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

Composition:

Active substance: domperidone;

1 ml of suspension contains 1 mg of domperidone;

Excipients: sucrose, polysorbate 80, colloidal anhydrous silicon dioxide, sodium carboxymethylcellulose, sodium chloride, propylene glycol, glycerin, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), Ponceau 4R (E 124), strawberry flavoring, purified water.

Pharmaceutical form. Oral suspension.

Main physicochemical properties: pink-colored suspension with a characteristic odor.

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 negligible extent. Extrapyramidal side effects are very rare with domperidone use, particularly in adults; however, domperidone stimulates prolactin release 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).

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/QTc and cardiac electrophysiology.

According to ICH-E14 international guidelines, a thorough QT interval study was conducted. This was a double-blind, placebo-controlled study involving healthy volunteers who received domperidone at doses up to 80 mg per day (10 or 20 mg four times daily).

In this study, the maximum difference in QTc between the domperidone group (20 mg four times daily) and placebo was observed on day 4 of therapy and amounted to 3.4 ms (baseline-adjusted, least-squares mean difference). The two-sided 90% upper confidence interval (1.0 to 5.9 ms) did not exceed 10 ms.

No clinically significant QTc effects were observed in this study with domperidone administered at doses up to 80 mg per day (i.e., a dose more than twice the maximum recommended dose).

However, two previous drug interaction studies clearly demonstrated QTc prolongation when domperidone was used as monotherapy (10 mg four times daily). The largest mean differences in QTcF between domperidone and placebo groups were 5.4 ms (95% confidence interval: 1.7–12.4) and 7.5 ms (95% confidence interval: 0.6–14.4), respectively.

Clinical study in children under 12 years of age.

A prospective, multicenter, double-blind, randomized, parallel-group, placebo-controlled clinical trial was conducted to evaluate the safety and efficacy of domperidone in 292 subjects aged from 6 months to 12 years (mean age 7 years) with acute gastroenteritis. Patients received oral rehydration therapy (ORT) three times daily, together with either domperidone suspension at a dose of 0.25 mg/kg (maximum dose up to 30 mg domperidone per day) or placebo. Treatment duration was up to 7 days. This study did not demonstrate greater efficacy (compared to placebo) of combination therapy with domperidone in relieving vomiting symptoms during the first 48 hours of treatment.

Pharmacokinetics.

Absorption.

Domperidone is rapidly absorbed after oral administration on an empty stomach, with peak plasma concentration (Cmax) reached approximately within 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to extensive first-pass metabolism in the intestinal wall and liver. Cmax and the area under the plasma concentration-time curve (AUC) of domperidone increase proportionally with doses in the range of 10 to 20 mg. With repeated dosing of domperidone over 4 days, four times daily (every 5 hours), a 2- to 3-fold increase in AUC was observed.

Although domperidone bioavailability increases when administered after food in healthy volunteers, patients with gastrointestinal complaints should take domperidone 15–30 minutes before meals. Reduced gastric acidity decreases domperidone absorption. Prior concomitant administration of cimetidine and sodium bicarbonate reduces oral bioavailability of domperidone.

Distribution.

After oral administration, domperidone does not accumulate and does not induce its own metabolism; the maximum plasma level at 90 minutes (21 ng/mL) after two weeks of oral dosing at 30 mg per day 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 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 showed that CYP3A4 is the primary cytochrome P450 isoenzyme involved in N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 contribute to aromatic hydroxylation of domperidone.

Elimination.

Excretion via urine and feces accounts for 31% and 66% of the oral dose, respectively. Excretion of unchanged drug is minimal (10% in feces and approximately 1% in urine). The elimination half-life in plasma after a single dose is 7–9 hours in healthy volunteers, but 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 half-life was prolonged from 15 to 23 hours. In patients with mild hepatic impairment, slightly lower exposure was observed compared to healthy volunteers (based on Cmax and AUC data), without changes in protein binding or half-life duration. The use of domperidone in patients with severe hepatic impairment has not been studied. Domperidone 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 was prolonged from 7.4 to 20.8 hours, but plasma drug concentrations were lower compared to individuals with normal renal function.

Since only a very small amount of the drug (approximately 1%) is excreted unchanged in urine, dose adjustment is unlikely to be necessary for single doses in patients with renal impairment. With chronic use, the dosing frequency of domperidone should be reduced to 1–2 times daily depending on the severity of impairment. A reduction in dose may also be required.

Clinical characteristics.

Indications.

For relief of symptoms of nausea and vomiting.

Contraindications.

Domrid® is contraindicated:

in patients with known hypersensitivity to domperidone or to any of the excipients of the medicinal product;
in patients with established prolactin-secreting pituitary tumor (prolactinoma);
in patients with moderate or severe 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 with 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;
in patients with hepatic insufficiency.

Concomitant use of ketoconazole, erythromycin, or other potent inhibitors of CYP3A4 (regardless of their ability to prolong the QT interval) is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of medicinal products that prolong the QT interval (except for apomorphine) is contraindicated, 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.

Antacids and antisecretory agents should not be taken simultaneously with domperidone, as they reduce its bioavailability after oral administration (see section "Special precautions for use"). When used concomitantly, Domrid® should be taken before meals, and antacids or antisecretory agents should be taken after meals.

Concomitant use with levodopa.

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

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

Domperidone is metabolized primarily 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 prolongation has been observed when domperidone is 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 of the following medicinal products with domperidone is contraindicated.

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

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 agents (e.g., cisapride, dolasetron, prucalopride);
certain antihistamines (e.g., mequitazine, mizolastine);
certain oncology drugs (e.g., toremifene, vandetanib, vincaamine);
certain other drugs (e.g., bepridil, methadone, diphenylperamine) (see section "Contraindications");
apomorphine, except when the benefit of concomitant use outweighs the risks, and only under strict adherence to recommendations for concomitant use (see section "Contraindications"). Safety recommendations for apomorphine use provided in its medical instructions should be taken into account.

Potent CYP3A4 inhibitors with which Domrid® use is contraindicated include:

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

* Prolongs QTc interval.

Concomitant use of the following substances requires caution.

Domperidone should be used cautiously 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 due to its potent CYP3A4 inhibition).

Caution is required when using domperidone concomitantly with potent CYP3A4 inhibitors that do not prolong the QT interval, 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 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 individual studies of pharmacokinetic/pharmacodynamic interaction in vivo, co-administration of ketoconazole or erythromycin with domperidone 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, with individual values ranging 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 plasma concentrations of domperidone 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) increased the QTc interval during observation by 3.8 ms and 4.9 ms, respectively.

Since domperidone exerts a prokinetic effect on the stomach, it may theoretically affect the absorption of concomitantly administered oral medicinal products, particularly prolonged-release or enteric-coated formulations. 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® is not recommended for use during lactation.

The drug should be used with caution in elderly patients and in patients with existing heart diseases, including in medical history.

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

Renal function 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). During long-term treatment, the dosing frequency of domperidone should be reduced to 1–2 times daily depending on the severity of impairment. Dose reduction may also be necessary.

Cardiovascular effects.

Domperidone has been associated with QT interval prolongation on ECG. In post-marketing surveillance, very rare cases of QT prolongation and ventricular tachycardia of the torsade de pointes type have been reported in patients taking domperidone. These reports included cases in patients with other risk factors, electrolyte disturbances, and concomitant therapies that could be contributing factors (see section "Adverse reactions"). According to ICH-E14 guidelines, a thorough QT interval 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.

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 has been reported in patients aged 60 years and older, in patients receiving doses exceeding 30 mg/day, and in patients receiving domperidone concomitantly with drugs capable of prolonging the QT interval or CYP3A4 inhibitors.

Domperidone should be administered at the lowest effective dose.

Due to the increased risk of ventricular arrhythmia, domperidone 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 underlying heart diseases such as congestive heart failure due to increased risk of ventricular arrhythmia (see section "Contraindications"). Electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia are known 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 seek medical advice without delay.

Patients should be informed of the necessity to report immediately any cardiovascular symptoms.

Antacid or antisecretory agents 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"). If used concomitantly, Domrid® should be taken before meals and antacid or antisecretory agents 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 outweighs the risks, and only under strict adherence to recommended measures for concomitant use. The safety recommendations for apomorphine use contained in its medical instructions should be considered.

Use with ketoconazole.
In interaction studies with oral ketoconazole, QT interval prolongation has been observed. Although the clinical significance of these data is not clearly established, an 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 benefit-risk ratio of domperidone use remains favorable.

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

The product contains the dye Ponceau 4R, which may cause allergic reactions. Methylparahydroxybenzoate and propylparahydroxybenzoate contained in the formulation may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding.

Pregnancy.

Data on post-marketing use of domperidone in pregnant women are limited. Reproductive toxicity was observed in rat studies following administration of high, maternally toxic doses. The potential risk in humans is unknown. Therefore, Domrid® should be prescribed during pregnancy only when, 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’s body via breast milk is estimated to be less than 0.1% of the maternal dose adjusted for body weight. Adverse effects, including cardiovascular effects, cannot be ruled out following exposure due to transfer of the drug into breast milk. Since it is unknown whether the medicinal product is harmful to the infant, mothers taking Domrid® should avoid breastfeeding.

The decision to discontinue breastfeeding or to discontinue/abstain from domperidone therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Caution should be exercised in the presence of risk factors for QTc interval prolongation in children who are breastfed.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

To relieve symptoms of nausea and vomiting, Domrid® should be used at the lowest effective dose for the shortest possible duration.

Adults and children aged 12 years and older with body weight of at least 35 kg: 10 mL of suspension (10 mg) up to 3 times daily.

Maximum daily dose – 30 mL of suspension (30 mg).

It is recommended to take Domrid® orally 15–30 minutes before meals. Absorption of the drug is somewhat delayed when taken after food intake.

Patients should take each dose at regular intervals. If a dose is missed, it should not be taken at an unscheduled time; instead, patients should continue following the prescribed dosing regimen. The dose should not be doubled to compensate for a missed dose.

The duration of treatment should not exceed 1 week.

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").

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 necessary. Patients with severe renal impairment should be monitored regularly (see sections "Pharmacological properties" and "Special precautions for use").

Children.

The efficacy of domperidone in children under 12 years of age has not been established (see section "Pharmacological properties"). The efficacy of domperidone in children aged 12 years and older with body weight less than 35 kg has not been established.

Adults aged ˃ 60 years.

Patients aged 60 years and older should consult a physician before taking the medication.

Children.

Domrid® should be used to treat children aged 12 years and older with body weight of at least 35 kg at the lowest effective dose for the shortest possible duration.

Overdose.

Cases of overdose have been reported, primarily in infants and children.

Symptoms.

Symptoms of overdose may include agitation, altered consciousness, seizures, disorientation, drowsiness, and extrapyramidal disorders.

Treatment.

There is no specific antidote for domperidone. In case of overdose, standard symptomatic treatment should be initiated immediately, including gastric lavage within 1 hour after drug intake, administration of activated charcoal, and supportive therapy. Close monitoring of the patient, including ECG monitoring, is required, as QT interval prolongation may occur. Anticholinergic drugs and medications 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. The frequency of occurrence is defined according to the following categories: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10,000 to <1/1000); very rare (<1/10,000). If the frequency cannot be estimated from clinical trial data, it is listed as unknown.

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

Immune system disorders:
Frequency unknown — 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; frequency unknown — convulsions, restless legs syndrome*.

Eye disorders:
Frequency unknown — oculogyric crises.

Cardiac and vascular disorders:
Very rare — oedema, 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 (see section "Special Warnings and Precautions for Use").

Gastrointestinal disorders:
Common — dry mouth; uncommon — diarrhoea; 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 oedema.

Reproductive system and breast disorders:
Rare — breast enlargement, galactorrhoea, breast oedema, lactation disorders, irregular menstrual cycle; uncommon — galactorrhoea, breast pain, breast tenderness; frequency unknown — gynaecomastia, amenorrhoea.

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.

Other:
Conjunctivitis, stomatitis.

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

* Exacerbation of restless legs syndrome in patients with Parkinson’s disease.

Since the pituitary gland lies outside the blood-brain barrier, domperidone may cause an increase in prolactin levels. In isolated cases, this hyperprolactinaemia may lead to neuroendocrine adverse effects such as galactorrhoea, gynaecomastia, and amenorrhoea.

During the post-marketing period, no differences in the safety profile of the drug 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 observed predominantly 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, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

After first opening of the bottle, the product should not be stored for more than 3 months.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

60 ml or 100 ml in bottles. Each bottle is packed in a cardboard box with a measuring spoon.

Prescription status. Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of business activity.

40020, Ukraine, Sumy region, city of Sumy, Skryabina St., 54.