Motilium^® (Tablets, Lyophilized tablets, Suspension) Instructions for Use

ATC Code

A03FA03 (Domperidone)

Active Substance

Domperidone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiemetic drug – central dopamine receptor blocker

Pharmacotherapeutic Group

Antiemetic agent – central dopamine receptor blocker

Pharmacological Action

Pharmacodynamics

Domperidone is a dopamine antagonist with antiemetic properties. Domperidone poorly penetrates the blood-brain barrier. The use of domperidone is rarely accompanied by extrapyramidal side effects, especially in adults, but Domperidone stimulates the release of prolactin from the pituitary gland. Its antiemetic effect is possibly due to a combination of peripheral (gastrokinetic) action and antagonism of dopamine receptors in the chemoreceptor trigger zone, which is located outside the blood-brain barrier. Animal studies and the low concentrations of the drug detected in the brain indicate a predominantly peripheral effect of domperidone on dopamine receptors.

When taken orally, Domperidone increases the duration of antral and duodenal contractions, accelerates gastric emptying, and increases lower esophageal sphincter pressure. Domperidone has no effect on gastric secretion.

Pharmacokinetics

Absorption

When taken on an empty stomach, Domperidone is rapidly absorbed after oral administration, peak plasma concentrations are reached within 30-60 minutes. The low absolute bioavailability of domperidone when taken orally (approximately 15%) is associated with intensive first-pass metabolism in the intestinal wall and liver.

Domperidone should be taken 15-30 minutes before meals. Reduced acidity in the stomach leads to impaired absorption of domperidone. Oral bioavailability is reduced with prior administration of cimetidine and sodium bicarbonate. When the drug is taken after a meal, it takes longer to achieve maximum absorption, and the AUC increases somewhat.

Distribution

When taken orally, Domperidone does not accumulate and does not induce its own metabolism; the peak plasma level of 21 ng/ml 90 minutes after 2 weeks of oral administration at a dose of 30 mg per day was practically the same as the level of 18 ng/ml after the first dose.

Domperidone is 91-93% bound to plasma proteins.

Distribution studies of the radiolabeled drug in animals showed its wide distribution in tissues, but low concentrations in the brain. Small amounts of the drug cross the placenta in rats.

Metabolism

Domperidone undergoes rapid and intensive metabolism by hydroxylation and N-dealkylation. In vitro metabolism studies with diagnostic inhibitors have shown that the CYP3A4 isoenzyme is the main form of cytochrome P450 involved in the N-dealkylation of domperidone, while the CYP3A4, CYP1A2 and CYP2E1 isoenzymes are involved in the aromatic hydroxylation of domperidone.

Excretion

Excretion in urine and feces is 31% and 66% of the oral dose, respectively. The proportion of the drug excreted unchanged is small (10% in feces and approximately 1% in urine). The plasma T_1/2 after a single oral dose is 7-9 hours in healthy volunteers, but is increased in patients with severe renal failure.

Pharmacokinetics in special clinical cases

In patients with severe renal failure (serum creatinine >6 mg/100 ml, i.e. >0.6 mmol/l), the T_1/2 of domperidone increases from 7.4 to 20.8 hours, but plasma concentrations of the drug are lower than in patients with normal renal function. A small amount of unchanged drug (about 1%) is excreted by the kidneys.

In patients with moderate hepatic impairment (Child-Pugh score 7-9), the AUC and C_max of domperidone were 2.9 and 1.5 times higher than in healthy volunteers, respectively. The unbound fraction increased by 25%, and T_1/2 increased from 15 to 23 hours. In patients with mild hepatic impairment, slightly reduced systemic drug levels were noted compared to healthy volunteers based on C_max and AUC without changes in protein binding or T_1/2. Patients with severe hepatic impairment have not been studied.

Indications

• For the relief of symptoms of nausea and vomiting.

ICD codes

Dosage Regimen

Tablets

Orally, with a glass of water.

Adults and adolescents over 12 years old – 1 tablet (10 mg) 3 times/day, the maximum daily dose is 3 tablets (30 mg).

The maximum duration of use of the drug should not exceed 7 days and is determined by the prescription of the attending physician.

Patients with renal impairment. Since the T_1/2 of domperidone in severe renal failure (with serum creatinine level >6 mg/100 ml, i.e. >0.6 mmol/l) increases, the frequency of administration of Motilium^®, film-coated tablets, should be reduced to 1 or 2 times/day, depending on the severity of renal failure. Regular examination of patients with severe renal failure is necessary (see section “Pharmacological Action”).

Patients with hepatic impairment. The use of Motilium^® is contraindicated in patients with moderate and severe hepatic failure. In patients with mild hepatic failure, no dose adjustment of the drug is required.

For elderly patients, no dose adjustment is required.

Motilium^® is not used in children under 12 years of age, since efficacy and safety have not been established. Data are not available.

Suspension

The drug is taken orally. It is recommended to take Motilium^® before meals; if the drug is taken after meals, the absorption of domperidone is slightly slowed down.

Adults and adolescents over 12 years of age weighing 35 kg and more 10 ml 3 times/day. Maximum daily dose – 30 ml (30 mg).

Motilium^® suspension should be used at the lowest effective dose. It is not recommended to exceed the maximum daily dose.

In children, overdose can cause nervous system disorders (see section “Overdose”).

In patients of all age groups, for the treatment of acute nausea and vomiting, the maximum duration of continuous use of the drug should not exceed 1 week. If nausea and vomiting persist for more than 1 week, the patient should re-consult their doctor.

Patients with renal impairment. Since the T_1/2 of domperidone increases in severe renal impairment, with repeated use, the frequency of administration of Motilium^® should be reduced to 1-2 times/day depending on the severity of the impairment, and a dose reduction may also be required.

Patients with hepatic impairment. The use of 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 failure (see section “Contraindications”). In patients with mild (5-6 points on the Child-Pugh scale) hepatic failure, no dose adjustment of the drug is required.

Directions for use

Before use, the contents of the bottle should be mixed by gently shaking it to avoid foaming.

Fig. 1

The suspension is supplied in child-resistant packaging. The bottle should be opened as follows

• Press down on the plastic cap of the bottle while turning it counterclockwise;
• Remove the unscrewed cap.

Fig. 2

A measuring cup is included. Before using it, make sure that the part with the scale is on top according to the arrow indication. Pour the drug into the upper part of the cup up to the 5 ml mark.

A single dose is 10 ml (2 measuring cups). Rinse the cup with water after use.

Lyophilized tablets

The drug is taken orally. It is recommended to take Motilium^® EXPRESS tablets 15-30 minutes before meals; if the drug is taken after meals, the absorption of domperidone may slow down.

Adults and children over 12 years of age and body weight ≥35 kg: 10 mg (1 tablet) 3 times/day. Maximum daily dose – 30 mg (3 tablets).

In pediatric practice, Motilium^® suspension should mainly be used.

For the treatment of acute nausea and vomiting, the maximum duration of continuous use of the drug should not exceed 1 week. If nausea and vomiting persist for more than 1 week, the patient should re-consult their doctor.

Patients with renal failure. Since the T_1/2 of domperidone in severe renal failure (with serum creatinine level >6 mg/100 ml, i.e. >0.6 mmol/l) increases, the frequency of administration of Motilium^® EXPRESS should be reduced to 1 or 2 times/day depending on the severity of the failure. Regular examination of patients with severe renal failure is necessary.

Patients with hepatic failure. The use of Motilium^® EXPRESS is contraindicated in patients with moderate (7-9 points on the Child-Pugh scale) or severe (>9 points on the Child-Pugh scale) hepatic failure. In patients with mild (5-6 points on the Child-Pugh scale) hepatic failure, no dose adjustment of the drug is required.

Directions for use

Since the lyophilized tablets are quite fragile, to avoid damage, they should not be pushed through the foil.

To remove a tablet from the blister, the following is necessary

• Take the foil by the edge and completely remove it from the cell containing the tablet;
• Gently press from below;
• Remove the tablet from the packaging.

Place the tablet on the tongue. Within a few seconds, it will disintegrate on the surface of the tongue and can be swallowed with saliva without drinking water.

Adverse Reactions

Based on clinical trial data

Adverse reactions observed in ≥1% of patients taking Motilium^® depression, anxiety, decreased or absent libido, headache, drowsiness, akathisia, diarrhea, dry mouth, rash, itching, breast enlargement/gynecomastia, breast pain and tenderness, galactorrhea, menstrual cycle disorders and amenorrhea, lactation disorder, asthenia.

Adverse reactions observed in <1% of patients taking Motilium^® hypersensitivity, urticaria, breast swelling, breast discharge.

The adverse effects listed below were classified as follows: very common (≥10%), common (≥1%, but <10%), uncommon (≥0.1%, but <1%), rare (≥0.01%, but <0.1%) and very rare (<0.01%, including isolated cases).

Based on spontaneous reports of adverse events identified during the post-marketing period of the drug

Immune system disorders: very rarely – anaphylactic reactions, including anaphylactic shock.

Psychiatric disorders: very rarely – agitation (mainly in children), nervousness.

Nervous system disorders: very rarely – dizziness, extrapyramidal disorders and convulsions (mainly in children).

Cardiac disorders: very rarely – QT interval prolongation, serious ventricular arrhythmias*, sudden cardiac death*.

Skin and subcutaneous tissue disorders: very rarely – urticaria, angioedema.

Renal and urinary disorders: very rarely – urinary retention.

Laboratory data: very rarely – abnormalities in liver function tests, increased blood prolactin levels.

Adverse reactions identified during post-registration clinical studies

Immune system disorders frequency unknown – anaphylactic reactions, including anaphylactic shock.

Psychiatric disorders uncommon – agitation (mainly in children), nervousness.

Nervous system disorders common – dizziness; rare – convulsions (mainly in children); frequency unknown – extrapyramidal disorders (mainly in children).

Cardiac disorders frequency unknown – QT interval prolongation, serious ventricular arrhythmias*, sudden cardiac death*.

Skin and subcutaneous tissue disorders frequency unknown – angioedema.

Renal and urinary disorders uncommon – urinary retention.

Laboratory and instrumental data uncommon – abnormalities in liver function tests; rare – increased blood prolactin levels.

*Some epidemiological studies have shown that the use of domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden death. The risk of these events is more likely in patients over 60 years of age and in patients taking the drug at a daily dose of more than 30 mg. It is recommended to use domperidone at the lowest effective dose in adults and children.

Contraindications

• Hypersensitivity to domperidone or any of the components of the drug;
• Pituitary prolactin-secreting tumor (prolactinoma);
• Concomitant use of oral forms of ketoconazole, erythromycin or other potent inhibitors of the CYP3A4 isoenzyme that cause QT_c interval prolongation, such as clarithromycin, itraconazole, fluconazole, posaconazole, ritonavir, saquinavir, amiodarone, telithromycin, telaprevir and voriconazole (see sections “Special Precautions”, “Drug Interactions”);
• Prolonged QT_c interval, severe electrolyte disturbances and heart disease, such as chronic heart failure;
• In cases where stimulation of gastric motility may be dangerous, for example, in gastrointestinal bleeding, mechanical obstruction or perforation;
• Moderate or severe hepatic impairment;
• Body weight less than 35 kg;
• Children under 12 years of age;
• Pregnancy;
• Breastfeeding period;
• Fructose intolerance.

With caution

• Renal impairment.

Use in Pregnancy and Lactation

Motilium^® is contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

The use of the drug is contraindicated in moderate and severe hepatic impairment. In mild hepatic impairment, no dose adjustment is required.

Use in Renal Impairment

The drug should be prescribed with caution in renal impairment.

Pediatric Use

Motilium^® Express is contraindicated in children under 12 years of age.

Geriatric Use

The use of domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden death. The risk may be more likely in patients over 60 years of age.

Special Precautions

When using Motilium^® concomitantly with antacids or antisecretory drugs, the latter should be taken after meals, not before meals, i.e., they should not be taken simultaneously with Motilium^®.

Use in cardiovascular diseases

Domperidone affects the duration of the QT_c interval on the ECG. Throughout the post-marketing surveillance period of the drug, rare cases of QT_c interval prolongation and torsades de pointes arrhythmia have been reported in patients taking Domperidone. These cases were noted in at-risk patients with electrolyte imbalances and concurrently taking drugs that could have influenced the described cases (see section “Adverse Reactions”).

Epidemiological studies have shown that Domperidone increases the risk of serious ventricular arrhythmia or sudden death. The highest risk was noted in patients over 60 years of age taking the drug at a dose of more than 30 mg daily, as well as in patients concurrently taking drugs that prolong the QT_c interval and inhibitors of the CYP3A4 isoenzyme.

Domperidone should be taken at the lowest effective doses.

Domperidone is contraindicated for use in patients with a prolonged QT_c interval, patients with severe electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) or bradycardia, as well as patients with cardiac diseases such as congestive heart failure, due to an increased risk of ventricular arrhythmias (see section “Contraindications”). Electrolyte imbalances (hypokalemia, hyperkalemia, hypomagnesemia) and bradycardia may increase the risk of the proarrhythmic effect of the drug. If signs or symptoms that may be associated with cardiac arrhythmia appear, therapy with the drug should be discontinued and a doctor should be consulted. Patients should immediately report any cardiac symptom. The drug contains sorbitol and may not be suitable for patients with fructose intolerance.

Use in renal diseases

In severe renal failure, the T_1/2 of domperidone increases. Consequently, with repeated administration of the drug, the frequency of domperidone administration should be reduced to 1-2 times/day, depending on the severity of renal failure (see section “Dosage Regimen”). A dose reduction may be required. During long-term therapy, patients should be under regular supervision.

Concomitant use with apomorphine

Domperidone is contraindicated for concomitant use with drugs that prolong the QT interval, with the exception of apomorphine. Concomitant use with apomorphine is possible only if the benefit of concomitant use of domperidone with apomorphine outweighs the risks and the recommended precautions for concomitant use of the drugs mentioned in the apomorphine prescribing information are strictly observed.

Potential for Drug Interaction

The primary metabolic pathway of domperidone is via CYP3A4. In vitro data and results from human studies indicate that concomitant use of drugs that significantly inhibit this enzyme may be accompanied by an increase in domperidone plasma concentration. The concomitant use of domperidone with potent CYP3A4 inhibitors that are known to cause QT interval prolongation is contraindicated (see section “Contraindications”).

Caution should be exercised when domperidone is used concomitantly with potent CYP3A4 inhibitors that do not cause QT interval prolongation (for example, indinavir); careful monitoring of patients for the occurrence of signs or symptoms of adverse reactions is necessary (see section “Drug Interactions”).

Caution should be exercised when domperidone is used concomitantly with drugs that are known to cause QT interval prolongation; careful monitoring of patients for the occurrence of signs or symptoms of cardiovascular adverse reactions is necessary.

Examples of such drugs

• Class IA antiarrhythmic agents (e.g., disopyramide, quinidine);
• Class III antiarrhythmic agents (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol);
• Certain antipsychotics (e.g., haloperidol, pimozide, sertindole);
• Certain antidepressants (e.g., citalopram, escitalopram);
• Certain antibiotics (e.g., levofloxacin, moxifloxacin);
• Certain antifungal agents (e.g., pentamidine);
• Certain antimalarial agents (e.g., halofantrine);
• Certain gastrointestinal drugs (e.g., dolasetron);
• Certain antineoplastic agents (e.g., toremifene, vandetanib);
• Some other drugs (e.g., bepridil, methadone).

Use in Pediatrics

Motilium^® may rarely cause neurological adverse effects (see section “Adverse Reactions”). Therefore, the recommended dose should be strictly adhered to (see section “Dosage and Administration”). Neurological adverse effects in children may be caused by drug overdose, but other possible causes of such effects should also be considered.

Excipients

Motilium^® oral suspension contains sorbitol and is not recommended for use in patients with sorbitol intolerance, as well as fructose intolerance.

Drug Disposal

If the medicine is no longer usable or has expired, it should not be poured down the drain or thrown onto the street. The medicine should be placed in a bag and put into a trash container. These measures will help protect the environment.

Effect on Ability to Drive and Operate Machinery

Caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, due to the risk of developing adverse reactions that may affect these abilities.

Overdose

Symptoms of overdose occur most frequently in infants and older children and may include increased excitability, altered consciousness, convulsions, disorientation, drowsiness, and extrapyramidal reactions.

Treatment: there is no specific antidote for domperidone. In case of overdose, gastric lavage within one hour of drug intake and administration of activated charcoal are recommended. Close monitoring of the patient’s condition and supportive therapy are recommended. Anticholinergic agents, drugs used to treat parkinsonism, or antihistamines may be effective if extrapyramidal reactions occur.

Drug Interactions

Anticholinergic drugs may neutralize the effect of Motilium^®.

The oral bioavailability of Motilium^® is reduced after prior administration of cimetidine or sodium bicarbonate. Antacid and antisecretory drugs should not be taken simultaneously with domperidone, as they reduce its oral bioavailability (see section “Special Instructions”).

The isoenzyme CYP3A4 plays a major role in the metabolism of domperidone. Results of in vitro studies and clinical experience indicate that simultaneous use of drugs that significantly inhibit this isoenzyme may cause an increase in domperidone plasma concentration. Therefore, the concomitant use of domperidone with potent CYP3A4 inhibitors that are known to cause QT interval prolongation is contraindicated. Caution should be exercised when domperidone is used concomitantly with potent CYP3A4 inhibitors that do not cause QT interval prolongation, as well as with drugs that are known to cause QT interval prolongation.

Potent CYP3A4 inhibitors include

• Azole antifungal agents such as fluconazole*, itraconazole, ketoconazole* and voriconazole*;
• Macrolide antibiotics, e.g., clarithromycin* and erythromycin*;
• HIV protease inhibitors, e.g., amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and saquinavir;
• Calcium channel blockers such as diltiazem and verapamil;
• Amiodarone*;
• Aprepitant;
• Nefazodone;
• Telithromycin*.

Drugs marked with an asterisk also prolong the QTc interval (see section “Contraindications”).

A number of pharmacokinetic and pharmacodynamic interaction studies of domperidone with oral ketoconazole and oral erythromycin in healthy volunteers have shown that these drugs significantly inhibit the primary metabolism of domperidone mediated by the CYP3A4 isoenzyme.

When 10 mg domperidone 4 times/day and 200 mg ketoconazole 2 times/day were taken concomitantly, the QTc interval was prolonged by an average of 9.8 ms over the entire observation period, with individual time point changes ranging from 1.2 to 17.5 ms. When 10 mg domperidone 4 times/day and 500 mg erythromycin 3 times/day were taken concomitantly, the QTc interval was prolonged by an average of 9.9 ms over the entire observation period, with individual time point changes ranging from 1.6 to 14.3 ms. In each of these studies, the C_max and AUC of domperidone were increased approximately 3-fold (see section “Contraindications”).

It is currently unknown to what extent increased domperidone plasma concentrations contribute to the change in the QTc interval.

In these studies, domperidone monotherapy (10 mg 4 times/day) resulted in a QTc interval prolongation of 1.6 ms (ketoconazole study) and 2.5 ms (erythromycin study), whereas ketoconazole monotherapy (200 mg 2 times/day) and erythromycin monotherapy (500 mg 3 times/day) resulted in a QTc interval prolongation of 3.8 and 4.9 ms, respectively, over the entire observation period.

In another multiple-dose study in healthy volunteers, no significant QTc interval prolongation was found during steady-state domperidone monotherapy (40 mg 4 times/day, total daily dose 160 mg, which significantly exceeds the recommended maximum daily dose). In this case, domperidone plasma concentrations were similar to those in the drug interaction studies of domperidone with other drugs.

Concomitant use of anticholinergic drugs (e.g., dextromethorphan, diphenhydramine) may counteract the development of the antidyseptic effects of Motilium^®.

Since Motilium^® has a gastrokinetic effect, it could theoretically affect the absorption of concomitantly administered oral drugs, in particular, drugs with prolonged release of the active substance or enteric-coated drugs. However, the use of domperidone in patients taking paracetamol or digoxin did not affect the blood concentrations of these drugs.

Motilium^® can be taken concomitantly

• With neuroleptics, which it does not potentiate;
• With dopamine receptor agonists (bromocriptine, levodopa), since it suppresses their undesirable peripheral effects, such as digestive disorders, nausea and vomiting, without affecting their central effects.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 15°C (59°F) and 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.