Instructions Motilium film-coated tablets 10 mg blister No. 10
Composition
active ingredient: domperidone;
1 tablet contains domperidone 10 mg;
Excipients: tablet core: lactose monohydrate; corn starch; microcrystalline cellulose; pregelatinized potato starch; povidone; magnesium stearate; hydrogenated cottonseed oil; sodium lauryl sulfate;
film coating: hypromellose, sodium lauryl sulfate.
Dosage form
Film-coated tablets.
Main physicochemical properties: round biconvex tablets, film-coated, white or slightly cream-colored, with the inscription "JANSSEN" on one side and "M 10" on the other.
Pharmacotherapeutic group
Drugs used in functional disorders of the gastrointestinal tract. Peristalsis stimulants. ATX code A03F A03.
Pharmacological properties
Pharmacodynamics
Domperidone is a dopamine antagonist with antiemetic properties. Domperidone crosses the blood-brain barrier to a limited extent. Extrapyramidal side effects are very rare with domperidone, especially in adults, but domperidone stimulates the release of prolactin from the pituitary gland. Its antiemetic effect is probably due to a combination of peripheral (gastrokinetic) action and antagonism of dopamine receptors in the chemoreceptor trigger zone, which is located outside the blood-brain barrier in the area postrema. Animal studies, as well as low concentrations determined in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.
Studies have shown that in humans, when administered orally, domperidone increases lower esophageal pressure, improves antroduodenal motility, and accelerates gastric emptying. Domperidone does not affect gastric secretion.
Effects on QT/QTc interval and cardiac electrophysiology
In accordance with the international ICH-E14 guidelines, a thorough QT interval study was conducted in healthy subjects. This study was double-blind, placebo-controlled, and was conducted using recommended and supratherapeutic doses (10 and 20 mg 4 times a day). With simultaneous administration of 20 mg of domperidone 4 times a day, a prolongation of the QT interval by 3.4–5.9 ms was observed throughout the entire observation period and this indicator did not exceed 10 ms. The QT prolongation observed in this study when using domperidone according to the recommended dosage is not clinically significant.
This lack of clinical relevance is supported by pharmacokinetic and QTc data from two older studies involving 5-day dosing of 20 mg and 40 mg domperidone 4 times daily. ECGs were recorded pre-study, on day 5, 1 hour (approximately tmax) after the morning dose, and 3 days later. In both studies, no difference was observed between QTc after active treatment and placebo. It was therefore concluded that domperidone 80 and 160 mg daily had no clinically significant effect on QTc in healthy volunteers.
Pharmacokinetics
Absorption
Domperidone is rapidly absorbed after oral administration in the fasted state, with peak plasma concentrations occurring approximately 60 minutes later. Domperidone Cmax and AUC increased dose-proportionally over the 10 to 20 mg dose range. A 2- to 3-fold accumulation of domperidone (AUC) was observed with repeated administration four times daily (every 5 hours) for 4 days. The low absolute bioavailability of oral domperidone (approximately 15%) is due to extensive first-pass metabolism in the intestinal wall and liver. Although in healthy subjects the bioavailability of domperidone is increased when administered after a meal, patients with gastrointestinal complaints should take domperidone 15 to 30 minutes before a meal. Reduced gastric acidity reduces the absorption of domperidone. Oral bioavailability is reduced by concomitant administration of cimetidine and sodium bicarbonate. When the drug is taken orally after a meal, maximum absorption is slightly delayed and AUC is slightly increased.
Distribution
Domperidone does not accumulate or induce its own metabolism when administered orally; peak plasma levels 90 minutes after 2 weeks of oral administration of 30 mg/day were similar to those after the first dose (18 ng/ml). Domperidone is 91–93% bound to plasma proteins. Animal distribution studies using radiolabelled domperidone showed extensive tissue distribution but low brain concentrations. In animals, small amounts of the drug cross the placenta.
Metabolism
Domperidone is rapidly and extensively metabolized in the liver by hydroxylation and N-dealkylation. In vitro metabolism studies with diagnostic inhibitors have shown that CYP3A4 is the major cytochrome P450 involved in the N-dealkylation of domperidone, while CYP3A4, CYP1A2 and CYP2E1 are involved in the aromatic hydroxylation of domperidone.
Breeding
1% in urine). The plasma elimination half-life after a single dose is 7–9 hours in healthy volunteers, but is prolonged in patients with severe renal insufficiency.
Special patient groups
Liver dysfunction
In patients with moderate hepatic impairment (Pugh score 7-9, Child-Pugh class B), the AUC and Cmax of domperidone were 2.9 and 1.5 times higher, respectively, than in healthy volunteers. The free fraction was increased by 25% and the terminal half-life was prolonged from 15 to 23 hours. In patients with mild hepatic impairment, slightly lower exposure was observed than in healthy volunteers, based on Cmax and AUC, without changes in protein binding and terminal half-life. The use of the drug in patients with severe hepatic impairment has not been studied. Motilium® is contraindicated in patients with moderate or severe hepatic impairment (see section "Contraindications").
Kidney dysfunction
In patients with severe renal impairment (serum creatinine < 30 ml/min/1.73 m2), the half-life of domperidone is prolonged from 7.4 to 20.8 hours, but plasma concentrations are lower than in patients with normal renal function. Since only a very small amount of the drug (approximately 1%) is excreted unchanged by the kidneys, it is unlikely that a dose adjustment will be required in patients with renal insufficiency after a single dose. However, with repeated administration, the frequency of administration should be reduced to 1-2 times a day, depending on the severity of the impairment, and the dose may also need to be reduced.
Indication
To relieve symptoms of nausea and vomiting.
Contraindication
Motilium® is contraindicated:
patients with established hypersensitivity to the active or auxiliary substances of the drug; patients with a prolactin-secreting pituitary tumor (prolactinoma);
patients with severe or moderate liver and/or kidney dysfunction (see sections "Special instructions for use", "Pharmacological properties");
patients with known prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte imbalances or underlying heart disease such as congestive heart failure (see section "Special warnings and precautions for use");
patients with hepatic insufficiency; if stimulation of gastric motility may be dangerous, for example, in gastrointestinal bleeding, mechanical obstruction or perforation; with simultaneous use of ketoconazole, erythromycin or other potent CYP3A4 inhibitors;
with simultaneous use of drugs that prolong the QT interval (except apomorphine), such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin (see sections "Special instructions" and "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions
Anticholinergic drugs may neutralize the antidyspeptic effect of Motilium®. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation is increased.
Antacids and antisecretory drugs should not be taken simultaneously with Motilium®, as they reduce its bioavailability after oral administration (see section "Special instructions").
Domperidone is metabolized primarily by CYP3A4. In vitro studies have shown that concomitant use of drugs that significantly inhibit this enzyme may lead to increased plasma levels of domperidone.
Clinically significant changes in the QT interval have been observed when domperidone was used concomitantly with potent CYP3A4 inhibitors that can prolong the QT interval. Therefore, the concomitant use of domperidone with certain drugs is contraindicated (see section "Contraindications").
Concomitant use with levodopa: Although dose adjustment of levodopa is not considered necessary, an increase in plasma concentrations of domperidone (maximum 30-40%) has been observed when co-administered with levodopa.
Concomitant use of the following drugs with domperidone is contraindicated.
All drugs that prolong the QT interval (risk of torsade de pointes):
apomorphine, except in cases where the benefits of concomitant use outweigh the risks, and subject to strict adherence to the precautions recommended for concomitant use (see the instructions for medical use of apomorphine, section "Contraindications").
Examples of strong CYP3A4 inhibitors with which Motilium® is contraindicated:
azole antifungals such as fluconazole*, itraconazole, ketoconazole*, posaconazole and voriconazole*; macrolide antibiotics such as clarithromycin* and erythromycin*; protease inhibitors* (e.g. ritonavir, saquinavir, telaprevir); HIV protease inhibitors such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and saquinavir; calcium antagonists such as diltiazem and verapamil; amiodarone*; amrepitant; nefazodone; telithromycin*.
*prolong the QTc interval.
The simultaneous use of the following substances requires caution.
Use with caution with drugs that cause bradycardia and hypokalemia, as well as with macrolides that can cause QT prolongation, such as azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).
Domperidone should be used with caution when used concomitantly with potent CYP3A4 inhibitors that have not been shown to prolong the QT interval, such as indinavir, and patients should be closely monitored for signs or symptoms of adverse reactions.
The above list is representative but not exhaustive.
Motilium® can be combined with:
neuroleptics, the effect of which it enhances; dopaminergic agonists (bromocriptine, L-dopa), the undesirable peripheral effects of which, such as indigestion, nausea, vomiting, it suppresses without neutralizing the basic properties.
In separate in vivo pharmacokinetic/pharmacodynamic interaction studies with concomitant oral administration of ketoconazole or erythromycin in healthy volunteers, it was confirmed that these drugs significantly inhibit the CYP3A4-mediated first-pass metabolism of domperidone. With concomitant administration of 10 mg domperidone orally 4 times a day and 200 mg ketoconazole orally 2 times a day, a prolongation of the QTc interval by an average of 9.8 msec was observed during the observation period; individual values ranged from 1.2 to 17.5 msec. With concomitant administration of 10 mg domperidone 4 times a day and 500 mg erythromycin orally 3 times a day, the QTc interval prolonged by an average of 9.9 msec during the observation period, the range of individual values was from 1.6 to 14.3 msec. The steady-state Cmax and AUC of domperidone increased approximately threefold in each of these interaction studies. The effect of increased plasma concentrations of domperidone on QTc prolongation is unknown. In these studies, domperidone monotherapy (10 mg orally 4 times a day) prolonged the QTc interval by an average of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole (200 mg twice a day) or erythromycin (500 mg three times a day) alone prolonged the QTc interval by 3.8 and 4.9 msec, respectively, during the observation period.
Theoretically, since Motilium® has a prokinetic effect on the stomach, this may affect the absorption of concomitant oral medications, in particular prolonged-release or enteric-coated formulations. However, in patients already stabilized on digoxin or paracetamol, concomitant use of domperidone did not affect the blood levels of these drugs.
Application features
Motilium® is not recommended for motion sickness.
Motilium® should be used with caution in elderly patients and in patients with existing heart disease or a history of heart disease.
Cardiovascular effects: Domperidone has been associated with QT prolongation on the ECG. Very rare cases of QT prolongation and ventricular flutter/fibrillation have been reported in post-marketing experience in patients taking domperidone. These reports included patients with other risk factors, electrolyte disturbances and concomitant medications that may have been contributing factors (see section 4.8).
A study was conducted in healthy subjects in accordance with ICH-E14 guidelines to investigate the QT interval. The QT prolongation observed in the study with domperidone at the recommended dosage regimen at the usual therapeutic doses (10 or 20 mg 4 times a day) is not clinically relevant.
Due to the increased risk of ventricular arrhythmias, Motilium® is contraindicated in patients with prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, and in patients with underlying cardiac disease such as congestive heart failure (see section "Contraindications"). Electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are known to be conditions that increase the proarrhythmic risk.
If signs or symptoms that may be associated with cardiac arrhythmia appear, Motilium® should be discontinued and the patient should consult a doctor immediately.
Caution: Domperidone should be used with caution in patients with mild hepatic and/or renal impairment.
Renal impairment. The elimination half-life of domperidone is prolonged in severe renal impairment. With prolonged use, the dosing frequency of domperidone should be reduced to once or twice daily, depending on the severity of the impairment. A dose reduction may also be required.
Antacids or antisecretory drugs should not be taken simultaneously with oral forms of Motilium®, as they reduce the oral bioavailability of domperidone (see section "Interaction with other medicinal products and other forms of interaction"). When used together, Motilium® should be taken before meals, and antacids or antisecretory drugs after meals.
Use with apomorphine. Domperidone is contraindicated for concomitant use with drugs that prolong the QT interval, including apomorphine, unless the benefit of concomitant use with apomorphine outweighs the risk, and only if the precautions given in the instructions for use of apomorphine are strictly followed.
Use with ketoconazole: In interaction studies with oral ketoconazole, prolongation of the QT interval was observed. Although the significance of this study is not clearly established, alternative treatment should be considered if antifungal therapy with ketoconazole is indicated (see section 4.5).
Excipients: Motilium® tablets contain lactose, so the drug should not be used in patients with lactose intolerance, galactosemia and glucose/galactose malabsorption.
The following information should be considered regarding the risk of cardiovascular complications associated with domperidone-containing medicinal products:
Some epidemiological studies have shown that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section "Adverse reactions").
The risk of serious ventricular arrhythmias or sudden cardiac death may be higher in patients over 60 years of age or at oral doses of the drug greater than 30 mg per day and in patients taking concomitant drugs that prolong the QT interval or CYP3A4 inhibitors. Therefore, Motilium® should be used with caution in elderly patients. Patients over 60 years of age should consult a doctor before taking Motilium®.
Domperidone should be prescribed to adults and children at the lowest effective dose.
The risk-benefit ratio of domperidone remains favorable.
Ability to influence reaction speed when driving vehicles or other mechanisms
Dizziness and drowsiness have been observed after the use of domperidone. Therefore, patients should be advised to refrain from driving, operating other machinery, or other activities that require concentration and coordination until they have established how Motilium® affects them.
Use during pregnancy or breastfeeding
Pregnancy
Data on post-marketing use of domperidone in pregnant women are limited. Therefore, Motilium® should be prescribed during pregnancy only if, in the opinion of the physician, the expected positive effect for the woman outweighs the potential risk to the fetus.
Breast-feeding
The amount of domperidone that can enter the infant through breast milk is extremely low. The maximum relative dose for infants (%) is estimated to be about 0.1% of the maternal dose adjusted for body weight. It is not known whether it is harmful to the infant, therefore mothers taking Motilium® should refrain from breastfeeding. A decision to discontinue breastfeeding or discontinue domperidone therapy should be made after assessing the benefit of breastfeeding for the child and the benefit of therapy for the mother. Caution should be exercised in the presence of risk factors for prolongation of the QTc interval in breastfed infants. After exposure through breast milk, adverse reactions, including cardiac effects, cannot be excluded.
Method of administration and doses
Motilium® should be used at the lowest effective dose for the shortest time necessary to relieve symptoms of nausea and vomiting.
Adults and children over 12 years of age with a body weight of at least 35 kg: 1 tablet (10 mg) 3 times a day.
The maximum daily dose is 3 tablets (30 mg per day).
It is recommended to take Motilium® before meals. Absorption of the drug is somewhat delayed if taken after meals. The patient should take the drug according to the recommended dosage regimen. If a dose is missed, the next dose should be taken according to the recommended regimen. Do not double the dose to make up for the missed one. The duration of treatment should not exceed 1 week.
Adults aged ˃ 60 years
Patients over 60 years of age should consult a doctor before taking the drug.
Since the half-life of domperidone is prolonged in severe renal impairment, the frequency of administration of Motilium® should be reduced to once or twice daily, depending on the severity of the impairment; a dose reduction may also be necessary. Patients with severe renal impairment should be monitored regularly (see section 5.2).
Liver dysfunction
Motilium® is contraindicated in patients with moderate (Child-Pugh score 7-9) or severe (Child-Pugh score >9) hepatic impairment (see Contraindications). No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh score 5-6) (see Pharmacological Properties).
Children
The drug should be used to treat children aged 12 years and older with a body weight of at least 35 kg.
Domperidone should be given to children at the lowest effective dose for the shortest period of time.
Overdose
Symptoms: Overdose has been reported mainly in infants and children. Symptoms of overdose may include agitation, impaired consciousness, convulsions, disorientation, drowsiness and extrapyramidal reactions.
Treatment. There is no specific antidote for domperidone, but in case of significant overdose, symptomatic treatment should be given immediately. Gastric lavage within 1 hour after ingestion and administration of activated charcoal are recommended, as well as close observation of the patient and supportive therapy. ECG monitoring should be performed due to the possibility of QT prolongation. Anticholinergic drugs, drugs for the treatment of Parkinson's disease may be effective in controlling extrapyramidal reactions.
Adverse reactions
The safety of Motilium® has been evaluated in clinical trials and during post-marketing use. Double-blind, placebo-controlled clinical trials included 1275 patients with dyspepsia, gastroesophageal reflux disease, irritable bowel syndrome, nausea and vomiting, or other related conditions. All patients were at least 15 years of age and received at least one dose of the drug. The mean total daily dose was 30 mg (range 10 to 80 mg), and the median duration of exposure was 28 days (range 1 to 28 days). Patients with diabetic gastroparesis or symptoms caused by chemotherapy or parkinsonism were not included in the studies.
Assessment of the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10000 to <1/1000); very rare (<1/10000). If it is not possible to determine the frequency based on clinical trial data, it is indicated as unknown.
Provided that the dosage and duration of treatment recommendations are followed, domperidone is usually well tolerated and adverse events occur infrequently.
Immune system disorders: frequency unknown - allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.
On the part of the endocrine system: rarely - increased prolactin levels.
Mental disorders: infrequently - decreased or absent libido, irritability, agitation, nervousness; very rarely - depression, anxiety.
Nervous system: infrequently - headache, drowsiness, dizziness, extrapyramidal disorders; very rarely - insomnia, thirst, lethargy, akathisia; frequency unknown - convulsions, restless legs syndrome (exacerbation of restless legs syndrome in patients with Parkinson's disease).
Cardiovascular system: very rarely - edema, palpitations, heart rate and rhythm disturbances, serious ventricular arrhythmias; frequency unknown - QT interval prolongation, ventricular arrhythmias such as "torsade de pointes", sudden cardiac death.
Gastrointestinal: often - dry mouth; infrequently - diarrhea; rarely - gastrointestinal disorders, including abdominal pain, regurgitation, change in appetite, nausea, heartburn, constipation; very rarely - short-term intestinal spasms.
Skin and subcutaneous tissue disorders: infrequently - rash, itching, urticaria; frequency unknown - angioedema.
Reproductive system and breast disorders: rare – breast enlargement, breast discharge, breast swelling, lactation disorder, irregular menstrual cycle; uncommon – galactorrhea, breast pain, breast tenderness; frequency unknown – gynecomastia, amenorrhea.
Musculoskeletal and connective tissue disorders: rarely – leg pain.
From the urinary system: very rarely - dysuria, frequent urination; frequency unknown - urinary retention.
General disorders: infrequently - asthenia.
On the part of the organs of vision: frequency unknown - oculogyric crises.
Other: conjunctivitis, stomatitis.
Changes in laboratory parameters: very rarely - increased levels of ALT, AST and cholesterol, frequency unknown - abnormal liver function tests, increased levels of prolactin in the blood.
Since the pituitary gland is located outside the blood-brain barrier, domperidone may cause an increase in prolactin levels. In rare cases, this hyperprolactinemia may lead to neuroendocrine side effects such as galactorrhea, gynecomastia, and amenorrhea.
During post-marketing use of the drug, no differences in the safety profile of the drug were noted between adults and children, with the exception of extrapyramidal disorders and other phenomena, seizures and agitation related to the central nervous system, which were observed mainly in children.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after the approval of a medicinal product is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
No special storage conditions are required.
Keep out of reach of children.
Packaging
10 tablets in a blister, 1 blister in a cardboard box.
Vacation category
Without a prescription.
Producer
JANSSEN-CILAG/JANSSEN-CILAG.
Location of the manufacturer and its business address
Domaine de Megremont, Val-de-Ruy, 27100, France.
