Itopride-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

A03FA07 (Itopride)

Active Substance

Itopride (Rec.INN registered by WHO)

Dosage Form

Itopride-SZ

Film-coated tablets, 50 mg: 20, 40, 60, 80, or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex with a score; the core of the tablet on the cross-section is white or almost white.

Excipients: lactose monohydrate (milk sugar) – 59.8 mg, corn starch, hypromellose (hydroxypropyl methylcellulose), colloidal silicon dioxide (aerosil), magnesium stearate.

Shell composition hypromellose, polysorbate-80 (tween-80), talc, titanium dioxide (E171).

20 pcs. – contour cell packs (1) – cardboard packs.
20 pcs. – contour cell packs (2) – cardboard packs.
20 pcs. – contour cell packs (3) – cardboard packs.
20 pcs. – contour cell packs (4) – cardboard packs.
20 pcs. – contour cell packs (5) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

A drug that increases the tone and motility of the gastrointestinal tract. Acetylcholine release stimulant

Pharmacotherapeutic Group

Drugs for the treatment of functional gastrointestinal disorders; gastrointestinal motility stimulants

Pharmacological Action

Itopride hydrochloride is an oral gastroprokinetic agent. The dosage form and composition of the tablets provide immediate release of the active substance.

Itopride is characterized by a dual mechanism of action: antagonism to dopamine D₂ receptors and inhibition of acetylcholinesterase. As a result of itopride’s action, the concentration of acetylcholine increases, which leads to enhanced gastric motility, increased tone of the lower esophageal sphincter (LES), accelerated gastric emptying process, and improved gastroduodenal coordination.

Itopride hydrochloride also has an antiemetic effect due to interaction with dopamine D₂ receptors located in the chemoreceptor trigger zone of the medulla oblongata. Itopride causes dose-dependent suppression of vomiting induced by apomorphine.

The drug’s action in patients with functional dyspepsia leads to a reduction in symptom severity (overall patient assessment, postprandial abdominal fullness, early satiety). The use of itopride by patients with diabetic gastroparesis contributed to the acceleration of the evacuation of liquid and solid food from the stomach. In patients with gastroesophageal reflux disease (GERD), Itopride reduces the number of transient relaxations of the lower esophageal sphincter and reduces the duration of time with high acidity in the esophagus (pH <4).

When itopride hydrochloride was used concomitantly with alpha-lipoic acid, an acceleration of the gastric emptying process and a decrease in the levels of gastrin and motilin were observed compared to itopride monotherapy.

Itopride hydrochloride has a highly specific effect on the upper gastrointestinal tract. Itopride hydrochloride accelerates gastric emptying. Itopride hydrochloride does not affect serum gastrin levels.

Pharmacokinetics

Absorption

Itopride hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. The relative bioavailability is 60%, which is associated with first-pass metabolism in the liver. Food does not affect bioavailability. C_max in plasma (0.28 µg/ml) is reached 0.5-0.75 hours after taking 50 mg of itopride hydrochloride.

With repeated oral administration of itopride hydrochloride at a dose of 50-200 mg 3 times/day for 7 days, the pharmacokinetics of the drug and its metabolites were linear, and accumulation was minimal.

Distribution

Itopride hydrochloride is 96% bound to plasma proteins, mainly albumin. Binding to alpha1-acid glycoprotein accounts for less than 15% of total binding.

Itopride is actively distributed in tissues (volume of distribution V_dβ= 6.1 L/kg) and is found in high concentrations in the kidneys, small intestine, liver, adrenal glands, and stomach. Penetration into the brain and spinal cord is minimal. Itopride penetrates into breast milk.

Metabolism

Itopride undergoes active biotransformation in the human liver. Three metabolites have been identified, only one of which exhibits slight activity that has no pharmacological significance (approximately 2-3% of that of itopride). The primary metabolite in humans is the N-oxide, which is formed by oxidation of the tertiary amino-N-dimethyl group.

Itopride is metabolized by the action of flavin-dependent monooxygenase (FMO3). The amount and efficiency of FMO isoenzymes in humans may vary depending on genetic polymorphism, which in rare cases leads to the development of an autosomal recessive condition known as trimethylaminuria (fish odor syndrome).

According to pharmacokinetic studies of CYP-mediated reactions in vivo, Itopride has no inhibitory or inducing effect on CYP2C19 and CYP2E1 isoenzymes. Itopride therapy does not affect CYP or uridine diphosphate glucuronosyltransferase activity.

Excretion

Itopride hydrochloride and its metabolites are excreted mainly in the urine. Renal excretion of itopride and its N-oxide after a single oral dose of the drug at a therapeutic dose (50 mg) in healthy individuals was 3.7% and 75.4%, respectively. T_1/2 of itopride hydrochloride is about 6 hours.

Indications

Adults and children over 16 years of age

• For the treatment of gastrointestinal symptoms associated with impaired gastric motility or its delayed emptying, such as: abdominal bloating, early satiety, feeling of fullness in the stomach after eating, pain or discomfort in the epigastric region, decreased appetite, heartburn, nausea and vomiting;
• Functional (non-ulcer) dyspepsia;
• Chronic gastritis.

ICD codes

Dosage Regimen

Adults and children over 16 years of age

The recommended dose is 50 mg (1 tablet) 3 times/day before meals.

The recommended daily dose is 150 mg. This dose may be reduced taking into account the patient’s age and symptoms.

In clinical studies, the duration of treatment with Itopride-SZ was up to 8 weeks.

Children

The safety and efficacy of itopride in children under 16 years of age have not been established to date.

Method of administration

Orally. Before meals, without chewing and with a sufficient amount of water.

Adverse Reactions

Summary of the safety profile

The adverse reactions listed below were observed in 998 patients using itopride at a standard daily dose of 150 mg or lower during 4 placebo-controlled, 4 comparative, and 13 uncontrolled interventional clinical studies.

Tabulated summary of adverse reactions

Adverse reactions are distributed by system-organ classes in descending order of their severity with an indication of the frequency of their occurrence: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

The following adverse reactions of itopride were identified during post-registration use; based on the available data, it is not possible to estimate their frequency.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to itopride or any auxiliary component of the drug;
• Patients with gastrointestinal bleeding, mechanical obstruction or perforation;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Children under 16 years of age (due to lack of safety data);
• Pregnancy;
• Breastfeeding period.

With caution

Itopride hydrochloride enhances the action of acetylcholine, which can cause cholinergic side reactions. The drug should be prescribed with caution to the category of patients for whom the occurrence of such reactions may worsen the course of the underlying disease.

Itopride should be prescribed with caution to elderly patients, taking into account the higher frequency of decreased liver and kidney function, the presence of concomitant diseases or other treatment.

Use in Pregnancy and Lactation

Pregnancy

Currently, there is a limited amount of data (less than 300 pregnancy outcomes) on the use of itopride in pregnant women. Animal studies have not revealed signs of direct or indirect adverse effects of itopride, indicating reproductive toxicity. As a precaution, the use of Itopride-SZ during pregnancy should be avoided.

Breastfeeding period

Itopride is excreted in milk in animals, however, there is currently insufficient data on the excretion of itopride in human breast milk. When breastfeeding, the risk of the drug affecting the child cannot be excluded. The decision to discontinue breastfeeding or discontinue/interrupt drug therapy should be made based on an assessment of the benefits of breastfeeding for the child and the benefits of the drug for the mother.

Fertility

There are no data on the effect of itopride on human fertility. However, animal studies have not revealed signs of an adverse effect of the drug on fertility.

Pediatric Use

Contraindicated for use in children under 16 years of age. The safety and efficacy of itopride in children under 16 years of age have not been established to date.

Geriatric Use

Itopride should be prescribed with caution to elderly patients.

Special Precautions

With caution

Itopride hydrochloride enhances the action of acetylcholine, which can cause cholinergic side reactions. The drug should be prescribed with caution to the category of patients for whom the occurrence of such reactions may worsen the course of the underlying disease.

Itopride should be prescribed with caution to elderly patients, taking into account the higher frequency of decreased liver and kidney function, the presence of concomitant diseases or other treatment.

There are no data on long-term use of the drug.

Excipients

Itopride-SZ contains lactose monohydrate (milk sugar). Patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this drug (see section “Contraindications”).

Influence on the ability to drive vehicles and mechanisms

No studies have been conducted on the effect of itopride on the ability to drive a car and operate machinery.

However, during treatment with the drug, caution should be exercised when performing potentially hazardous activities that require increased concentration and speed of psychomotor reactions (driving vehicles, working with moving mechanisms, work of a dispatcher and operator), because the use of the drug may cause dizziness.

Overdose

In case of overdose, gastric lavage and symptomatic therapy are indicated.

Drug Interactions

Metabolic interaction is not expected, because Itopride is primarily metabolized by the action of flavin monooxygenase, and not with the participation of the cytochrome CYP450 system.

With simultaneous use of warfarin, diazepam, diclofenac sodium, ticlopidine hydrochloride, nifedipine and nicardipine hydrochloride, no changes in protein binding were observed.

Itopride enhances gastric motility, so the drug may affect the absorption of other orally administered drugs. Particular caution should be exercised when using drugs with a low therapeutic index, as well as sustained-release dosage forms or enteric-coated drugs.

Antiulcer drugs such as cimetidine, ranitidine, teprenone and cetraxate do not affect the prokinetic effect of itopride.

Anticholinergic agents may weaken the effect of itopride.

Storage Conditions

The drug should be stored out of the reach of children at a temperature below 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the package.

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.