Instructions for Motorix film-coated tablets 10 mg blister No. 30
Composition
active ingredient: domperidone;
1 tablet contains domperidone 10 mg;
Excipients: lactose monohydrate; pregelatinized starch; croscarmellose sodium; microcrystalline cellulose; sodium lauryl sulfate; povidone; magnesium stearate;
shell: Opadry II White film-coating mixture (hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; polyethylene glycol; titanium dioxide (E 171); triacetin).
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, white in color, with a biconvex surface, with a score.
Pharmacotherapeutic group
Peristaltic 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. The low concentrations determined in the brain indicate a predominantly peripheral effect of the drug on dopamine receptors.
When administered orally, domperidone increases pressure in the lower esophagus, improves antroduodenal motility, and accelerates gastric emptying. Domperidone does not affect gastric secretion.
Effects on QT/QTc interval and cardiac electrophysiology
It is known that, in accordance with the international recommendations ICH-E14, a thorough study of the QT interval was conducted in healthy subjects. This study was double-blind, placebo-controlled, and was conducted using recommended and supratherapeutic doses (10 and 20 mg administered 4 times a day). With simultaneous administration of 20 mg of domperidone 4 times a day, a prolongation of the QT interval was noted and the changes ranged from 3.4 to 5.9 ms throughout the entire observation period, and this indicator did not exceed 10 ms. The QT prolongation observed in this study when domperidone was administered 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 treatment with 20 mg and 40 mg domperidone 4 times daily. ECGs were recorded before the study, on day 5, 1 hour (approximately at 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 on an empty stomach, with peak plasma concentrations occurring after approximately 60 minutes. 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 15-30 minutes before a meal. Reduced gastric acidity reduces the absorption of domperidone. When the drug is administered orally after a meal, peak absorption is somewhat delayed.
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 daily were similar to those after the first dose (18 ng/ml). Domperidone is 91-93% bound to plasma proteins. Distribution studies of domperidone have shown 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.
Elimination. Urinary and faecal excretion account for 31% and 66% of the oral dose, respectively. Excretion of unchanged drug is small (10% in faeces and approximately 1% in urine). The plasma half-life after a single dose is 7-9 hours in healthy volunteers, but is prolonged in patients with severe renal impairment.
Hepatic impairment. In patients with moderate hepatic impairment (Pugh score 7-9, Child-Pugh class B), the AUC and Cmax of domperidone were 2.9-fold and 1.5-fold 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 or terminal half-life. The use of the drug in patients with severe hepatic impairment has not been studied (see section "Contraindications").
Renal impairment: In patients with severe renal impairment (serum creatinine > 6 mg/100 ml, i.e. > 0.6 mmol/l), 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. A very small amount of the drug (approximately 1%) is excreted unchanged by the kidneys (see section 4.2).
Indication
To relieve symptoms of nausea and vomiting.
Contraindication
Motorix is contraindicated:
- patients with established hypersensitivity to the drug or excipients;
- patients with a prolactin-secreting pituitary tumor (prolactinoma);
- patients with severe or moderate liver and/or kidney dysfunction (see sections "Special instructions for use", "Pharmacokinetic 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 liver failure;
- if stimulation of gastric motor function may be dangerous, for example, in case of gastrointestinal bleeding, mechanical obstruction or perforation;
- Concomitant use of ketoconazole, erythromycin, or other potent CYP3A4 inhibitors is contraindicated;
- Concomitant use of drugs that prolong the QT interval, such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin is contraindicated (see sections “Special warnings and precautions for use” 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 Motorix. 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 Motorix, as they reduce its bioavailability after oral administration (see section "Special instructions").
Domperidone is metabolized primarily by CYP3A4.
According to in vitro studies, 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 medicinal products is contraindicated (see section "Contraindications").
Concomitant use of the following drugs with domperidone is contraindicated.
All drugs that prolong the QT interval:
- Class IA antiarrhythmic drugs (e.g., disopyramide, quinidine, hydroquinidine);
- class III antiarrhythmic drugs (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
- some neuroleptic medicines (e.g. haloperidol, pimozide, sertindole);
- some antidepressants (e.g. citalopram, escitalopram);
- certain antibiotics (e.g. levofloxacin, moxifloxacin, erythromycin, spiramycin);
- some antifungal medicines (e.g. pentamidine);
- certain antimalarial medicines (e.g. halofantrine, lumefantrine);
- certain gastrointestinal medications (e.g., cisapride, dolasetron, prucalopride);
- some antihistamine medicines (e.g. mecitazine, mizolastine);
- some medicines used for cancer (e.g. toremifene, vandetanib, vincamine);
- some other medicines (e.g. bepridil, methadone, diphemanil).
Examples of strong CYP3A4 inhibitors with which Motorix is contraindicated include:
- azole antifungal medicines such as fluconazole*, itraconazole, ketoconazole* and voriconazole*;
- macrolide antibiotics such as clarithromycin* and erythromycin*;
- protease inhibitors*;
- 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.
Use with caution with drugs that cause bradycardia and hypokalemia, as well as with the following macrolides that may cause QT prolongation: 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.
Motorix can be combined with:
- neuroleptics, the effect of which it enhances;
- dopaminergic agonists (bromocriptine, L-dopa), whose undesirable peripheral effects, such as digestive disorders, 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. Steady-state Cmax and AUC of domperidone increased approximately threefold in each of these interaction studies. The contribution of increased plasma concentrations of domperidone to the observed effect on QTc 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 increased the QTc interval by 3.8 and 4.9 msec, respectively, during the observation period.
Theoretically, since Motorix has a prokinetic effect on the stomach, this could affect the absorption of concomitant oral medications, particularly 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 medications.
Application features
The drug Motorix is not recommended for shaking.
Motorix should be used with caution in elderly patients or in patients with existing heart disease or a history of heart disease.
Cardiovascular effects. Domperidone has been associated with prolongation of the QT interval on the ECG. Very rare cases of QT prolongation and ventricular fibrillation have been reported in post-marketing experience in patients taking domperidone. These reports included patients with other predisposing risk factors, electrolyte disturbances and concomitant medications that may have been contributing factors.
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.
Caution: Domperidone should be used with caution in patients with mild hepatic and/or renal impairment.
Due to the increased risk of ventricular arrhythmia, Motorix is contraindicated in patients with prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, or in patients with underlying cardiac disease such as congestive heart failure. Electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are known to be conditions that increase proarrhythmic risk.
If signs or symptoms that may be associated with cardiac arrhythmia appear, Motorix should be discontinued and the patient should consult a doctor immediately.
Motorix tablets contain lactose, so the drug should not be used in patients with lactose intolerance, galactosemia and glucose/galactose malabsorption.
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.
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).
The following information should be considered regarding the risk of cardiovascular complications caused by medicines containing domperidone:
- some epidemiological studies have shown that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death;
- The risk of serious ventricular arrhythmias or sudden cardiac death may be higher in patients over 60 years of age or with oral doses of the drug greater than 30 mg per day. Therefore, Motorix should be used with caution in elderly patients. Patients over 60 years of age should consult a doctor before taking Motorix;
- Domperidone should be prescribed to adults and children at the lowest effective dose.
The risk-benefit ratio of domperidone remains favorable.
Use during pregnancy or breastfeeding
There are limited post-marketing data on the use of domperidone in pregnant women. Therefore, Motorix should be prescribed during pregnancy only if, in the opinion of the physician, the expected benefit to the mother outweighs the potential risk to the fetus.
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 Motorix should refrain from breastfeeding. Caution should be exercised in the presence of risk factors for prolongation of the QTc interval in breast-fed infants. After exposure through breast milk, adverse effects, including cardiac effects, cannot be excluded.
Ability to influence reaction speed when driving vehicles or other mechanisms
Dizziness and drowsiness have been reported after the use of domperidone. Therefore, patients should be advised to refrain from driving, operating machinery, or engaging in other activities that require concentration and coordination until they know how the drug affects them.
Method of administration and doses
To relieve symptoms of nausea and vomiting.
Adults and children over 12 years of age and weighing 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 Motorix before meals. Absorption of the drug is somewhat delayed if taken after meals. The duration of treatment should not exceed 1 week.
Adults aged 60 years and over: Patients aged 60 years and over should consult a doctor before taking this medicine.
Renal impairment. Since the half-life of domperidone is prolonged in severe renal impairment (serum creatinine > 6 mg/100 ml, i.e. > 0.6 mmol/l), the frequency of administration of Motorix 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 5.1).
Hepatic impairment. Motorix is contraindicated in patients with moderate (Child-Pugh score 7-9) or severe (Child-Pugh score >9) hepatic impairment. No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh score 5-6).
Children.
The medicine should be used to treat children aged 12 years and over and weighing at least 35 kg.
Domperidone should be given to children at the lowest effective dose for the shortest period of time.
Overdose
Symptoms: Symptoms of overdose may include agitation, impaired consciousness, convulsions, disorientation, drowsiness, and extrapyramidal reactions.
Treatment. There is no specific antidote for domperidone, but in the case of a significant overdose, gastric lavage within 1 hour after taking the drug and the use of activated charcoal are recommended, as well as close observation of the patient and supportive therapy. Anticholinergic drugs, drugs for the treatment of Parkinson's disease may be effective in controlling extrapyramidal reactions.
Side effects
Provided that the dosage and duration of treatment recommendations are followed, domperidone is usually well tolerated and adverse events occur infrequently.
Immune system disorders: allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.
On the part of the endocrine system: increased prolactin levels.
Nervous system: insomnia, dizziness, thirst, convulsions, lethargy, headache, drowsiness, akathisia, extrapyramidal disorders.
Cardiovascular system: edema, palpitations, heart rate and rhythm disturbances, QT interval prolongation (frequency unknown), serious ventricular arrhythmias, torsade de pointes-type ventricular arrhythmias, sudden cardiac death.
Gastrointestinal: gastrointestinal disorders, including abdominal pain, regurgitation, changes in appetite, nausea, heartburn, constipation; dry mouth, short-term intestinal spasms, diarrhea.
Skin and subcutaneous tissue disorders: itching, rash, urticaria, angioedema.
Reproductive system and breast disorders: galactorrhea, breast enlargement/gynecomastia, breast tenderness, breast discharge, amenorrhea, breast swelling, breast pain, lactation disorder, irregular menstrual cycle.
Musculoskeletal and connective tissue disorders: leg pain.
From the urinary system: urinary retention, dysuria, frequent urination.
General disorders: asthenia.
On the part of the organs of vision: oculogyric crises.
Other: conjunctivitis, stomatitis.
Changes in laboratory parameters: increased levels of ALT, AST and cholesterol, 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 use in adults and children were noted, with the exception of extrapyramidal disorders and other phenomena, seizures and agitation related to the central nervous system, which were observed mainly in children.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 tablets in a blister; 1 blister in a pack.
10 tablets in a blister; 3 blisters in a pack.
Vacation category
Without a prescription.
Producer
JSC "KYIV VITAMIN FACTORY".
Location of the manufacturer and address of its place of business.
04073, Ukraine, Kyiv, Kopylivska St., 38.
