INSTRUCTION for medical use of the medicinal product DOPROKIN (DOPROKIN)

Composition:

Active substance: domperidone;

1 tablet contains domperidone (as domperidone maleate) 10 mg;

Excipients: lactose monohydrate; maize starch; pregelatinized starch; povidone (K 90); sodium lauryl sulfate; microcrystalline cellulose; hydrogenated vegetable oil; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, round, biconvex tablets.

Pharmacotherapeutic group.

Agents used in functional gastrointestinal disorders. 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. Extrapyramidal side effects are very rare during domperidone use, particularly in adults, but domperidone stimulates prolactin release from the pituitary gland. Its antiemetic effect is likely due to a combination of peripheral (gastrokinetic) action and antagonism at dopamine receptors in the chemoreceptor trigger zone located outside the blood-brain barrier in the posterior region (area postrema).

Animal studies, as well as low brain concentrations detected, indicate that domperidone acts predominantly on peripheral dopamine receptors.

Studies in humans have shown that oral administration of domperidone increases lower esophageal sphincter pressure, improves antroduodenal motility, and accelerates gastric emptying. Domperidone does not affect gastric secretion.

Effect on QT interval and cardiac electrophysiology

A thorough QT interval study was conducted in healthy subjects. This was a double-blind, placebo-controlled study using both recommended and supratherapeutic doses (10 and 20 mg four times daily). When 20 mg of domperidone was administered four times daily, QT interval prolongation ranged from 3.4 to 5.9 ms throughout the observation period, and this value did not exceed 10 ms. The QT prolongation observed in this study with domperidone administered at the recommended dose is not considered clinically significant.

This lack of clinical significance is supported by pharmacokinetic parameters and QTc interval data from two earlier studies involving five-day treatment with 20 mg and 40 mg of domperidone four times daily. ECGs were recorded before the study, on day 5, one hour (approximately at tmax) after the morning dose, and on day 3. In both studies, no differences in QTc were observed between active treatment and placebo. Therefore, it was concluded that administration of domperidone at doses of 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 concentration (Cmax) reached approximately within 60 minutes. Cmax and area under the concentration-time curve (AUC) of domperidone increased proportionally with doses ranging from 10 to 20 mg. A 2–3-fold accumulation of domperidone (AUC) was observed with repeated administration four times daily (every 5 hours) over 4 days. The low absolute oral bioavailability of domperidone (approximately 15%) is due to extensive first-pass metabolism in the intestinal wall and liver. Although domperidone bioavailability increases when administered after food in healthy individuals, patients with gastrointestinal symptoms should take domperidone 15–30 minutes before meals. Reduced gastric acidity decreases domperidone absorption. Oral bioavailability is reduced when co-administered with cimetidine and sodium bicarbonate. When domperidone is taken orally after food, peak absorption is slightly delayed, and AUC is slightly increased.

Distribution.

After oral administration, domperidone does not accumulate and does not induce its own metabolism; Cmax at 90 minutes (21 ng/mL) after two weeks of oral administration of 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 in animals using radiolabeled domperidone showed extensive tissue distribution but low brain concentrations. In animals, small amounts of domperidone 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 primary cytochrome P450 isoform involved in N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 are involved in aromatic hydroxylation of domperidone.

Elimination.

Excretion of domperidone in urine and feces accounts for 31% and 66% of the oral dose, respectively. Excretion in unchanged form is minimal (10% in feces and approximately 1% in urine). The elimination half-life (t1/2) from plasma after a single dose of domperidone is 7–9 hours in healthy volunteers but is prolonged in patients with severe renal impairment.

Special patient populations.

Hepatic impairment.

In patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale, class B), the area under the concentration-time curve (AUC) and Cmax of domperidone were 2.9 and 1.5 times higher, respectively, compared to healthy volunteers. The free fraction increased by 25%, and the terminal t1/2 was prolonged from 15 to 23 hours. In patients with mild hepatic impairment, exposure was slightly lower than in healthy volunteers based on Cmax and AUC, with no changes in protein binding or terminal t1/2. Domperidone has not been studied in patients with severe hepatic impairment (see section "Contraindications").

Domperidone is contraindicated in patients with moderate or severe hepatic impairment (see section "Contraindications").

Renal impairment.

In patients with severe renal impairment (plasma creatinine clearance < 30 mL/min/1.73 m²), the t1/2 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 domperidone (approximately 1%) is excreted unchanged in urine, dose adjustment is unlikely to be required after single administration in patients with renal impairment. However, with repeated administration, the dosing frequency should be reduced to 1–2 times daily depending on the severity of impairment, and dose reduction may also be necessary.

Clinical characteristics.

Indications.

Relief of symptoms of nausea and vomiting.

Contraindications.

The medicinal product is contraindicated:

in case of known hypersensitivity to domperidone or to any excipients of the medicinal product;
prolactin-secreting pituitary tumor (prolactinoma);
severe or moderate impairment of liver and/or kidney function (see section "Special warnings and precautions for use", "Pharmacokinetic properties");
known prolongation of cardiac conduction intervals, particularly QTc, significant electrolyte imbalances, or underlying heart diseases such as congestive heart failure (see section "Special warnings and precautions for use");
hepatic failure;
when stimulation of gastric motility may be dangerous, e.g., in gastrointestinal hemorrhage, mechanical obstruction, or perforation;
concomitant use with ketoconazole, erythromycin, or other potent CYP3A4 inhibitors;
concomitant use with 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 warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Anticholinergic drugs may counteract the antidyspeptic effect of Domperidone. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation is increased.

Antacids and antisecretory agents should not be taken simultaneously with Domperidone, as they reduce its bioavailability after oral administration (see section "Special warnings and precautions for use").

Domperidone is primarily metabolized via CYP3A4. In vitro studies have shown that concomitant use of drugs 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 drugs is contraindicated (see section "Contraindications").

Concomitant use with levodopa. Although dose adjustment of levodopa is not considered necessary, an increase in plasma concentration of domperidone (up to 30–40%) has been observed when administered concurrently with levodopa.

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 antimalarial agents (e.g., halofantrine, lumefantrine);
certain gastrointestinal agents (e.g., cisapride, dolasetron, prucalopride);
certain antihistamines (e.g., mequitazine, mizolastine);
certain oncology drugs (e.g., toremifene, vandetanib, vincamine);
certain other drugs (e.g., bepridil, methadone, diphenylbutylpiperidine);
apomorphine, except when benefit outweighs risk and strict adherence to recommended precautions for concomitant use is ensured (see apomorphine prescribing information, section "Contraindications").

Examples of potent CYP3A4 inhibitors with which Domperidone must not be used:

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 channel blockers such as diltiazem and verapamil;
amiodarone*;
amperozide;
nefazodone;
telithromycin*.

*Prolong QTc interval.

Concomitant use of the following substances requires caution.

Use with caution when coadministering with drugs that cause bradycardia and hypokalemia, as well as with macrolides that may prolong the QT interval, such as azithromycin and roxithromycin (clarithromycin is contraindicated because it is a potent CYP3A4 inhibitor).

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

The above list is representative but not exhaustive.

Domperidone 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.

In specific in vivo pharmacokinetic/pharmacodynamic interaction studies, concomitant oral administration of ketoconazole or erythromycin in healthy volunteers confirmed that these drugs 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 interval prolongation averaged 9.8 msec during the observation period; individual values ranged 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 domperidone plasma concentrations on QTc prolongation is unknown. In these studies, monotherapy with domperidone (10 mg orally four times daily) prolonged QTc interval 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.

Theoretically, since Domperidone exerts a prokinetic effect on the stomach, it may affect the absorption of concomitantly administered oral drugs, particularly prolonged-release formulations or enteric-coated preparations. However, in patients already stabilized on digoxin or paracetamol, concomitant administration of domperidone did not affect blood levels of these drugs.

Special precautions for use.

The medicinal product is not recommended for use in case of dizziness.

The medicinal product should be used with caution in elderly patients or patients with heart diseases, including in medical history.

Cardiovascular effects.

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

According to ICH-E14 guidance, a thorough QT interval study was conducted in healthy volunteers. The QT interval prolongation observed in the study with domperidone administered according to the recommended dosage regimen at usual therapeutic doses (10 or 20 mg four times daily) is not considered clinically significant.

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

If signs or symptoms that may be related to cardiac arrhythmia occur, administration of the medicinal product should be discontinued immediately, and the patient should consult a physician without delay.

Patients should immediately report any cardiac symptoms.

The following information regarding the risk of cardiovascular complications associated with domperidone should be considered:

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 aged 60 years or older or in those receiving oral doses exceeding 30 mg per day. Therefore, the medicinal product should be used with caution in elderly patients. Patients aged 60 years or older should consult a physician before using the medicinal product.
The medicinal product should be administered to adults and children at the lowest effective dose.

The benefit-risk ratio of domperidone remains favorable.

Use in patients with hepatic impairment.

The medicinal product should be used with caution in patients with mild hepatic impairment.

Use in patients with renal impairment.

The t1/2 of domperidone is prolonged in severe renal impairment. With long-term use, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of the impairment. Dose reduction may also be necessary.

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

Concomitant use with antacids or antisecretory agents.

Concomitant use with antacids or antisecretory agents is not recommended, as they reduce the oral bioavailability of domperidone (see section "Interaction with other medicinal products and other types of interactions"). When used concomitantly, the medicinal product should be taken before meals, and antacids or antisecretory agents should be taken after meals.

Concomitant use with apomorphine.

Domperidone is contraindicated for concomitant use with medicinal products that prolong the QT interval, including apomorphine, except when the benefit of concomitant use with apomorphine outweighs the risk, and only if strict adherence to the warnings provided in the apomorphine product information is ensured.

Concomitant use with ketoconazole.

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

Precautions related to excipients.

The medicinal product contains lactose and therefore should not be used in patients with lactose intolerance, galactosemia, or glucose/galactose malabsorption.

The medicinal product contains less than 1 mmol/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Data on post-marketing use of domperidone in pregnant women are limited. Therefore, the medicinal product should be used 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 may pass into an infant's body through breast milk is extremely low. The maximum relative infant dose (%) is estimated at approximately 0.1% of the maternal dose adjusted for body weight. It is unknown whether it harms the infant; therefore, mothers taking the medicinal product should refrain from breastfeeding. The decision to discontinue breastfeeding or to stop domperidone treatment should be made after evaluating the benefits of breastfeeding for the child and the benefits of therapy for the mother. Caution should be exercised in the presence of risk factors for QTc interval prolongation in breastfed infants. After exposure due to domperidone passage into breast milk, adverse effects, particularly cardiovascular effects, cannot be excluded.

Ability to affect reaction speed when driving vehicles or operating machinery.

Dizziness and somnolence have been reported after administration of domperidone. Therefore, patients should be advised to refrain from driving vehicles, operating machinery, or engaging in any other activities requiring concentration and coordination until they know how the medicinal product affects them.

Method of Administration and Dosage

The medicinal product should be used at the lowest effective dose for the shortest duration necessary to relieve symptoms of nausea and vomiting.

Adults and children aged 12 years or older, or with body weight of 35 kg or more.

The medicinal product should be administered at a dose of 1 tablet (10 mg) three times daily.

Maximum daily dose – 3 tablets (30 mg per day).

It is recommended to take the medicinal product before meals. Absorption of domperidone is somewhat delayed when taken after food. The patient should take the medicinal product according to the recommended dosing schedule. If a dose is missed, the next dose should be taken according to the recommended schedule. The dose should not be doubled to make up for a missed dose.

The duration of treatment should not exceed 1 week.

Patients aged 60 years and older.

Patients aged 60 years and older should consult a physician before using the medicinal product.

Patients with renal impairment.

Since the t1/2 of domperidone is prolonged in patients with severe renal impairment, the frequency of administration should be reduced to once or twice daily, depending on the severity of impairment; dose reduction may also be necessary. Patients with severe renal impairment should be monitored regularly (see section “Pharmacological Properties”).

Patients with hepatic impairment.

The medicinal product is contraindicated in patients with moderate (7–9 points on the Child–Pugh scale) or severe (˃9 points on the Child–Pugh scale) hepatic impairment (see section “Contraindications”). Dose adjustment is not required in patients with mild hepatic impairment (5–6 points on the Child–Pugh scale) (see section “Pharmacological Properties”).

Children.

The medicinal product should be used for the treatment of children aged 12 years and older and with body weight of 35 kg or more.

The medicinal product should be used in children at the lowest effective dose for the shortest possible duration.

Overdose.

Symptoms.

Overdose has been reported primarily in infants and children. Symptoms of overdose may include agitation, altered consciousness, convulsions, disorientation, drowsiness, and extrapyramidal reactions.

Treatment.

There is no specific antidote for domperidone; however, in cases of significant overdose, immediate symptomatic treatment should be initiated. Gastric lavage within 1 hour after ingestion of the medicinal product and administration of activated charcoal are recommended, along with close monitoring of the patient’s condition and supportive therapy. ECG monitoring should be performed due to the potential for QT interval prolongation. Anticholinergic medicinal products and drugs used in the treatment of Parkinson’s disease may be effective in controlling extrapyramidal reactions.

Adverse Reactions.

The safety of domperidone was evaluated during clinical trials and post-marketing use. A total of 1275 patients with dyspepsia, gastroesophageal reflux disease, irritable bowel syndrome, nausea and vomiting, or other related conditions participated in double-blind, placebo-controlled clinical trials. All patients were at least 15 years of age and received at least one dose of the medicinal product. The mean total daily dose was 30 mg (range from 10 to 80 mg), and the median duration of exposure was 28 days (range from 1 to 28 days). Patients with diabetic gastroparesis or symptoms induced by chemotherapy or Parkinsonism were not included in the studies.

Assessment of the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10000, <1/1000); very rare (<1/10000), including isolated reports; unknown (frequency cannot be estimated from available data).

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

Immune system:

unknown – allergic reactions, including anaphylaxis, anaphylactic shock, hypersensitivity.

Endocrine system:

rare – increased prolactin levels.

Psychiatric disorders:

uncommon – decreased or absent libido, irritability, restlessness, nervousness; very rare – depression, anxiety.

Nervous system:

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

Eye disorders:

unknown – oculogyric crises.

Cardiovascular system:

very rare – edema, palpitations, disturbances in heart rate and rhythm, serious ventricular arrhythmias; unknown – QT interval prolongation, ventricular arrhythmias of the torsade de pointes type, 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.

Skin and subcutaneous tissue disorders:

uncommon – pruritus, rash, urticaria; unknown – angioneurotic edema.

Reproductive system and breast disorders:

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

Musculoskeletal and connective tissue disorders:

rare – leg pain.

Renal and urinary disorders:

very rare – dysuria, frequent urination; unknown – urinary retention.

General disorders:

uncommon – asthenia.

Other:

conjunctivitis, stomatitis.

Laboratory test abnormalities:

very rare – increased levels of ALT, AST, and cholesterol; unknown – liver function test abnormalities; rare – increased plasma prolactin levels.

In 45 studies where domperidone was used at higher doses, for longer durations, and for additional indications including diabetic gastroparesy, the frequency of adverse reactions (except dry mouth) was significantly higher. This was particularly evident in pharmacologically predictable cases related to elevated prolactin levels.

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

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

Reporting suspected adverse reactions

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

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 tablets in a blister, 2 blisters in a cardboard box;
10 tablets in a blister, 3 blisters in a cardboard box.

Dispensing category.

Over-the-counter.

Manufacturer.

UORLД MEDICINE ILAC SAN. VE TIC. A.Ш./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing authorization holder.

WORLD MEDICINE, LLC, Ukraine.

Doprokin