Preductal^® OD (Capsules) Instructions for Use

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Servier Rus, LLC (Russia)

Or

Egis Pharmaceuticals PLC (Hungary)

Contact Information

SERVIER AO (Russia)

ATC Code

C01EB15 (Trimetazidine)

Active Substance

Trimetazidine (Rec.INN registered by WHO)

Dosage Form

Preductal® OD

Prolonged-release capsules 80 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release capsules hard gelatin, with a white body and an orange-red cap with the Servier company logo and the inscription “80” printed in white; the capsule contents are spherical granules from white to almost white in color.

Excipients:
Capsule sugar spheres (containing sucrose (33.75 mg) and corn starch), hypromellose, ethylcellulose, tributyl acetylcitrate, talc, magnesium stearate;
capsule shell gelatin, titanium dioxide (E171), iron oxide red (E172);
logo and inscription printing on the capsule shellac (E904), titanium dioxide (E171), simethicone, propylene glycol (E1520), ammonium hydroxide 28% (E527).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Antianginal drug

Pharmacotherapeutic Group

Cardiological drugs. Other cardiological drugs. Trimetazidine

Pharmacological Action

Pharmacodynamics

Mechanism of action

By preserving the energy metabolism of cells subjected to hypoxia or ischemia, Trimetazidine prevents the decrease in intracellular adenosine triphosphate (ATP) concentration, thereby ensuring the normal functioning of membrane ion channels and the transmembrane transfer of potassium and sodium ions while maintaining cellular homeostasis.

Trimetazidine inhibits β-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation. In an ischemically damaged cell, the energy obtained during glucose oxidation requires less oxygen consumption than during β-oxidation. Potentiation of glucose oxidation optimizes cellular energy processes, thereby supporting proper energy metabolism during ischemia.

Pharmacodynamic effects

In patients with coronary artery disease, Trimetazidine acts as a metabolic agent, preserving high-energy phosphate levels in myocardial cells. The anti-ischemic effect is achieved without concomitant hemodynamic effects.

Clinical efficacy and safety

The results of conducted clinical studies confirmed the efficacy and safety of trimetazidine in patients with stable angina, both in monotherapy and in cases where the effect of other antianginal drugs was insufficient.

In a double-blind, placebo-controlled study involving 426 patients (TRIMPOL-II), the addition of trimetazidine (60 mg/day) to metoprolol therapy 100 mg/day (50 mg twice/day) for 12 weeks statistically significantly improved exercise test results and clinical symptoms compared to placebo: total duration of exercise tests (+20.1s, p=0.023), total exercise time (+0.54 METs, p=0.001), time to 1 mm ST-segment depression (+33.4 s, p=0.003), time to angina attack (+33.9 s, p< 0.001), number of angina attacks per week (-0.73, p=0.014) and short-acting nitrate consumption per week (-0.63, p=0.032), without hemodynamic changes.

In a double-blind, placebo-controlled study involving 223 patients (Sellier), the addition of trimetazidine in the form of a modified-release tablet at a dose of 35 mg (twice/day) to atenolol therapy at a dose of 50 mg (once/day) for 8 weeks led to an increase in the time to ischemic ST-segment depression of 1 mm (+34.4 s, p=0.03) during exercise tests in a subgroup of patients (n=173), compared to placebo, 12 hours after drug administration. This difference was also shown for the time to angina attacks (p=0.049). No significant differences between groups were found for other secondary endpoints (total duration of exercise tests, total exercise time and clinical endpoints).

In a 3-month randomized, double-blind study (Vasco) involving 1962 patients, Trimetazidine at two doses (70 mg/day and 140 mg/day) compared to placebo was added to atenolol 50 mg/day therapy. In the general population, including both asymptomatic and symptomatic angina patients, Trimetazidine did not demonstrate benefits in ergometric (total duration of exercise tests, time to 1 mm ischemic ST-segment depression and time to angina attack) and clinical endpoints. However, in a retrospective analysis in a subgroup of symptomatic angina patients (n=1574), it was shown that Trimetazidine (140 mg) significantly improved total exercise test time (+23.8 s compared to +13.1 s for placebo; p=0.001) and time to angina attack (+46.3 s compared to +32.5 for placebo; p=0.005).

In a 3-month randomized, double-blind study involving 165 patients, when trimetazidine was added to usual antianginal therapy and secondary prevention therapy, it was shown that the safety profile of trimetazidine at a dose of 80 mg once/day is similar to the profile of trimetazidine in the form of a modified-release tablet at a dose of 35 mg (twice/day). No unexpected adverse reactions were reported, and no problems regarding the use of trimetazidine at a dose of 80 mg once/day were identified during the study.

Preductal^® OD has not been studied in one or more subgroups of children (see the “Dosage Regimen” section).

Pharmacokinetics

Absorption

After oral administration of the Preductal^® OD capsule, Trimetazidine has a linear pharmacokinetic profile and reaches C_max in plasma approximately 14 hours after administration. Between doses (i.e., over 24 hours), the plasma concentration of trimetazidine remains at a level of at least 75% of C_max for 15 hours after administration.

Steady state is achieved after the 3rd dose (after 3 days). Food intake does not affect the pharmacokinetics of trimetazidine when taking Preductal^® OD.

Distribution

V_d is 4.8 L/kg, the degree of binding to plasma proteins is low (about 16% in vitro).

Elimination

Trimetazidine is excreted mainly by the kidneys, primarily unchanged. T_1/2 in young healthy volunteers is about 7 hours, in elderly patients (over 65 years) – 12 hours.

The total clearance of trimetazidine consists mainly of renal clearance, which is directly correlated with creatinine clearance, and to a lesser extent of hepatic clearance, which decreases with the patient’s age.

Pharmacokinetics in special patient groups

Elderly patients. Elderly patients may have increased exposure to trimetazidine due to age-related decline in renal function. A specific pharmacokinetic study involving elderly patients (75-84 years) or very elderly (≥85 years) patients showed that moderate renal impairment (CrCl 30-60 ml) increased trimetazidine exposure by 1.0 and 1.3 times, respectively, compared to younger patients (30-65 years) with moderate renal impairment.

A specific clinical study conducted in a population of elderly patients (over 75 years) using trimetazidine (in the form of a modified-release tablet containing 35 mg of trimetazidine) at a dose of 2 tablets/day (in 2 doses), showed on average a twofold increase in plasma exposure in patients with severe renal failure (CrCl below 30 ml/min) compared to patients with CrCl above 60 ml/min. No safety concerns were identified in patients over 75 years of age compared to the general population.

Patients with renal impairment. Trimetazidine exposure was on average increased by 1.7 times in patients with moderate renal impairment (CrCl 30-60 ml/min), and on average by 3.1 times in patients with severe renal failure (CrCl below 30 ml/min) compared to healthy volunteers with normal renal function. No specific safety concerns were found in this patient population compared to the general population.

Use in children and adolescents. The pharmacokinetics of trimetazidine in children and adolescents under 18 years of age have not been studied.

Preclinical safety data

Chronic toxicity studies with oral administration in dogs (from 5 to 40 mg/kg/day) and rats (from 5 to 200 mg/kg/day) showed a good safety profile.

Neither embryofetotoxic effects nor teratogenicity were detected in mice and rabbits. A general study of reproductive function and embryogenesis in 3 generations of rats revealed no abnormalities.

The genotoxic potential was thoroughly studied in in vitro studies, including assessment of mutagenic and clastogenic potential, and in one in vivo study. All tests were negative.

Indications

• In adult patients as an add-on therapy for the symptomatic treatment of stable angina pectoris when first-line antianginal therapy is inadequately controlled or not tolerated.

ICD codes

Dosage Regimen

The drug Preductal^® OD is taken orally, 1 capsule once/day, in the morning, during breakfast. Capsules should be taken whole, without opening the capsule.

Assessment of the benefit of treatment can be made after 3 months of taking the drug. Trimetazidine should be discontinued if no improvement occurs during this time.

Special patient groups

In patients with moderate renal impairment (CrCl 30-60 ml/min) (see sections “Pharmacokinetics” and “Special Precautions”) a dose reduction by half is recommended, i.e., 1 tablet containing 35 mg of trimetazidine once/day, in the morning during breakfast.

In elderly patients, increased exposure to trimetazidine may be observed due to age-related decline in renal function (see section “Pharmacokinetics”). In patients with moderate renal impairment (CrCl 30-60 ml/min), a dose reduction by half is recommended, i.e., 1 tablet containing 35 mg of trimetazidine once/day, in the morning during breakfast. Dose adjustment in elderly patients should be done with caution (see section “Special Precautions”).

The safety and efficacy of trimetazidine in patients under 18 years of age have not been established. No data available.

Adverse Reactions

The table lists the adverse reactions that were identified during clinical studies.

These adverse reactions were classified by system-organ class and frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), frequency unknown (cannot be estimated from the available data).

Contraindications

• Hypersensitivity to the active substance or any of the excipients included in the drug;
• Parkinson’s disease, parkinsonian symptoms, tremor, restless legs syndrome and other related movement disorders;
• Severe renal failure (CrCl< 30 ml/min);
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

There are no data on the use of trimetazidine in pregnant women.

Animal studies have not revealed any direct or indirect negative effects regarding reproductive function (see subsection “ Preclinical safety data”). As a precautionary measure, it is preferable to avoid the use of trimetazidine during pregnancy.

Breastfeeding period

Data on the excretion of trimetazidine into breast milk are not available. Risk to the newborn/infant cannot be excluded. The drug Preductal^® OD should not be used during breastfeeding.

Fertility

Reproductive toxicity studies showed no effect on fertility in rats of both sexes (see subsection “ Preclinical safety data”).

Use in Renal Impairment

In patients with moderate renal impairment (CrCl 30-60 ml/min), a dose reduction by half is recommended, i.e., 1 tablet containing 35 mg of trimetazidine once/day, in the morning during breakfast.

Pediatric Use

The safety and efficacy of trimetazidine in patients under 18 years of age have not been established. No data available.

Geriatric Use

In elderly patients, increased exposure to trimetazidine may be observed due to age-related decline in renal function. In patients with moderate renal impairment (CrCl 30-60 ml/min), a dose reduction by half is recommended, i.e., 1 tablet containing 35 mg of trimetazidine once/day, in the morning during breakfast. Dose adjustment in elderly patients should be done with caution.

Special Precautions

The drug Preductal^® OD is not intended for the relief of angina attacks and is not indicated for the initial course of therapy for unstable angina or myocardial infarction in the pre-hospital phase or in the first days of hospitalization.

In the event of an angina attack, the extent of coronary artery disease should be reassessed and, if necessary, treatment should be adapted (drug therapy or possible revascularization procedure).

Trimetazidine may cause or worsen parkinsonian symptoms (tremor, akinesia, increased tone), so regular monitoring of patients, especially the elderly, should be carried out. In doubtful cases, patients should be referred to a neurologist for appropriate examination.

If movement disorders occur, such as parkinsonian symptoms, restless legs syndrome, tremor, unsteady gait, Trimetazidine should be permanently discontinued. Such cases are rare and symptoms usually resolve after discontinuation of therapy. In most patients, symptoms resolve within 4 months after discontinuation of trimetazidine. If parkinsonian symptoms persist for more than 4 months after drug discontinuation, a neurologist should be consulted.

Cases of falls associated with unsteady gait or arterial hypotension may occur, especially in patients taking antihypertensive drugs (see section “Adverse Reactions”).

Trimetazidine should be prescribed with caution to patients in whom its exposure may be increased

• In moderate renal impairment (see sections “Pharmacokinetics” and “Dosage Regimen”);
• In elderly patients over 75 years of age (see section “Dosage Regimen”).

Excipients

The drug contains sucrose, therefore the drug is not recommended for patients with rare hereditary fructose intolerance, glucose-galactose malabsorption syndrome and sucrase-isomaltase deficiency.

Effect on ability to drive vehicles and operate machinery

Clinical studies have not revealed any effect of trimetazidine on hemodynamic parameters, however, during post-registration use, cases of dizziness and drowsiness have been observed (see section “Adverse Reactions”), which may affect the ability to drive vehicles and operate machinery.

Overdose

There is only very limited information on trimetazidine overdose.

In case of overdose, symptomatic therapy should be administered.

Drug Interactions

No interaction with other medicinal products has been identified.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.