As a result of the aforementioned procedure, Marketing Authorisation Holders (MAHs) in the EU for domperidone products have made a commitment to enhanced surveillance, by rigorous follow up of all reports of suspected adverse drug reactions (ADRs) involving domperidone. If you wish to report a suspected ADR concerning any type of cardiac effect, or any other kind of adverse effect, with Wockhardt UK Limited’s Domperidone 10mg Film-Coated Tablets, please complete the questionnaire entitled: ‘Domperidone (Cardiac Effects) Adverse Drug Reaction Follow Up Form For Healthcare Professionals' and return to the Drug Safety and Information Department by email (email@example.com) or fax (+44 1978 669 430).
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
Adults and adolescents (over 12 years and weighing 35kg or more)One 10mg tablet up to three times a day with a maximum dose of 30mg per day.
Neonates, infants, children (less than 12 years of age) and adolescents weighing less than 35 kgDue to the need for accurate dosing, tablets, effervescent granules and suppositories are unsuitable for use in children and adolescents weighing less than 35 kg.
Hepatic ImpairmentDomperidone is contraindicated in moderate or severe hepatic impairment (see section 4.3). Dose modification in mild hepatic impairment is however not needed (see section 5.2).
Renal ImpairmentSince the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced.
Use in infantsAlthough neurological side effects are rare (see section 4.8), the risk of neurological side effects is higher in young children since metabolic functions and the blood-brain barrier are not fully developed in the first months of life.Overdosing may cause extrapyramidal symptoms in children, but other causes should be taken into consideration.
Renal impairmentThe elimination half-life of domperidone is prolonged in severe renal impairment. For repeated administration, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of the impairment., The dose may also need to be reduced. Such patients on prolonged therapy should be reviewed regularly.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 (see section 4.8).Epidemiological studies showed that domperidone was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8). 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 children.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 (see section 4.3.). 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.
Concomitant use of the following substances is contraindicatedQTc-prolonging medicinal products • anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)• anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)• certain antipsychotics (e.g., haloperidol, pimozide, sertindole)• certain antidepressants (e.g., citalopram, escitalopram)• certain antibiotics (e.g., erythromycin, levofloxacin, moxifloxacin, spiramycin)• certain antifungal agents (e.g., pentamidine) • certain antimalarial agents (in particular halofantrine, lumefantrine) • certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)• certain antihistaminics (e.g., mequitazine, mizolastine)• certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)• certain other medicines (e.g., bepridil, diphemanil, methadone) (see section 4.3). Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e : protease inhibitors • systemic azole antifungals• some macrolides (erythromycin, clarithromycin and telithromycin)(see section 4.3).
Concomitant use of the following substances is not recommendedModerate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides. (see section 4.3)
Concomitant use of the following substances requires caution in useCaution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation: azithromycin and roxithromycin (clarithromycin is contra-indicated as it is a potent CYP3A4 inhibitor). The above list of substances is representative and not exhaustive.Opioids may antagonise the effects of domperidone on gastric emptying.
PregnancyThere are limited post-marketing data on the use of domperidone in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose. The potential risk for humans is unknown. Therefore, domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit.
Breast-feedingDomperidone 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.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
DistributionOral 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.
MetabolismDomperidone 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.
ExcretionUrinary 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.
Hepatic impairmentIn subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and Cmax of domperidone is 2.9- and 1.5- fold higher, respectively, than in healthy subjects. The unbound fraction is increased by 25 %, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on Cmax and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied. Domperidone is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).
Renal impairmentIn subjects with severe renal insufficiency (creatinine clearance<30 ml/min/1.73m2) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours, but plasma drug levels were lower than in healthy volunteers. Since very little unchanged drug (approximately 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency. However, on repeated administration, the dosing frequency should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced.
Tablet coatingTitanium dioxide (E171) Hypromellose Macrogol
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Changes to indications, contraindications and dosage
In May 2014, the MHRA issued the following information:
Domperidone (Motilium) is associated with a small increased risk of serious cardiac side effects. Its use is now restricted to the relief of nausea and vomiting and the dosage and duration of use have been reduced. It should no longer be used for the treatment of bloating and heartburn. Domperidone is now contraindicated in those with underlying cardiac conditions and other risk factors (see below). Patients with these conditions and patients receiving long-term treatment with domperidone should be reassessed at a routine appointment, in light of the new advice
Further information is available on the MHRA website .
An Information sheet for patients has also been issued.
Educational Risk Minimisation Materials to help reduce the risk associated with using this medicine.
As a result of the aforementioned procedure, Marketing Authorisation Holders (MAHs) in the EU for domperidone products have made a commitment to enhanced surveillance, by rigorous follow up of all reports of suspected adverse drug reactions (ADRs) involving domperidone. Patients must consult their doctor straight away if they suspect they have experienced an ADR whilst taking domperidone. If you wish to report a suspected ADR concerning any type of cardiac effect, or any other kind of adverse effect, with Wockhardt UK Limited’s Domperidone 10mg Film-Coated Tablets, please complete the questionnaire entitled: ‘Domperidone (Heart Associated Effects) Follow up Form For Non-Healthcare Professionals' and return to the Drug Safety and Information Department by email (firstname.lastname@example.org) or fax (+44 1978 669 430).
Risk Minimisation Measures (RMMs) have been implemented for domperidone-containing products licensed in the European Union (EU), following the outcome of a review under Article 31 of Directive 2001/83/EC, of serious effects on the heart with domperidone, including prolongation of the QT interval (an alteration of the electrical activity of the heart) and arrhythmias (unstable heartbeats). Further details of the outcome of this procedure can be found at the following link:
Wockhardt UK Ltd
Ash Road North, Wrexham Industrial Estate, Wrexham, LL13 9UF
+44 (0)1978 660 130
+44 (0)1978 661 261