Pretidal® mr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PREDUCTAL® MR (PREDUCTAL® MR)

Composition:

Active substance: trimetazidine;

1 tablet contains: trimetazidine dihydrochloride 35 mg;

Excipients:

Tablet core: calcium hydrogen phosphate dihydrate, hypromellose 4000, magnesium stearate, povidone, colloidal anhydrous silicon dioxide;

Coating: glycerin, macrogol 6000, magnesium stearate, hypromellose, iron oxide red (E 172), titanium dioxide (E 171).

Pharmaceutical form. Film-coated modified-release tablets.

Main physicochemical characteristics: pink, biconvex film-coated tablets, with or without embossing 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 decline in intracellular ATP levels, thereby ensuring proper functioning of ion 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 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 thus maintains 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.

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. A randomized, double-blind, placebo-controlled study involving 426 patients demonstrated that adding trimetazidine 60 mg daily to metoprolol 100 mg (50 mg twice daily) over 12 weeks led to significant improvements 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, without changes in hemodynamic parameters.

SELLIER study. A randomized, double-blind, placebo-controlled study involving 223 patients showed that in the subgroup of patients (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 study involving 1962 patients lasting 3 months, trimetazidine 70 mg or 140 mg daily, or placebo, was added to atenolol therapy at a dose of 50 mg daily. In the overall population, including symptomatic and asymptomatic patients, trimetazidine did not demonstrate advantages either in ergometric parameters (total exercise time, time to 1 mm ST-segment depression, and time to angina onset) or in 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 angina onset (+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. Over 24 hours, plasma concentration remains stable: for 11 hours after tablet intake, plasma concentration of trimetazidine 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.

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

Special patient populations

Elderly patients.

A specific clinical study was conducted in elderly patients using trimetazidine 35 mg (1 tablet) twice daily. Population pharmacokinetic analysis showed increased plasma concentrations. In elderly patients, increased trimetazidine concentration may occur 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. Trimetazidine plasma concentration 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.

In adults, trimetazidine is indicated for the symptomatic treatment of stable angina pectoris when first-line antianginal medications are insufficiently effective or not tolerated.

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.
• 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.

Special precautions for use

This medicinal product is not intended for the treatment of 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.

In the event of an episode of unstable angina occurring during ongoing treatment, the patient's condition must be reassessed and therapy adjusted accordingly (including pharmacological treatment and consideration of revascularization).

Trimetazidine may induce or exacerbate 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, trimetazidine should be discontinued.

These cases are infrequent and usually resolve after treatment withdrawal; in most patients, within 4 months after stopping trimetazidine. If parkinsonism symptoms persist beyond 4 months after discontinuation of the drug, consultation with a neurologist is required.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) have been reported with trimetazidine treatment, 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. Patients should be informed about the signs and symptoms of SCARs before initiating treatment, and skin reactions should be closely monitored. If symptoms suggestive of these reactions occur, trimetazidine should be immediately discontinued and alternative therapy considered (if necessary).

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

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

• patients with moderate renal impairment (see section "Dosage and administration" and "Pharmacokinetics");
• elderly patients aged 75 years and older (see section "Dosage and administration").

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

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of trimetazidine in pregnant women are lacking. Animal studies have not shown any direct or indirect toxic effects on the reproductive system. To prevent any potential 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 potential risk to newborns/infants, the use of PREDUKTAL® MR is not recommended during breastfeeding.

Ability to affect driving and use of machines

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.

For oral use.

1 tablet of 35 mg trimetazidine twice daily, in the morning and evening, during meals.

After 3 months of treatment, the therapeutic efficacy should be evaluated, and if no effect is observed, trimetazidine 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 1 tablet daily in the morning with breakfast (see sections "Special precautions for use" and "Pharmacokinetics").

Elderly patients

In elderly patients, increased plasma concentrations of trimetazidine may occur 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 1 tablet of 35 mg in the morning with breakfast.

Dose titration should be performed with caution in elderly patients (see section "Special precautions for use").

Children

The 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.

For side effects related to the use of trimetazidine, see also section "Special precautions".

The table below lists side effects reported in spontaneous reports and scientific literature.

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 available data).

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization of the medicinal product is of great importance. This 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 at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

30 tablets per blister (PVC/aluminum); 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Laboratoires Servier Industrie / Les Laboratoires Servier Industrie.

Manufacturer's address and location of operations.

905 route de Saran, 45520 Gidy, France / 905 route de Saran, 45520 Gidy, France.

Manufacturer.

ANPHARM Przedsiebiorstwo Farmaceutyczne S.A.

Manufacturer's address and location of operations.

ul. Annopol 6B, Warszawa, 03-236, Poland / ul. Annopol 6B, Warszawa, 03-236, Poland.

Marketing Authorization Holder.

TOV "Servier Ukraine".

Address of the Marketing Authorization Holder.

41 Naberezhno-Khreshchatytska Street, 2nd and 3rd floors, Kyiv, 04070, Ukraine.

For any questions regarding this medicinal product, please contact the Marketing Authorization Holder (registration certificate holder) at: (044) 490 3441.