Edardin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EDARDIN (EDARDIN®)

Composition:

Active substance: itopride hydrochloride;

One film-coated tablet contains 50 mg of itopride hydrochloride;

Excipients: lactose monohydrate, sodium croscarmellose, corn starch (type B), colloidal anhydrous silicon dioxide, magnesium stearate, coating "Opadry II White 85F18422"*;

* Opadry II White 85F18422: polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets with a score line on one side and smooth on the other side.

Pharmacotherapeutic group. Prokinetic agents. ATC code A03FA07.

Pharmacological Properties

Pharmacodynamics

Itopride hydrochloride enhances propulsive gastrointestinal motility due to its antagonism at dopamine D2 receptors and inhibitory activity on acetylcholinesterase. It stimulates the release of acetylcholine 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 60%, which is attributed to the first-pass liver effect. Food does not influence the bioavailability of the drug. 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 the drug 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 (primarily to albumin). Binding to α1-acid glycoprotein is less than 15%.

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

Itopride hydrochloride 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, the T1/2 is prolonged.

According to pharmacokinetic studies, itopride hydrochloride does not inhibit or induce CYP2C19 and CYP2E1 in vivo. Administration of itopride hydrochloride does not affect CYP content or uridine diphosphate glucuronosyltransferase activity.

Elimination. Itopride hydrochloride and its metabolites are primarily excreted via the 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 medicinal product.
• Conditions in which increased gastrointestinal motility may be harmful, such as gastrointestinal bleeding, mechanical obstruction, or perforation.

Interaction with other medicinal products and other types of interactions

Metabolic interactions are not expected, as 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 orally administered medicinal products taken simultaneously.

Medicinal products with a narrow therapeutic index, delayed release, or enteric coating should be used with particular caution.

Anti-ulcer medicinal products 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 effect of acetylcholine and may lead to cholinergic adverse effects. Data on long-term use are lacking.

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

If a patient has intolerance to certain sugars, medical advice should be sought before taking this medicinal product, as it contains lactose.

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 (fewer than 300 pregnancy outcomes). Animal studies have not revealed any direct or indirect toxic effect on reproductive function. To avoid potential risks, it is advisable to avoid the use of itopride during pregnancy.

Breastfeeding. Itopride is excreted in 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 to discontinue breastfeeding or to discontinue/withhold itopride therapy should be made considering the benefit of breastfeeding to the infant and the benefit of treatment to the woman.

Ability to influence reaction speed when driving or operating machinery. Information regarding the possible effect on reaction speed is lacking; however, when making decisions about driving or operating 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) three times daily before meals). This dose may be adjusted depending on the patient's age and symptoms (see "Special Precautions").

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

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

Overdose. 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 in patients receiving itopride in placebo-controlled, comparative, and uncontrolled interventional clinical trials with a standard daily dose of itopride of 150 mg or less. The adverse reactions observed during the use of itopride are listed below by system organ class (according to MedDRA [Medical Dictionary for Regulatory Activities]) and frequency of 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), not known (cannot be estimated based on available data).

Gastrointestinal disorders:

common — abdominal pain, diarrhoea; uncommon — increased salivation.

Nervous system disorders:

uncommon — dizziness, headache.

Skin and subcutaneous tissue disorders:

uncommon — rash.

Investigations:

uncommon — increased levels of aminotransferase and prolactin, decreased white blood cell count.

The following adverse reactions have been reported voluntarily during post-marketing use. Frequency cannot be estimated precisely based on available data.

Blood and lymphatic system disorders:

leukopenia, thrombocytopenia.

Immune system disorders:

hypersensitivity, including anaphylactoid reactions.

Endocrine disorders:

elevated blood prolactin levels.

Nervous system disorders:

dizziness, headache, tremor.

Gastrointestinal disorders:

diarrhoea, constipation, abdominal pain, increased salivation, nausea.

Hepatobiliary disorders:

jaundice.

Skin and subcutaneous tissue disorders:

rash, erythema, pruritus.

Reproductive system and breast disorders:

gynecomastia.

Investigations:

elevated levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and bilirubin in blood.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

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

Prescription status. Prescription only.

Manufacturer. LLC "KUSUM PHARM".

Manufacturer's address and location of its business activity. 54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.