Domrid® sr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOMRID® SR (DOMRID® SR)

Composition:

Active substance: domperidone maleate;

1 tablet contains 30 mg of domperidone maleate calculated as domperidone;

Excipients: lactose monohydrate, povidone, quinoline yellow (E 104), sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide, hydroxypropylmethylcellulose, talc.

Pharmaceutical form. Extended-release tablets.

Main physicochemical properties: white-yellowish, two-layered, round, flat tablets with bevelled edges and the logo "K" on the yellow layer of the tablet.

Pharmacotherapeutic group. Prokinetic agents. ATC code A03FA03.

Pharmacological properties.

Pharmacodynamics.

Domperidone is a dopamine antagonist with antiemetic properties. Domperidone penetrates the blood-brain barrier to a minimal extent. The use of domperidone is very rarely associated with extrapyramidal side effects, especially in adults, but domperidone stimulates the release of prolactin from the pituitary gland. Its antiemetic effect is likely due to a combination of peripheral (gastrokinetic) action and antagonism of dopamine receptors in the chemoreceptor trigger zone located outside the blood-brain barrier in the posterior region (area postrema).

Studies in animals, as well as low concentrations detected in the brain, indicate that domperidone acts predominantly peripherally on dopamine receptors.

Studies have shown that in humans, following oral administration, domperidone increases pressure in the lower esophageal sphincter, 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 reached in 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 the bioavailability of domperidone increases when administered after food in healthy individuals, patients with gastrointestinal complaints should take domperidone 15–30 minutes before meals. Reduced gastric acidity decreases domperidone absorption. Oral bioavailability is reduced when domperidone is taken concomitantly with cimetidine and sodium bicarbonate. When administered orally after food, peak absorption is slightly delayed, and the area under the curve (AUC) is slightly increased.

Distribution.

After oral administration, domperidone does not accumulate and does not induce its own metabolism; the maximum plasma concentration at 90 minutes (21 ng/mL) after two weeks of oral administration at 30 mg daily was nearly 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 radiolabeled drug showed extensive tissue distribution but low concentrations in the brain. In animals, small amounts of the drug cross the placenta.

Metabolism.

Domperidone is rapidly and extensively metabolized in the liver via hydroxylation and N-dealkylation.

In vitro metabolism studies using diagnostic inhibitors have shown that CYP3A4 is the main cytochrome P450 isoenzyme involved in the N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 are involved in the aromatic hydroxylation of domperidone.

Excretion.

Excretion via urine and feces accounts for 31% and 66% of the oral dose, respectively. Excretion of the unchanged drug is minimal (10% in feces and approximately 1% in urine). The elimination half-life from plasma after a single dose is 7–9 hours in healthy volunteers, but it is prolonged in patients with severe renal impairment.

Clinical characteristics.

Indications.

For relief of symptoms of nausea and vomiting.

Contraindications.

Domrid® SR is contraindicated:

• in patients with known hypersensitivity to the active substance or to any of the excipients;
• in patients with prolactin-secreting pituitary tumors (prolactinoma);
• in patients with moderate or severe hepatic impairment (see section "Special precautions");
• in patients with known prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalances or underlying cardiac diseases such as congestive heart failure (see section "Special precautions");
• when stimulation of gastric motility may be dangerous, e.g., in gastrointestinal hemorrhage, mechanical obstruction, or perforation;
• during concomitant use of ketoconazole, erythromycin, or other potent inhibitors of CYP3A4 (regardless of their ability to prolong the QT interval) (see section "Interaction with other medicinal products and other forms of interaction");
• during concomitant use of medicinal products 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 precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Anticholinergic medicinal products may counteract the anti-dyspeptic effect of domperidone. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation is increased.

Antacids and antisecretory medicinal products should not be taken simultaneously with domperidone, as they reduce its bioavailability after oral administration (see section "Special precautions").

Domperidone is primarily metabolized via CYP3A4. According to in vitro and human studies, concomitant administration of medicinal products that strongly inhibit this enzyme may lead to increased plasma levels of domperidone.

Clinically significant QT interval changes have been observed when domperidone was used concomitantly with potent CYP3A4 inhibitors capable of prolonging the QT interval. Therefore, concomitant use of domperidone with certain medicinal products is contraindicated (see section "Contraindications").

Concomitant use with levodopa. Although dose adjustment of levodopa is not considered necessary, increased plasma concentrations (up to 30–40%) have been observed when levodopa is used concomitantly with domperidone (see section "Special precautions").

Concomitant use of the following medicinal products with domperidone is contraindicated.

All medicinal products that prolong the QT interval (risk of torsade de pointes):

• class IA antiarrhythmics (e.g., disopyramide, quinidine, hydroquinidine);
• class III antiarrhythmics (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
• certain neuroleptics (e.g., haloperidol, pimozide, sertindole);
• certain antidepressants (e.g., citalopram, escitalopram);
• certain antibiotics (e.g., levofloxacin, moxifloxacin, erythromycin, spiramycin);
• certain antifungal agents (e.g., fluconazole, pentamidine);
• certain antimalarials (e.g., halofantrine, lumefantrine);
• certain gastrointestinal medicinal products (e.g., cisapride, dolasetron, prucalopride);
• certain antihistamines (e.g., mequitazine, mizolastine);
• certain oncology medicinal products (e.g., toremifene, vandetanib, vincamine);
• certain other medicinal products (e.g., bepridil, methadone, diphenylamine) (see section "Contraindications");
• apomorphine, except when benefit outweighs risk, and only under strict adherence to recommended measures for concomitant use (see apomorphine product information, section "Contraindications").

In specific in vivo pharmacokinetic/pharmacodynamic interaction studies, concomitant oral administration of ketoconazole or erythromycin in healthy volunteers confirmed that these medicinal products significantly inhibit the presystemic metabolism of domperidone mediated by CYP3A4.

When 10 mg domperidone was administered orally four times daily concomitantly with 200 mg ketoconazole orally twice daily, QTc prolongation averaged 9.8 msec during the observation period, with individual values ranging from 1.2 to 17.5 msec. When 10 mg domperidone four times daily was administered concomitantly with 500 mg erythromycin orally three times daily, QTc interval was prolonged on average by 9.9 msec, with individual values ranging from 1.6 to 14.3 msec.

Steady-state Cmax and AUC values of domperidone increased approximately threefold in each of these interaction studies. The impact of elevated plasma concentrations of domperidone on QTc prolongation is unknown. In these studies, monotherapy with domperidone (10 mg orally four times daily) prolonged QTc by an average of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while administration of ketoconazole alone (200 mg twice daily) or erythromycin alone (500 mg three times daily) resulted in QTc prolongation of 3.8 and 4.9 msec, respectively, during the observation period.

Examples of strong CYP3A4 inhibitors with which Domrid® SR should not be used include:

• azole antifungals such as fluconazole*, itraconazole, ketoconazole*, posaconazole, and voriconazole*;
• macrolide antibiotics such as clarithromycin*, erythromycin*, and telithromycin* (see section "Contraindications");
• protease inhibitors such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, telaprevir*, ritonavir*, and saquinavir*;
• calcium channel antagonists such as diltiazem and verapamil;
• amiodarone*;
• amrepitant;
• nefazodone.

*Prolongs QTc interval.

Concomitant use of the following substances requires caution.

Use with caution when co-administered with medicinal products that cause bradycardia and hypokalemia, as well as with macrolides that may cause QT interval prolongation: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).

Domperidone should be used cautiously with potent CYP3A4 inhibitors that do not cause QT prolongation, such as indinavir. Patients should be closely monitored for signs or symptoms of adverse reactions.

The above list is representative but not exhaustive.

Domrid® SR may be combined with:

• neuroleptics, whose effects it enhances;
• dopaminergic agonists (bromocriptine, L-dopa), whose undesirable peripheral effects such as digestive disturbances, nausea, and vomiting it suppresses without neutralizing their main properties.

Since domperidone exerts a prokinetic effect on the stomach, this may theoretically affect the absorption of concomitantly administered oral medicinal products, particularly prolonged-release formulations or enteric-coated dosage forms. However, in patients already stabilized on digoxin or paracetamol, concomitant administration of domperidone did not affect blood levels of these medicinal products.

Special precautions for use.

Domrid® SR is not recommended for use in patients with tremor.

Domrid® SR should be used with caution in elderly patients or in patients with existing heart disease or a history of cardiac disorders.

Cardiovascular effects. Domperidone has been associated with QT interval prolongation on ECG. During post-marketing surveillance, very rare cases of QT prolongation and ventricular fibrillation/torsades de pointes have been reported in patients taking domperidone. These reports included information on patients with other risk factors, electrolyte disturbances, and concomitant therapies that could be contributing factors (see section "Adverse reactions").

QT interval prolongation observed in healthy subjects receiving domperidone at doses up to 80 mg/day (10 or 20 mg four times daily) was not considered clinically significant.

Warnings. Domperidone should be used with caution in patients with mild hepatic and/or renal impairment.

Due to an increased risk of ventricular arrhythmia, Domrid® SR is contraindicated in patients with prolonged cardiac conduction intervals, particularly QTc, those with significant electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia), bradycardia, or underlying heart diseases such as congestive heart failure (see section "Contraindications"). Electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia are known conditions that increase the proarrhythmic risk.

If signs or symptoms suggestive of cardiac arrhythmia occur, treatment with Domrid® SR should be discontinued immediately and the patient should seek immediate medical advice.

Patients should promptly report any cardiac symptoms.

Renal function. The elimination half-life of domperidone is prolonged in severe renal impairment (serum creatinine > 6 mg/100 mL, i.e., > 0.6 mmol/L). Dose reduction may also be required.

Concomitant use with levodopa. Although dose adjustment of levodopa is not considered necessary, increased plasma concentrations (up to 30–40%) have been observed when levodopa is used concomitantly with domperidone (see section "Interaction with other medicinal products and other forms of interaction").

Antacid or antisecretory medicinal products 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 forms of interaction"). When used concomitantly, Domrid® SR should be taken before meals, and antacid or antisecretory agents should be taken after meals.

Use with apomorphine. Domperidone is contraindicated for concomitant use with medicinal products that prolong the QT interval, including apomorphine, except when the benefit outweighs the risk and only under strict adherence to the precautions outlined in the apomorphine product information.

Use with ketoconazole. In interaction studies with oral ketoconazole, QT interval prolongation was observed. Although the clinical significance of this finding is not fully established, alternative treatment should be considered if antifungal therapy with ketoconazole is indicated (see section "Interaction with other medicinal products and other forms of interaction").

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 aged 60 years or older, in those receiving oral doses exceeding 30 mg per day, and in patients concurrently taking medicinal products that prolong the QT interval or CYP3A4 inhibitors. Therefore, Domrid® SR should be used with caution in elderly patients. Patients aged 60 years or older should consult their physician before taking Domrid® SR.

• Domperidone should be prescribed to adults at the lowest effective dose.

The benefit-risk balance of domperidone use remains favorable.

If you have an intolerance to certain sugars, consult your doctor before taking this medicinal product, as it contains lactose.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

Data on post-marketing use of domperidone in pregnant women are limited. Therefore, Domrid® SR should be used during pregnancy only if the physician considers that the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding.

The amount of domperidone that may pass into breast milk and reach the infant is extremely low. The maximum relative infant dose (%) is estimated to be approximately 0.1% of the maternal dose, adjusted for body weight. It is unknown whether it harms the infant; therefore, mothers taking Domrid® SR should avoid breastfeeding.

The decision to discontinue breastfeeding or to discontinue domperidone therapy should be based on an assessment of the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Adverse effects, particularly cardiovascular effects, cannot be ruled out after exposure due to transfer of the medicinal product into breast milk. Caution should be exercised if risk factors for QTc interval prolongation are present in breastfed infants.

Ability to influence reaction speed when driving or operating machinery.

Dizziness and somnolence have been reported after domperidone use (see section "Adverse reactions"). Therefore, patients should be advised to refrain from driving, operating machinery, or engaging in any activity requiring mental alertness and coordination until they know how Domrid® SR affects them.

Method of administration and dosage.

For relief of nausea and vomiting symptoms.

Adults. 1 tablet once daily, 15–30 minutes before a meal.

The duration of treatment should not exceed 1 week.

The maximum daily dose of the medicinal product is 30 mg.

Children.

The medicinal product should be administered to children in another pharmaceutical form.

Overdose.

Symptoms. Symptoms of overdose may include agitation, impaired consciousness, seizures, drowsiness, disorientation, and extrapyramidal reactions, especially in children.

Treatment. There is no specific antidote for domperidone. In case of significant overdose, standard symptomatic treatment should be initiated immediately. Gastric lavage is recommended within 1 hour after ingestion of the medicinal product, along with administration of activated charcoal, close monitoring of the patient, and supportive therapy.

ECG monitoring should be performed due to the potential for QT interval prolongation. Anticholinergic medicinal products and drugs used to treat Parkinson's disease may be effective in controlling extrapyramidal reactions.

Adverse Reactions

Adverse reactions identified during clinical trials with domperidone are listed below by system organ class and frequency of occurrence: 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 the frequency cannot be determined from clinical trial data, it is listed as unknown.

When dosage and duration recommendations are followed, domperidone is generally well tolerated and adverse reactions occur infrequently.

Immune system disorders: unknown frequency – allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.

Endocrine disorders: rare – increased prolactin levels.

Psychiatric disorders: uncommon – decreased or absent libido, nervousness, irritability, agitation; very rare – depression, anxiety.

Nervous system disorders: uncommon – headache, drowsiness, dizziness, extrapyramidal disorders; very rare – insomnia, thirst, lethargy, akathisia; unknown frequency – convulsions, restless legs syndrome (exacerbation of restless legs syndrome in patients with Parkinson's disease).

Cardiac disorders: very rare – edema, palpitations, disturbances in heart rate and rhythm, serious ventricular arrhythmias; unknown frequency – QT interval prolongation, ventricular arrhythmias such as torsade de pointes, sudden cardiac death.

Gastrointestinal disorders: common – dry mouth; uncommon – diarrhea; rare – gastrointestinal disorders including abdominal pain, regurgitation, appetite changes, nausea, heartburn, constipation; very rare – transient intestinal spasms.

Eye disorders: unknown frequency – oculogyric crises.

Skin and subcutaneous tissue disorders: uncommon – itching, rash, urticaria; unknown frequency – angioedema.

Reproductive system and breast disorders: rare – breast enlargement, breast discharge, breast swelling, lactation disorders, irregular menstrual cycle; uncommon – galactorrhea, breast pain, breast tenderness; unknown frequency – gynecomastia, amenorrhea.

Musculoskeletal and connective tissue disorders: rare – leg pain.

Renal and urinary disorders: very rare – dysuria, frequent urination; unknown frequency – urinary retention.

General disorders: uncommon – asthenia.

Other: conjunctivitis, stomatitis.

Laboratory test abnormalities: very rare – increased ALT, AST, and cholesterol levels; unknown frequency – abnormal liver function tests, increased blood prolactin levels.

Since the pituitary gland lies outside the blood-brain barrier, domperidone may cause elevated prolactin levels. In isolated cases, this hyperprolactinemia may lead to neuroendocrine adverse effects such as galactorrhea, gynecomastia, and amenorrhea.

During the post-marketing period, no differences in the safety profile of the drug in adults and children have been observed, except for extrapyramidal disorders and other central nervous system-related events such as convulsions and agitation, which were observed predominantly in children.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

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 per blister. 1 or 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's location and address of its business activity.

54 Skryabina Street, Sumy, Sumy Oblast, 40020, Ukraine.

or

Manufacturer.

LLC "GLEDFARM LTD".

Manufacturer's location and address of its business activity.

54 Hryhoriya Davydovskoho Street, Sumy, Sumy Oblast, 40020, Ukraine.