Pharmacodynamics. Mechanism of action. due to the maintenance of energy metabolism in cells under conditions of hypoxia or ischemia, trimetazidine prevents a decrease in the content of ATP inside the cell, thereby ensuring the proper functioning of ion pumps and transmembrane sodium-potassium flow while maintaining cellular homeostasis.
Trimetazidine inhibits β-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase (3-CAT), which increases glucose oxidation. In cells under ischemic conditions, the process of obtaining energy through the oxidation of glucose requires less oxygen compared to the process of obtaining energy through β-oxidation of fatty acids. Strengthening the glucose oxidation process optimizes energy processes in cells and, accordingly, maintains a sufficient energy metabolism under conditions of ischemia.
Pharmacodynamic effects. In patients with coronary artery disease, trimetazidine acts as a metabolic agent, maintaining 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 in the treatment of patients with stable angina pectoris as monotherapy or when added to other antianginal preparations if they are not effective enough.
TRIMPOL-II, a randomized, double-blind, placebo-controlled study in 426 patients, showed that the addition of trimetazidine 60 mg / day to metoprolol 100 mg (50 mg twice daily) for 12 weeks resulted in a significant improvement in stress test scores and improvement of clinical symptoms compared with those with placebo: total duration of the load - +20.1 s, p = 0.023; total work performed - +0.54 MET s, p = 0.001; the time before the appearance of a decrease in the ST segment by 1 mm - +33.4 s, p = 0.003; the time before the onset of an attack of angina pectoris - +33.9 s, p0.001; the number of angina attacks / week –0.73, p = 0.014; the use of short-acting nitrates / week - -0.63, p = 0.032, without changing the hemodynamic parameters.
The SELLIER study, a randomized, double-blind, placebo-controlled study in 223 patients, showed that in a subgroup of patients (n = 173) who received trimetazidine, modified release tablets of 35 mg (2 times daily), to 50 mg of atenolol (1 once a day) for 8 weeks, there was a significant increase (+34.4 s, p = 0.03) in the time to the appearance of a decrease in the ST segment by 1 mm in stress tests compared with that when using placebo 12 hours after taking the preparation. Also, a significant difference was confirmed in terms of time to the onset of an angina attack (p = 0.049). There was no significant difference in other secondary endpoints between the two patient groups (total duration of exercise, total work performed, and clinical endpoints).
In a randomized, double-blind VASCO study involving 1962 patients, which lasted 3 months, trimetazidine at a dose of 70 or 140 mg / day or placebo was added to therapy with atenolol at a dose of 50 mg / day. In the general population, which included patients with and without symptoms, trimetazidine did not show any advantages in terms of both ergometric parameters (total time of exercise, time to the appearance of a 1 mm ST segment decrease and time to the onset of angina pectoris) or clinical endpoints. ... But a post-hock analysis of a subgroup of patients with symptoms (n = 1574) showed that when trimetazidine was used at a dose of 140 mg / day, there was a significant improvement in the total time of physical activity (+23.8 s versus +13.1 s placebo; p = 0.001) and the time to the onset of an angina attack (+46.3 s versus +32.5 s with placebo; p = 0.005).
Pharmacokinetics. Cmax of trimetazidine in the blood is noted on average 5 hours after taking the pill. During the day, the concentration in the blood plasma is stable: for 11 hours after taking the tablet, the concentration of trimetazidine in the blood plasma is equal to or higher than 75% Cmax. The latest state of stable concentration is established at the 60th hour. Food intake does not affect the pharmacokinetic characteristics of trimetazidine. The volume of distribution is 4.8 l / kg; protein binding is low: according to in vitro measurements - 16%.
Trimetazidine is excreted mainly in the urine, mainly unchanged. T½ of the preparation averages 7 hours for healthy young volunteers and 12 hours for people over the age of 65 years. Complete elimination of trimetazidine results mainly from renal clearance, which is directly correlated with creatinine clearance and to a lesser extent the result of hepatic clearance, which decreases with age.
Special patient groups
Elderly patients. A special clinical study was conducted with the participation of elderly patients using trimetazidine 35 mg (1 tablet) 2 times a day. The analysis, carried out by the kinetic population method, showed an increase in the concentration in the blood plasma. In elderly patients, an increase in the concentration of trimetazidine is possible due to an age-related decrease in renal function. Special pharmacokinetic studies in patients aged 75–84 years or ≥85 years showed that in patients with moderate renal insufficiency (creatinine clearance 30–60 ml / min), the concentration of trimetazidine increased by 1.0 and 1.3 times, respectively, compared with young patients (aged 30–65 years) with moderate renal impairment.
Impaired renal function. The concentration of trimetazidine in the blood increases on average 1.7 times in patients with moderate renal insufficiency (creatinine clearance 30-60 ml / min) and 3.1 times in patients with severe renal insufficiency (creatinine clearance 30 ml / min) compared with healthy volunteers with normal kidney function. There was no additional safety risk in this population compared to the general population.
For adults, trimetazidine is indicated for the symptomatic treatment of stable angina pectoris with insufficient efficacy or intolerance to first-line antianginal preparations.
For oral administration. 1 tablet of 35 mg trimetazidine 2 times a day, morning and evening with meals. after 3 months of treatment, it is necessary to evaluate the results of treatment, and in the absence of an effect, trimetazidine should be canceled.
Special patient groups
Patients with renal impairment. For patients with moderate renal impairment (creatinine clearance - 30-60 ml / min), the recommended dose is 1 tablet per day in the morning during breakfast (see SPECIAL INSTRUCTIONS and Pharmacokinetics).
Elderly patients. In elderly patients, the concentration of trimetazidine in the blood may be increased due to age-related decline in renal function (see PHARMACOLOGICAL PROPERTIES). For patients with moderate renal impairment (creatinine clearance - 30-60 ml / min), the recommended dose is 1 tablet 35 mg in the morning with breakfast. For elderly patients, it is necessary to carefully titrate the dose (see SPECIAL INSTRUCTIONS).
Hypersensitivity to the active substance or any excipient; Parkinson's disease, Parkinson's symptoms, tremors, restless legs syndrome and other movement disorders related to the above; severe renal failure (creatinine clearance 30 ml / min).
Adverse reactions, which are defined as side effects that may be associated with the use of trimetazidine, are listed below in accordance with a certain frequency: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (? 1/10 000, 1/1000), very rarely (1/10 000), the frequency is unknown (cannot be determined from the available information).
| Organ system classes | Frequency | Adverse reaction |
From the nervous system | Often | Dizziness, headache |
| Frequency unknown | Parkinson's symptoms (tremors, akinesia, muscle hypertonicity), unsteadiness of gait, restless legs syndrome and other movement disorders related to the above, which usually disappear after stopping treatment; sleep disorders (insomnia, drowsiness) | |
| On the part of the organ of hearing and vestibular apparatus | Frequency unknown | Vertigo |
| From the side of the heart | Seldom | Palpitation, extrasystole, tachycardia |
| From the side of the vessels | Seldom | Arterial hypotension, orthostatic hypotension, which may be associated with malaise, dizziness, or falling, especially in patients using antihypertensive preparations, facial flushing |
From the digestive tract | Often | Abdominal pain, diarrhea, indigestion, nausea and vomiting |
| Frequency unknown | Constipation | |
From the skin of the subcutaneous tissue | Often | Rash, itching, urticaria |
| Frequency unknown | Acute generalized exanthematous pustular rash, angioedema | |
| General violations | Often | Asthenia |
| On the part of the blood and lymphatic system | Frequency unknown | Agranulocytosis, thrombocytopenia, thrombocytopenic purpura |
| From the hepatobiliary system | Frequency unknown | Hepatitis |
The preparation is not intended to relieve angina attacks. it should not be prescribed for unstable angina or myocardial infarction as primary therapy in the prehospital phase or in the early days of hospitalization.
In the event of an attack of unstable angina pectoris against the background of current therapy, it is necessary to review the patient's condition and adjust the treatment (preparation therapy and the possibility of revascularization).
Trimetazidine can cause or worsen symptoms of parkinsonism (tremor, akinesia, muscle hypertonicity), which should be monitored regularly, especially in elderly patients. In doubtful cases, patients should be referred to a neurologist for appropriate examinations.
If movement disorders appear, such as parkinsonism symptoms, restless legs syndrome, tremors, unsteadiness of gait, trimetazidine should be discontinued.
These cases have a low incidence and usually disappear after stopping treatment, in most patients within 4 months after stopping trimetazidine. If the symptoms of parkinsonism persist for more than 4 months after discontinuation of the preparation, it is necessary to consult a neurologist.
Falls associated with unsteadiness of gait or arterial hypotension are possible, especially in patients receiving antihypertensive treatment (see SIDE EFFECTS).
It is necessary to prescribe trimetazidine with caution to patients at risk of increasing its concentration:
patients with moderate renal impairment (see APPLICATION and Pharmacokinetics);
patients over the age of 75 (see APPLICATION).
Use during pregnancy and lactation. Pregnancy. There are no data on the use of trimetazidine in pregnant women. Animal studies show no direct or indirect hazardous toxic effects on the reproductive system. To prevent any risk, the use of trimetazidine during pregnancy is not recommended.
Lactation. It is not known whether trimetazidine or its metabolites passes into breast milk. To prevent any risk to the newborn / infant, the use of trimetazidine is not recommended during breastfeeding.
Children. The safety and effectiveness of trimetazidine for children (under the age of 18) have not been established. No data available.
The ability to influence the reaction rate when driving or working with other mechanisms. According to clinical studies, trimetazidine does not affect hemodynamics, however, in the post-marketing period, cases of dizziness and drowsiness were recorded (see SIDE EFFECTS), which can affect the ability to drive a vehicle and work with mechanisms.
No interactions with other preparations have been reported.
The amount of data regarding trimetazidine overdose is limited. symptomatic treatment.
Does not require special storage conditions. Keep out of the reach of children.
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