Instructions for Domrid SR prolonged-release tablets 30 mg No. 30
Composition
active ingredient: domperidone maleate;
1 tablet contains domperidone maleate equivalent to domperidone 30 mg;
excipients: lactose monohydrate, povidone, quinoline yellow (E 104), croscarmellose sodium, magnesium stearate, colloidal anhydrous silica, hydroxypropylmethylcellulose, talc.
Dosage form
Extended-release tablets.
Main physicochemical properties: white-yellow bilayer, round flat tablets with beveled edges and the “K” logo on the yellow layer of the tablet.
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.
Animal studies, as well as low concentrations determined in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.
Studies in humans have shown that when administered orally, domperidone increases lower esophageal pressure, improves antroduodenal motility, and accelerates gastric emptying. Domperidone does not affect gastric secretion.
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, the maximum absorption is somewhat delayed and the area under the curve (AUC) is slightly increased.
Distribution.
When administered orally, domperidone does not accumulate and does not induce its own metabolism; the maximum plasma level after 90 minutes (21 ng/ml) after two weeks of oral administration of 30 mg per day was almost the same as after the first dose (18 ng/ml). Domperidone is 91-93% bound to plasma proteins. Distribution studies of domperidone conducted in animals using a radioactively labeled drug showed its extensive distribution in tissues, but low concentrations in the brain. In animals, small amounts of the drug penetrate the placenta.
Metabolism.
Domperidone is rapidly and extensively metabolized in the liver by hydroxylation and N-dealkylation.
Breeding.
Urinary and fecal excretion account for 31% and 66% of the oral dose, respectively. Excretion of unchanged drug is small (10% in feces 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 insufficiency.
Indication
To relieve symptoms of nausea and vomiting.
Contraindication
Domrid® SR 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 section "Special warnings and precautions for use");
- 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
Antacids and antisecretory drugs should not be taken simultaneously with domperidone, as they reduce its bioavailability after oral administration (see section "Special instructions").
Domperidone is metabolized primarily by CYP3A4. In vitro and human studies suggest that concomitant use of medicinal products 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 use of domperidone with certain drugs 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 drugs (e.g. haloperidol, pimozide, sertindole);
- some antidepressants (e.g. citalopram, escitalopram);
- some antibiotics (e.g. levofloxacin, moxifloxacin, erythromycin, spiramycin);
- some antifungal drugs (e.g. pentamidine);
- some antimalarial drugs (e.g. halofantrine, lumefantrine);
- some gastrointestinal drugs (e.g. cisapride, dolasetron, prucalopride);
- some antihistamines (e.g. mecitazine, mizolastine);
- some drugs used in cancer (e.g. toremifene, vandetanib, vincamine);
- some other drugs (e.g. bepridil, methadone, diphemanil).
Concomitant oral administration of ketoconazole or erythromycin in vivo has been shown to significantly inhibit the CYP3A4-mediated first-pass metabolism of domperidone. Concomitant administration of 10 mg domperidone orally 4 times daily and 200 mg ketoconazole orally 2 times daily during the observation period resulted in an average prolongation of the QTc interval by 9.8 msec; individual values ranged from 1.2 to 17.5 msec. Concomitant administration of 10 mg domperidone 4 times daily and 500 mg erythromycin orally 3 times daily during the observation period resulted in an average prolongation of the QTc interval by 9.9 msec; individual values ranged 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 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 the use of ketoconazole (200 mg 2 times a day) or erythromycin (500 mg 3 times a day) alone resulted in an increase in the QTc interval during the observation period of 3.8 and 4.9 msec, respectively.
Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT prolongation is increased.
Examples of strong CYP3A4 inhibitors with which Domrid® SR is not recommended:
- azole antifungals 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.
The simultaneous use of the following substances requires caution.
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.
Domrid® SR 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.
Since domperidone has a prokinetic effect on the stomach, it could theoretically affect the absorption of concomitant oral medications, particularly extended-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
Domrid® SR is not recommended for use in case of shaking.
Cardiovascular effects. Domperidone has been associated with prolongation of the QT interval on the ECG. During post-marketing surveillance, very rare cases of QT prolongation and ventricular fibrillation have been reported in patients taking domperidone. These reports included patients with other adverse risk factors, electrolyte disturbances and concomitant therapy that may have been predisposing factors. The prolongation of the QT interval observed in healthy subjects when domperidone was administered according to the recommended dosage regimen at usual therapeutic doses (10 or 20 mg 4 times a day) was not clinically significant.
Caution: Domperidone should be used with caution in patients with mild hepatic and/or renal impairment.
Due to the increased risk of ventricular arrhythmia, Domrid® SR is not recommended for use 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, Domrid® SR should be discontinued and the patient should consult a doctor immediately.
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 Domrid® SR, as they reduce the oral bioavailability of domperidone (see section “Interaction with other medicinal products and other types of interactions”). When used together, Domrid® SR should be taken before meals, and antacids or antisecretory drugs should be taken after meals.
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 severe 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, Domrid® SR should be used with caution in elderly patients. Patients over 60 years of age should consult a doctor before taking Domrid® SR.
Domperidone should be prescribed to adults and children at the lowest effective dose.
The risk-benefit ratio of domperidone remains favorable.
If the patient has been diagnosed with an intolerance to some sugars, contact your doctor before taking this medicinal product, as the product contains lactose.
Use during pregnancy or breastfeeding
There are limited post-marketing data on the use of domperidone in pregnant women. Therefore, Domperidone SR 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 DomridÒ SR should refrain from breastfeeding. After exposure as a result of the drug passing into breast milk, side effects, including cardiological effects, cannot be excluded. Caution should be exercised in the presence of risk factors for prolongation of the QTc interval in breastfed infants.
Ability to influence reaction speed when driving vehicles or other mechanisms
Given the side effects on the nervous system, patients need to be careful when driving or working with other mechanisms.
Method of administration and doses
To relieve symptoms of nausea and vomiting.
Adults: 1 tablet once daily 15-30 minutes before meals.
The duration of treatment should not exceed 1 week.
The maximum daily dose of the drug is 30 mg.
Children
For children, the drug should be used in a different dosage form.
Overdose
Treatment. There is no specific antidote for domperidone, but in the case of a significant overdose, gastric lavage within 1 hour after ingestion and administration of activated charcoal are recommended, as well as close patient observation and supportive therapy. Anticholinergic drugs, agents for the treatment of Parkinson's disease may be effective in controlling extrapyramidal reactions.
Adverse reactions
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.
Mental disorders: nervousness, irritability, agitation, depression, anxiety, decreased or absent libido.
From the nervous system: extrapyramidal disorders, insomnia, dizziness, thirst, convulsions, lethargy, headache, drowsiness, akathisia.
Cardiovascular system: edema, palpitations, heart rate and rhythm disturbances, QT interval prolongation, serious ventricular arrhythmias, ventricular arrhythmias such as torsade de pointes, sudden cardiac death.
Gastrointestinal: dry mouth, short-term intestinal spasms, diarrhea, gastrointestinal disorders, including abdominal pain, regurgitation, changes in appetite, nausea, heartburn, constipation.
On the part of the organs of vision: oculogyric crises.
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.
Other: conjunctivitis, stomatitis.
Changes in laboratory parameters: abnormal liver function tests, increased ALT, AST and cholesterol levels, increased prolactin levels 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.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging
10 tablets in a blister. 1 or 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
"KUSUM FARM" LLC.
Location of the manufacturer and address of its place of business
40020, Ukraine, Sumy region, Sumy city, Skryabina st., 54.
