Preduktal OD, 80 mg 60 pcs

Trimetazidine prevents decrease in intracellular concentration of adenosine triphosphate (ATP) by preserving energy metabolism of cells under hypoxia. Thus, the drug ensures normal functioning of membrane ion channels, transmembrane transport of potassium and sodium ions and preservation of cellular homeostasis.

Trimetazidine inhibits fatty acid oxidation through selective inhibition of the enzyme 3-ketoacyl-CoA-thiolase (3-CAT) mitochondrial long-chain fatty acid isoform, which leads to increased glucose oxidation and accelerated glycolysis with glucose oxidation, which leads to myocardial protection from ischemia.

The switch of energy metabolism from fatty acid oxidation to glucose oxidation underlies the pharmacological properties of trimetazidine.

Pharmacodynamic properties

– Supports energy metabolism of the heart and neurosensory tissues during ischemia;

– reduces the severity of intracellular acidosis and changes in transmembrane ion flow occurring during ischemia;

– decreases the level of migration and infiltration of polynuclear neutrophils in ischemic and reperfused heart tissues;

– reduces the size of myocardial damage;

– has no direct effect on hemodynamic parameters.

In patients with angina pectoris, trimetazidine increases coronary reserve, thereby delaying the onset of exercise-induced ischemia from day 15 of therapy; it limits exercise-induced BP fluctuations without significant changes in HR; significantly reduces the frequency of angina attacks and the need for short-acting nitroglycerin; improves left ventricular contractile function in patients with ischemic dysfunction.

The results of clinical studies have confirmed efficacy and safety of trimetazidine in patients with stable angina pectoris both in monotherapy and in combination therapy when other antianginal drugs have insufficient effect.

In a study involving 426 patients with stable angina pectoris, the addition of trimetazidine (60 mg/day) to therapy with metoprolol 100 mg/day (50 mg 2 times/day) for 12 weeks statistically significantly improved exercise test results and clinical symptoms compared with placebo: total exercise test duration was +20.1 s, p=0.023, total time to load performance +0.54 METs, p=0.001, time to ST-segment depression of 1 mm +33.4 s, p=0.003, time to angina attack development +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, no hemodynamic changes.

In a study involving 223 patients with stable angina pectoris, the addition of trimetazidine at a dose of 35 mg (2 times/day) to therapy with atenolol at 50 mg (once/day) for 8 weeks resulted in a 1-mm increase in time to development of ischemic ST-segment depression (+34.4 s, p=0.03) on loading tests in a subgroup of patients (n=173), compared with placebo, 12 h after drug administration. This difference was also shown for the timing of angina attacks (p=0.049). No significant differences were found between groups for other secondary endpoints (total exercise test duration, total exercise time, and clinical endpoints).

In a study involving 1962 patients with stable angina pectoris, trimetazidine at two doses (70 mg/day and 140 mg/day) was added to therapy with atenolol 50 mg/day compared with placebo.

In the general population, including both asymptomatic and symptomatic patients with angina, trimetazidine showed no advantage in ergometric (total duration of exercise tests, time to onset of ischemic ST-segment depression by 1 mm and time to angina attack) and clinical endpoints. However, in a retrospective analysis in a subgroup of patients with symptomatic angina (n=1574), trimetazidine (140 mg) significantly improved total time to load test (+23.8 s versus +13.1 s for placebo; p=0.001) and time to angina attack development (+46.3 s versus +32.5 for placebo; p=0.005).

Pharmacokinetics

Intake

Trimetazidine has a linear pharmacokinetic profile after oral administration of Preduktal® OD capsule and reaches Cmax in plasma approximately 14 hours after administration. At inter-dose intervals (i.e. within 24 hours), the plasma concentration of trimetazidine is maintained at at least 75% of Cmax for 15 hours after drug administration. The equilibrium state is reached after the 3rd dose (after 3 days). Food intake does not affect the bioavailability of trimetazidine when taking Preduktal® OD 80 mg.

Distribution

The Vd is 4.8 l/kg, which indicates good distribution of trimetazidine in the tissues (the degree of binding to plasma proteins is quite low, about 16% in vitro). </Excretion

Trimetazidine is mainly excreted by the kidneys, mostly unchanged. The T1/2 in young healthy volunteers is about 7 h, in patients older than 65 years – about 12 h.

The renal clearance of trimetazidine directly correlates with CK, hepatic clearance decreases with patient age.

Pharmacokinetics in Special Patient Groups

In patients over 75 years of age, increased exposure to trimetazidine may be observed due to age-related decline in renal function. A specific study was conducted in a population of patients over 75 years of age when trimetazidine tablets were used at a dose of 35 mg twice daily. A population-based kinetic analysis showed, on average, a twofold increase in plasma exposure in patients with severe renal impairment (CK less than 30 mL/min) compared with patients with CK greater than 60 mL/min.

No differences were found regarding safety in patients older than 75 years compared to the general population.

Trimetazidine exposure was on average 2.4-fold increased in patients with moderate renal impairment (CKR 30-60 ml/min), and on average 4-fold increased in patients with severe renal impairment (CKR less than 30 ml/min) compared to healthy volunteers with normal renal function. No differences in safety were found in this patient population compared to the general population.

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

Indications

– long-term therapy of coronary artery disease: prevention of attacks of stable angina as part of mono- or combination therapy.

Pharmacological effect

Trimetazidine prevents a decrease in intracellular adenosine triphosphate (ATP) concentration by maintaining the energy metabolism of cells in a state of hypoxia. Thus, the drug ensures the normal functioning of membrane ion channels, transmembrane transport of potassium and sodium ions and the preservation of cellular homeostasis.

Trimetazidine inhibits the oxidation of fatty acids due to the selective inhibition of the enzyme 3-ketoacyl-CoA thiolase (3-CAT) of the mitochondrial long-chain isoform of fatty acids, which leads to increased oxidation of glucose and acceleration of glycolysis with oxidation of glucose, which determines the protection of the myocardium from ischemia.

The switch of energy metabolism from fatty acid oxidation to glucose oxidation underlies the pharmacological properties of trimetazidine.

Pharmacodynamic properties

– supports the energy metabolism of the heart and neurosensory tissues during ischemia;

– reduces the severity of intracellular acidosis and changes in the transmembrane ion flow that occur during ischemia;

– reduces the level of migration and infiltration of polynuclear neutrophils in ischemic and reperfused heart tissues;

– reduces the size of myocardial damage;

– does not have a direct effect on hemodynamic parameters.

In patients with angina pectoris, trimetazidine increases coronary reserve, thereby slowing the onset of exercise-induced ischemia, starting from the 15th day of therapy; limits fluctuations in blood pressure caused by physical activity without significant changes in heart rate; significantly reduces the frequency of angina attacks and the need for short-acting nitroglycerin; improves contractile function of the left ventricle in patients with ischemic dysfunction.

The results of clinical studies have confirmed the effectiveness and safety of trimetazidine in patients with stable angina, both in monotherapy and as part of combination therapy when the effect of other antianginal drugs is insufficient.

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

In a study of 223 patients with stable angina, the addition of trimetazidine 35 mg twice daily to atenolol 50 mg once daily for 8 weeks resulted in a 1 mm increase in time to ischemic ST segment depression (+34.4 s, p = 0.03) during exercise testing in a subgroup of patients (n = 173) compared with placebo. 12 hours after taking the drug. This difference was also shown for the time of development of angina attacks (p=0.049). There were no significant differences between groups for other secondary endpoints (total exercise test duration, total exercise time, and clinical endpoints).

In a study of 1962 patients with stable angina, trimetazidine at two doses (70 mg/day and 140 mg/day) was added to atenolol 50 mg/day versus placebo.

In the general population, including patients with both asymptomatic and symptomatic angina, trimetazidine did not demonstrate benefit on ergometric (total duration of exercise tests, time to onset of ischemic ST-segment depression of 1 mm and time to onset of angina) and clinical endpoints. However, in a post-hoc analysis of a subgroup of patients with symptomatic angina (n=1574), trimetazidine (140 mg) significantly improved total exercise test time (+23.8 s versus +13.1 s for placebo; P=0.001) and time to onset of angina (+46.3 s versus +32.5 for placebo; P=0.005).

Pharmacokinetics

Suction

After ­administration ­orally ­capsule Preductal® OD ­trimetazidine ­has a ­linear ­pharmacokinetic ­profile ­and ­reaches Cmax ­in ­plasma ­approximately ­through­ 14­ hours after ­dose. In the intervals between doses of the drug (i.e., within 24 hours), the concentration of trimetazidine in the blood plasma for 15 hours after taking the drug remains at a level of at least 75% of Cmax. An equilibrium state is achieved after taking the 3rd dose (after 3 days). Food intake does not affect the bioavailability of trimetazidine when taking Preductal® OD 80 mg.

Distribution

Vd is 4.8 l/kg, which indicates good distribution of trimetazidine in tissues (the degree of binding to plasma proteins is quite low, about 16% in vitro).

Removal

Trimetazidine is excreted mainly by the kidneys, mainly unchanged. T1/2 in young healthy volunteers is about 7 hours, in patients over 65 years old – about 12 hours.

Renal clearance of trimetazidine directly correlates with creatinine clearance; hepatic clearance decreases with patient age.

Pharmacokinetics in special groups of patients

Patients over 75 years of age may experience increased exposure to trimetazidine due to age-related decline in renal function. A special study was conducted in a population of patients over 75 years of age using trimetazidine tablets at a dose of 35 mg 2 times a day. An analysis conducted by a kinetic population method showed an average twofold increase in plasma exposure in patients with severe renal failure (creatinine clearance less than 30 ml/min) compared with patients with creatinine clearance more than 60 ml/min.

No safety differences were found in patients over 75 years of age compared with the general population.

Trimetazidine exposure was increased on average by 2.4 times in patients with moderate renal insufficiency (creatinine clearance 30-60 ml/min), and on average by 4 times in patients with severe renal failure (creatinine clearance less than 30 ml/min) compared to healthy volunteers with normal renal function. No significant safety differences were observed in this patient population compared with the general population.

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

Special instructions

Preductal® OD is not intended for the relief of angina attacks and is not indicated for the initial course of treatment of unstable angina or myocardial infarction in the prehospital stage or in the first days of hospitalization.

If an attack of angina occurs, treatment (drug therapy or revascularization procedure) should be reviewed and adapted. Preductal® OD can cause or worsen symptoms of parkinsonism (tremor, akinesia, increased tone), so patients should be regularly monitored, especially the elderly. In doubtful cases, the patient should be referred to a neurologist for appropriate examination.

If movement disorders appear, such as symptoms of parkinsonism, restless legs syndrome, tremor, or “wobbly” gait, Preductal® OD should be permanently discontinued. Such cases are rare and symptoms usually resolve after discontinuation of therapy: in most patients, within 4 months after discontinuation of the drug. If symptoms of parkinsonism persist more than 4 months after discontinuation of the drug, you should consult a neurologist.

Cases of falls associated with instability in the Romberg position and “wobbly” gait or a pronounced decrease in blood pressure may occur, especially in patients taking antihypertensive drugs (see section “Side Effects”).

Preductal® OD should be prescribed with caution to patients in whom increased exposure may occur:

– in case of moderate renal failure (see sections “Pharmacological action” and “Dosage regimen”);

– in elderly patients over 75 years of age (see section “Dosage regimen”).

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

Impact on the ability to drive vehicles and operate machinery

During clinical studies, no effect of trimetazidine on hemodynamic parameters was revealed, however, during post-registration use, cases of dizziness and drowsiness were observed (see section “Side effects”). These symptoms can affect the ability to drive vehicles and perform work that requires increased speed of physical and mental reactions.

Active ingredient

Trimetazidine

Composition

1 caps.

trimetazidine dihydrochloride (granules) 80 mg.

1 extended-release hard capsule contains:

film-coated granules with a layer of trimetazidine dihydrochloride: 144.85 mg.

Excipients:

sugar spheres** (710-850 microns) – 36.68 mg,

hypromellose – 6.4 mg.

Composition of the film shell of granules:

ethylcellulose – 8 mg,

tributylacetyl citrate – 1.2 mg,

talc – 12 mg.

Composition of the mixture for dusting granules:

talc – 0.43 mg,

magnesium stearate – 0.14 mg.

Hard gelatin capsule No. 2 with a white body and an orange-red cap, the company logo and the inscription “80” in white* are printed on the cap: 61,000 mg.

Composition of the capsule body:

titanium dioxide (E171) – 0.732 mg,

gelatin*** – 35.868 mg.

Capsule cap composition:

titanium dioxide (E171) – 0.122 mg,

iron oxide red (E172) – 0.366 mg,

gelatin*** – 23.912 mg.

* The logo and inscription on the capsule are printed with white ink containing shellac, titanium dioxide, simethicone, propylene glycol, ammonium hydroxide. The total amount of ink per capsule is approximately 0.15 mg.

** Composition of sugar spheres: sucrose – no more than 92% (in terms of dry matter), corn starch. May also contain starch hydrolysis products and dyes.

*** Contains an average of 14.5% water (mass loss on drying).

Contraindications

– severe renal failure (creatinine clearance less than 30 ml/min);

– Parkinson’s disease, symptoms of parkinsonism, tremor, restless legs syndrome and other associated movement disorders;

– fructose/sucrose intolerance, glucose-galactose malabsorption syndrome, sucrase/isomaltase deficiency and other enzymopathies associated with intolerance to sucrose, which is part of the drug;

– age under 18 years (due to lack of sufficient clinical data);

– hypersensitivity to any of the components of the drug.

The drug should be prescribed with caution to patients with severe liver failure (from 10 to 15 points on the Child-Pugh scale), moderate renal failure (creatinine clearance 30-60 ml/min), and patients over 75 years of age (see sections “Dosage regimen” and “Special instructions”).

Side Effects

Adverse reactions, defined as adverse events at least possibly related to treatment with trimetazidine, are given in the following gradation: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (< 1/10,000), unspecified frequency (frequency cannot be calculated from available data).

From the side of the central nervous system: often – dizziness, headache; unspecified frequency – symptoms of parkinsonism (tremor, akinesia, increased tone), “unsteadiness” of gait, restless legs syndrome, other associated motor disorders, usually reversible after cessation of therapy. Sleep disorders (insomnia, drowsiness).

From the cardiovascular system: rarely – a feeling of palpitations, extrasystole, tachycardia, a marked decrease in blood pressure, orthostatic hypotension, which may be accompanied by general weakness, dizziness or loss of balance, especially with the simultaneous use of antihypertensive drugs, “flushes” of blood to the skin of the face.

From the digestive system: often – abdominal pain, diarrhea, dyspepsia, nausea, vomiting; unspecified frequency – constipation.

From the liver and biliary tract: unspecified frequency – hepatitis.

From the hematopoietic system: unspecified frequency – agranulocytosis, thrombocytopenia, thrombocytopenic purpura.

From the skin and subcutaneous fat: often – skin rash, itching, urticaria; unspecified frequency – Quincke’s edema, acute generalized exanthematous pustulosis.

General disorders: often – asthenia.

Interaction

Not observed. The patient must inform the doctor about all medications taken.

Overdose

There is only very limited information on trimetazidine overdose.

Treatment: in case of overdose, symptomatic therapy should be carried out.

Manufacturer

Servier Rus LLC, Russia