Trimetazidine-astrapharm

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIMETAZIDINE-aStRApharm (Trimetazidin-aStRApharm)

Composition:

Active substance: trimetazidine;

One tablet contains 20 mg of trimetazidine dihydrochloride;

Excipients: maize starch, mannitol E 421, povidone, talc, magnesium stearate, coating "SeleCoat™" (hypromellose, polyethylene glycol (macrogol) 6000, titanium dioxide E 171), colouring agent "Azorubine" (carmoisine) E 122, colouring agent "Yellow West FCF" E 110.

Medicinal form. Film-coated tablets.

Main physicochemical properties: red, round, biconvex film-coated tablets. Two layers are visible upon breaking.

Pharmacotherapeutic group.

Cardiological preparations. Trimetazidine. ATC code C01EB15.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

By preserving cellular 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, maintaining cellular homeostasis.

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

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.

Clinical efficacy and safety.

Clinical studies have demonstrated the efficacy and safety of trimetazidine in the treatment of patients with chronic angina, either as monotherapy or in combination with other antianginal therapies in patients with inadequate control.

In a randomized, double-blind, placebo-controlled trial (TRIMPOL-II) involving 426 patients over 12 weeks, trimetazidine (60 mg/day) in combination with metoprolol 100 mg/day (50 mg twice daily) demonstrated statistically significant improvements in exercise test parameters and clinical symptoms compared to placebo: total exercise duration +20.1 s, p=0.023; total work +0.54 METs, 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; frequency of angina attacks per week -0.73, p=0.014; weekly consumption of short-acting nitrates -0.63, p=0.032, without changes in hemodynamics.

In a randomized, double-blind, placebo-controlled study (Sellier) involving 223 patients receiving 50 mg atenolol once daily, adding modified-release tablets of trimetazidine 35 mg twice daily for 8 weeks resulted in a significant increase (+34.4 s, p=0.03) in time to 1 mm ST-segment depression during exercise testing in the subgroup (n=173) assessed 12 hours after dosing, compared to placebo. A significant difference was also observed in time to onset of angina (p=0.049). No significant differences between groups were observed for secondary endpoints (total exercise duration, total work, and clinical assessment criteria).

In a randomized, double-blind study (Vasco study) conducted over three months involving 1962 patients receiving 50 mg atenolol daily, two doses of trimetazidine (70 mg/day and 140 mg/day) were evaluated against placebo. Trimetazidine showed no benefit in the overall population, including symptomatic and asymptomatic patients, regarding ergometric endpoints (total exercise duration, time to 1 mm ST-segment depression, time to onset of angina) and clinical outcomes. However, in a post-hoc analysis of the symptomatic subgroup (n=1574), trimetazidine (140 mg/day) significantly improved total exercise duration (+23.8 s vs. +13.1 s with placebo, p=0.001) and time to onset of angina (+43.6 s vs. +32.5 s with placebo; p=0.005).

Pharmacokinetics.

Absorption.

After oral administration, trimetazidine is rapidly absorbed, with peak plasma concentrations observed within less than 2 hours after intake. Maximum plasma concentration following a single oral dose of 20 mg trimetazidine is approximately 55 ng/mL. The steady state, reached between 24 and 36 hours during repeated dosing, remains very stable throughout treatment.

Distribution.

The apparent volume of distribution is 4.8 L/kg, indicating good tissue diffusion. Protein binding is low, with an in vitro measured value of 16%.

Elimination.

Trimetazidine is primarily excreted via urine, mainly in unchanged form. The elimination half-life averages 6 hours.

Linearity.

The pharmacokinetics of trimetazidine are linear after single doses up to 0.100 mg. Repeated doses demonstrate linear pharmacokinetics over time.

Special patient populations.

Elderly patients. Increased trimetazidine concentrations may occur in elderly patients due to age-related decline in renal function. A specific pharmacokinetic study in patients aged 75–84 years or ≥85 years showed that trimetazidine concentrations were increased by 1.0 and 1.3 times, respectively, in patients with moderate renal impairment (creatinine clearance 30–60 mL/min) compared to younger patients (aged 30–65 years) with similar renal impairment. No safety concerns were observed in elderly patients compared to the general population.

Renal impairment. Trimetazidine blood concentrations increase 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. No safety concerns were observed in this population compared to the general population.

Children. The pharmacokinetics of trimetazidine have not been studied in patients under 18 years of age.

Clinical characteristics.

Indications.

Trimetazidine is indicated in combination for the symptomatic treatment of adult patients with inadequately controlled stable angina or with intolerance to first-line antianginal medications.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients, 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 interactions.

No drug interactions have been identified.

Special precautions for use

Trimetazidine may cause 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.

Trimetazidin-Astrafarm should not be used to treat acute angina attacks. It should not be prescribed for unstable angina or myocardial infarction as primary therapy at the pre-hospital stage or during the first days of hospitalization.

In case of an attack of unstable angina occurring during ongoing therapy, the patient's condition should be reassessed and treatment adjusted (medication therapy and possibility of revascularization).

If movement disorders occur, such as symptoms of parkinsonism, restless legs syndrome, tremor, or gait instability, trimetazidine should be discontinued.

These cases are rare and usually resolve within 4 months after discontinuation of the drug in most patients. If parkinsonism symptoms persist for more than 4 months after stopping the drug, a neurologist should be consulted.

Cases of falls associated with gait instability or arterial hypotension have been reported, particularly in patients receiving antihypertensive medications (see section "Adverse reactions").

Trimetazidine should be prescribed with caution in patients at risk of increased drug concentration:

• patients with moderate renal impairment (see sections "Pharmacokinetics" and "Dosage and administration");
• elderly patients over 75 years of age (see section "Dosage and administration").

In such patients, monitoring of functional parameters is recommended, and dose reduction may be necessary.

There is no information available regarding use of the drug in patients with hepatic impairment.

In diabetic patients, no dose adjustment is required.

The use of the drug does not affect preparation for anesthesia.

The presence of a dye in the formulation may cause allergic-type reactions, including bronchial asthma, particularly in patients with known hypersensitivity to acetylsalicylic acid.

The presence of dyes in the formulation ["Azorubine" (Carmoisine) (E 122), "Yellow West FCF" (E 110)] may cause allergic-type reactions, including bronchial asthma, particularly in patients with known hypersensitivity to acetylsalicylic acid.

Severe skin adverse reactions (SSARs)

Severe skin adverse reactions (SSARs), including drug-induced eosinophilia with systemic symptoms (DRESS syndrome) and acute generalized exanthematous pustulosis (AGEP), some of which may be life-threatening or lead to fatal outcomes, have been reported in association with trimetazidine therapy. Patients should be informed of the signs and symptoms of these reactions and closely monitored for skin reactions during treatment. If signs or symptoms suggestive of these reactions occur, trimetazidine should be discontinued immediately and alternative treatment options considered (if necessary).

Athletes. This medicinal product contains an active substance that may result in a positive 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 harmful toxic effects on the reproductive system. To prevent any potential risk, trimetazidine is not recommended during pregnancy.

Breastfeeding

It is unknown whether trimetazidine is excreted in human breast milk. Risk to newborns/infants cannot be excluded. Trimetazidine should not be used during breastfeeding.

Fertility

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

Ability to affect 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 impair the ability to drive or operate machinery.

Dosage and Administration.

Trimetazidine-Astrafarm is taken orally, 1 tablet (20 mg) three times daily during meals, with a glass of water. The duration of treatment is determined by the physician depending on the severity and course of the disease.

Patients with renal impairment

In patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the recommended dose of trimetazidine is 1 tablet (20 mg) twice daily, in the morning and evening, during meals.

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 of trimetazidine is 1 tablet (20 mg) twice daily, in the morning and evening, during meals.

Careful dose titration is required in elderly patients.

Children

The safety and efficacy of trimetazidine in children (under 18 years of age) have not been studied. Data are lacking.

Overdose.

Cases of overdose have not been reported.

In the event of overdose, symptomatic therapy is indicated.

Adverse reactions.

Adverse reactions identified as adverse effects possibly related to the use of trimetazidine are listed below according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions during the post-marketing period of the medicinal product is important. This enables continuous monitoring of the benefit/risk balance of the drug.

Healthcare professionals are obliged to report any cases of suspected adverse reactions through the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

30 tablets in a blister pack, 1 or 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and place of business.

6, Kyivska Street, Vyshneve, Kyiv-Sviatoshyn district, 08132, Ukraine.