Domperidone-stoma

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOMPERIDONE-STOMA

Composition:

Active substance: domperidone;

1 tablet contains 10 mg of domperidone;

Excipients: lactose monohydrate, potato starch, povidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white tablets with a biconvex surface.

Pharmacotherapeutic group. Agents used for functional gastrointestinal disorders. Prokinetic agents. ATC code A03F A03.

Pharmacological Properties.

Pharmacodynamics.

Domperidone is a dopamine antagonist with antiemetic properties. Domperidone penetrates the blood-brain barrier to a minimal extent. The use of domperidone is very rarely associated with extrapyramidal side effects, particularly in adults, but domperidone stimulates prolactin release from the pituitary gland. Its antiemetic effect results from 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.

Human studies 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.

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

This lack of clinical significance is supported by pharmacokinetic parameters and QTc interval data obtained from two earlier studies involving 5-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 after 3 days. In both studies, no difference was observed between QTc intervals after 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 reached within approximately 60 minutes. Cmax and AUC values of domperidone increased proportionally with dose in the range of 10 to 20 mg. A 2- to 3-fold accumulation of domperidone (AUC) was observed upon 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 in healthy volunteers, 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, 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; maximum 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 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 demonstrated 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.

Excretion.

Excretion via urine and feces accounts for 31% and 66% of the oral dose, respectively. Only a small percentage of the drug is excreted unchanged (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 unbound 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 was observed compared to healthy volunteers, based on Cmax and AUC, without changes in protein binding or terminal elimination half-life. The use of the drug in patients with severe hepatic impairment has not been studied. The drug is contraindicated in patients with moderate or 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. Since only a very small amount of the drug (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 (see section "Dosage and administration").

Clinical characteristics.

Indications.

For relief of symptoms of nausea and vomiting.

Contraindications.

The drug is contraindicated:

• in patients with known hypersensitivity to the active substance or to any of the excipients;
• in patients with prolactin-secreting pituitary tumor (prolactinoma);
• in patients with severe or moderate impairment of liver and/or kidney function (see sections "Pharmacological properties", "Special precautions for use");
• in patients with known prolongation of cardiac conduction intervals underlying cardiac disorders or diseases, particularly QTc interval, 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 "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 antidyspeptic effect of domperidone. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation increases.

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

Domperidone is predominantly metabolized via CYP3A4. In vitro studies have shown that co-administration with medicinal products that strongly inhibit this enzyme may lead to increased plasma levels of domperidone.

Clinically significant changes in QT interval 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, an increase in domperidone plasma concentration (up to 30–40%) has 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 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, vinca alkaloids);
• certain other agents (e.g., bepridil, methadone, diphenylmethylpiperidyl methiodide).
• apomorphine, except when benefit outweighs risks and strict adherence to recommended precautions for concomitant use is ensured (see apomorphine product information, section "Contraindications").

Examples of potent CYP3A4 inhibitors with which concomitant use of domperidone is contraindicated:

• azole antifungal agents 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*;
• amperitan;
• nefazodone;
• telithromycin*.

*prolong QTc interval.

Concomitant use of the following substances requires caution.

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

Domperidone should be used cautiously 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 above list is representative but not exhaustive.

Domperidone 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 specific in vivo pharmacokinetic/pharmacodynamic interaction studies, co-administration of ketoconazole or erythromycin orally has confirmed that these medicinal products significantly inhibit presystemic metabolism of domperidone mediated by CYP3A4 in healthy volunteers.

When 10 mg domperidone four times daily was administered concomitantly with 200 mg ketoconazole orally twice daily, QTc interval was prolonged on average by 9.8 msec; 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 during the observation period, 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 the observed QTc effect is unknown. In these studies, monotherapy with domperidone (10 mg orally four times daily) prolonged QTc interval on average by 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 an increase in QTc interval during observation period by 3.8 and 4.9 msec, respectively.

Theoretically, since domperidone exerts a prokinetic effect on the stomach, it may influence the absorption of concurrently administered oral medicinal products, 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 medicinal products.

Special precautions for use.

Domperidone is not recommended for use in shaken conditions.

Domperidone should be used with caution in elderly patients and/or patients with existing heart disease or history of heart disease.

Cardiovascular effects.

Domperidone has been associated with QT interval prolongation on ECG. Very rare cases of QT prolongation and ventricular fibrillation/flutter have been reported during post-marketing surveillance in patients taking domperidone. These reports included information on patients with other predisposing risk factors, electrolyte disturbances, and concomitant therapies that could be contributing factors (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 according to the recommended dosage regimen at usual therapeutic doses (10 or 20 mg four times daily) was not considered clinically significant.

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

If signs or symptoms suggestive of cardiac arrhythmia occur, treatment with domperidone should be discontinued immediately and the patient should seek medical advice without delay.

Patients should promptly report any cardiac symptoms.

Warnings.

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

Excipients.

The medicinal product contains lactose; therefore, patients with rare hereditary forms of lactose intolerance, galactose intolerance, galactosemia, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicinal product.

Renal impairment.

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

Antacid or antisecretory medicinal products should not be taken simultaneously with domperidone, as they reduce the oral bioavailability of domperidone (see section "Interaction with other medicinal products and other forms of interaction"). When used concomitantly, domperidone 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.

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

The following information regarding the risk of cardiovascular complications associated with domperidone-containing medicinal products 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 (see section "Adverse reactions");
• 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, and in patients concurrently taking medicinal products that prolong the QT interval or CYP3A4 inhibitors. Therefore, domperidone should be used with caution in elderly patients. Patients aged 60 years or older should consult a physician before taking the medicinal product;
• Domperidone should be prescribed to adults and children at the lowest effective dose.

The benefit-risk balance of domperidone remains favorable.

Use during pregnancy or breastfeeding.

Pregnancy.

Data on post-marketing use of domperidone in pregnant women are limited. Therefore, domperidone 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.

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 harms the infant; therefore, mothers taking domperidone should avoid breastfeeding. The decision to discontinue breastfeeding or to stop domperidone therapy should be made after weighing the benefits of breastfeeding for the child and the benefits of therapy for the mother.

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

Ability to affect reaction speed when driving or operating machinery.

Dizziness and somnolence have been reported after administration of domperidone. 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 the medicinal product affects them.

Dosage and method of administration

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

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).

The drug should be taken orally before meals. Absorption of the drug is slightly delayed when administered after food intake. The patient should take the drug according to the recommended dosing regimen. If a dose has been 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.

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 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 required. Patients with severe renal impairment should be monitored regularly (see section "Pharmacological properties").

Hepatic impairment.

The drug 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 in 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.

Symptoms: Overdose has been reported primarily in infants and children. Symptoms of overdose may include agitation, altered consciousness, seizures, somnolence, disorientation, and extrapyramidal disorders.

Treatment: There is no specific antidote for domperidone. However, in cases of significant overdose, immediate symptomatic treatment should be provided. 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 antiparkinsonian agents may be effective in managing extrapyramidal reactions.

Side effects.

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 studies. 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 (≥ 1/10,000 to <1/1000); very rare (<1/10,000). If the 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 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, irritability, nervousness; 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, clinically significant ventricular arrhythmias; frequency unknown – QT interval prolongation, ventricular arrhythmias of the type 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 – itching, rash, urticaria; frequency unknown – angioneurotic edema.

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

Musculoskeletal and connective tissue disorders: rare – leg pain.

Urinary system 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 – deviations from normal 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 use between adults and children were 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 approval is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children.

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

Packaging.

10 tablets per blister; 3 blisters per carton.

Prescription status. Over-the-counter.

Manufacturer. JSC "STOMA".

Manufacturer's address and location of operations.

3, Newtona Street, Kharkiv, 61105, Ukraine.