- 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 Fertility, 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 (12 years of age and older and weighing 35 kg or more)One 10mg tablet up to three times per day with maximum dose of 30 mg per day. Neonates, infants, children (less than 12 years of age) and adolescents weighing less than 35 kgDue to the need for accurate dosing, Domperidone tablets 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 tablets 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 (see sections 4.4 and 5.2)
Use in infantsNeurological side effects are rare (see "Undesirable effects" section). Since metabolic functions and the blood-brain barrier are not fully developed in the first months of life the risk of neurological side effects is higher in young children.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.Cardiovascular effectsDomperidone 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 patient 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 patient should consult their physician.Patient 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 recommended Moderate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides. (see section 4.3) Concomitant use of the following substances requires caution in use Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).The above list of substances is representative and not exhaustive.Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3A4 mediated first pass metabolism by these drugs.With the combination of oral domperidone 10mg four times daily and ketoconazole 200mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10mg four times daily and oral erythromycin 500mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while Ketoconazole monotherapy (200mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.
|System Organ Class||Adverse Drug Reaction Frequency|
|Psychiatric disorders||Loss of libido Anxiety|
|Nervous system disorders||Somnolence Headache|
|Gastrointestinal disorders||Dry mouth||Diarrhoea|
|Skin and subcutaneous tissue disorder||Rash Pruritus|
|Reproductive system and breast disorders||Galactorrhoea Breast pain Breast tenderness|
|General disorders and administration site conditions||Asthenia|
Post marketing experienceIn addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported.
Immune System Disorder:Not know: anaphylactic reactions including anaphylactic shock, angioedema, allergic reaction
Psychiatric System Disorder:Not known: agitation, nervousness
Nervous system disorders:Not known; extrapyramidal disorder, convulsions,
Eye disorders: Not known: Oculogyric crisis
Skin and subcutaneous tissue disorders:Not known: urticaria, angioedema
Reproductive system and breast disorders:Not known:, gynaecomastia, amenorrhoea.
Cardiac disorders:Not known; ventricular arrhythmias, QTc prolongation, Torsade de pointes, sudden cardiac death (See sections 4.4).
Investigations:Not known: liver function test abnormal, blood prolactin increasedAs the hypophysis is outside the blood brain barrier, domperidone may cause an increase in prolactin levels. In rare cases this hyperprolactinaemia may lead to neuro- endocrinological side effects such as galactorrhoea, gynaecomastia and amenorrhoea.Extrapyramidal side effects are very rare in neonates and infants, and exceptional in adults. These side effects reverse spontaneously and completely as soon as the treatment is stopped.Other central nervous system-related effects of convulsion, agitation and somnolence also are very rare and primarily reported in infants and children.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorization of 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.
SymptomsOverdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsions, disorientation, somnolence and extrapyramidal reactions.
TreatmentThere 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.
AbsorptionDomperidone is rapidly absorbed after oral administration with peak plasma concentrations occurring at approximately 1 hr 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 gastrointestinal 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.
DistributionOral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21ng/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 crossed 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 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 severity of the impairment, and the dose may need to be reduced.
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.
Aurobindo Pharma - Milpharm Ltd.
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