Itopride-pharmak

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ITOPRID-FARMAK (ITOPRID-FARMAK)

Composition:

Active substance: itopride hydrochloride;

One tablet contains 50 mg of itopride hydrochloride;

Excipients: lactose monohydrate; pregelatinized starch; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets with a score line on one side. The tablet can be divided into equal doses.

Pharmacotherapeutic group. Prokinetic agents. ATC code A03F A07.

Pharmacological properties.

Pharmacodynamics.

Hydrochloride itopride activates propulsive gastrointestinal motility due to antagonism at dopamine D2 receptors and inhibitory activity against acetylcholinesterase. Hydrochloride itopride promotes acetylcholine release and inhibits its degradation. Hydrochloride itopride also exerts an antiemetic effect through interaction with D2 receptors located in the chemoreceptor trigger zone, as demonstrated by dose-dependent inhibition of apomorphine-induced vomiting in animals. The action of hydrochloride itopride is highly specific to the upper gastrointestinal tract.

Hydrochloride itopride does not affect serum gastrin levels.

Pharmacokinetics.

Absorption. Hydrochloride itopride is rapidly and almost completely absorbed from the gastrointestinal tract. Its relative bioavailability is 60%, which is related to the "first-pass" effect through the liver. Food does not affect bioavailability. After administration of 50 mg of hydrochloride itopride, maximum concentration (Cmax) is reached within 0.5–0.75 hours and amounts to 0.28 µg/mL. With continued administration of the drug at doses of 50 to 200 mg three times daily for 7 days, the pharmacokinetics of hydrochloride itopride and its metabolites were linear with minimal accumulation.

Distribution. Approximately 96% of hydrochloride itopride is bound to plasma proteins (mainly to albumin). Binding to α1-acid glycoprotein is less than 15%.

Metabolism. Hydrochloride itopride is actively biotransformed in the liver. Three metabolites have been identified, only one of which exhibits negligible activity without pharmacological significance (approximately 2–3% of hydrochloride itopride). The primary metabolite is the N-oxide, formed by oxidation of the quaternary amino-N-dimethyl group.

Hydrochloride itopride is metabolized by flavin-dependent monooxygenase (FMO3). The amount and activity of FMO isoenzymes in humans may vary depending on genetic polymorphism, which occasionally leads to the development of an autosomal recessive condition known as trimethylaminuria ("fish odor syndrome"). In patients with trimethylaminuria, the T1/2 is prolonged.

According to pharmacokinetic studies in vivo, hydrochloride itopride does not exert inhibitory or inductive effects on CYP2C19 and CYP2E1. Administration of hydrochloride itopride does not affect CYP content or uridine diphosphate glucuronosyltransferase activity.

Excretion. Hydrochloride itopride and its metabolites are primarily excreted via urine. Renal excretion of hydrochloride itopride and its N-oxide accounted for 3.7% and 75.4%, respectively, after single oral administration of the drug at a therapeutic dose to healthy volunteers.

The terminal T1/2 of hydrochloride itopride is approximately 6 hours.

Clinical characteristics.

Indications.

Treatment of gastrointestinal symptoms of functional non-ulcer dyspepsia (chronic gastritis), namely:

• abdominal bloating;
• feeling of early satiety;
• pain and discomfort in the upper abdomen;
• anorexia;
• heartburn;
• nausea;
• vomiting.

Contraindications.

• Hypersensitivity to itopride hydrochloride and to other components of the drug.
• Conditions in which increased gastrointestinal contractile activity may be harmful, for example, gastrointestinal bleeding, mechanical obstruction, or perforation.

Interaction with other medicinal products and other forms of interaction.

Metabolic interactions are not expected because itopride hydrochloride is primarily metabolized by flavin monooxygenase, not by cytochrome P450 isoenzymes.

No changes in protein binding were observed when itopride hydrochloride was administered concomitantly with warfarin, diazepam, sodium diclofenac, ticlopidine hydrochloride, nifedipine, or nicardipine hydrochloride. Since itopride hydrochloride exerts a gastrokinetic effect, it may influence the absorption of other orally administered medicinal products taken concomitantly.

Particular caution is required when administering medicinal products with a narrow therapeutic index, modified release formulations, or enteric coating.

Anti-ulcer medicinal products such as cimetidine, ranitidine, teprenone, and cetrazac does not affect the prokinetic action of itopride hydrochloride.

Anticholinergic medicinal products may reduce the effect of itopride hydrochloride.

Special precautions for use

Hydrochloride itopride enhances the action of acetylcholine and may lead to cholinergic adverse reactions. Data on long-term use are lacking.

In general, hydrochloride itopride should be prescribed to elderly patients with appropriate caution and subsequent monitoring, taking into account the increased frequency of impaired renal or hepatic function, concomitant diseases, or concomitant therapy with other medicinal products in such patients.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e. essentially sodium-free.

If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of itopride in pregnant women are absent or limited (less than 300 pregnancy outcomes). Animal studies have not revealed any direct or indirect harmful toxic effects on reproductive function. As a precautionary measure, it is advisable to avoid using itopride during pregnancy.

Breastfeeding

Itopride passes into animal milk; however, data on the passage of itopride into human breast milk are insufficient. The risk to the breastfed infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from itopride treatment should be made taking into account the benefit of breastfeeding for the infant and the benefit of treatment for the woman.

Fertility

There are no data regarding the effect of itopride on human fertility; however, animal studies have not revealed any harmful effects of itopride.

Ability to affect reaction speed when driving vehicles or operating machinery.

Information regarding the possible effect on reaction speed is lacking; however, when considering the ability to drive vehicles or operate machinery, the possibility of dizziness should be taken into account.

Dosage and Administration.

The recommended dose for adults is 150 mg daily (1 tablet (50 mg) 3 times daily before meals). This dose may be adjusted according to the patient's age and symptoms (see section "Special Warnings and Precautions for Use").

During clinical studies, the duration of treatment with itopride hydrochloride was up to 8 weeks.

Children.

The safety of itopride hydrochloride in children under 16 years of age has not been established.

Overdose.

Treatment. In case of overdose, standard measures such as gastric lavage should be performed, along with symptomatic treatment.

Adverse Reactions

The adverse reactions listed below were observed at the following frequencies in 998 patients treated with itopride in 4 placebo-controlled clinical trials, 4 comparative clinical trials, and 13 uncontrolled interventional clinical trials, using a standard daily dose of itopride of 150 mg or less. Adverse reactions are classified by organ systems (according to MedDRA) and by frequency of occurrence: common (≥ 1/100 to <1/10) and uncommon (≥ 1/1000 to <1/100). No adverse reactions were identified in the categories "very common" (>1/10), "rare" (≥1/10000 to <1/1000), or "very rare" (<1/10000).

Gastrointestinal disorders: common – abdominal pain, diarrhea; uncommon – increased salivation.

Nervous system disorders: uncommon – dizziness, headache.

Skin and subcutaneous tissue disorders: uncommon – rash.

Laboratory investigations: uncommon – elevated aminotransferase levels, decreased white blood cell count.

Adverse reactions from spontaneous reports during post-marketing use*. The frequency of occurrence cannot be precisely estimated based on available data.*

Blood and lymphatic system disorders: leukopenia, thrombocytopenia.

Immune system disorders: hypersensitivity, including anaphylactoid reactions.

Endocrine disorders: increased prolactin levels in blood.

Nervous system disorders: dizziness, headache, tremor.

Gastrointestinal disorders: diarrhea, constipation, abdominal pain, increased salivation, nausea.

Hepatobiliary disorders: jaundice.

Skin and subcutaneous tissue disorders: rash, erythema, and pruritus.

Reproductive system and breast disorders: gynecomastia.

Laboratory investigations: increased levels of AST, ALT, GGT, alkaline phosphatase, and bilirubin in blood.

Reporting of Adverse Reactions

Reporting adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf Life. 2 years.

Storage Conditions. Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging. 10 tablets in a blister; 1, 4, or 10 blisters per cardboard pack.

Prescription Category. Prescription only.

Manufacturer. Saneca Pharmaceuticals AT.

Manufacturer's Address and Location of Business Activity. Nitrianska 100, 920 27 Glogovec, Slovak Republic.

Marketing Authorization Holder. JSC "Farmak".

Address of the Marketing Authorization Holder. 63 Kyrylivska St., Kyiv, 04080, Ukraine.