Trimetazidine-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIMETAZIDINE-DARNITSA (TRIMETAZIDINE-DARNITSA)

Composition:

Active substance: trimetazidine;

One tablet contains 20 mg of trimetazidine dihydrochloride;

Excipients: maize starch, lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, talc, calcium stearate, Sepifilm 752 white.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: round, biconvex, film-coated tablets of white color.

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 adenosine triphosphate (ATP) levels, thereby ensuring proper functioning of ion pumps and transmembrane sodium-potassium flux, maintaining cellular homeostasis.

Trimetazidine inhibits β-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase (3-KAT), which enhances glucose oxidation. In cells under ischemic conditions, energy production via glucose oxidation requires less oxygen compared to energy production via β-oxidation of fatty acids. Enhanced glucose oxidation optimizes cellular energy processes and thus 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. These effects are achieved without concomitant hemodynamic effects.

Pharmacokinetics.

Maximum plasma concentration of trimetazidine is observed on average 5 hours after tablet intake. Plasma concentration remains stable over 24 hours: for 11 hours after administration, plasma concentration of trimetazidine is at least 75% of the maximum concentration. Steady-state concentration is achieved by no later than 60 hours. Food intake does not affect the pharmacokinetic characteristics of trimetazidine. The volume of distribution is 4.8 L/kg; protein binding is low: in vitro measurements indicate 16%.

Trimetazidine is primarily excreted in urine, mainly in unchanged form. The elimination half-life averages 7 hours in healthy young volunteers and 12 hours in individuals over 65 years of age. Complete elimination of trimetazidine results 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. In elderly patients, increased trimetazidine concentration may occur due to age-related decline in renal function.

Renal impairment. Plasma concentration of trimetazidine increases in patients with moderate renal impairment (creatinine clearance − 30–60 mL/min) and in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Clinical characteristics.

Indications.

In adults, trimetazidine is indicated for the symptomatic treatment of stable angina pectoris when first-line antianginal medicinal products 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.
• Severe renal impairment (creatinine clearance < 30 ml/min).

Interaction with other medicinal products and other forms of interaction.

No interactions with other medicinal products have been reported. In particular, trimetazidine may be administered in combination with heparin, calciparine, vitamin K antagonists, oral lipid-lowering medicinal products, acetylsalicylic acid, β-blocker medicinal products, calcium antagonists, and digitalis preparations (trimetazidine does not affect plasma digoxin levels).

Special precautions for use.

The medicinal product should not be used to relieve angina attacks, for unstable angina or myocardial infarction as primary 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 (medicinal treatment and possibility of revascularization).

Trimetazidine may induce or worsen symptoms of parkinsonism (tremor, akinesia, muscle hypertonia), which should be regularly monitored, especially in elderly patients. In doubtful cases, patients should be referred to a neurologist for appropriate evaluation.

If movement disorders occur, such as parkinsonism symptoms, restless legs syndrome, tremor, or gait instability, the medicinal product should be discontinued. Such disorders occur infrequently and usually resolve after treatment cessation, in most patients within 4 months after stopping trimetazidine. If parkinsonism symptoms persist beyond 4 months after discontinuation of the medicinal product, a neurologist should be consulted.

Falls may occur due to gait instability or arterial hypotension, particularly in patients receiving antihypertensive therapy (see section "Adverse reactions").

Trimetazidine should be prescribed with caution:

• in patients with moderate renal impairment (see section "Dosage and administration");
• in patients aged over 75 years (see section "Dosage and administration").

These patients should undergo monitoring of functional parameters, and dose reduction should be considered if necessary.

Information regarding the use of the medicinal product in hepatic impairment is lacking.

In patients with diabetes mellitus, dosage adjustment of the medicinal product is not required.

The use of the medicinal product does not affect preparation for anesthesia.

Important information about excipients.

The medicinal product contains lactose. The medicinal product should not be administered to patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. Patients with intolerance to certain sugars should consult their physician.

Use during pregnancy or breastfeeding.

Due to insufficient clinical data, the medicinal product is not recommended during pregnancy.

If use of the medicinal product is necessary, breastfeeding should be discontinued, as its ability to pass into breast milk has not been studied.

Ability to influence reaction speed when driving or operating machinery.

Trimetazidine does not affect hemodynamics; however, cases of dizziness and somnolence have been reported (see section "Adverse reactions"), which may affect the ability to drive or operate machinery.

Dosage and Administration.

Administer the medicinal product orally, 1 tablet (20 mg) three times daily during meals. After 3 months of treatment, the therapeutic response should be evaluated, and if no effect is observed, trimetazidine should be discontinued.

Patients with renal impairment.

For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended dose is 1 tablet twice daily, in the morning and evening, taken during meals (see section "Special Instructions").

Elderly patients.

Elderly patients are more sensitive to the effects of trimetazidine due to age-related decline in renal function (see section "Pharmacological Properties"). For elderly patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended dose is 1 tablet (20 mg) twice daily, in the morning and evening, taken during meals.

Careful dose titration is required for elderly patients (see section "Special Instructions").

Children.

The safety and efficacy of trimetazidine in children have not been established. Data are lacking.

Overdose.

Information regarding trimetazidine overdose is limited.

Treatment is symptomatic.

Adverse Reactions.

Auditory and vestibular system disorders: vertigo.

Gastrointestinal disorders: nausea, vomiting, abdominal pain, dyspepsia, diarrhea, constipation.

Hepatobiliary disorders: hepatitis.

Nervous system disorders: dizziness, headache, symptoms of parkinsonism (tremor, akinesia, muscle hypertonia, gait instability), restless legs syndrome and other movement disorders related to the above, which usually resolve after discontinuation of treatment; sleep disturbances (insomnia, somnolence).

Cardiovascular disorders: palpitations, extrasystoles, tachycardia, arterial hypotension, orthostatic hypotension, which may be associated with malaise, dizziness or falls, particularly in patients taking antihypertensive agents; facial flushing.

Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia, thrombocytopenic purpura.

Immune system, skin and subcutaneous tissue disorders: hypersensitivity reactions, including rash, pruritus, urticaria, acute generalized exanthematous pustulosis, angioneurotic edema.

General disorders: asthenia.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 6 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer: JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of business activity:

13, Borispilska Street, Kyiv, 02093, Ukraine.