Domidon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOMIDON® (DOMIDONE)

Composition:

Active substance: domperidone;

1 tablet contains 10 mg of domperidone;

Excipients: lactose monohydrate; corn starch; microcrystalline cellulose; pregelatinized starch; povidone; magnesium stearate;

film coating: Sepifilm 752 Blanc (hypromellose, microcrystalline cellulose, polyethylene glycol (macrogol 40), titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Drugs 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 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 observed, indicate that domperidone primarily exerts its effects 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/QTc interval and cardiac electrophysiology

According to ICH-E14 international guidelines, a thorough QT interval study was conducted in healthy subjects. This was a double-blind, placebo-controlled study using recommended and supratherapeutic doses (10 and 20 mg four times daily). With administration of 20 mg domperidone four times daily, QT interval prolongation was observed, with changes ranging from 3.4 to 5.9 ms throughout the observation period, and this parameter did not exceed 10 ms. The QT prolongation observed in this study when domperidone was administered at the recommended dose was not considered clinically significant.

This lack of clinical significance is supported by pharmacokinetic parameters and QTc data from two earlier studies involving 5-day treatment with 20 mg and 40 mg of domperidone four times daily. ECGs were recorded before treatment, on day 5 at approximately 1 hour (around tmax) after the morning dose, and 3 days after treatment. In both studies, no difference in QTc was observed between active treatment and placebo. Therefore, it was concluded that domperidone administration 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 reached approximately within 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 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 administered orally after food, maximum absorption is slightly delayed, and AUC is slightly increased.

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 daily was 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 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 primary cytochrome P450 isoenzyme involved in N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 are involved in aromatic hydroxylation of domperidone.

Elimination

Excretion via urine and feces accounts for 31% and 66% of the oral dose, respectively. Unchanged drug 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 groups

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, exposure was slightly lower than in healthy volunteers based on Cmax and AUC, with no changes in protein binding or terminal half-life. 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 clearance < 30 mL/min/1.73 m²), the elimination half-life of domperidone is prolonged from 7.4 to 20.8 hours, but plasma drug concentrations are lower than in patients with normal renal function. A very small amount of the drug (approximately 1%) is excreted unchanged in urine. It is unlikely that dose adjustment will be required for single doses 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.

For relief of symptoms of nausea and vomiting.

Contraindications.

Domidon® is contraindicated:

• in patients with known hypersensitivity to the drug or to excipients;
• in patients with established prolactin-secreting pituitary tumor (prolactinoma);
• in patients with severe or moderate hepatic and/or renal impairment (see section "Special precautions for use", "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");
• in patients with hepatic insufficiency;
• 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 inhibitors of CYP3A4 is contraindicated;
• 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 precautions for use" and "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Anticholinergic drugs may counteract the antidyspeptic effect of Domidon®. 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 Domidon®, as they reduce its bioavailability after oral administration (see section "Special precautions for use").

Domperidone is metabolized predominantly via CYP3A4. According to in vitro studies, concomitant use of drugs that significantly inhibit this enzyme may lead to increased plasma levels of domperidone.

When domperidone is used concomitantly with potent CYP3A4 inhibitors capable of prolonging the QT interval, clinically significant changes in the QT interval have been observed. 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, increased plasma concentrations of domperidone (up to 30–40%) have been observed when administered concomitantly 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);
• some neuroleptics (e.g., haloperidol, pimozide, sertindole);
• some antidepressants (e.g., citalopram, escitalopram);
• some antibiotics (e.g., levofloxacin, moxifloxacin, erythromycin, spiramycin);
• some antifungal agents (e.g., fluconazole, pentamidine);
• some antimalarials (e.g., halofantrine, lumefantrine);
• some gastrointestinal agents (e.g., cisapride, dolasetron, prucalopride);
• some antihistamines (e.g., mizolastine, mequitazine);
• some oncology drugs (e.g., toremifene, vandetanib, vincamine);
• some other drugs (e.g., bepridil, methadone, diphenylamine);
• apomorphine, except when benefit outweighs risk and under strict adherence to recommended precautions for concomitant use (see apomorphine prescribing information, section "Contraindications").

Examples of strong CYP3A4 inhibitors with which Domidon® use is contraindicated:

• 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 together with drugs causing bradycardia and hypokalemia, as well as with the following macrolides that may cause QT interval prolongation: azithromycin and roxithromycin (clarithromycin is contraindicated due to being a potent CYP3A4 inhibitor).

Domperidone should be used cautiously concomitantly 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 list of active substances above is representative but not exhaustive.

Domidon® may be combined with:

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

In individual studies of pharmacokinetic/pharmacodynamic interaction in vivo, concomitant oral administration of ketoconazole or erythromycin in healthy volunteers confirmed that these drugs significantly inhibit 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 prolonged on average by 9.9 ms, 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 the observed QTc effect is unknown. In these studies, monotherapy with domperidone (10 mg orally four times daily) prolonged 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 interval increases of 3.8 ms and 4.9 ms, respectively, during the observation period.

Theoretically, since Domidon® 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 whose condition has already been stabilized on digoxin or paracetamol, concomitant administration of domperidone did not affect blood levels of these drugs.

Special precautions for use.

Domidon® is not recommended during pregnancy.

Domidon® should be used with caution in elderly patients or in patients with existing heart disease or 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/torsades de pointes have been reported in patients taking domperidone. These reports included information on patients with other risk factors, electrolyte imbalances, and concomitant therapies that may contribute to the development of this condition (see section "Adverse reactions").

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

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

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

If signs or symptoms suggestive of cardiac arrhythmia occur, Domidon® 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. In long-term treatment, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of impairment. A dose reduction may also be necessary.

Antacid or antisecretory agents should not be taken simultaneously with oral formulations of Domidon® as they reduce the oral bioavailability of domperidone (see section "Interaction with other medicinal products and other forms of interaction"). When used concomitantly, Domidon® should be taken before meals and antacid or antisecretory agents 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 risk and only if strict adherence to the precautions stated in the apomorphine product information is ensured.

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").

Domidon® tablets contain lactose and therefore should not be administered to patients with lactose intolerance, galactosemia, or glucose/galactose malabsorption.

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

The benefit-risk ratio of domperidone remains favorable.

Use during pregnancy or breastfeeding.

Pregnancy

Data on post-marketing use of domperidone in pregnant women are limited. Therefore, Domidon® should be administered during pregnancy only if, in the opinion of the physician, 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 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 Domidon® should avoid breastfeeding. The decision to discontinue breastfeeding or to discontinue domperidone therapy should be made after considering the benefits of breastfeeding to the child and the benefits of therapy to the mother. Caution should be exercised in the presence of risk factors for QTc interval prolongation in breastfed infants. Adverse effects, including cardiovascular effects, cannot be excluded after exposure due to passage of the drug into breast milk.

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 other activities requiring concentration and coordination until they know how Domidon® affects them.

Dosage and Administration

For relief of nausea and vomiting symptoms, the drug 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: 1 tablet (10 mg) three times daily.

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

It is recommended to take Domidon® before meals. Absorption of the drug is slightly delayed when taken after food. The patient should take the drug according to the recommended dosing regimen. If a dose is missed, the next dose should be taken according to the recommended schedule. Do not double the dose to compensate for a missed dose. The duration of treatment should not exceed 1 week.

Adults aged ˃ 60 years

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

Renal impairment

Since the elimination half-life of domperidone is prolonged in patients with severe renal impairment, the frequency of Domidon® administration 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 section "Pharmacological Properties").

Hepatic impairment

Domidon® 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 drug is indicated for treatment of children 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

Overdose has been reported primarily in infants and children.

Symptoms: symptoms of overdose may include agitation, impaired consciousness, convulsions, disorientation, drowsiness, and extrapyramidal reactions.

Treatment: there is no specific antidote for domperidone. However, in cases of significant overdose, immediate symptomatic treatment is required. 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 anti-Parkinsonian agents may be effective in controlling extrapyramidal reactions.

Adverse Reactions

The safety of domperidone has been evaluated during clinical studies 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 drug. 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 caused by chemotherapy or Parkinsonism were not included in the studies.

Assessment of the frequency of adverse reactions: 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 estimated from clinical trial data, it is listed as unknown.

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

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 – seizures, 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, QT interval prolongation (frequency unknown), serious ventricular arrhythmias, 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, change in appetite, 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 levels of ALT, AST, and cholesterol; 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 may cause increased prolactin levels. In isolated cases, such hyperprolactinemia may lead to neuroendocrine side effects such as galactorrhea, gynecomastia, and amenorrhea.

During the post-marketing period, 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 effects such as seizures 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 and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Do not use after the expiry date stated on the packaging.

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

Keep out of reach of children.

Packaging. 10 tablets per blister. 1 or 3 blisters per carton.

Prescription status. Over-the-counter.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of its business activities.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.