Motinorm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MOTINORM (MOTINORM)

Composition:

Active substance: domperidone;

1 tablet contains 10 mg of domperidone;

Excipients: lactose monohydrate; maize starch; magnesium stearate.

Pharmaceutical form. Tablets.

Main physical and chemical properties: white or almost white, round tablets with a break line on one side and the inscription "Medley" on the other side.

Pharmacotherapeutic group. Drugs used in 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 adverse effects, particularly in adults, but domperidone stimulates prolactin release from the pituitary gland. Its antiemetic effect is likely due to a combination of peripheral (gastrokinetic) action and antagonism 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 concentrations detected in the brain, indicate that domperidone acts predominantly peripherally on 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.

Pharmacokinetics.

Absorption. Domperidone is rapidly absorbed after oral administration on an empty stomach, with peak plasma concentration 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. Although domperidone bioavailability increases when administered after food intake in healthy individuals, patients with gastrointestinal complaints should take domperidone 15–30 minutes before meals. Reduced gastric acidity decreases domperidone absorption. Oral administration of the drug after food intake slightly delays peak absorption.

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 demonstrated significant 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.

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 is prolonged in patients with severe renal impairment.

Clinical characteristics.

Indications.

For relief of symptoms of nausea and vomiting.

Contraindications.

Motinorm is contraindicated:

• in patients with known hypersensitivity to domperidone or to excipients;
• in patients with prolactin-secreting pituitary tumor (prolactinoma);
• in patients with severe or moderate hepatic and/or renal impairment (see section "Special precautions", "Pharmacological properties");
• in patients with prolonged cardiac conduction intervals, particularly QTc, patients with significant electrolyte imbalances or underlying heart diseases such as congestive heart failure (see section "Special precautions");
• in patients with hepatic insufficiency;
• when stimulation of gastric motility may be dangerous, e.g. in gastrointestinal bleeding, mechanical obstruction or perforation.

Concomitant use of ketoconazole, erythromycin or other potent CYP3A4 inhibitors is contraindicated.

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 is contraindicated (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Anticholinergic drugs may counteract the anti-dyspeptic effect of Motinorm. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation increases.

Antacid and antisecretory drugs should not be taken simultaneously with Motinorm, as they reduce its bioavailability after oral administration (see section "Special precautions").

Domperidone is metabolized predominantly via CYP3A4. In vitro studies indicate that 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 used 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);
• 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 drugs (e.g., cisapride, dolasetron, prucalopride);
• certain antihistamines (e.g., mequitazine, mizolastine);
• certain oncology drugs (e.g., toremifene, vandetanib, vincamine);
• certain other drugs (e.g., bepridil, methadone, difemalane);
• apomorphine — except when benefit outweighs risks, and provided all recommended precautions are taken (see apomorphine product information, section "Contraindications").

Potent CYP3A4 inhibitors:

• 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 with drugs causing bradycardia and hypokalemia, as well as with macrolides that may cause QT interval prolongation, namely 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.

Motinorm may be combined with:

• neuroleptics, whose effects 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 in vivo pharmacokinetic/pharmacodynamic interaction studies, concomitant oral administration of ketoconazole or erythromycin to healthy volunteers confirmed that these drugs significantly inhibit the presystemic metabolism of domperidone mediated by CYP3A4. During coadministration of 10 mg domperidone orally four times daily and 200 mg ketoconazole orally twice daily, QTc interval prolongation averaged 9.8 ms (range: 1.2 to 17.5 ms). During coadministration of 10 mg domperidone four times daily and 500 mg erythromycin orally three times daily, QTc interval was prolonged on average by 9.9 ms (range: 1.6 to 14.3 ms). Steady-state Cmax and AUC values of domperidone increased approximately threefold in each of these interaction studies. The role of elevated plasma concentrations of domperidone in the observed QTc effects is unknown. In these studies, monotherapy with domperidone (10 mg orally four times daily) prolonged QTc interval by 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 QTc interval during observation period by 3.8 ms and 4.9 ms, respectively.

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

Special precautions for use.

Motinorm is not recommended during shaking.

Motinorm should be used with caution in elderly patients or in patients with existing heart disease or a history of heart disease.

Cardiovascular effects. The use of 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 patients also had other risk factors, including electrolyte disturbances and concomitant therapy (see section "Adverse reactions").

According to ICH-E14 guidelines, a QT interval study was conducted in healthy subjects. The QT interval prolongation observed in the study with domperidone administered according to the recommended dosing regimen (10 or 20 mg four times daily) was not considered clinically significant.

Warnings. Domperidone should be used with caution in patients with mild impairment of liver and/or kidney function.

Due to the increased risk of ventricular arrhythmia, Motinorm is contraindicated in patients with prolonged cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia), bradycardia, or underlying heart diseases 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, Motinorm should be discontinued immediately and the patient should seek immediate medical advice. Patients should promptly report any cardiac symptoms.

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

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

Excipients. Motinorm 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 developing cardiovascular complications associated with medicinal products containing domperidone:

• Some epidemiological studies have shown that domperidone increases the risk of serious ventricular arrhythmias or sudden cardiac death (see section "Adverse reactions").
• The risk of serious ventricular arrhythmias or sudden cardiac death is higher in patients aged 60 years and older, with oral doses exceeding 30 mg per day, and in patients taking concomitant medications that prolong the QT interval or CYP3A4 inhibitors. Therefore, Motinorm should be used with caution in elderly patients. Patients aged 60 years and older should consult a physician before taking Motinorm.
• 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, Motinorm should be prescribed 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 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 may harm the infant; therefore, mothers taking Motinorm 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 if risk factors for QTc interval prolongation are present in breastfed infants. If the drug passes into breast milk, adverse effects, including cardiovascular effects, cannot be excluded.

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 other activities requiring concentration and coordination until they have determined how Motinorm affects them.

Method of administration and dosage.

For relief of nausea and vomiting symptoms.

Adults and children aged 12 years and older with body weight of at least 35 kg: 1 tablet (10 mg) 3 times daily.

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

It is recommended to take Motinorm before meals. Drug absorption is slightly delayed when taken after food. The duration of treatment should not exceed 1 week.

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 administered to children at the lowest effective dose for the shortest possible duration.

Overdose.

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

Treatment. There is no specific antidote for domperidone. However, in case 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 anti-Parkinson agents may be effective in controlling extrapyramidal reactions.

Adverse Reactions

The safety of domperidone has been evaluated during clinical trials and post-marketing use.

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, including isolated cases). If the frequency cannot be determined 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 events occur uncommonly.

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, irritability, excitement, 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).

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, changes in appetite, nausea, heartburn, constipation; very rare – transient intestinal spasms.

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

Reproductive system and breast disorders: Rare – breast enlargement/gynecomastia, breast tenderness, galactorrhea, amenorrhea, breast swelling, breast pain, lactation disorders, irregular menstrual cycle; uncommon – galactorrhea.

Musculoskeletal and connective tissue disorders: Rare – leg pain.

Renal and urinary disorders: Very rare – urinary retention, dysuria, frequent urination.

General disorders: Uncommon – asthenia.

Eye disorders: Frequency unknown – oculogyric crises.

Other: conjunctivitis, stomatitis.

Laboratory test abnormalities: Very rare – increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and cholesterol; uncommon – deviations from normal liver function test results; rare – increased blood prolactin levels. Since the pituitary gland lies outside the blood-brain barrier, domperidone may cause an increase in prolactin levels. In isolated cases, such hyperprolactinemia may lead to neuroendocrine adverse effects such as galactorrhea, gynecomastia, and amenorrheal.

During the post-marketing period, no differences in the safety profile of the drug in adults and children were observed, except for extrapyramidal disorders and other central nervous system-related events such as convulsions and excitement, which were observed predominantly in children.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug approval is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 4 years.

Storage conditions. Store in the original packaging at a temperature not exceeding +25 °C, in a place inaccessible to children.

Packaging. 10 tablets in a blister, 3 blisters in a cardboard pack; 10 tablets in a blister, 1 blister in a paper envelope; 10 blisters in a cardboard pack.

Prescription status. Over-the-counter.

Manufacturer.

Medley Pharmaceuticals Ltd.

Manufacturer's address and place of business.

Plot No. 18 and 19, Survey No. 378/7 and 8, 379/2 and 3, Zari Coastway Road, Kachigam, Daman, 396 210, India.