Domperidone 10mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
▼ 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.
1 NAME OF THE MEDICINAL PRODUCT
Domperidone 10mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains an amount of domperidone maleate equivalent to 10mg Domperidone.
For excipients, see 6.1
3 PHARMACEUTICAL FORM
Tablet
White coloured, round, biconvex tablets.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Domperidone is indicated for the relief of the symptoms of nausea and vomiting.
4.2 Posology and method of administration
Domperidone 10mg Tablets are for oral administration.
Domperidone should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting.
It is recommended to take oral domperidone 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.
See section 4.4
Neonates, infants, children (less than 12 years of age) and adolescent weighing less than 35kg
Due to the need for accurate dosing, Domperidone tablets are unsuitable for use in children and adolescents weighing less than 35kg.
Adults and adolescents (12 years of age and older and weighing 35kg or more)
One 10mg tablet up to three times per day with a maximum dose of 30mg per day.
Hepatic impairment
Domperidone 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 impairment
Since 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.
4.3 Contraindications
Domperidone is contraindicated in the following situations:
• Hypersensitivity to domperidone or to any of the excipients
• Indications in which stimulation of gastric motility is dangerous e.g. gastrointestinal haemorrhage, mechanical obstruction or perforation
• Patients with prolactin releasing pituitary tumours (prolactinoma)
• Patients with moderate or severe hepatic impairment (see section 5.2).
• 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 (see section 4.4)
• Co-administration with QT-prolonging drugs (see section 4.5)
• Co-administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects) (see section 4.5)
4.4 Special warnings and precautions for use
Domperidone should only be taken according to the above posology (See section 4.2).
Patients who find that their nausea and vomiting persist for more than 48 hours should be referred to their doctor.
The patient should be advised that Domperidone is not recommended for the treatment of motion sickness.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or gluclose-galactose malabsorption should not take this medicine.
Renal impairment:
The 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 effects:
Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT prolongation and torsade 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 30mg, 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 patient 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 proarrhythmic 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.
4.5 Interaction with other medicinal products and other forms of interaction
The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.
Increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.
Concomitant use of the following substances is contraindicated
QTc-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 gastrointestinal medicines (e.g. cisapride, dolasetron, prucalopride)
• Certain antihistamines (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)
Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3 A4 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 9.8msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5msec. 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 9.9msec, with changes at individual time points ranging from 1.6 to 14.3msec. 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 1.6msec (ketoconazole study) and 2.5msec (erythromycin study), while ketoconazole monotherapy (200mg twice daily) and erythromycin monotherapy (500mg three times daily) led to increases in QTc of 3.8 and 4.9msec, respectively, over the observation period.
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.
Dopaminergics: There is an increased risk of extrapyramidal side-effects when domperidone is given with amantadine.
Analgesics: The effects of domperidone on gastrointestinal activity are antagonised by opioid analgesics.
Antimuscarinics: The effects of domperidone on gastrointestinal activity are antagonised by antimuscarinics.
Domperidone possibly antagonises hypoprolactinaemic effects of bromocriptine and cabergoline.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is insufficient data to judge the possible damage that domperidone may cause during pregnancy in humans. 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-feeding
Domperidone is excreted in human breast milk and breast-fed infants receive less than 0.1% of the maternal weigh-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.
4.7 Effects on ability to drive and use machines
There is no data available concerning the effect of this product on the ability to drive or operate machines. However such an effect is not likely.
4.8 Undesirable effects
At the dosages and duration recommended, domperidone is generally well tolerated with few undesirable effects.
The adverse drug reactions are ranked below by frequency, using the following convention:
Very common (>1/10);
Common (>1/100 to <1/10);
Uncommon (>1/1,000 to <1/100);
Rare (>1/10,000 to <1/1,000);
Very rare (<1/10,000);
Not known (cannot be estimated from the available data).
o Immune System disorders:
Very rare; anaphylactic reactions including anaphylactic shock, anaphylaxis, angioedema, allergic reaction
o Psychiatric disorders:
Uncommon; loss of libido, anxiety Very rare; agitation, nervousness
o Nervous system disorders:
Uncommon; somnolence, headache
Very rare; extrapyramidal side effects, convulsions
o Eye disorders:
Not known; Oculogyric crisis
o Cardiac disorders:
Not known; QTc prolongation, torsades de pointes, ventricular arrhythmias, sudden cardiac death (See section 4.4)
o Gastrointestinal disorders:
Common; dry mouth Uncommon; diarrhoea
Rare; gastro-intestinal disturbances, including very rare transient intestinal cramps
o Skin and subcutaneous tissue disorders:
Uncommon; rash, pruritus Very rare; urticaria
o Renal and urinary disorders:
Not known; Urinary retention
o Reproductive system and breast disorders:
Uncommon; galactorrhoea, breast pain, breast tenderness Rare; gynaecomastia, amenorrhoea
o General disorders and administration site conditions:
Uncommon; Asthenia
o Investigations:
Very rare; liver function test abnormal, blood prolactin increased
As the hypophysis is outside the blood brain barrier, domperidone may cause an increase in prolactin levels. In rare cases this hyperprolactinaemia may lead to neuroendocrinological 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 convulsions, agitation and somnolence also are very rare and primarily reported in infants and children.
Reporting of suspected adverse reactions
Reporting 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:
4.9 Overdose
Symptoms: Overdose has been reported primarily in infants and children. Symptoms of overdose may include; disorientation, agitation, altered consciousness, convulsions, somnolence and extrapyramidal reactions.
Treatment: There is no specific antidote to domperidone, but in the event of an overdose, standard symptomatic treatment should be given immediately. Gastric lavage and the administration of active 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 or antihistamines with anticholinergic properties, may be used as antidote to the extrapyramidal reactions.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Propulsives, ATC code: A03F A03
Domperidone is a dopamine antagonist with anti-emetic properties. Domperidone crosses only slightly the blood brain barrier, which is why extrapyramidal effects occur only rarely in patients who take these tablets. Since the pituitary body lies outside the blood brain barrier, domperidone releases prolactin from it. The anti-emetic action of domperidone may be due to the combination of peripheral gastrokinetic effects and antagonism of the dopamine receptors at 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 oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.
In accordance with ICH-E14 guidelines, a thorough QT study was performed. This study included a placebo, an active comparator and a positive control and was conducted in healthy subjects with up to 80mg per day 10 or 20mg administered 4 times a day of domperidone. This study found a maximal difference of QTc between domperidone and placebo in LS-means in the change from baseline_of 3.4msec for 20mg domperidone administered 4 times a day on Day 4. The 2-sided 90% CI (1.0 to 5.9msec) did not exceed 10msec. No clinically relevant QTc effects were observed in this study when domperidone was administered at up to 80mg/day (i.e., more than twice the maximum recommended dosing).
However, two previous drug-drug interaction studies showed some evidence of QTc prolongation when domperidone was administered as monotherapy (10mg 4 times a day). The largest time-matched mean difference of QTc between domperidone and placebo was 5.4msec (95% CI: -1.7 to 12.4) and 7.5msec (95% CI: 0.6 to 14.4), respectively.
5.2 Pharmacokinetic properties
Absorption
Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations occurring at approximately 1 hour after dosing. The Cmax and
AUC values of domperidone increased proportionally with dose in the 10mg to 20mg 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 biological availability of orally administered domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and the liver.
Although the bioavailability of domperidone is enhanced in normal subjects when taken after a meal, it is advised that patients with gastrointestinal complaints should take these tablets 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. The oral bioavailability is decreased by prior concomitant administration of cimetidine or sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when domperidone is taken after a meal.
Distribution
Orally taken domperidone does not accumulate or induce its own metabolism; a peak plasma level after the first dose of 30mg per day of 18ng/ml in comparison to 21ng/ml after two weeks oral therapy of 30mg per day. The plasma protein binding of domperidone is 91-93%.
Distribution studies in animals with radiolabelled domperidone have shown wide tissue distribution, but low brain concentration. Small amounts of domperidone 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 orally administered dose respectively. The proportion of domperidone 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. However this half-life is prolonged in patients with severe renal insufficiency.
Hepatic impairment
In 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 impairment
In subjects with severe renal insufficiency (creatinine clearance <30ml/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.
5.3 Preclinical safety data
Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of domperidone to prolong the QTc interval in humans. In in vitro experiments on isolated cells transfected with hERG and on isolated guinea pig myocytes, exposure ratios ranged between 26- and 47-fold, based on IC50 values inhibiting currents through IKr ion channels in comparison to the free plasma concentrations in humans after administration of the maximum daily dose of 10mg administered 3 times a day.
Safety margins for prolongation of action potential duration in in vitro experiments on isolated cardiac tissues exceeded the free plasma concentrations in humans at maximum daily dose (10mg administered 3 times a day) by 45-fold.
However, safety margins in in vitro pro-arrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10mg administered 3 times a day) by 9- up to 45-fold. In in vivo models the no effect levels for QTc prolongation in dogs and induction of arrhythmias in a rabbit model sensitised for torsades de pointes exceeded the free plasma concentrations in humans at maximum daily dose (10mg administered 3 times a day) by more than 22fold and 435-fold, respectively. In the anesthetized guinea pig model following slow intravenous infusions, there were no effects on QTc at total plasma concentrations of 45.4ng/mL which are 3-fold higher than the total plasma level in humans at maximum daily dose (10mg administered 3 times a day). The relevance of the latter study for humans following exposure to orally administered domperidone is uncertain.
In the presence of inhibition of the metabolism via CYP3A4 free plasma concentrations of domperidone can rise up to 3-fold.
At a high maternally toxic dose (more than 40 times the recommended human dose) teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Maize starch
Povidone
Sodium laurilsulfate Micro-crystalline cellulose Colloidal anhydrous silica Magnesium stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
36 months
6.4 Special precautions for storage
Store the tablets in the original package.
Keep out of the reach and sight of children.
6.5 Nature and contents of container
PVC/AL blister; 10 tablets per blister.
Pack sizes of 10, 30 and 100 tablets.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Athlone Pharmaceuticals Limited,
Ballymurray,
County Roscommon,
Ireland
8 MARKETING AUTHORISATION NUMBER(S)
PL 30464/0093
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11/11/2004
10 DATE OF REVISION OF THE TEXT
23/10/2014