Motilium

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MОTILIUM® (MOTILIUM®)

Composition:

Active substance: domperidone;

One tablet contains 10 mg of domperidone;

Excipients:
Tablet core: lactose monohydrate; corn starch; microcrystalline cellulose; pregelatinized potato starch; povidone; magnesium stearate; hydrogenated cottonseed oil; sodium lauryl sulfate;

Film coating: hypromellose, sodium lauryl sulfate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or slightly cream-colored, round, biconvex film-coated tablets with "JANSSEN" marked on one side and "M 10" on the other side.

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. The use of domperidone is very rarely associated with extrapyramidal side effects, particularly in adults, but domperidone stimulates the release of prolactin from the pituitary gland. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) action and antagonism at dopamine receptors in the chemoreceptor trigger zone located outside the blood-brain barrier in the posterior region (area postrema). Animal studies, as well as low concentrations detected in the brain, indicate that domperidone acts predominantly on peripheral dopamine receptors.

Studies have shown that in humans, following oral administration, 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 study was double-blind, placebo-controlled, and performed using recommended and supratherapeutic doses (10 and 20 mg four times daily). With concomitant administration of 20 mg domperidone four times daily, QT interval prolongation of 3.4–5.9 ms was observed throughout the observation period, and this value did not exceed 10 ms. The QT prolongation observed in this study with domperidone administered at the recommended dosage is not clinically significant.

This lack of clinical significance is supported by pharmacokinetic parameters and QTc interval data obtained from two earlier studies involving 5-day administration of 20 mg and 40 mg domperidone four times daily. ECGs were recorded before the study, on day 5 one hour (approximately at tmax) after the morning dose, and after 3 days. In both studies, no difference was observed between QTc values after active treatment and placebo. Thus, it was concluded that administration of domperidone at doses of 80 and 160 mg daily had no clinically relevant 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 dose in the dose range of 10 to 20 mg. A 2–3-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 in healthy individuals when taken after food, patients with gastrointestinal complaints should take domperidone 15–30 minutes before meals. Reduced gastric acidity decreases domperidone absorption. Bioavailability after oral administration is reduced when taken concomitantly with cimetidine and sodium bicarbonate. When the drug is taken 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 administration at 30 mg daily was almost the same as after the first dose (18 ng/mL). Domperidone is 91–93% bound to plasma proteins. Distribution studies of domperidone conducted in animals using radiolabeled compound showed 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. In vitro metabolism studies using diagnostic inhibitors have shown that CYP3A4 is the main cytochrome P450 isoform involved in N-dealkylation of domperidone, while CYP3A4, CYP1A2, and CYP2E1 are involved in aromatic hydroxylation of domperidone.

Elimination.

Excretion via urine and feces accounts for 31% and 66% of the oral dose, respectively. Excretion of the unchanged drug constitutes a small percentage (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 it 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, 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. Motilium® 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, dosage adjustment is unlikely to be required after a single dose 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 nausea and vomiting symptoms.

Contraindications.

Motilium® is contraindicated:

• in patients with known hypersensitivity to the active substance or to any of the excipients;
• in patients with prolactin-secreting pituitary tumors (prolactinoma);
• in patients with severe or moderate hepatic and/or renal impairment (see sections "Special precautions", "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");
• in patients with hepatic insufficiency;
• when stimulation of gastric motility may be dangerous, e.g., in gastrointestinal hemorrhage, mechanical obstruction, or perforation;
• during concomitant use of ketoconazole, erythromycin, or other potent inhibitors of CYP3A4;
• during concomitant use of medicinal products that prolong the QT interval (with the exception of apomorphine), such as fluconazole, erythromycin, itraconazole, oral ketoconazole, posaconazole, ritonavir, saquinavir, telaprevir, voriconazole, clarithromycin, amiodarone, telithromycin (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 Motilium®. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation is increased.

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

Domperidone is predominantly metabolized via CYP3A4. In vitro studies indicate that concomitant use of drugs that strongly inhibit this enzyme may lead to increased plasma levels of domperidone.

Clinically significant changes in QT interval have been observed when domperidone is used concomitantly with potent CYP3A4 inhibitors capable of prolonging the QT interval. 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 drugs (e.g., cisapride, dolasetron, prucalopride);
• some antihistamines (e.g., mequitazine, mizolastine);
• some oncology drugs (e.g., toremifene, vandetanib, vincaamine);
• some other drugs (e.g., bepridil, methadone, diphenylamine);
• apomorphine, except when benefit outweighs risk and strict adherence to recommended precautions for concomitant use (see apomorphine prescribing information, section "Contraindications").

Examples of strong CYP3A4 inhibitors with which concomitant use of Motilium® 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*;
• amrepitant;
• nefazodone;
• telithromycin*.

* prolong QTc interval.

Concomitant use of the following substances requires caution.

Use with caution together with drugs that may cause bradycardia and hypokalemia, as well as with macrolides that may prolong the QT interval, such as azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).

Domperidone should be used cautiously with potent CYP3A4 inhibitors that do not cause QT prolongation, such as indinavir, and patients should be closely monitored for signs or symptoms of adverse reactions.

The above list is representative but not exhaustive.

Motilium® may be combined with:

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

In specific in vivo pharmacokinetic/pharmacodynamic interaction studies, concomitant oral administration of ketoconazole or erythromycin in healthy volunteers confirmed that these drugs 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 msec during the observation period; individual values ranged from 1.2 to 17.5 msec. When 10 mg domperidone was administered four times daily concomitantly with 500 mg erythromycin orally three times daily, QTc interval was prolonged on average by 9.9 msec, 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 QTc prolongation is unknown. In these studies, monotherapy with domperidone (10 mg orally four times daily) prolonged QTc interval by 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), respectively, 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 and 4.9 msec, respectively, during the observation period.

Theoretically, since Motilium® 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 already stabilized on digoxin or paracetamol, concomitant administration of domperidone did not affect blood levels of these drugs.

Special precautions for use.

Motilium® is not recommended for use in children under 12 years of age.

Motilium® should be used with caution in elderly patients and in patients with existing heart disease or a history of cardiac disorders.

Cardiovascular effects. Domperidone has been associated with QT interval prolongation on ECG. In post-marketing surveillance, very rare cases of QT prolongation and ventricular fibrillation/torsade de pointes have been reported in patients treated with domperidone. These reports included patients with other risk factors, electrolyte disturbances, and concomitant therapies that could be contributing factors (see section "Adverse reactions").

According to ICH-E14 guidance, 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, Motilium® is contraindicated in patients with prolonged cardiac conduction intervals, particularly QTc, in patients with significant electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, and 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, Motilium® should be discontinued immediately and the patient should seek medical advice without delay.

Patients should promptly report any cardiac symptoms.

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

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

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

Use with apomorphine. Domperidone is contraindicated for concomitant use with medicinal products that prolong the QT interval, including apomorphine, except when the benefit of concomitant use with apomorphine outweighs the risk, and only under strict adherence to the precautions specified in the apomorphine product information.

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. Motilium® tablets contain lactose; therefore, the product 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 suggested 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 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, Motilium® should be used with caution in elderly patients. Patients aged 60 years or older should consult their physician before taking Motilium®.
• 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

Post-marketing data on the use of domperidone in pregnant women are limited. Therefore, Motilium® 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 via breast milk is extremely low. The maximum relative infant dose (%) is estimated to be approximately 0.1% of the maternal dose adjusted for body weight. It is unknown whether it may harm the infant; therefore, mothers taking Motilium® 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. Adverse reactions, including cardiac effects, cannot be ruled out following exposure due to drug transfer through breast milk.

Ability to influence reaction time while 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 activity requiring mental alertness and coordination until they know how Motilium® affects them.

Method of Administration and Dosage

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

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 Motilium® before meals. Absorption of the drug is slightly delayed when taken after food. The patient should take the medication according to the recommended dosing schedule. If a dose is missed, the next dose should be taken according to the recommended schedule. The dose should not be doubled to make up for a missed dose. Treatment duration should not exceed 1 week.

Adults aged ˃ 60 years

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

Renal impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, the dosing frequency of Motilium® 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 section "Pharmacological properties").

Hepatic impairment

Motilium® 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 medication 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 may include agitation, altered 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 is advised due to the potential for QT interval prolongation. Anticholinergic drugs and medications used to treat Parkinson’s disease may be effective in controlling extrapyramidal reactions.

Adverse Reactions

The safety of Motilium® 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: 10–80 mg), and the median duration of exposure was 28 days (range: 1–28 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 estimated from clinical trial data, it is listed as unknown.

When used according to recommended dosage and treatment duration, 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, agitation, nervousness; 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 – oedema, palpitations, tachycardia, arrhythmias, serious ventricular arrhythmias; frequency unknown – QT interval prolongation, ventricular arrhythmias of the type "torsade de pointes", sudden cardiac death.

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 – rash, pruritus, urticaria; frequency unknown – angioedema.

Reproductive system and breast disorders: rare – breast enlargement, galactorrhoea, breast swelling, 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 micturition; frequency unknown – urinary retention.

General disorders: uncommon – asthenia.

Eye disorders: frequency unknown – oculogyric crisis.

Other: conjunctivitis, stomatitis.

Laboratory test abnormalities: very rare – increased levels of ALT, AST, and cholesterol; frequency unknown – abnormal liver function tests, increased blood prolactin levels.

In 45 studies where domperidone was used at higher doses, for longer durations, and for additional indications including diabetic gastroparesy, the frequency of adverse reactions (except for 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 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 in adults and children were observed, except for extrapyramidal disorders and other central nervous system-related events 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 professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Packaging. 10 tablets per blister, 1 or 3 blisters per cardboard pack.

30 tablets per blister, 1 blister per cardboard pack.

Prescription status. Over-the-counter.

Manufacturer.

JNTL Consumer Health (France) SAS.

Address of manufacturer.

Domaine de Maigremont, Val-de-Reuil, 27100, France.

Marketing authorization holder.

McNeil Products Limited.

Address of marketing authorization holder.

50-100 Holmers Farm Way, High Wycombe, HP12 4EG, England.

Representative of the marketing authorization holder.

Johnson & Johnson Ukraine LLC, Ukraine.

Address of the representative.

32/2 Ostrivskykh Knyaziv St., Kyiv, 01010, Ukraine.

+38 (044) 498 0888

+38 (044) 498 7392