Ganaton

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GANATON®

Composition:

Active substance: itopride hydrochloride;

One tablet contains 50 mg of itopride hydrochloride;

Excipients: lactose monohydrate, corn starch, carmellose, anhydrous silicic acid, magnesium stearate;

Tablet coating: hypromellose, macrogol 6000, titanium dioxide (E 171), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white in color, round-shaped, with a score line on one side and embossing «НС 803» on the other.

Pharmacotherapeutic group. Peristaltic stimulants. ATC code A03F A07.

Pharmacological properties.

Pharmacodynamics.

Itopride hydrochloride enhances propulsive gastrointestinal motility due to its antagonism at dopamine D2 receptors and inhibitory activity on acetylcholinesterase. Itopride hydrochloride promotes acetylcholine release and inhibits its degradation. Itopride hydrochloride 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 itopride hydrochloride is highly specific to the upper gastrointestinal tract.

Itopride hydrochloride does not affect serum gastrin levels.

Pharmacokinetics.

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

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

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

Itopride hydrochloride is metabolized by flavin-containing monooxygenase (FMO3). The amount and activity of FMO isoenzymes in humans may vary due to genetic polymorphism, occasionally leading to an autosomal recessive condition known as trimethylaminuria (fish odor syndrome). In patients with trimethylaminuria, the T1/2 is prolonged.

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

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

The terminal T1/2 of itopride hydrochloride 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 other components of the drug.
• Conditions in which increased gastrointestinal motility may be harmful, such as 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 has a gastrokinetic effect, it may influence the absorption of other medicinal products administered concomitantly by oral route.

Medicinal products with a narrow therapeutic index, modified release formulations, or enteric-coated formulations should be used with particular caution.

Anti-ulcer drugs such as cimetidine, ranitidine, teprenone, and cetraxate do 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 effects. Data on long-term use are lacking.

In general, hydrochloride itopride should be administered to elderly patients with appropriate caution and ongoing 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.

Use during pregnancy or breastfeeding

Fertility

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

Pregnancy

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

Breastfeeding

Itopride is excreted in breast milk in animals, but there is insufficient data regarding excretion of itopride in human breast milk. A risk to the breastfed infant cannot be excluded. The decision on whether to discontinue breastfeeding or to discontinue/withhold itopride therapy should be made considering the benefit of breastfeeding for the infant and the benefit of treatment for the mother.

Ability to influence reaction speed when driving or operating machinery

Information regarding a potential effect on reaction speed is lacking; however, when deciding whether to drive or operate machinery, the possibility of dizziness should be taken into account.

Method of administration and dosage.

The recommended dose for adults is 150 mg per day (1 tablet (50 mg) 3 times daily before meals). This dose may be adjusted downward based on the patient's age and symptoms (see "Special 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 excessive 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 specified 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 system organ class (according to MedDRA) and 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" (≥ 1/10,000 to < 1/1000), and "very rare" (< 1/10,000).

Gastrointestinal disorders:
Common – abdominal pain, diarrhea;
Uncommon – increased salivation.

Nervous system disorders:
Uncommon – dizziness, headache.

Skin and subcutaneous tissue disorders:
Uncommon – rash.

Investigations:
Uncommon – increased aminotransferase levels, decreased white blood cell count.

Adverse reactions from spontaneous reports during post-marketing use. Frequency cannot be estimated precisely with available data.

Blood and lymphatic system disorders: leukopenia, thrombocytopenia.

Immune system disorders: hypersensitivity, including anaphylactoid reactions.

Endocrine disorders: increased blood prolactin levels.

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, pruritus.

Reproductive system and breast disorders: gynecomastia.

Investigations: increased blood levels of AST, ALT, GGT, alkaline phosphatase, and bilirubin.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

10 tablets in a blister, 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Katsuyama Pharmaceuticals K.K., Katsuyama Plant, Japan / Katsuyama Pharmaceuticals K.K., Katsuyama Plant, Japan.

Address. 2-1, Inokuchi 37, Katsuyama, Fukui 911-8555, Japan / 2-1, Inokuchi 37, Katsuyama, Fukui 911-8555, Japan.