Composition, form of production and packaging
Tablets with modified release, film-coated, pink, round, biconvex; on the bend - white.
1 tab.
trimetazidine dihydrochloride 35 mg
Excipients: calcium hydrophosphate dihydrate - 80.9 mg, povidone - 8.7 mg, hypromellose - 74 mg, magnesium stearate - 1 mg, silicon dioxide colloid - 0.4 mg, macrogol-6000 - 0.1317 mg.
The composition of the film shell: Premix No. 5361 dry (titanium dioxide - 0.6908 mg, iron oxide red oxide - 0.0103 mg, glycerol 0.2191 mg, hypromellose - 3.6414 mg, magnesium stearate 0.2191 mg, macrogol-6000-0.0876 mg).
30 pcs. - blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
PHARMACHOLOGIC EFFECT
Trimetazidine prevents a decrease in the intracellular content of 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 transfer of potassium and sodium ions and preservation of cellular homeostasis.
Trimetazidine slows the oxidation of fatty acids due to the selective inhibition of long-chain 3-ketoacetyl-CoA thiolase, which leads to an increase in glucose oxidation and acceleration of glycolysis with glucose oxidation and causes myocardial protection from ischemia. The switching of the energy metabolism of the oxidation of fatty acids to the oxidation of glucose underlies the antianginal action of trimetazidine.
It has been experimentally confirmed that trimetazidine has the following properties:
- supports the energy metabolism of the heart and neurosensory organs during ischemia;
- reduces the severity of intracellular acidosis and changes in the transmembrane ion flow that occur with ischemia;
- lowers the level of migration and infiltration of polynucleated neutrophils in ischemic and reperfusion tissues of the heart;
- reduces the size of myocardial damage;
- does not directly affect the parameters of hemodynamics.
In patients with angina pectoris, trimetazidine:
- increases the coronary reserve, thereby slowing the development of ischemia caused by physical exertion, starting from the 15th day of therapy;
- limits sharp fluctuations in blood pressure caused by physical activity, without any significant changes in heart rate;
- significantly reduces the frequency of angina attacks and the need for short-acting nitroglycerin;
- improves the contractile function of the left ventricle in patients with ischemic dysfunction.
The results of clinical trials have confirmed the efficacy and safety of trimetazidine in patients with stable angina pectoris, both in monotherapy and in combination therapy with insufficient effectiveness of treatment with other antianginal drugs.
In a randomized, double-blind, placebo-controlled study of 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 was statistically significant 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 exercise time +0.54 METs, p = 0.001, the time to progression of ST-segment depression by 1 mm +33.4 s, p = 0.003, time to development of an attack of stenocarp diis +33.9 s, p <0.001, the number of attacks of angina in the 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 study involving 223 patients with stable angina (Sellier), the addition of trimetazidine 35 mg twice daily for atenolol therapy at a dose of 50 mg once per day for 8 weeks resulted in an increase in time to development of ischemic depression of the ST segment by 1 mm (+34.4 s, p = 0.03) during load tests in a subgroup of patients (n = 173), compared with placebo, 12 hours after the drug was administered. 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 duration of stress tests, total load time and clinical endpoints).
In a three-month, randomized, double-blind study of 1962 patients with stable angina (Vasco), trimetazidine was added to atenolol (50 mg / d) in two doses (70 mg / day and 140 mg / day), compared with placebo. In the general population, including patients, both asymptomatic and symptomatic of angina, trimetazidine did not demonstrate an advantage in ergometric (total duration of stress tests, time to onset of ischemic depression of the ST segment by 1 mm and time to the onset of angina attacks) and clinical endpoints . However, in a retrospective analysis in a subset of patients with symptoms of angina pectoris (n = 1574) trimetazidine (140 mg) significantly improved the total time of the stress test (+23.8 s compared with +13.1 s for placebo, p = 0.001) and time until the onset of angina attack +46.3 s compared with +32.5 s for placebo, p = 0.005).
PHARMACOKINETICS
Suction
After oral administration, trimetazidine is rapidly absorbed. C max is reached after 5 hours. For more than 24 hours the concentration in the plasma remains at a level exceeding 75% of the concentration, determined after 11 hours. Food intake does not affect the bioavailability of the drug.
Distribution
With ss achieved after 60 h V d is 4.8 l / kg, which indicates a good distribution of trimetazidine in tissues.
Binding to plasma proteins is low, about 16% (in vitro).
Excretion
Trimetazidine is excreted from the body mainly by the kidneys in an unchanged form. T 1/2 in young healthy volunteers - about 7 hours, in patients older than 65 years - about 12 hours.
Renal clearance of trimetazidine directly correlates with QC, hepatic clearance decreases with age.
Pharmacokinetics in specific patient groups
Patients over the age of 75 may experience increased exposure to trimetazidine because of an age-related decline in kidney function. A special study was conducted in the population of patients over the age of 75 years when taking trimetazidine tablets 35 mg twice daily. An analysis of the kinetic population method showed, on average, a twofold increase in plasma exposure in patients with severe renal insufficiency (CK <30 mL / min) compared with patients with CK> 60 mL / min. There were no specific features regarding the safety of the drug in patients over the age of 75 compared with the general population.
Exposure of trimetazidine on average was increased by 2.4 times in patients with moderate renal insufficiency (KK 30-60 ml / min) and, on average, 4 times - in patients with severe renal insufficiency (CK <30 ml / min) compared with healthy volunteers with normal renal function. No specific features regarding the safety of the use of the drug in this population of patients were found in comparison with the general population.
The pharmacokinetics of trimetazidine in children and adolescents under the age of 18 years have not been studied.
INDICATIONS
- long-term therapy of ischemic heart disease: prevention of attacks of stable angina in the form of monotherapy or as part of combination therapy.
DOSING MODE
Preductal В® MV appoint 1 tab. 2 times / day during meals in the morning and evening. The maximum daily dose is 70 mg.
The duration of treatment is determined by the doctor.
Tablets should be taken whole inside without chewing and drinking with water.
In patients with moderate renal insufficiency (KK 30-60 ml / min) daily dose is 35 mg (1 tab.). Tablets should be taken in the morning, during breakfast.
Patients over the age of 75 may experience increased exposure to trimetazidine because of an age-related decline in kidney function. Choose a dose with caution.
SIDE EFFECT
Undesirable reactions, defined as undesirable events, at least that are possibly related to treatment with trimetazidine, are given in the following gradation: 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); frequency (frequency can not be calculated from available data).
From the digestive system: often - abdominal pain, diarrhea, indigestion, nausea, vomiting; Unspecified frequency - constipation.
From the side of the central nervous system: often - dizziness, headache; (eg, tremor, akinesia, increased tonus), instability in Romberg's posture and the "unsteadiness" of the gait, restless leg syndrome, and other associated motor disorders, usually reversible after discontinuation of the drug, sleep disturbances (insomnia, drowsiness) .
From the skin and subcutaneous fat: often - skin rash, itching, urticaria; Unspecified frequency - acute generalized exanthematous pustulosis, angioedema.
From the cardiovascular system: rarely - a feeling of heartbeat, extrasystole, tachycardia, a marked decrease in blood pressure, orthostatic hypotension, which can be accompanied by general weakness, dizziness or loss of balance, especially with the simultaneous use of antihypertensive drugs, "tides" of blood to the skin of the face.
From the hematopoietic system: unspecified frequency - agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
From the liver and bile ducts: unspecified frequency - hepatitis.
Common violations: often - asthenia.
CONTRAINDICATIONS
- marked renal failure (CC less than 30 ml / min);
- Parkinson's disease, symptoms of parkinsonism, tremor, restless legs syndrome and other associated motor disorders;
- Hypersensitivity to any of the components of the drug.
Due to the lack of sufficient clinical data, it is not recommended to prescribe the drug to children and adolescents under the age of 18 years.
Caution should be given to patients with severe renal insufficiency (CK <30 ml / min) (clinical data are limited), patients with moderate renal insufficiency (CK 30-60 ml / min), patients over the age of 75 years.
PREGNANCY AND LACTATION
There are no data on the use of Preductal В® MB in pregnant women.
Studies in animals have not revealed the presence of direct or indirect reproductive toxicity.
Studies of reproductive toxicity have shown no effect of trimetazidine on reproductive function in rats of both sexes.
As a precaution, it is not recommended to use Preductal В® MB during pregnancy.
Data on the release of trimetazidine or its metabolites with breast milk are not available. The risk to a newborn / child can not be ruled out. Do not use Preductal В® MB during breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Contraindicated in severe renal failure (CC less than 30 ml / min).
Caution should be given to patients with moderate renal insufficiency.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Caution should be given to patients with severe hepatic insufficiency (clinical data are limited).
APPLICATION FOR CHILDREN
Due to the lack of sufficient clinical data, it is not recommended to prescribe the drug to children and adolescents under the age of 18 years.
APPLICATION IN ELDERLY PATIENTS
Caution should be used to prescribe Preductal В® MB to elderly patients over 75 years of age who may have an increase in exposure.
SPECIAL INSTRUCTIONS
Preductal В® MB is not intended for relief of angina attacks and is not indicated for the initial course of therapy for unstable angina or myocardial infarction at the prehospital stage or in the first days of hospitalization.
In the case of an angina attack, treatment should be reviewed and adapted (drug therapy or revascularization procedure).
Preductal В® MB can cause or worsen symptoms of parkinsonism (tremor, akinesia, tone increase), therefore, regular monitoring of patients, especially the elderly, should be carried out. In doubtful cases, patients should be referred to a neurologist for an appropriate examination.
When motor disorders such as Parkinsonism symptoms, restless legs syndrome, tremor, Romberg pose instability and gait unsteadiness, Preductal В® MB should be finally canceled.
Such cases are rare and symptoms usually go away after discontinuation of therapy: in most patients - within 4 months after discontinuation of the drug. If the symptoms of parkinsonism persist for more than 4 months after discontinuation of the drug, you should consult a neurologist.
There may be cases of falls associated with instability in the Romberg position and the "shakiness" of the gait or pronounced decrease in blood pressure, especially in patients taking antihypertensive drugs.
Caution should be used to prescribe Preductal В® MB to patients who can increase its exposure:
- with renal insufficiency of moderate and severe degree;
- in elderly patients older than 75 years.
Impact on the ability to drive vehicles and manage mechanisms
In the course of clinical studies, the effect of Preductal В® MB on hemodynamics was not revealed, however, in the period of postgrade use, cases of dizziness and drowsiness were observed, which could affect the ability to drive vehicles and carry out work requiring increased rates of physical and mental reactions.
OVERDOSE
There is limited information on the overdose of trimetazidine.
In case of an overdose, symptomatic therapy is performed.
DRUG INTERACTION
Drug interaction of the drug Preductal В® MB is not described.
TERMS OF RELEASE FROM PHARMACY
The drug is released on prescription.
TERMS AND CONDITIONS OF STORAGE
Special storage conditions are not required. Keep out of the reach of children. Shelf life - 3 years. Do not use after the expiration date stated on the package.
