Carmetadine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARMETADIN (CARMETADIN)

Composition:

Active ingredient: trimetazidine dihydrochloride;

1 tablet contains trimetazidine dihydrochloride 35 mg;

Excipients: calcium hydrogen phosphate anhydrous, silicon dioxide colloidal anhydrous, polyethylene oxide, povidone, xanthan gum, magnesium stearate;

Film coating: Opadry® II Brown 85G565010 (polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide (E 171), lecithin (soy)); ferric oxide red (E 172); magnesium stearate, glycerin.

Pharmaceutical form. Film-coated tablets with modified release.

Main physicochemical properties: round, biconvex, film-coated tablets, pinkish-brown in color, with engraving "TZN" and "35" on one side.

Pharmacotherapeutic group. Cardiology agents. Trimetazidine. ATC code C01EB15.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

By preserving energy metabolism in cells suffering from hypoxia or ischemia, trimetazidine prevents the decrease in intracellular ATP levels, thereby ensuring proper functioning of ionic pumps and transmembrane sodium-potassium flux while maintaining cellular homeostasis.

Trimetazidine inhibits fatty acid β-oxidation by blocking long-chain 3-ketoacyl-CoA thiolase (3-KAT), thus enhancing glucose oxidation. In cells under ischemic conditions, energy production via glucose oxidation requires less oxygen compared to energy production via fatty acid β-oxidation. Enhanced glucose oxidation optimizes cellular energy processes and consequently supports adequate energy metabolism during ischemia.

Pharmacodynamic effects.

In patients with ischemic heart disease, trimetazidine acts as a metabolic agent, preserving intracellular levels of high-energy phosphates in the myocardium. Anti-ischemic effects are achieved without concomitant hemodynamic effects.

Pharmacokinetics.

Absorption.

After oral administration, maximum plasma concentration of trimetazidine is observed on average within 5 hours. Plasma concentration remains stable throughout the day: for 11 hours after tablet intake, trimetazidine plasma concentration equals or exceeds 75% of the maximum concentration. Steady-state concentration is reached by no later than 60 hours. Food intake does not affect the pharmacokinetic characteristics of trimetazidine.

Distribution.

Volume of distribution is 4.8 L/kg; protein binding is low: in vitro measurements indicate 16%.

Elimination.

Trimetazidine is mainly excreted in urine, primarily in unchanged form. Elimination half-life averages 7 hours in healthy young volunteers and 12 hours in individuals aged 65 years and older. Complete elimination of trimetazidine results mainly from renal clearance, which directly correlates with creatinine clearance, and to a lesser extent from hepatic clearance, which decreases with age.

Special patient groups.

Elderly patients.

A specific clinical study was conducted in elderly patients using trimetazidine 35 mg twice daily. Population kinetic analysis showed increased plasma concentrations. In elderly patients, increased trimetazidine concentrations may occur due to age-related decline in renal function. A specific pharmacokinetic study in patients aged 75–84 years or ≥ 85 years demonstrated that in patients with moderate renal impairment (creatinine clearance 30–60 mL/min), trimetazidine concentration increased by 1.0 and 1.3 times, respectively, compared to younger patients (aged 30–65 years) with moderate renal impairment.

Patients with renal impairment.

Plasma concentration of trimetazidine increases on average by 1.7 times in patients with moderate renal impairment (creatinine clearance 30–60 mL/min) and by 3.1 times in patients with severe renal impairment (creatinine clearance < 30 mL/min), compared to healthy volunteers with normal renal function. In this population, no additional safety concerns were observed compared to the general population.

Clinical characteristics.

Indications.

Symptomatic treatment of stable angina in adults when first-line antianginal medications are insufficiently effective or not tolerated.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Parkinson's disease, symptoms of parkinsonism, tremor, restless legs syndrome, and other movement disorders related to the above-mentioned conditions.
• Severe renal impairment (creatinine clearance < 30 ml/min).

Interaction with other medicinal products and other forms of interaction.

No interactions between trimetazidine and other medicinal products have been reported.

Special precautions for use

The medicinal product should not be used to treat acute angina attacks. It should also not be used in the treatment of unstable angina or myocardial infarction as initial therapy at the pre-hospital stage or during the first days of hospitalization.

If an episode of unstable angina occurs during ongoing treatment, the patient's condition should be reassessed and therapy adjusted accordingly (including pharmacological treatment and consideration of revascularization options).

The medicinal product may cause or worsen symptoms of parkinsonism (tremor, akinesia, muscle hypertonia), which should be regularly monitored, especially in elderly patients. In cases of diagnostic uncertainty, patients should be referred to a neurologist for appropriate evaluation. If motor disorders occur, such as parkinsonism symptoms, restless legs syndrome, tremor, or gait instability, the medicinal product should be discontinued. These events are rare and usually resolve after treatment discontinuation, in most patients within 4 months after stopping trimetazidine. If parkinsonism symptoms persist for more than 4 months after treatment cessation, patients should be referred to a neurologist.

During treatment with the medicinal product, falls may occur due to gait instability or arterial hypotension, particularly in patients receiving antihypertensive therapy (see section "Adverse reactions").

The medicinal product should be used with caution in patients at risk of increased plasma concentration: patients with moderate renal impairment (see sections "Pharmacokinetics" and "Dosage and administration") and patients aged 75 years and older (see section "Dosage and administration").

Athletes.

The medicinal product contains an active substance that may result in a positive anti-doping test.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no data available on the use of trimetazidine in pregnant women. Animal studies have not revealed any direct or indirect toxic effects on reproductive organs. However, to avoid any potential risk, the medicinal product is not recommended during pregnancy.

Breastfeeding period.

It is unknown whether trimetazidine or its metabolites are excreted in human milk. To avoid any potential risk to newborns or infants, the medicinal product is not recommended during breastfeeding.

Fertility.

Reproductive toxicity studies showed no effect of trimetazidine on fertility in male and female rats.

Ability to affect reaction speed when driving or operating machinery.

Clinical studies indicate that trimetazidine does not affect hemodynamics. However, during the post-marketing period, cases of dizziness and somnolence have been reported (see section "Adverse reactions"), which may impair the ability to drive or operate machinery.

Dosage and Administration

The medicinal product is intended for oral use.

The recommended dose is 35 mg (1 tablet) twice daily, in the morning and evening, during meals.

After 3 months of treatment, treatment efficacy should be evaluated and if no effect is observed, the medicinal product should be discontinued.

Special patient groups.

Patients with renal impairment.

For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended dose is 35 mg (1 tablet) once daily in the morning with breakfast (see sections "Pharmacokinetics" and "Special precautions").

Elderly patients.

In elderly patients, plasma concentrations of trimetazidine may be increased due to age-related decline in renal function (see section "Pharmacokinetics"). For elderly patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended dose is 35 mg (1 tablet) once daily in the morning with breakfast. Dose titration should be performed with caution in elderly patients (see section "Special precautions").

Children.

The safety and efficacy of trimetazidine in children (under 18 years of age) have not been established. No data are available.

Overdose.

Data regarding trimetazidine overdose are limited. In case of overdose, symptomatic treatment should be administered.

Adverse Reactions

The adverse reactions listed below are classified by MedDRA system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Central and peripheral nervous system disorders:

Common – dizziness, headache; frequency not known – Parkinsonism symptoms (tremor, akinesia, muscle rigidity), gait instability, restless legs syndrome, and other movement disorders related to the above (usually resolve after discontinuation of treatment), sleep disorders (insomnia, somnolence).

Ear and labyrinth disorders:

Frequency not known – vertigo.

Cardiac disorders:

Rare – palpitations, extrasystoles, tachycardia.

Vascular disorders:

Rare – arterial hypotension, orthostatic hypotension which may be associated with malaise, dizziness, or falls (particularly in patients taking antihypertensive agents), facial flushing.

Gastrointestinal disorders:

Common – abdominal pain, diarrhoea, dyspepsia, nausea, vomiting; frequency not known – constipation.

Hepatobiliary disorders:

Frequency not known – hepatitis.

Skin and subcutaneous tissue disorders:

Common – rash, pruritus, urticaria; frequency not known – acute generalized exanthematous pustulosis, angioneurotic edema.

Blood and lymphatic system disorders:

Frequency not known – agranulocytosis, thrombocytopenia, thrombocytopenic purpura.

General disorders and administration site conditions:

Common – asthenia.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 25°C in a place inaccessible to children.

Packaging.

30 modified-release film-coated tablets in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICINE ILAC SAN. VE TIC. A.S., Turkey /
WORLD MEDICINE ILAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address and location of operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

UORLД MEDICINE ILAC SAN. VE TIC. A.S., Turkey /
WORLD MEDICINE ILAC SAN. VE TIC. A.S., Turkey.