Motoryx

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

Composition:

Active substance: domperidone;

1 tablet contains 10 mg of domperidone;

Excipients: lactose monohydrate; pregelatinized starch; sodium croscarmellose; microcrystalline cellulose; sodium lauryl sulfate; povidone; magnesium stearate;

Coating: Opadry II White film-coating system (hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; polyethylene glycol; titanium dioxide (E 171); triacetin).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white, biconvex, with a score line.

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 prolactin release 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). Low concentrations of domperidone detected in the brain indicate that the drug acts predominantly peripherally on dopamine receptors.

When administered orally, domperidone increases pressure in the lower esophageal sphincter, improves antroduodenal motility, and accelerates gastric emptying. Domperidone does not affect gastric secretion.

Effect on QT/QTc interval and cardiac electrophysiology

According to international ICH-E14 guidelines, a thorough QT study was conducted in healthy subjects. This was a double-blind, placebo-controlled study 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 ms 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 considered clinically significant.

This lack of clinical significance is supported by pharmacokinetic parameters and QTc interval data obtained from two earlier studies involving five-day treatment with 20 mg and 40 mg of domperidone four times daily. ECGs were recorded before treatment, on day 5 one hour (approximately at tmax) after the morning dose, and three days after. In both studies, no difference was observed between QTc intervals after active treatment and placebo. Thus, 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 concentrations reached approximately within 60 minutes. Cmax and AUC values of domperidone increased proportionally with dose 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 taken after food, 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 the drug is taken 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; 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. 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 showed that CYP3A4 is the main 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. Excretion of the unchanged drug accounts for 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 is prolonged in patients with severe renal impairment.

Special patient populations

Hepatic impairment.

In patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale, class B), AUC and Cmax of domperidone were 2.9 and 1.5 times higher, respectively, than in healthy volunteers. The free fraction increased by 25%, and the terminal half-life was prolonged from 15 to 23 hours. In patients with mild hepatic impairment, exposure was slightly lower than in healthy volunteers with respect to Cmax and AUC, without changes in protein binding or terminal half-life. The use of the drug has not been studied in patients with severe hepatic impairment. 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 concentrations of the drug 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 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.

MOTORIX 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 moderate or severe hepatic or renal impairment (see sections "Special warnings and 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 warnings and 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;
• 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 warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Anticholinergic medicinal products may counteract the anti-dyspeptic effect of MOTORIX. Due to pharmacodynamic and/or pharmacokinetic interactions, the risk of QT interval prolongation is increased.

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

Domperidone is predominantly metabolized via CYP3A4.

In vitro data indicate that concomitant use of 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 plasma concentration of domperidone (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 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 antimalarial agents (e.g., halofantrine, lumefantrine);
• certain gastrointestinal medicinal products (e.g., cisapride, dolasetron, prucalopride);
• certain antihistamines (e.g., mequitazine, mizolastine);
• certain oncology medicinal products (e.g., toremifene, vandetanib, vincaamine);
• certain other medicinal products (e.g., bepridil, methadone, diphenylhydramine);
• apomorphine, except when the benefit of concomitant use outweighs the risks and under strict adherence to precautionary measures recommended for concomitant use (see the apomorphine product information, section "Contraindications").

Examples of strong CYP3A4 inhibitors with which concomitant use of MOTORIX 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 antagonists such as diltiazem and verapamil;
• amiodarone*;
• amperozide;
• nefazodone;
• telithromycin*.

* Prolong QTc interval.

Concomitant use of the following substances requires caution.

Use with caution in combination with agents causing bradycardia and hypokalemia, and with the following macrolides that may cause QT interval prolongation: azithromycin and roxithromycin (clarithromycin is contraindicated due to its potent CYP3A4 inhibition).

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

The above list is representative but not exhaustive.

MOTORIX may be combined with:

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

In specific in vivo pharmacokinetic/pharmacodynamic interaction studies, co-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 by an average of 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) increased QTc by 3.8 and 4.9 msec, respectively, during the observation period.

Theoretically, since MOTORIX exerts a prokinetic effect on the stomach, it may affect the absorption of concomitantly administered oral medicinal products, 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 medicinal products.

Special precautions for use.

The medicinal product Motilium is not recommended during shaking.

The medicinal product Motilium 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. Post-marketing surveillance has reported very rare cases of QT prolongation and ventricular fibrillation/flutter in patients taking domperidone. These reports included information on patients with other predisposing risk factors, electrolyte disturbances, and concomitant therapies that may 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 at the recommended dosage regimen at usual therapeutic doses (10 or 20 mg four times daily) is not considered clinically significant.

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

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

If signs or symptoms suggestive of cardiac arrhythmia occur, treatment with Motilium should be discontinued immediately and the patient should consult a physician without delay.

Patients should promptly report any cardiac symptoms.

Motilium tablets contain lactose; therefore, the medicinal product should not be administered to patients with lactose intolerance, galactosemia, or glucose/galactose malabsorption.

Renal impairment. The elimination half-life of domperidone is prolonged in severe renal impairment. During long-term treatment, 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 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 medicinal products 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 if strict adherence to the warnings stated in the apomorphine product information is ensured.

Use with ketoconazole. QT interval prolongation has been observed in interaction studies with oral ketoconazole. 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 should be considered regarding the risk of cardiovascular complications associated with medicinal products containing domperidone:

• 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 patients receiving oral doses exceeding 30 mg per day, and in patients taking concomitant 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 a 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

Data on post-marketing use of domperidone in pregnant women are limited. Therefore, Motilium should be prescribed during pregnancy only when, 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 the drug 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 in the presence of risk factors for QTc prolongation in breastfed infants. Adverse effects, including cardiovascular effects, cannot be ruled out following exposure via 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 other activities requiring mental alertness and coordination until it is known how the drug affects them.

Dosage and Administration

MOTORIX 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).

It is recommended to take MOTORIX before meals. Absorption of the drug is slightly delayed when taken after food. The patient should take the medication according to the recommended dosing regimen. 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.

Patients over 60 years of age. 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 patients with severe renal impairment, the dosing frequency of MOTORIX 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. MOTORIX 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 administered 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. 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 medications used to treat Parkinson’s disease may be effective in controlling extrapyramidal reactions.

Adverse Reactions

The safety of the medicinal product Motoryx was evaluated during clinical trials and in the post-marketing period. 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 (≥ 1/10000 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 effects 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, 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, 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 – diarrhea; 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 – 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 ALT, AST, and cholesterol levels; frequency unknown – liver function test abnormalities, 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 an increase in prolactin levels. In isolated cases, such hyperprolactinemia may lead to neuroendocrine adverse effects such as galactorrhea, gynecomastia, and amenorrhea.

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

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing 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.

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

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 1 blister per carton.

10 tablets in a blister; 3 blisters per carton.

Availability category. Over-the-counter.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business activity.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua.