Pretidal® od 40 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PREDUCTAL® OD 40 mg (PREDUCTAL® OD 40 mg) PREDUCTAL® OD 80 mg (PREDUCTAL® OD 80 mg)

Composition:

Active substance: trimetazidine;

Preductal® OD 40 mg

1 prolonged-release hard capsule contains 40 mg of trimetazidine dihydrochloride;

Excipients: spherical sugar*, hypromellose, ethylcellulose, acetyltributyl citrate, talc, magnesium stearate;

capsule shell: titanium dioxide (E 171), gelatin; ink: shellac (E 904), propylene glycol (E 1520), concentrated ammonia solution (E 527), potassium hydroxide (E 525), titanium dioxide (E 171), iron oxide black (E 172);

Preductal® OD 80 mg

1 prolonged-release hard capsule contains 80 mg of trimetazidine dihydrochloride;

Excipients: spherical sugar*, hypromellose, ethylcellulose, acetyltributyl citrate, talc, magnesium stearate;

capsule shell: titanium dioxide (E 171), gelatin, iron oxide red (E 172); ink: 45% shellac glaze (20% esterified) in ethanol, titanium dioxide (E 171), simethicone, propylene glycol (E 1520), ammonium hydroxide 28% (E 527).

* Spherical sugar (710–850 μm) contains sucrose and corn starch

Pharmaceutical form. Prolonged-release hard capsules.

Main physicochemical characteristics:

Preductal® OD 40 mg: white hard capsules of size 3 containing spherical granules coated with a film, white or almost white, with the company logo and the inscription "40" printed in grey ink on the cap of the capsule.

Preductal® OD 80 mg: hard capsules of size 2 with a white body and an orange-red cap, containing spherical granules coated with a film, white or almost white, with the company logo and the inscription "80" printed in white ink on the cap of the capsule.

Pharmacotherapeutic group. Cardiological 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, 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 supports adequate energy metabolism 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. Anti-ischemic effects are achieved without concomitant hemodynamic effects.

Clinical efficacy and safety

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

A randomized, double-blind, placebo-controlled study (TRIMPOL-II) involving 426 patients showed that adding trimetazidine 60 mg daily to metoprolol 100 mg (50 mg twice daily) for 12 weeks led to significant improvements in exercise test parameters and clinical symptoms compared to placebo: total exercise duration − +20.1 sec, p=0.023; total work performed − +0.54 MET sec, p=0.001; time to 1 mm ST-segment depression − +33.4 sec, p=0.003; time to onset of angina attack − +33.9 sec, 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.

A randomized, double-blind, placebo-controlled study (Sellier) involving 223 patients demonstrated 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 sec, p=0.03) in time to 1 mm ST-segment depression during exercise testing compared to placebo, measured 12 hours after drug intake. A significant difference was also confirmed for the time to onset of angina attack (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).

In a randomized, double-blind study (Vasco study) involving 1962 patients lasting 3 months, trimetazidine 70 mg/day, 140 mg/day, or placebo was added to atenolol therapy at a dose of 50 mg/day. In the overall population, including both 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 onset of angina attack) or in clinical endpoints. However, in the subgroup of symptomatic patients (n=1574), trimetazidine 140 mg/day significantly improved total exercise time (+23.8 sec vs. +13.1 sec with placebo; p=0.001) and time to onset of angina attack (+46.3 sec vs. +32.5 sec with placebo; p=0.005).

A randomized, double-blind tolerability study involving 165 patients lasting 3 months demonstrated that the safety profile of trimetazidine 80 mg once daily, both against the background of routine antianginal therapy and secondary preventive therapy, was consistent with that of trimetazidine MR 35 mg twice daily. No unexpected adverse reactions were reported, and the study showed no safety concerns related to once-daily administration of trimetazidine 80 mg.

Pharmacokinetics.

Absorption

After oral administration of 80 mg trimetazidine capsules, the pharmacokinetic profile of trimetazidine is uniform, with maximum concentration reached approximately 14 hours after dosing. During the dosing interval (24 hours), plasma concentration remains at least 75% of maximum concentration for 15 hours. Steady-state concentration is achieved after the third dose (on day 3).

Food intake does not affect the pharmacokinetic characteristics of trimetazidine.

Distribution

Volume of distribution is 4.8 L/kg; protein binding is low (16%).

Elimination

Trimetazidine is primarily excreted via urine, mainly in unchanged form. The elimination half-life averages 7 hours in healthy young volunteers and 12 hours in elderly subjects (aged 65 years and older). Complete elimination of trimetazidine is primarily due to renal clearance, which correlates with creatinine clearance, and to a lesser extent due to hepatic clearance, which decreases with age.

Special patient populations

Elderly patients. In elderly patients, trimetazidine concentration may increase 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. A specific clinical study in elderly patients (aged ≥75 years) receiving trimetazidine MR 35 mg (1 tablet) twice daily, analyzed using population kinetic methods, showed an average 2-fold increase in plasma concentration in patients with severe renal impairment (creatinine clearance <30 mL/min) compared to patients with creatinine clearance >60 mL/min. In this population, no safety concerns were observed compared to the general population.

Renal impairment. Trimetazidine blood 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 safety concerns were observed compared to the general population.

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

Clinical characteristics.

Indications.

In adults, trimetazidine is indicated for the symptomatic treatment of stable angina pectoris when first-line antianginal therapies 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.

Not observed.

Special precautions for use

This medicinal product is not intended for the acute relief of angina attacks. It should not be prescribed as initial therapy at the pre-hospital stage or during the first days of hospitalization for unstable angina or myocardial infarction.

In the event of an unstable angina attack occurring during ongoing treatment, the patient's clinical course should be reassessed and therapy adjusted accordingly (medication regimen and potential revascularization).

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.

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

Movement disorders are infrequent and usually resolve after discontinuation of treatment. In most patients, these symptoms disappeared within 4 months after stopping trimetazidine. If parkinsonism symptoms persist beyond 4 months after discontinuation of the drug, consultation with a neurologist is necessary.

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

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

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

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

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

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the use of trimetazidine in pregnant women. Animal studies have not shown 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.

***Effect on ability to drive and use 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 a car or operate machinery.

Dosage and Administration

For oral use.

The recommended dose is 1 capsule of trimetazidine 80 mg once daily in the morning with breakfast. The capsules should be taken unopened and swallowed with water.

After 3 months of treatment, the therapeutic response should be evaluated, and if there is no response to treatment, trimetazidine should be discontinued.

Special patient categories

Renal impairment

In patients with moderate renal impairment (creatinine clearance 30–60 mL/min) (see section "Special precautions" and "Pharmacokinetics"), the dose should be halved. The recommended dose is 1 capsule of trimetazidine 40 mg or 1 tablet of trimetazidine 35 mg in the morning with breakfast.

Elderly patients

In elderly patients, increased plasma concentrations of trimetazidine may occur due to age-related decline in renal function (see section "Pharmacokinetics"). In patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the dose should be halved. The recommended dose is 1 capsule of trimetazidine 40 mg or 1 tablet of trimetazidine 35 mg in the morning with breakfast.

Elderly patients require careful dose titration (see section "Special precautions").

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 should be symptomatic.

Undesirable effects.

Undesirable effects identified as adverse reactions 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 use of the medicinal product is important. This allows 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.

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

Packaging.

10 capsules per blister made of polyamide-aluminum-PVC and aluminum foil; 3 or 9 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

EGIS Pharmaceuticals Plc.

Manufacturer's address and location of operations.

118-120 Bokenyfoldi Street, Budapest, 1165, Hungary / Bokenyfoldi ut 118-120., Budapest, 1165, Hungary.

Marketing Authorization Holder.

Les Laboratoires Servier.

Address of the Marketing Authorization Holder.

50, rue Carnot, 92284 Suresnes Cedex, France / 50, rue Carnot, 92284 Suresnes Cedex, France.