There is only limited information about trimetazidine overdose.
Treatment: symptomatic therapy.
hypersensitivity to the drug,
renal insufficiency (Creatinine Cl below 15 ml / min),
severe liver function disorders,
pregnancy,
breastfeeding period,
age under 18 (efficacy and safety not established).
hypersensitivity to any of the components of the drug,
Parkinson's disease, symptoms of parkinsonism, tremor, restless legs syndrome, and other related motor disorders,
severe renal insufficiency (creatinine Cl less than 30 ml / min) - clinical data is limited,
patients under 18 years of age (due to the lack of sufficient clinical data, the administration of the drug is not recommended).
With caution: patients with severe renal insufficiency (creatinine Cl less than 30 ml / min) (clinical data are limited), patients with moderate renal insufficiency (creatinine Cl 30-60 ml / min), use in patients over 75 years of age
Common for both doses
hypersensitivity to any component of the drug,
pregnancy,
breastfeeding period,
age under 18 (efficacy and safety not established).
Additionally for Deprenorm® MV 35 mg
severe renal insufficiency (creatinine Cl less than 15 ml / min),
severe liver function disorders.
Additionally for Deprenorm® MV 70 mg
severe renal insufficiency (creatinine Cl less than 30 ml / min),
Parkinson's disease, symptoms of parkinsonism, tremor, restless legs syndrome and other related motor disorders.
With caution: severe hepatic insufficiency (limited clinical data), impaired renal function (creatinine Cl greater than 30 ml / min), age over 75 years.
hypersensitivity to any component of the drug,
Parkinson's disease, symptoms of parkinsonism, tremor, restless legs syndrome, and other similar motor disorders,
severe renal insufficiency (creatinine Cl less than 30 ml / min),
age under 18 (due to lack of sufficient clinical data).
With caution: patients with severe renal insufficiency (clinical data are limited), patients with moderate renal insufficiency.
hypersensitivity to any component of the drug,
renal insufficiency (Creatinine Cl less than 15 ml / min),
severe liver function disorders,
pregnancy, lactation,
age under 18 (efficacy and safety not established).
Hypersensitivity.
Interaction with other drugs is not described.
Allergic reactions: hypersensitivity reactions to the drug or any of its components, skin itching.
From the gastrointestinal tract: rarely-gastralgia, nausea, vomiting.
From the nervous system: headache.
From the cardiovascular system: the feeling of a strong heartbeat.
Adverse reactions defined as adverse events that are at least possibly relevant to trimetazidine treatment are graded as follows: very common (≥1/10), common (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), unspecified frequency (frequency cannot be calculated from available data).
From the digestive system: often-abdominal pain, diarrhea, dyspepsia, nausea, vomiting, unspecified frequency-constipation.
General violations: often-asthenia.
From the central nervous system: often-dizziness, headache, unspecified frequency-symptoms of parkinsonism (tremor, akinesia, increased tone), instability in the Romberg position and "shakiness" of gait, "restless" legs syndrome, other related motor disorders, usually reversible after discontinuation of therapy, sleep disorders (insomnia, drowsiness).
From the skin and subcutaneous fat: often-skin rash, itching, urticaria, unspecified frequency-acute generalized exanthematous pustulosis, Quincke's edema.
From the CCC side: rarely-a feeling of palpitation, extrasystole, tachycardia, a marked decrease in blood pressure, orthostatic hypotension, which may be accompanied by general weakness, dizziness or loss of balance, especially when taking antihypertensive drugs, flushes of blood to the skin of the face.
From the circulatory and lymphatic system: unspecified frequency — agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
From the liver and biliary tract: unspecified frequency-hepatitis.
The frequency of side effects observed when taking trimetazidine is given in the following gradation: very common (more than 1/10), common (more than 1/100, less than 1/10), infrequent (more than 1/1000, less than 1/100), rare (more than 1/10000, less than 1/1000), very rare (less than 1/10000, including individual reports), unspecified frequency (frequency cannot be calculated from available data).
From the digestive system: often-abdominal pain, diarrhea, dyspepsia, nausea, vomiting, unspecified frequency (for long-acting, film-coated tablets, 70 mg) - constipation.
From the central nervous system: often-dizziness, headache, asthenia, unspecified frequency-symptoms of parkinsonism (tremor, akinesia, increased tone), instability in the Romberg position and unsteadiness of gait, restless legs syndrome, other related motor disorders, usually reversible after discontinuation of therapy, sleep disorders (insomnia, drowsiness).
From the skin: often-skin rash, itching, urticaria, unspecified frequency (for long-acting, film-coated tablets, 70 mg) - acute generalized exanthematous pustulosis, Quincke's edema.
From the CCC side: rarely-orthostatic hypotension, flushes of blood to the skin of the face, rarely (for long-acting tablets, film-coated, 70 mg) - palpitations, extrasystole, tachycardia, marked decrease in blood pressure.
Additionally, for long-acting, film-coated tablets, 70 mg
From the circulatory and lymphatic system: unspecified frequency — agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
From the liver and biliary tract: unspecified frequency-hepatitis.
General violations: often-asthenia.
Adverse reactions defined as adverse events, at least possibly related to trimetazidine treatment, are given in the following gradation: very often - ≥1/10, often - ≥1/100, <1/10, infrequently - ≥1/1000, <1/100, rarely - ≥1/10000, <1/1000, very rarely - <1/10000, frequency is not established (frequency cannot be calculated from available data).
From the gastrointestinal tract: often-abdominal pain, diarrhea, dyspepsia, nausea, vomiting, the frequency is not established-constipation.
General disorders: often-asthenia.
From the central nervous system: often-dizziness, headache, frequency not established-symptoms of parkinsonism (tremor, akinesia, increased tone), instability in the Romberg position and unsteadiness of gait, restless legs syndrome, other similar motor disorders, usually reversible after discontinuation of therapy, sleep disorders (insomnia, drowsiness).
From the skin and subcutaneous tissues: often-skin rash, itching, urticaria, the frequency is not established-acute generalized exanthematous pustulosis, Quincke's edema.
From the CCC side: rarely-a feeling of palpitation, extrasystole, tachycardia, a marked decrease in blood pressure, orthostatic hypotension, which may be accompanied by general weakness, dizziness or loss of balance, especially when taking antihypertensive drugs, flushes of blood to the skin of the face.
From the blood and lymphatic system: the frequency is not established-agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
From the liver and biliary tract: the frequency is not established-hepatitis.
The frequency of side effects observed when taking trimetazidine is given in accordance with the WHO classification: very often - ≥1/10, often - ≥1/100 and <1/10, infrequently - ≥1/1000 and <1/100, rarely - ≥1/10000 and <1/1000, very rarely - <1/10000, including individual reports.
From the digestive system: often-abdominal pain, diarrhea, dyspepsia, nausea, vomiting.
General violations: often-asthenia.
From the central nervous system: often-dizziness, headache, very rarely-extrapyramidal disorders (tremor, rigidity, akinesia), reversible after discontinuation of the drug.
From the skin and subcutaneous fat: often-skin rash, itching, urticaria.
From the CCC side: rarely-orthostatic hypotension, flushes of blood to the skin of the face.
Gastrointestinal disorders (rare).
CHD, angina pectoris (as part of complex therapy),
chorioretinal vascular disorders,
vertigo of vascular origin,
cochleovestibular disorders of ischemic nature (tinnitus, hearing impairment).
Long-term therapy of coronary heart disease: prevention of stable angina attacks as part of mono-or combination therapy.
Common for both doses
Ischemic heart disease: prevention of stable angina attacks (as part of combination therapy).
Additionally for Deprenorm® MV 35 mg
chorioretinal disorders with an ischemic component,
vestibulocochlear disorders of ischemic nature, such as dizziness, tinnitus, hearing impairment.
Long-term therapy of coronary heart disease: prevention of stable angina attacks as part of mono-or combination therapy.
ischemic heart disease-prevention of angina attacks (in complex therapy),
cochleovestibular disorders of ischemic nature (dizziness, tinnitus, hearing impairment).
Angina.
Directly affecting the cardiomyocytes and neurons of the brain, optimizes their metabolism and function. The cytoprotective effect is due to an increase in the energy potential, activation of oxidative decarboxylation and rationalization of oxygen consumption (increased aerobic glycolysis and blockade of fatty acid oxidation). Supports myocardial contractility, prevents intracellular depletion of ATP and phosphocreatinin. Under conditions of acidosis, it normalizes the functioning of the ion channels of the membranes, prevents the accumulation of calcium and sodium in cardiomyocytes, and normalizes the intracellular content of potassium ions. Reduces intracellular acidosis and phosphate content due to myocardial ischemia and reperfusion. Prevents the damaging effect of free radicals, preserves the integrity of cell membranes, prevents the activation of neutrophils in the ischemic area, increases the duration of the electrical potential, reduces the release of creatine phosphokinase from cells and the severity of ischemic myocardial damage. With angina, it reduces the frequency of attacks (reduces the consumption of nitrates), after 2 weeks of treatment, the tolerance to physical activity increases, and blood pressure drops decrease. Improves hearing and vestibular test results in patients, reduces dizziness and tinnitus. In case of vascular pathology of the eye, it restores the functional activity of the retina
Mechanism of action
Trimetazidine prevents a decrease in the intracellular concentration of ATP by maintaining the energy metabolism of cells in a state of hypoxia. Thus, the drug ensures the normal functioning of the membrane ion channels, the transmembrane transfer of potassium and sodium ions, and the preservation of cellular homeostasis.
Trimetazidine inhibits the oxidation of fatty acids by selectively inhibiting the enzyme 3-ketoacyl-CoA-thiolase (3-CAT) of the mitochondrial long-chain isoform of fatty acids, which leads to increased glucose oxidation and accelerated glycolysis with glucose oxidation, which determines the protection of the myocardium from ischemia. Switching energy metabolism from fatty acid oxidation to glucose oxidation is the basis of the pharmacological properties of trimetazidine.
It has been experimentally confirmed that trimetazidine has the following properties:
- supports the energy metabolism of the heart and sensorineural 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 the hemodynamic parameters.
In patients with angina, trimetazidine:
- increases the coronary reserve, thereby slowing the onset of exercise-induced ischemia, starting on the 15th day of therapy,
- limits fluctuations in blood pressure caused by physical exertion, without significant changes in heart rate,
- significantly reduces the frequency of angina attacks and the need to take short-acting nitroglycerin,
- improves the contractile function of the left ventricle in patients with ischemic dysfunction.
The results of the conducted clinical studies confirmed the efficacy and safety of trimetazidine in patients with stable angina, both in monotherapy and as part of combination therapy with insufficient effect of other antianginal drugs.
In a randomized, double-blind, placebo-controlled trial involving 426 patients with stable angina (TRIMPOL-II), the addition of trimetazidine (60 mg/day) to metoprolol 100 mg/day (50 mg 2 times/day) for 12 weeks statistically significantly improved the results of stress tests and clinical symptoms compared with placebo: the total duration of stress tests was 20.1 s, p=0.023, the total time to perform the load was 0.54 METs, p=0.001, the time to the development of ST segment depression by 1 mm — 33.4 s, p=0.003, the time to the development of an angina attack — 33.9 c, p<0.001, the number of angina attacks per week — -0.73, p=0.014 and the consumption of short — acting nitrates per week — -0.63, p=0.032, without hemodynamic changes.
In a randomized, double-blind, placebo-controlled trial involving 223 patients with stable angina (Sellier), the addition of trimetazidine at a dose of 35 mg (2 times / day) to atenolol therapy at a dose of 50 mg (1 time/day) for 8 weeks led to an increase in the time to the development of ST-segment ischemic depression by 1 mm ( 34.4 s, p=0.03) during stress tests 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 the groups for other secondary endpoints (total duration of load tests, total load time, and clinical endpoints).
In a three-month randomized, double-blind study involving 1,962 patients with stable angina (Vasco), trimetazidine in two dosages (70 and 140 mg/day) compared to placebo was added to atenolol therapy 50 mg / day. In the general population, including patients with both no symptoms and symptoms of angina pectoris, trimetazidine did not demonstrate benefits for ergometric (total duration of stress tests, time to ST-segment ischemic depression by 1 mm, and time to angina attack) and clinical endpoints.
However, in a retrospective analysis in a subgroup of patients with angina symptoms (n=1574), trimetazidine (140 mg) significantly improved the overall load test time ( 23.8 s compared to 13.1 c for placebo, p=0.001) and the time to angina attack ( 46.3 s compared to 32.5 for placebo, p=0.005).
It has an antihypoxic effect. Trimetazidine prevents a decrease in the intracellular concentration of ATP by maintaining the energy metabolism of cells in a state of hypoxia. Thus, the drug ensures the normal functioning of the membrane ion channels, the transmembrane transfer of potassium and sodium ions, and the preservation of cellular homeostasis. Trimetazidine inhibits the oxidation of fatty acids by selectively inhibiting the enzyme 3-ketoacyl-CoA-thiolase of the mitochondrial long-chain isoform of fatty acids, which leads to increased glucose oxidation and accelerated glycolysis with glucose oxidation, and leads to the protection of the myocardium from ischemia. Switching energy metabolism from fatty acid oxidation to glucose oxidation is the basis of the pharmacological properties of trimetazidine. It has been experimentally confirmed that trimetazidine has the following properties:
- supports the energy metabolism of the heart and sensorineural 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 the hemodynamic parameters.
In patients with angina pectoris:
- increases the coronary reserve, thereby slowing the onset of exercise-induced ischemia, starting on the 15th day of therapy,
- limits fluctuations in blood pressure caused by physical exertion, without significant changes in heart rate,
- reduces the frequency of angina attacks and the need to take short-acting nitroglycerin,
- improves the contractile function of the left ventricle in patients with ischemic dysfunction.
Trimetazidine has an antihypoxic effect. Directly affecting the cardiomyocytes and neurons of the brain, it optimizes their metabolism and function.
The cytoprotective effect is due to an increase in the energy potential, activation of oxidative decarboxylation and rationalization of oxygen consumption (increased aerobic glycolysis and blockade of fatty acid oxidation).
Supports myocardial contractility, prevents intracellular depletion of ATP and phosphocreatinin. Under conditions of acidosis, it normalizes the functioning of membrane ion channels, prevents the accumulation of calcium and sodium in cardiomyocytes, and normalizes the intracellular concentration of potassium ions. Reduces intracellular acidosis and phosphate content due to myocardial ischemia and reperfusion. Prevents the damaging effect of free radicals, preserves the integrity of cell membranes, prevents the activation of neutrophils in the ischemic area, increases the duration of the electrical potential, reduces the release of CPK from cells and the severity of ischemic myocardial damage. With angina, it reduces the frequency of attacks (the need for nitrates decreases), after 2 weeks of treatment, the tolerance to physical activity increases, and blood pressure drops decrease. Improves hearing and vestibular test results in patients with ENT pathology, reduces dizziness and tinnitus. In case of vascular pathology of the eye, it restores the functional activity of the retina
Trimetazidine has an antihypoxic effect. Directly affecting the cardiomyocytes and neurons of the brain, it optimizes their metabolism and function. The cytoprotective effect is due to an increase in the energy potential, activation of oxidative decarboxylation and rationalization of oxygen consumption (increased aerobic glycolysis and blockade of fatty acid oxidation).
Supports the contractility of the myocardium, prevents a decrease in the intracellular content of ATP and phosphocreatine. Under conditions of acidosis, it normalizes the functioning of membrane ion channels, prevents the accumulation of calcium and sodium ions in cardiomyocytes, and normalizes the intracellular content of potassium ions.
Reduces intracellular acidosis and increased phosphate content due to myocardial ischemia and reperfusion. Prevents the damaging effect of free radicals, preserves the integrity of cell membranes, prevents the activation of neutrophils in the ischemic area, increases the duration of the electrical potential, reduces the release of CK from cells and the severity of ischemic myocardial damage.
With angina, it reduces the frequency of attacks and the need for the use of nitroglycerin, after 2 weeks of treatment, the tolerance to physical activity increases, the contractile function of the left ventricle improves in patients with ischemic dysfunction, and blood pressure drops decrease. Reduces dizziness and tinnitus. In case of vascular pathology of the eye, it improves the functional activity of the retina.
It preserves the energy metabolism of the myocardial cells and provides their protection in hypoxia or ischemia.
It is quickly and almost completely absorbed by the intestinal mucosa. Cmax (after a single oral dose of 20 mg) is 55 ng / ml, the time to reach Cmax in blood plasma — 2 hours. Bioavailability-90%. Binding to plasma proteins — 16%. Easily passes through histohematic barriers. It is excreted by the kidneys (about 60% - unchanged). T1/2 it is 4.5–5 hours.
Absorption. After oral administration, trimetazidine is rapidly absorbed and reaches Cmax in the blood plasma after about 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. Vd it is 4.8 l / kg, which indicates a good distribution of trimetazidine in the tissues (the degree of binding to plasma proteins is quite low, about 16% in vitro).
Output. Trimetazidine is mainly excreted by the kidneys, mainly in unchanged form. T1/2 in young healthy volunteers, about 7 hours, in patients older than 65 years — about 12 hours.
Renal clearance of trimetazidine is directly correlated with creatinine Cl, and hepatic clearance decreases with age.
Special groups
Patients over 75 years of age. Patients over 75 years of age may experience increased trimetazidine exposure due to age-related decline in renal function. A special study was conducted in a population of patients over 75 years of age when taking trimetazidine tablets of 35 mg 2 times a day. The analysis performed by the kinetic population method showed an average twofold increase in plasma exposure in patients with severe renal insufficiency (creatinine Cl less than 30 ml / min) compared to patients with creatinine Cl more than 60 ml/min.
No safety features were found in patients over 75 years of age compared to the general population.
Patients with renal insufficiency. Trimetazidine exposure was increased by an average of 2.4 times in patients with moderate renal insufficiency (creatinine Cl 30-60 ml / min), and by an average of 4 times in patients with severe renal insufficiency (creatinine Cl less than 30 ml/min) compared to healthy volunteers with normal renal function.
No safety features 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 the age of 18 years have not been studied.
After oral administration, trimetazidine is absorbed from the gastrointestinal tract and reaches Cmax in the blood plasma after about 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.
Vd it is 4.8 l / kg, which indicates a good distribution of trimetazidine in the tissues (the degree of binding to plasma proteins is quite low, about 16% in vitro).
Trimetazidine is mainly excreted by the kidneys, mainly in unchanged form. Renal clearance of trimetazidine is directly correlated with creatinine Cl, and hepatic clearance decreases with age.
After oral administration, trimetazidine is rapidly and almost completely absorbed from the gastrointestinal tract. Bioavailability-90%. Tmax in blood plasma — 5 h. Cmax after a single dose of 35 mg of trimetazidine-about 115 ng / ml. Easily penetrates through histohematic barriers. T1/2 it is about 6.5 hours. The connection with plasma proteins is 16%. It is excreted by the kidneys (about 60% - unchanged).
After oral administration, trimetazidine is rapidly and almost completely absorbed in the gastrointestinal tract, bioavailability-90%. Tmax the concentration in the blood plasma is approximately 5 hours. After 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 pharmacokinetic properties of trimetazidine. Visible Vd it is 4.8 (l / kg), which explains the good diffusion in the tissues (the connection with plasma proteins is low, about 16%), easily penetrates through histohematic barriers. Trimetazidine is mainly excreted from the body by the kidneys (about 60% - in unchanged form). T1/2 in healthy volunteers, it is about 7 hours, in patients older than 65 years-about 12 hours. Renal clearance of trimetazidine is directly correlated with creatinine clearance, and hepatic clearance decreases with age. Increase T1/2 trimetazidine in elderly patients has no clinical significance.
It is well absorbed from the gastrointestinal tract. T1/2 — from 4 h 30 min to 5 h 10 min. It is mainly excreted by the kidneys.
Bustidin
Trimetazidine
Inside, while eating.
The recommended dosage regimen is 1 tablet (20 mg) 2-3 times a day (40-60 mg/day).
The course of treatment is recommended by a doctor.
Inside, during meals, 3 tablets (60 mg) per day in 2-3 doses. The course of treatment - on the recommendation of a doctor.
Inside, whole, without chewing, with water, 1 table. 2 times a day, in the morning and in the evening, during meals.
The duration of treatment is determined by the doctor.
The maximum daily dose is 70 mg.
Special groups
Patients with renal insufficiency. In patients with moderate renal insufficiency (creatinine Cl 30-60 ml / min), the daily dose is 35 mg (1 table), in the morning, during breakfast.
Patients over 75 years of age. Patients over 75 years of age may experience increased trimetazidine exposure due to age-related decline in renal function (see "Pharmacokinetics").
In patients with moderate renal insufficiency (creatinine Cl 30-60 ml / min), the recommended daily dose is 35 mg (1 table), in the morning during breakfast.
Dose selection in patients over 75 years of age should be carried out with caution (see "Special instructions").
Inside, while eating.
The course of treatment - on the recommendation of a doctor.
Deprenorm® MB 35 mg is taken on 1 table. 2 times a day (morning and evening).
Deprenorm® MB 70 mg is taken 1 table. 1 time a day (in the morning).
Inside, during meals. Angiosil® retard is prescribed 1 tablet (35 mg) 2 times a day (morning and evening). The duration of therapy is set individually.
Inside, 1 table. 35 mg 2 times a day, in the morning and in the evening with meals.
The duration of the course is based on the doctor's recommendation.
Inside, during meals-20 mg 3 times a day.
