Triductan mv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Triductane mr (Triductane mr)

Composition:

Active substance: trimetazidine;

One tablet contains 35 mg of trimetazidine dihydrochloride;

Excipients: mannite (E 421), microcrystalline cellulose, glycol montan wax, magnesium stearate, ammonium methacrylate copolymer (type B), Opadry II Pink coating (iron oxide red (E 172), polyethylene glycol, iron oxide yellow (E 172), polyvinyl alcohol, talc, titanium dioxide (E 171), iron oxide black (E 172)).

Pharmaceutical form. Film-coated tablets with modified release.

Main physicochemical properties: round, biconvex, film-coated tablets of pink color. Two layers are visible upon cross-section.

Pharmacotherapeutic group. Cardiology preparations. Trimetazidine.

ATC code C01EB15.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

By preserving cellular energy metabolism in cells affected by hypoxia or ischemia, trimetazidine prevents the decrease in intracellular ATP levels, thereby maintaining proper function of ionic pumps and transmembrane sodium-potassium flux, preserving 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 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 changes.

Clinical efficacy and safety

Clinical studies have demonstrated the efficacy and safety of trimetazidine in the treatment of patients with stable angina, both as monotherapy and as an add-on to other antianginal medications when their efficacy is insufficient.

TRIMPOL-II study. In a randomized, double-blind, placebo-controlled trial involving 426 patients, adding trimetazidine 60 mg daily to metoprolol 100 mg (50 mg twice daily) for 12 weeks demonstrated significant improvement in exercise test parameters and clinical symptoms compared to placebo: total exercise duration − +20.1 s, p = 0.023; total work performed − +0.54 MET s, p = 0.001; time to 1 mm ST-segment depression − +33.4 s, p = 0.003; time to onset of angina − +33.9 s, p < 0.001; number of angina attacks/week − -0.73, p = 0.014; use of short-acting nitrates/week − -0.63, p = 0.032, with no changes in hemodynamic parameters.

SELLIER study. A randomized, double-blind, placebo-controlled trial involving 223 patients showed that in the subgroup (n = 173) receiving modified-release trimetazidine tablets 35 mg twice daily added to atenolol 50 mg once daily for 8 weeks, there was a significant increase (+34.4 s, p = 0.03) in time to 1 mm ST-segment depression during exercise testing compared to placebo, measured 12 hours after drug administration. A significant difference was also confirmed for time to onset of angina (p = 0.049). No significant differences between the two patient groups were observed for other secondary endpoint parameters (total exercise duration, total work performed, and clinical endpoints).

VASCO study. In a randomized, double-blind trial involving 1962 patients lasting 3 months, trimetazidine 70 mg or 140 mg daily, or placebo, was added to atenolol 50 mg daily. In the overall population, including both symptomatic and asymptomatic patients, trimetazidine showed no advantage either in ergometric parameters (total exercise time, time to 1 mm ST-segment depression, time to onset of angina) or clinical endpoints. However, a post-hoc analysis of the symptomatic subgroup (n = 1574) showed that with trimetazidine 140 mg daily, there was a significant improvement in total exercise time (+23.8 s vs. +13.1 s with placebo; p = 0.001) and time to onset of angina (+46.3 s vs. +32.5 s with placebo; p = 0.005).

Pharmacokinetics

Maximum plasma concentration of trimetazidine is reached on average 5 hours after tablet intake. Plasma concentration remains stable over 24 hours: for 11 hours after administration, plasma trimetazidine concentration is equal to or exceeds 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, and plasma protein binding is low, at 16%. Trimetazidine is primarily excreted in the urine, mostly in unchanged form. The elimination half-life averages 7 hours in healthy young volunteers and 12 hours in elderly subjects. Complete elimination of trimetazidine results from renal clearance, which is directly related to 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 receiving trimetazidine 35 mg (1 tablet) twice daily. Population pharmacokinetic analysis showed increased plasma trimetazidine concentrations. Elevated trimetazidine concentrations in elderly patients may be due to age-related decline in renal function. A specific pharmacokinetic study in patients aged 75–84 years or ≥ 85 years showed 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.

Renal impairment. Plasma trimetazidine concentration increases 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 adult patients with stable angina, when first-line antianginal medicinal products are insufficiently effective or not tolerated.

Contraindications.

• Hypersensitivity to trimetazidine or to any of the excipients.
• Parkinson's disease, symptoms of parkinsonism, tremor, restless legs syndrome, and other movement disorders.
• Severe renal impairment (creatinine clearance < 30 ml/min).

Interaction with other medicinal products and other forms of interactions.

To date, no interactions with other medicinal products have been reported.

Special precautions for use.

The drug should not be used to treat acute angina attacks. It should not be prescribed for 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 must be reassessed and therapy adjusted accordingly (medication regimen 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, tremor, restless legs syndrome, or gait instability, the drug should be discontinued.

The incidence of movement disorders is low. Generally, these disorders are reversible and resolve within 4 months of stopping trimetazidine in most patients. If parkinsonism symptoms persist for more than 4 months after discontinuation of the drug, patients should seek advice from a neurologist.

Falls may occur due to gait instability or arterial hypotension, particularly in patients receiving antihypertensive medications.

Use with caution in patient groups at risk of increased drug concentration:

• with moderate renal impairment (see sections "Administration and dosage" and "Pharmacokinetics");
• in elderly patients (aged ≥ 75 years) (see section "Administration and dosage").

Severe skin adverse reactions. Severe skin adverse reactions have been reported with trimetazidine, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) and acute generalized exanthematous pustulosis, which may be life-threatening or lead to fatal outcomes (see section "Adverse reactions"). When prescribing the drug, patients should be informed about the signs and symptoms of severe skin reactions, and careful monitoring during treatment is required. If signs indicating such reactions occur, trimetazidine should be discontinued immediately and alternative treatment considered (if necessary).

A special tablet structure (matrix) has been developed to ensure modified (prolonged) release of the active substance. The active ingredient responsible for the drug's therapeutic effect is gradually released from the tablet as it passes through the gastrointestinal tract. However, in some cases, the matrix framework may be excreted from the body in the form of a tablet. This feature does not affect the drug's therapeutic properties.

Athletes. This medicinal product contains an active substance that may lead to a positive doping test result.

This medicinal product contains mannitol and therefore may have a mild laxative effect.

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 harmful toxic effects on the reproductive system. To prevent any risk, the use of trimetazidine during pregnancy is not recommended.

Breastfeeding.

It is unknown whether trimetazidine or its metabolites are excreted in breast milk. To prevent any risk to newborns/infants, the use of trimetazidine is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Trimetazidine does not affect hemodynamics. Cases of dizziness and somnolence have been reported, which may impair the ability to drive a vehicle or operate machinery.

Dosage and Administration.

Take 1 tablet twice daily: in the morning and in the evening, during meals, with sufficient amount of water. The duration of treatment is determined individually by a physician depending on the nature and course of the disease. If necessary, the treatment regimen may be reviewed after 3 months.

Special patient groups.

Patients with renal impairment.

For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended dose is 1 tablet once daily in the morning with breakfast.

Elderly patients.

Elderly patients are more sensitive to the effects of trimetazidine due to age-related decline in renal function. For elderly patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended dose is 1 tablet once daily in the morning during a meal.

Dose titration in elderly patients should be performed with caution.

Children.

Safety and efficacy of trimetazidine in children (under 18 years of age) have not been established. Data are lacking.

Overdose.

Data regarding trimetazidine overdose are limited. Treatment is symptomatic.

Side effects

The adverse reactions identified as side effects possibly related to the use of trimetazidine are listed below with their defined frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data):

• Nervous system disorders: common – headache, dizziness; uncommon – paresthesia; frequency not known – possible development of Parkinsonism symptoms (tremor, akinesia, muscle hypertonia), gait instability, restless legs syndrome, and other movement disorders related to the above-mentioned, which are reversible after discontinuation of the drug; 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, diarrhea, dyspepsia, nausea and vomiting; frequency not known – constipation;
• Hepatobiliary disorders: frequency not known – hepatitis;
• Skin and subcutaneous tissue disorders: common – rash, pruritus, urticaria; frequency not known – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (see section "Special precautions");
• Blood and lymphatic system disorders: frequency not known – agranulocytosis, thrombocytopenia, thrombocytopenic purpura;
• General disorders: common – asthenia.

Shelf life. 3 years.

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

Packaging.

10 tablets in a blister pack, 3 or 6 blisters per cardboard pack.

20 tablets in a blister pack, 1, 3 or 4 blisters per cardboard pack.

Prescription category. Prescription only.

Manufacturer. LLC "Pharma Start", Ukraine.

Manufacturer's address and location of business activity.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

If you experience any side effects or have questions regarding the safety of this medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINA" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine; tel/fax: +38 044 281 2333.