportion of domperidone excreted unchanged is small (10% in feces and 1% in urine).
The elimination half-life of domperidone is about 7 to 9 hours in healthy individuals.
However, the elimination half-life of domperidone can be prolonged to 20 hours in people with severe renal dysfunction.
Chemistry
Domperidone is a derivative of benzimidazolinone. It is structurally related to
butyrophenone like
haloperidol.
History
Domperidone was synthesized at Janssen Pharmaceutica in 1974 following their research on
Antipsychotic.
Janssen pharmacologists discovered that some antipsychotic drugs had a significant effect on dopamine receptors in the central chemoreceptor trigger zone that regulated
vomiting, and started searching for a dopamine antagonist that would not pass the blood–brain barrier, thereby being free of the extrapyramidal side effects that were associated with drugs of this type.
This led to the discovery of domperidone as a strong antiemetic with minimal central effects.
Domperidone was
in the United States in 1978, with the patent filed in 1976. In 1979, domperidone was first marketed, under the brand name Motilium, in Switzerland and West Germany.
Domperidone was subsequently introduced in the forms of orally disintegrating tablets (based on
Zydis technology) in 1999.
In April 2014, the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) published an official press release suggesting restricting the use of domperidone-containing medicines. It also approved earlier published suggestions by Pharmacovigilance Risk Assessment Committee (PRAC) to use domperidone only for treating nausea and vomiting and reduce maximum daily dosage to 10mg.
Society and culture
Generic names
Domperidone is the
generic term of the drug and its , , , and .
Regulatory approval
It was reported in 2007 that domperidone is available in 58 countries,
but the uses or
indications of domperidone vary between nations. In Italy it is used in the treatment of gastroesophageal reflux disease and in Canada, the drug is indicated in upper gastrointestinal motility disorders and to prevent gastrointestinal symptoms associated with the use of dopamine agonist antiparkinsonian agents.
[ "Domperidone - heart rate and rhythm disorders." Canadian adverse reactions newsletter. Government of Canada. January 2007 17(1)] In the United Kingdom, domperidone is only indicated for the treatment of nausea and vomiting and the treatment duration is usually limited to 1 week.
In the United States, domperidone is not a legally marketed human drug and it is not approved for sale there.
It is available over-the-counter to treat gastroesophageal reflux disease and functional dyspepsia in many countries, such as Ireland, the Netherlands, Italy, South Africa, Mexico, India, Chile, and China.
Formulations
|
|
10 mg scored tablets |
From 2013 only by prescription in Belgium. |
| 10 mg scored tablets |
| 10 mg scored tablets |
| 10 mg scored tablets |
| - |
| Generic brands available |
| 10 mg tablets only with prescription generic domperidone available |
| 10 mg scored tablets |
| pantoprazole 40 mg and domperidone SR 30 mg |
| Rabeprazole 20 mg and Domperidone SR 30 mg |
| domperidone 5, 10 and 20 mg tablets. |
domperidone 1 mg/ml, 30 ml suspension. |
- |
| 10 mg domperidone and 40 mg pantoprazole |
| 10 mg Domperidone and 40 mg pantoprazole |
| Pantaprazole 40 mg and Domperione 30 mg |
| 10 mg caplet |
| 10 mg tablet |
| 10 mg tablet |
| 10 mg tablet |
| domperidone 5 mg/ml, 60 ml suspension |
| 10 mg tablet |
| 10 mg orally disintegrating tablet (ODT) |
| domperidone 10 mg tablets; 30 ml suspension |
| - |
| |
| domperidone 10 mg tablets; 30 ml suspension |
| domperidone 10 mg tablets |
| domperidone 10 mg tablets |
| - |
| - |
| domperidone 1 mg/mL oral suspension, 1 mg/mL oral drops |
| domperidone 10 mg fast-melting tablets |
| domperidone 1 mg/ml oral suspension (200 ml) |
| domperidone 10 mg film-coated tablets & ODT; 1 mg/ml suspension (100 ml) |
| domperidone 10 mg film-coated tablets & chewable tablets |
| domperidone/omeprazole (10 mg/10 mg) |
| Domperidone 10 mg tablets |
| Spain | Laboratorios Dr. Esteve, SA | Motilium | domperidone 1 mg/ml oral suspension (200 ml) |
| domperidone 10 mg ODT and peppermint |
| Domperidone 10 mg Tablets and 1 mg/ml Oral Suspension |
| - |
| - |
| - |
| - |
Research
Domperidone has been studied as a potential hormonal contraceptive to prevent
pregnancy in women.
