Polprid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT POLPRID (POLPRID)

Composition:

Active substance: itopride hydrochloride;

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

Excipients: lactose monohydrate, carmellose, pregelatinized corn starch, colloidal anhydrous silicon dioxide, magnesium stearate;

Tablet coating: hypromellose 2910, titanium dioxide E 171, macrogol 6000, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets, 7 mm in diameter.

Pharmacotherapeutic group. Agents used in functional gastrointestinal disorders. Prokinetic agents. ATC code A03FA07.

Pharmacological Properties

Pharmacodynamics

Itopride hydrochloride enhances propulsive gastrointestinal motility through antagonism of dopamine D2 receptors and inhibition of acetylcholinesterase activity. It stimulates the release of acetylcholine and inhibits its degradation. Itopride hydrochloride also exerts an antiemetic effect by interacting 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 first-pass effect in the liver. Food does not influence the bioavailability of the drug. After administration of 50 mg of itopride hydrochloride, Cmax is reached within 30–45 minutes and amounts to 0.28 µg/mL. With repeated administration of doses ranging from 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 (mainly 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, which occasionally leads to an autosomal recessive condition known as trimethylaminuria ("fish odor syndrome"). In patients with trimethylaminuria, the elimination half-life (T1/2) is prolonged.

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

Excretion. 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 a single oral dose of the drug at the therapeutic dose in healthy volunteers.

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

Clinical characteristics

Indications

Relief 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 or to any of the excipients.
• 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, since itopride hydrochloride is primarily metabolized by flavin-containing 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 concomitantly.

Particular caution should be exercised when administering medicinal products with a narrow therapeutic index, modified release formulations, or enteric coatings.

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. There is no data on long-term use.

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

Excipients

The medicinal product contains lactose; therefore, patients with established sugar intolerance should consult their physician before taking this medicine.

Use during pregnancy or breastfeeding

Pregnancy

The safety of using itopride hydrochloride during pregnancy has not been established. Therefore, the drug should not be prescribed during this period except when the expected benefit of treatment outweighs the potential risk.

Breastfeeding

Itopride is excreted in breast milk in animals, but there is insufficient data regarding excretion of itopride in human breast milk. Risk to the breastfed infant cannot be excluded. A decision on discontinuation of breastfeeding or discontinuation/pause of itopride therapy should be made taking into account the benefit of breastfeeding for the infant and the benefit of therapy for the woman.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

There is no information on the effect on reaction speed; however, when making decisions about driving or operating machinery, the possibility of dizziness should be taken into account.

Administration and Dosage

Administration

The medicinal product should be taken orally, without chewing, and with sufficient amount of water.

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 clinical symptoms (see "Special Warnings and Precautions for Use").

The exact dosage and duration of treatment depend on the patient's clinical condition.

Patients with hepatic and/or renal impairment

Itopride hydrochloride is metabolized in the liver. Itopride and its metabolites are primarily excreted via the kidneys. The drug should be administered under appropriate medical supervision; if necessary, the dose should be reduced or therapy discontinued.

Elderly patients

Clinical studies have shown that the incidence of adverse effects in patients aged 65 years and older was not higher than in younger patients. Itopride hydrochloride should be used with caution in elderly patients due to the increased prevalence of impaired hepatic and renal function, other diseases, or concomitant use of other medicinal products.

Duration of treatment

In clinical studies, the duration of treatment was up to 8 weeks.

Children. The safety of itopride hydrochloride in children (under 18 years of age) has not been established.

Overdose

There have been no reported cases of overdose in humans.

In case of overdose, standard procedures such as gastric lavage and symptomatic treatment should be performed.

Side effects

The side effects listed below were observed in 998 patients who received itopride in 4 placebo-controlled clinical studies, 4 comparative clinical studies, and 13 uncontrolled interventional clinical studies with a standard daily dose of itopride of 150 mg or less. Side effects are classified by system organ class (according to MedDRA [Medical Dictionary for Regulatory Activities]) and by frequency of occurrence: common (from >1/100 to <1/10) and uncommon (from >1/1000 to <1/100).

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

Central and peripheral nervous system disorders:
Uncommon — dizziness, headache.

Skin and subcutaneous tissue disorders:
Uncommon — rash.

Laboratory investigations:
Uncommon — increased aminotransferase levels, decreased white blood cell count.

The following side effects have been reported during post-marketing use. The frequency cannot be estimated precisely from the available data.

Blood and lymphatic system disorders:
leukopenia, thrombocytopenia.

Immune system disorders:
hypersensitivity, including anaphylactoid reactions.

Endocrine system disorders:
elevated 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.

Laboratory investigations:
elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin in blood.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

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 pack, 4 blisters in a cardboard box.

Prescription status
Prescription-only medicine.

Manufacturer
Medochemie Ltd (Central Plant)

Manufacturer's address and site of operations
1-10 Konstantinoupoleos Street, 3011, Limassol, Cyprus