INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOMRIDÒ

Composition:

Active ingredient: domperidone maleate;

1 tablet contains domperidone maleate equivalent to domperidone 10 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II 31 G 58920 white*.

*Opadry II 31 G 58920 white: hypromellose, lactose monohydrate, titanium dioxide (E 171), polyethylene glycol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Prokinetic agents. ATC code A03F A03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

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, particularly in adults; however, domperidone stimulates prolactin secretion from the pituitary gland. Its antiemetic effect may be 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 concentrations detected in the brain, indicate that domperidone acts predominantly on peripheral dopamine receptors.

In humans, orally administered domperidone increases lower esophageal sphincter pressure, improves antroduodenal motility, and accelerates gastric emptying. Domperidone does not affect gastric secretion.

Effect on QT/QTc interval and cardiac electrophysiology.

According to ICH E14 guidelines, a thorough QT interval study was conducted. This study was double-blind, placebo-controlled, and involved healthy volunteers receiving recommended and supratherapeutic doses (10 and 20 mg four times daily). With administration of 20 mg domperidone 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. No clinically significant effects on QTc were observed in the study with domperidone doses up to 80 mg daily (more than double the maximum recommended dose).

These results are further supported by pharmacokinetic parameters and QTc data from two earlier studies involving 5-day administration of 20 mg and 40 mg domperidone four times daily. ECGs were recorded before the study, on day 5 at 1 hour (approximately at tmax) after the morning dose, and after 3 days. In both studies, no difference in QTc was observed between active treatment and placebo. Thus, it was concluded that domperidone administration at doses of 80 mg 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 within approximately 60 minutes. Cmax and AUC values of domperidone increased proportionally with doses in the range of 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 bioavailability of oral domperidone (approximately 15%) is due to extensive first-pass metabolism in the intestinal wall and liver. Although domperidone bioavailability increases when taken after food, patients with gastrointestinal symptoms should take domperidone 15–30 minutes before meals.

Reduced gastric acidity decreases domperidone absorption. Bioavailability after oral administration is reduced when co-administered with cimetidine and sodium bicarbonate. When the drug 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; peak plasma levels at 90 minutes (21 ng/mL) after two weeks of oral dosing at 30 mg daily were nearly the same as after the first dose (18 ng/mL). Domperidone is 91–93% bound to plasma proteins. Animal distribution studies 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 showed that CYP3A4 is the main cytochrome P450 isoform involved in N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 are involved in aromatic hydroxylation of domperidone.

Elimination. Excretion in urine and feces accounts for 31% and 66% of the oral dose, respectively. Unchanged domperidone excretion represents a small fraction (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 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), 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 elimination half-life was prolonged from 15 to 23 hours. In patients with mild hepatic impairment, slightly lower exposure (based on Cmax and AUC data) was observed compared to healthy volunteers, without changes in protein binding or elimination half-life duration. The use of the drug in patients with severe hepatic impairment has not been studied. Domrid® is contraindicated in patients with moderate to severe hepatic impairment (see section "Contraindications").

Renal impairment. In patients with severe renal impairment (serum creatinine > 6 mg/100 mL, i.e., > 0.6 mmol/L), the elimination 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 domperidone (approximately 1%) is excreted unchanged by the kidneys, 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.

Paediatric population. Pharmacokinetic data in children are lacking.

Clinical characteristics.

Indications.

For relief of symptoms of nausea and vomiting.

Contraindications.

Domrid® is contraindicated:

in patients with known hypersensitivity to the active substance or to any of the excipients;
in patients with prolactin-secreting pituitary tumors (prolactinomas);
in patients with severe or moderate hepatic impairment (see sections "Special precautions for use" and "Pharmacological properties");
in patients with known prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalances or underlying heart diseases such as congestive heart failure (see section "Special precautions for use");
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 "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

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.

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

Domperidone is metabolized predominantly via CYP3A4. In vitro and human studies have shown that concomitant use 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 for use").

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 antiarrhythmic agents (e.g., disopyramide, quinidine, hydroquinidine);
Class III antiarrhythmic agents (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 agents (e.g., toremifene, vandetanib, vincaamine);
certain other agents (e.g., bepridil, methadone, difemanyl) (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").

Examples of potent CYP3A4 inhibitors with which Domrid® must 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*;
amrepidant;
nefazodone.

* Prolong QTc interval.

Concomitant use of the following substances requires caution.

Use with caution with medicinal products that cause bradycardia and hypokalemia, as well as with macrolides that may prolong the QT interval: 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® may be combined with:

neuroleptics, whose action 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 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 interval prolongation averaged 9.8 ms during the observation period; individual values ranged from 1.2 to 17.5 ms. When 10 mg domperidone was administered four times daily concomitantly with 500 mg erythromycin orally three times daily, QTc interval prolongation averaged 9.9 ms during the observation period, with individual values ranging from 1.6 to 14.3 ms. 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 the QTc interval by an average of 1.6 ms (ketoconazole study) and 2.5 ms (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 ms and 4.9 ms, respectively, during the observation period.

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

Special precautions for use.

Domrid® is not recommended for use in cases of dehydration.

The medicinal product should be used with caution in elderly patients or in patients with existing heart diseases or a history of heart disease.

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/flutter have been reported in patients taking domperidone. These reports included information on patients who had other risk factors, electrolyte disturbances, and were receiving concomitant therapy that could be a contributing factor (see section "Adverse reactions"). According to ICH E14 guidelines, a thorough QT study was conducted in healthy subjects. The QT interval prolongation observed in the study with domperidone administered at doses up to 80 mg/day (10 or 20 mg four times daily) was not considered clinically significant.

Due to the increased risk of ventricular arrhythmia, Domrid® is contraindicated in patients with prolonged cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, as well as in patients with concomitant 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 suggestive of cardiac arrhythmia occur, treatment with Domrid® should be discontinued immediately and the patient should consult a physician without delay.

Patients should report any cardiac symptoms immediately.

Warning. 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 (serum creatinine > 6 mg/100 mL, i.e., > 0.6 mmol/L). In long-term treatment, the dosing frequency of domperidone should be reduced to 1–2 times daily depending on the severity of impairment. A dose reduction may also be necessary.

Antacid or antisecretory medicinal products should not be taken simultaneously with Domrid® as they reduce the oral bioavailability of domperidone (see section "Interaction with other medicinal products and other forms of interaction"). When used concomitantly, Domrid® 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 of concomitant use with apomorphine outweighs the risks, and only if strict adherence to the precautions outlined in the apomorphine product information is maintained.

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

The following information regarding the risk of cardiovascular complications associated with domperidone-containing medicinal products should be taken into account:

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 and older, with oral doses exceeding 30 mg/day, and in patients concurrently taking medicinal products that prolong the QT interval or CYP3A4 inhibitors. Therefore, Domrid® should be used with caution in elderly patients. Patients aged 60 years and older should consult their physician before taking the medicinal product.
Domperidone should be prescribed to adults and adolescents aged 12 years and older at the lowest effective dose.

The benefit-risk balance of domperidone use remains favorable.

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

If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking Domrid®, as this medicinal product contains lactose.

Use during pregnancy or breastfeeding.

Pregnancy. Data on post-marketing use of domperidone in pregnant women are limited. Animal studies have shown reproductive toxicity at maternally toxic doses. Therefore, Domrid® should be used during pregnancy only if, in the physician’s opinion, the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding. The amount of domperidone that may pass into the infant via 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 may harm the infant; therefore, mothers taking Domrid® should avoid breastfeeding. The decision to discontinue breastfeeding or to discontinue domperidone therapy should be made after considering 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 prolongation in breastfed infants. The occurrence of adverse reactions due to the passage of the medicinal product into breast milk, particularly cardiovascular effects, cannot be excluded.

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

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

Adults and adolescents aged 12 years and older with body weight of at least 35 kg: 1 tablet (10 mg) three times daily.

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

It is recommended to take Domrid® orally 15–30 minutes before meals. Absorption of the drug is slightly delayed when taken after food. The patient should take the medicinal product according to the recommended dosing regimen. 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 the missed dose.

The treatment duration should not exceed 1 week.

Adults aged > 60 years.

Patients aged 60 years and older should consult a physician before taking Domrid®.

Patients with renal impairment.

Since the elimination half-life of domperidone is prolonged in patients with severe renal impairment (serum creatinine > 6 mg/100 mL, i.e. > 0.6 mmol/L), the frequency of administration of Domrid® should be reduced to once or twice daily, depending on the severity of impairment. Dose reduction may also be required. Patients with severe renal impairment should be monitored regularly (see sections “Pharmacological properties” and “Special precautions for use”).

Patients with hepatic impairment.

Domrid® 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 efficacy of domperidone in children under 12 years of age has not been established.

The efficacy of domperidone in adolescents aged 12 years and older with body weight less than 35 kg has not been established.

The medicinal product is indicated for treatment in adolescents aged 12 years and older with body weight of at least 35 kg.

Domperidone should be prescribed to children at the lowest effective dose for the shortest possible duration.

Overdose.

Symptoms. Overdose has been observed mainly in infants and children. Symptoms of overdose may include agitation, impaired consciousness, seizures, drowsiness, disorientation, and extrapyramidal reactions.

Treatment. There is no specific antidote for domperidone. However, in cases of significant overdose, standard symptomatic treatment should be initiated immediately. Gastric lavage within 1 hour after drug intake and administration of activated charcoal are recommended, along with close patient monitoring and supportive therapy. ECG monitoring should be performed due to the potential for QT interval prolongation.

Anticholinergic drugs and medications used to treat Parkinson’s disease may be effective in managing extrapyramidal reactions.

Adverse Reactions

Adverse reactions identified from clinical trials with domperidone are listed below by organ system and frequency of occurrence: very common (≥ 1/10); common (from ≥ 1/100 to <1/10); uncommon (from ≥ 1/1000 to <1/100); rare (from ≥ 1/10000 to <1/1000); very rare (<1/10000). If frequency cannot be determined from clinical trial data, it is listed as unknown.

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

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

Endocrine system 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; frequency unknown — convulsions, restless legs syndrome (exacerbation of restless legs syndrome in patients with Parkinson’s disease).

Cardiovascular system disorders: very rare — edema, palpitations, disturbances in heart rate and rhythm, serious ventricular arrhythmias; frequency unknown — 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.

Skin and subcutaneous tissue disorders: uncommon — pruritus, rash, urticaria; frequency unknown — angioneurotic edema.

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

Musculoskeletal and connective tissue disorders: rare — leg pain.

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

General disorders: uncommon — asthenia.

Eye disorders: frequency unknown — oculogyric crises.

Other: conjunctivitis, stomatitis.

Laboratory test abnormalities: very rare — increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and cholesterol levels; frequency unknown — abnormal liver function test results, increased blood prolactin levels.

In 45 studies where domperidone was used at higher doses, for longer durations, and for additional indications including diabetic gastroparesis, 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 can cause increased prolactin levels. In isolated cases, this hyperprolactinemia may lead to neuroendocrine adverse effects such as galactorrhea, gynecomastia, and amenorrhea.

During post-marketing use, no differences in safety profile 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 of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and 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.

4 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 1 or 3 blisters in a cardboard package.

Prescription status.

Over-the-counter.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and place of business.

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

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and place of business.

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