Trimectal CF, 35 mg 60 pcs

Indications

Long-term therapy of coronary heart disease: prevention of attacks of stable angina as part of mono- or combination therapy.

Pharmacological effect

Pharmacotherapeutic group
Antianginal agent.

ATC code

С01ЭВ15

Pharmacological properties

Pharmacodynamics

Mechanism of action

Trimetazidine prevents a decrease in the intracellular concentration of adenosine triphosphate (ATP) 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 glucose oxidation and acceleration of glycolysis with glucose oxidation, 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 energy metabolism of the heart and neurosensory tissues during ischemia;
reduces the severity of intracellular acidosis and changes in 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, trimetazidine:

increases coronary reserve, thereby slowing down the onset of ischemia caused by physical activity, starting from the 15th day of therapy;
limits fluctuations in blood pressure (BP) caused by exercise 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 (TRIMPOL-II), the addition of trimetazidine (60 mg/day) to metoprolol 100 mg/day (50 mg twice daily) for 12 weeks statistically significantly improved exercise test results and clinical symptoms compared with placebo: total duration of exercise tests, total exercise time, time to 1 mm ST segment depression, time to development of an angina attack, number of angina attacks per week and consumption of short-acting nitrates per week, without hemodynamic changes.

In a study of 223 patients with stable angina (Sellier), 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 during exercise testing in a subgroup of patients compared with placebo. A significant difference was also shown for the time of development of angina attacks. 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 (Vasco), trimetazidine (70 mg/day and 140 mg/day) was added to atenolol 50 mg/day compared with placebo. In the general population, including both asymptomatic and symptomatic patients with angina, trimetazidine did not demonstrate benefit on ergometric and clinical endpoints. However, in a retrospective analysis of a subgroup of patients with symptomatic angina, trimetazidine (140 mg) significantly improved total exercise test time and time to angina onset.

Pharmacokinetics

Suction

After oral administration, trimetazidine is rapidly absorbed and reaches maximum plasma concentrations after approximately 5 hours.

Over 24 hours, the concentration in the blood plasma remains at a level exceeding 75% of the concentration determined after 11 hours.

The equilibrium state is reached after 60 hours. Food intake does not affect the bioavailability of trimetazidine.

Distribution

The volume of distribution 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).

Withdrawal

Trimetazidine is excreted mainly by the kidneys, mainly unchanged.

The half-life 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 (CC), hepatic clearance decreases with patient age.

Pharmacokinetics in special groups of patients

Patients with impaired renal function

The exposure of trimetazidine was increased on average by 1.7 times in patients with moderate renal impairment (creatinine clearance 30-60 ml/min) and on average by 3.1 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 found in this patient population compared to the general population.

Elderly patients

A special clinical study conducted in a population of elderly patients using a dose of trimetazidine MB 35 mg, 2 tablets per day (in 2 divided doses), showed an increase in plasma levels of the drug according to population pharmacokinetic analysis.

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

Children and teenagers

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

Special instructions

The drug 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 develops, the degree of damage to the coronary arteries should be re-evaluated and, if necessary, treatment should be adapted (drug therapy or a revascularization procedure).

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

If movement disorders appear, such as symptoms of parkinsonism, restless legs syndrome, tremor, gait instability, trimetazidine 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.

Falls associated with gait instability or hypotension may occur, especially in patients taking antihypertensive drugs (see section “Side effects”).

The drug trimetazidine should be prescribed with caution to patients in whom its exposure may be increased: with moderate renal impairment (see sections “Pharmacological properties” and “Method of administration and dosage”), as well as elderly patients over 75 years of age (see section “Method of administration and dosage”).

Influence on the ability to drive vehicles and machinery

Clinical studies did not reveal the effect of trimetazidine on hemodynamic parameters, however, during post-registration use, cases of dizziness and drowsiness were observed (see section “Side Effects”), which may affect the ability to drive vehicles and perform work requiring an increased speed of physical and mental reactions.

Active ingredient

Trimetazidine

Composition

One modified-release film-coated tablet contains:

active ingredient: trimetazidine dihydrochloride – 35.0 mg;

excipients: Kollidon SR (polyvinyl acetate 80%, povidone 19%, sodium lauryl sulfate 0.8%, silicon dioxide 0.2%) – 137.5 mg; calcium hydrogen phosphate dihydrate – 73.8 mg; magnesium stearate – 2.5 mg; colloidal silicon dioxide – 1.2 mg;

film coating: [hypromellose – 4.80 mg, talc – 1.60 mg, titanium dioxide – 0.88 mg, macrogol 4000 (polyethylene glycol 4000) – 0.72 mg] or [dry mixture for film coating containing hypromellose (60%), talc (20%), titanium dioxide (11 %), macrogol 4000 (polyethylene glycol 4000) (9%)] – 8.0 mg.

Pregnancy

Pregnancy
There are no data on the use of trimetazidine in pregnant women. Animal studies have not revealed the presence of direct or indirect negative effects on reproductive function.
The use of trimetazidine during pregnancy is contraindicated.
Breastfeeding period
There are no data on the excretion of trimetazidine or its metabolites into breast milk. Risk to the newborn/child cannot be excluded. If it is necessary to use the drug during lactation, breastfeeding should be stopped.
Fertility
Reproductive toxicity studies revealed no effect of trimetazidine in rats of either sex.

Contraindications

hypersensitivity to the active substance or any of the excipients included in the medicinal product;
Parkinson’s disease, symptoms of parkinsonism, tremor, restless legs syndrome and other related movement disorders;
severe renal failure (creatinine clearance less than 30 ml/min);
pregnancy;
breastfeeding period;
age under 18 years (due to lack of sufficient clinical data).

With caution

renal failure of moderate severity (creatinine clearance 30-60 ml/min);
age over 75 years (see sections “Method of administration and dosage” and “Special instructions”).

Side Effects

Classification of the frequency of side effects according to the recommendations of the World Health Organization (WHO):

very often ≥ 1/10;

often from ≥ 1/100 to <1/10;

infrequently from ≥ 1/1000 to <1/100;

rarely from ≥ 1/10000 to <1/1000;

very rare <1/10000, including individual messages;

frequency unknown – based on available data, it is not possible to determine the frequency of occurrence.

Blood and lymphatic system disorders:

frequency unknown – agranulocytosis, thrombocytopenia, thrombocytopenic purpura.

Nervous system disorders:

often – dizziness, headache;

frequency unknown – symptoms of parkinsonism (tremor, akinesia, increased tone), gait instability, restless legs syndrome, other associated motor disorders, usually reversible after cessation of therapy; sleep disorders (insomnia, drowsiness).

Disorders of the hearing organ and labyrinth:

frequency unknown – vertigo.

Heart disorders:

rarely – palpitations, extrasystole, tachycardia.

Vascular disorders:

rarely – arterial hypotension, orthostatic hypotension, which may be accompanied by general malaise, dizziness or falling, especially when taking antihypertensive drugs at the same time, “flushes” of blood to the facial skin.

Gastrointestinal disorders:

often – abdominal pain, diarrhea, dyspepsia, nausea, vomiting;

frequency unknown – constipation.

Disorders of the liver and biliary tract:

frequency unknown – hepatitis.

Skin and subcutaneous tissue disorders:

often – skin rash, itching, urticaria;

frequency unknown – acute generalized exanthematous pustulosis (AGEP), angioedema.

General disorders and reactions at the injection site:

often – asthenia.

Interaction

There were no interactions with other drugs.

Overdose

There is only limited information on trimetazidine overdose. In case of overdose, symptomatic therapy should be carried out.

Storage conditions

Store at a temperature not exceeding 25 ºС.
Keep out of the reach of children.

Shelf life

3 years.
Do not use after expiration date.

Manufacturer

Vertex, Russia