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 10 mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Domperidone 10 mg (as maleate).
For the full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Tablet
White, round, biconvex tablets with ‘BL’ on one side, ‘10’ on the reverse
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
Posology
Domperidone should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting.
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 (over 12 years and weighing 35 kg or more):
One 10 mg tablet up to three times per day with a maximum dose of 30 mg per day.
Neonates, Infants, children (less than 12 years of age) and adolescents weighing less than 35kg:
Due to the need for accurate dosing, the tablets are unsuitable for use in children weighing less than 35 kg.
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.
Method of Administration
For oral use.
It is recommended to take Domperidone tablets before meals. If taken after meals, absorption of the drug is somewhat delayed.
4.3. Contraindications
Domperidone is contraindicated in the following situations:
- Hypersensitivity to domperidone or any of the excipients listed in section 6.1 .
- In patients with moderate or severe hepatic impairment (see section 5.2).
- 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 (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)
- Prolactin-releasing pituitary tumour (prolactinoma).
Domperidone should not be used when stimulation of the gastric motility could be harmful i.e.
gastro-intestinal haemorrhage, mechanical obstruction or perforation.
4.4. Special warnings and precautions for use
Precautions for use
Domperidone tablets contain lactose. Patients with lactose intolerance, galactosaemia or glucose/galactose malabsorption should not take this medicine.
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 may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8.) The risk may be higher 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.
Renal impairment
The elimination half-life of domperidone is prolonged in severe renal impairment.For repeated administration, the dosing frequency should be reduced to once or twice daily depending on the severity of impairment, and the dose may need to be reduced.
4.5. Interactions 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 gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride) o certain antihistaminics (e.g., mequitazine, mizolastine) certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine) o 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 contra-indicated 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 ketaconazole 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 9.8 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 (200 mg twice daily) and erythromycin monotherapy (500 mg three times daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.
4.6. Fertility, Pregnancy and lactation
There 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 (see section 5.3). Therefore, domperidone should only be used in pregnancy when justified by the anticipated therapeutic benefit.
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 6 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
Domepridone has no or negligible influence on the ability to drive and use machines.
4.8. 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 (frequency cannot be estimated from the available data)
Immune System Disorders: Very rare: Allergic reactions including anaphylaxis, anaphylactic shock, anaphylactic reaction and angioedema.
Endocrine disorders: Rare: increased prolactin levels.
Psychiatric disorders: Very rare: agitation, nervousness.
Nervous system disorders: Very rare: extrapyramidal side effects, convulsion, somnolence, headache.
Cardiac disorders: Unknown: Ventricular arrhythmias, QTc prolongation, Torsade de Pointes and sudden cardiac death (See section 4.4)
Gastrointestinal disorders: Rare: gastro-intestinal disorders, including very rare transient intestinal cramps; very rare: diarrhoea.
Skin and subcutaneous tissue disorders: Very rare: urticaria, pruritus, rash.
Reproductive system and breast disorders: Rare: galactorrhoea, gynaecomastia, amenorrhea.
Investigations: Very rare: liver function test abnormal.
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 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 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: www.mhra.gov.uk/yellowcard.
4.9. Overdose Symptoms
Overdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsion, disorientation, somnolence and extrapyramidal reactions.
T reatment
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.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
ATC Code: AO3F A03 Pharmacotherapeutic Group: Propulsives
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.
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 80 mg per day 10 or 20 mg 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 3.4 msec for 20 mg domperidone administered 4 times a day on Day 4. The 2-sided 90 % CI (1.0 to 5.9 msec) did not exceed 10 msec. No clinically relevant QTc effects were observed in this study when domperidone was administered at up to 80 mg/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 (10 mg 4 times a day).The largest time-matched mean difference of QTcF between domperidone and placebo was 5.4 msec (95 % CI: -1.7 to 12.4) and 7.5 msec (95 % CI: 0.6 to 14.4), respectively.
5.2. Pharmacokinetic properties Absorption
Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 60 minutes 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.
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.
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<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.
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 concentraion. 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.
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 - 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 10 mg 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 (10 mg administered 3 times a day) by 45-fold. Safety margins in in vitro proarrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10 mg 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 sensitized for torsade de pointes exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by more than 22-fold 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 45.4 ng/mL, which are 3-fold higher than the total plasma levels at in humans at maximum daily dose (10 mg 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 Microcrystalline Cellulose
Colloidal Anhydrous Silica Magnesium Stearate
6.2. Incompatibilities
Not applicable
6.3. Shelf life
36 months
6.4. Special precautions for storage
No special precautions.
6.5. Nature and contents of container
Al/PVC blister, pack sizes of 10, 20, 30, 50 or 100 tablets. Not all packs sizes may be marketed
6.6. Instruction for use and handling
Not applicable.
7. MARKETING AUTHORISATION HOLDER
Bristol Laboratories Limited Unit 3, Canalside Northbridge Road Berkhamsted
Hertfordshire HP4 1EG United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 17907/0096
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
24th May 2005
10 DATE OF REVISION OF THE TEXT
19/11/2014