Ithomed®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ITOMED® (ITOMED®)

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; Opadry II White 85F 18422 (titanium dioxide (E 171), polyvinyl alcohol, talc, polyethylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, biconvex, film-coated tablets with a score line on one side, approximately 7 mm in diameter.

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 enhances 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 attributed to the "first-pass" effect in the liver. Food does not influence bioavailability. After administration of 50 mg of hydrochloride itopride, Cmax is reached within 30–45 minutes 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 (predominantly 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 activity).

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, occasionally leading to an autosomal recessive condition known as trimethylaminuria ("fish odor syndrome"). In patients with trimethylaminuria, half-life (T½) is prolonged.

According to pharmacokinetic data from in vivo studies, 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 therapeutic dose to healthy volunteers.

The terminal half-life (T1/2) of hydrochloride itopride is approximately 6 hours.

Clinical characteristics.

Indications.

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

• abdominal bloating;
• sensation of stomach fullness;
• 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. Due to the gastrokinetic effect of itopride hydrochloride, it may influence the absorption of other medicinal products administered concomitantly by the oral route.

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

Anti-ulcer drugs such as cimetidine, ranitidine, teprenone, and cetaxate 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 effect of acetylcholine and may lead to cholinergic adverse effects. Data on long-term use are lacking.

If a dose is missed, it should be taken as soon as possible; do not take if it is almost time for the next dose; do not double the dose.

The product contains lactose and therefore should not be administered to patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome. If you have a known intolerance to certain sugars, consult your doctor before taking this medicinal product.

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 effects 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 using itopride during pregnancy.

Breastfeeding

Itopride is excreted in breast milk in animals, but data on excretion of itopride in human breast milk are insufficient. Risk to the breastfed infant cannot be excluded. A decision on whether to discontinue breastfeeding or to discontinue/abstain from itopride therapy should be made taking into account the benefits of breastfeeding for the infant and the benefits of therapy for the mother.

Ability to affect reaction speed when driving or operating machinery.

There is no information available on the possible influence on reaction speed; however, when deciding whether to drive or operate machinery, the possibility of dizziness occurring should be taken into account.

Method of Administration and Dosage

The recommended dose for adults is 150 mg per day (1 tablet (50 mg) three times daily before meals).

This dose may be reduced according to the patient's age and symptoms (see "Use in Specific Populations").

The duration of treatment should be determined by the physician.

During clinical studies, the duration of itopride hydrochloride administration was up to 8 weeks. Long-term use of itopride hydrochloride is not recommended if there is no improvement in gastrointestinal symptoms.

Elderly Patients

Clinical studies have shown that the frequency of adverse reactions in patients aged 65 years and older was not higher than in younger patients. However, itopride hydrochloride should be prescribed to elderly patients with appropriate caution and ongoing monitoring, taking into account the increased likelihood of impaired renal or hepatic function, concomitant diseases, or concomitant therapy with other medicinal products in this population.

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 receiving itopride in 4 placebo-controlled clinical trials, 4 comparative clinical trials, and 13 uncontrolled interventional clinical trials with 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: frequent (from >1/100 to <1/10) and infrequent (from >1/1000 to <1/100). No adverse reactions were identified in the categories "very common" (>1/10), "rare" (from >1/10,000 to <1/1,000), and "very rare" (<1/10,000).

Gastrointestinal disorders: frequent – abdominal pain, diarrhea; infrequent – increased salivation.

Central nervous system disorders: infrequent – dizziness, headache.

Skin and subcutaneous tissue disorders: infrequent – rash.

Laboratory investigations: infrequent – increased aminotransferase levels, decreased white blood cell count.

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

Blood and lymphatic system disorders: leukopenia, thrombocytopenia.

Immune system disorders: hypersensitivity, including anaphylactoid reactions.

Endocrine system 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, and pruritus.

Reproductive system and breast disorders: gynecomastia.

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

Shelf life.

5 years.

Storage conditions.

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

Packaging.

15 tablets in a blister pack, 1 blister pack in a cardboard box.

20 tablets in a blister pack, 2 or 5 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

PRO.MED.CS Prague a.s. / PRO.MED.CS Prahа a.s.

Manufacturer's address.

Telčska 377/1, Michle, Praha 4, 140 00, Czech Republic /
Telčska 377/1, Michle, Praha 4, 140 00, Czech Republic.