Cynara

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CINARA CINARA

Composition:

Active substance: cinitapride hydrotartrate;

1 tablet contains 1.37 mg of cinitapride hydrotartrate, equivalent to 1.00 mg of cinitapride;

Excipients: microcrystalline cellulose (type 102), lactose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: yellow, round, biconvex tablets.

Pharmacotherapeutic group.

Medicinal products used in functional gastrointestinal disorders. Gastrointestinal motility stimulants. ATC code A03F A08.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Cinitapride is an orthopramide with prokinetic activity in the gastrointestinal tract (GIT) and pronounced procholinergic effects. By blocking presynaptic serotonin receptors, it increases the release of serotonin, resulting in enhanced serotonergic activity. Its antidopaminergic activity, although discrete, contributes to the therapeutic effect.

Pharmacodynamic effects

Administration of cinitapride to experimental animals demonstrated prokinetic effects from the lower esophageal sphincter to the colon. Cinitapride promotes gastric emptying in rats, stimulates motility of the isolated ileum of guinea pigs, increases intraluminal pressure in the stomach, duodenum, and ileum of conscious dogs, enhances lower esophageal sphincter pressure, and increases mechanical activity of the duodenum and colon in anesthetized dogs. It accelerates intestinal transit in mice.

Clinical efficacy and safety

In clinical studies involving patients and healthy volunteers, cinitapride was shown to antagonize L-dopa-induced gastroparesis and vomiting.

In a placebo-controlled study, cinitapride significantly accelerated gastric emptying in patients with pathologically delayed gastric emptying. Cinitapride improves clinical symptoms in patients with dyspepsia associated with delayed gastric emptying and delayed gastrointestinal transit of food.

In patients with gastroesophageal reflux, cinitapride reduces the number and duration of reflux episodes, as well as the time with esophageal pH below 4, significantly alleviating symptoms of the disease. This efficacy may be attributed both to increased lower esophageal sphincter pressure and improved gastric emptying.

Pharmacokinetics.

Distribution

The pharmacokinetics of cinitapride in rats after intravenous administration best fit a two-compartment model with a large volume of distribution (9.9 L/kg) and relatively low elimination rate (51–83 min). After intravenous administration, metabolites were not detected in plasma.

Following oral administration, a significant first-pass metabolism was observed. Thirty percent of the administered dose was excreted in bile within 48 hours.

Metabolism

In vitro studies using recombinant microsomes indicate that cinitapride metabolism is mediated primarily by CYP3A4 and to a lesser extent by CYP2C8.

Excretion

Pharmacokinetic studies in humans were conducted after oral and intramuscular administration at doses exceeding the therapeutic dose, due to the lack of an analytical method with sufficient sensitivity to measure plasma concentrations achieved after administration of the recommended dose.

These studies showed that after oral administration of cinitapride, maximum plasma levels are reached within two hours. The elimination half-life is 3 to 5 hours during the first 8 hours, followed by a prolonged terminal half-life of more than 15 hours, although plasma levels are extremely low at this stage.

This pharmacokinetic profile supports a dosing regimen of three times daily in divided doses as the most appropriate. No accumulation of cinitapride was observed after repeated administration.

Clinical characteristics.

Indications.

The medicinal product Cynara is indicated for adult patients:

• for the treatment of mild to moderate dyskinetic dyspepsia;
• as an adjunctive agent in the treatment of gastroesophageal reflux in patients in whom proton pump inhibitors have proven insufficient.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Cynara should not be administered to patients in whom stimulation of gastric motility may be harmful, particularly in the presence of bleeding, obstruction, or perforation, as well as in patients with proven tardive dyskinesia induced by neuroleptics.

Interaction with other medicinal products and other forms of interactions.

Stimulation of gastric emptying by cinitapride may alter the absorption of certain medicinal products. The patient should inform their physician if they are taking other medicinal products.

Cinitapride enhances the effects of phenothiazines and other medicinal products with antidopaminergic action on the central nervous system.

Cinitapride may reduce the effect of digoxin due to decreased absorption.

Anticholinergic drugs with atropine-like effects and opioid analgesics may reduce the gastrointestinal effects of cinitapride.

Concomitant use of cinitapride with alcohol, tranquilizers, sedatives, or narcotic drugs enhances the sedative effect.

In vitro studies show that cinitapride is metabolized predominantly via CYP3A4 (to a lesser extent via CYP2C8); therefore, concomitant oral or parenteral administration of medicinal products that strongly inhibit this isoenzyme may alter its pharmacokinetics.

Examples of such medicinal products include:

• Azole antifungal agents, such as ketoconazole, itraconazole, miconazole, and fluconazole. In any case, human studies involving repeated doses of cinitapride in the absence and presence of ketoconazole showed that the pharmacokinetic interaction is minor, as the mean area under the cinitapride concentration-time curve increased approximately 2-fold (range: 0.9–4.3; 95% CI: 1.5–2.4).
• HIV protease inhibitors, particularly indinavir and ritonavir.
• Macrolide antibiotics, such as erythromycin, clarithromycin, or troleandomycin.
• The antidepressant nefazodone.

Special precautions for use.

In elderly patients undergoing long-term treatment, late dyskinesias may occur.

Although in vitro studies at concentrations significantly exceeding plasma concentrations observed in clinical studies suggest that cinitapride may prolong cardiac repolarization, in vivo studies in both animals and humans have not shown any effect on the electrocardiogram, particularly on the QT interval.

Warning about excipients.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of cinitapride in pregnant women. Animal studies have not revealed any direct or indirect adverse effects of the drug with regard to reproductive toxicity. As a precautionary measure, it is advisable to avoid using the medicinal product Cynara during pregnancy.

If use is necessary, the physician should evaluate the risk-benefit ratio.

Breastfeeding period

It is unknown whether cinitapride is excreted in breast milk. As a precautionary measure, it is advisable to avoid using the medicinal product Cynara during breastfeeding.

Fertility

There are no data on the effect of cinitapride on human fertility.

Ability to influence the reaction rate when driving vehicles or operating machinery.

During treatment with the medicinal product Cynara, situations requiring high alertness and rapid reaction, such as driving vehicles or operating dangerous machinery, should be avoided.

Dosage and Administration

Dosage

Adults (aged 20 years and older): 1 tablet three times daily, 15 minutes before each meal. Increasing the recommended dose is neither more effective nor more convenient.

Children

Cinitapride is not recommended for use in children due to lack of experience with its use in this age group.

Administration method

For oral use.

Children

The medicinal product should not be used in children.

Overdose

Overdose may cause drowsiness, disorientation, and extrapyramidal effects, which usually resolve after discontinuation of treatment. If symptoms persist, gastric lavage should be performed and symptomatic therapy administered. Extrapyramidal reactions are controlled by administration of antiparkinsonian, anticholinergic, or antihistamine medicinal products possessing anticholinergic properties.

Adverse reactions

Cinitapride has been widely studied in healthy adult volunteers and in patients with gastrointestinal motility disorders, both in placebo-controlled studies and in other open-label, controlled and uncontrolled clinical trials. Post-marketing experience is also available since the first registration of cinitapride in 1989.

Adverse reactions reported in clinical trials and during the post-marketing period are listed in the table below, categorized according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated based on available data).

* Extrapyramidal effects may occur, with muscle spasms of the face, neck, and tongue, which disappear after discontinuation of treatment.

Reporting of suspected adverse reactions

Reporting of adverse reactions after authorization of the medicinal product is of great importance. It allows 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 of the medicinal product via the automated pharmacovigilance information system (https://aisf.dec.gov.ua).

Shelf life.

2 years.

Storage conditions.

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

Packaging.

10 tablets per blister, 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

SAG MANUFACTURING S.L.

Manufacturer's address and place of business.

Carretera Nacional 1 Km 36, San Agustin del Guadalix, 28750, Spain.