Preductal od capsules with prolonged action 80mg N60
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Active ingredients
Trimetazidine
Composition
1 caps. # Trimetazidine dihydrochloride (in granules) 80 mg. Excipients: sugar spheres ** (710-850 microns) - 36.
Pharmacological effect
Trimetazidine prevents the decrease in 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 transfer of potassium and sodium ions and the preservation of cellular homeostasis. Trimetazidine inhibits fatty acid oxidation by selectively inhibiting 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 causes myocardial protection from ischemia. Switching 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 transmembrane ion flow arising during ischemia; - reduces the level of migration and infiltration of polynuclear neutrophils in ischemic and reperfused cardiac tissues; - reduces the size of myocardial damage; - does not have a direct impact on hemodynamic parameters. In patients with angina, trimetazidine increases coronary reserve, thereby slowing the onset of exercise-induced ischemia, starting from the 15th day of therapy; limits blood pressure fluctuations caused by physical activity, without significant changes in heart rate; significantly reduces the frequency of strokes and the need to take short-acting nitroglycerin; improves the contractile function of the left ventricle in patients with ischemic dysfunction. The results of 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 study involving 426 patients with stable angina, adding trimetazidine (60 mg / day) to metoprolol therapy 100 mg / day (50 mg 2 times / day) for 12 weeks, statistically significantly improved the results of exercise tests and clinical symptoms compared to placebo: the total duration of stress tests was +20.1 s, p = 0.023, the total load time was +0.54 METs, p = 0.001, the time before the development of ST-segment depression by 1 mm +33.4 s, p = 0.003, the time before the development of angina + 33.9 s, less than 0.001, the number of strokes per week is 0 .73, p = 0.014 and consumption of short-acting nitrates per week is -0.63, p = 0.032, without hemodynamic changes. In a study involving 223 patients with stable angina, 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 resulted in an increase in the period of development of ischemic depression of the ST segment on 1 mm (+34.4 s, p = 0.03) when performing stress tests in the subgroup of patients (n = 173), compared with placebo, 12 hours after taking the drug. This difference was also shown for the time of the development of strokes (p = 0.049). There were no significant differences between the groups for other secondary endpoints (total duration of stress tests, total load time and clinical endpoints). In a study involving 1962 patients with stable angina, trimetazidine in two dosages (70 mg / day and 140 mg / day) compared with placebo was added to atenolol therapy 50 mg / day. In the general population, including patients, both without symptoms and with symptoms of stenocardia, trimetazidine did not demonstrate advantages in ergometric (total duration of exercise tests, time to the onset of ischemic depression of the ST segment by 1 mm and time to the development of an attack of angina) and clinical endpoints . However, in a retrospective analysis in a subgroup of patients with symptoms of angina pectoris (n = 1574), trimetazidine (140 mg) significantly improved the total exercise time (+23.8 s compared to +13.1 s for placebo; p = 0.001) and the time before the onset of angina pectoris (+46.3 s compared with +32.5 for placebo; p = 0.005).
Pharmacokinetics
Absorption: After ingestion of the preductal OD capsule, trimetazidine has a linear pharmacokinetic profile and reaches Cmax in plasma approximately 14 hours after ingestion. In the intervals between doses of the drug (ie, within 24 hours), the concentration of Trimetazidine in the blood plasma for 15 hours after taking the drug remains at least 75% of Cmax.The equilibrium state is reached after taking the 3rd dose (after 3 days). Food intake does not affect the bioavailability of trimetazidine when taking the drug Preductal OD 80 mg. Distribution: Vd is 4.8 l / kg, which indicates a good distribution of trimetazidine in the tissues (the degree of binding to plasma proteins is rather low, about 16% in vitro). Withdrawal: 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. The kidney clearance of trimetazidine correlates directly with CC, the hepatic clearance decreases with the patient's age. Pharmacokinetics in special patient groups: Patients older than 75 years 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 old with the use of Trimetazidine pills at a dose of 35 mg 2 times / day. The analysis carried out by the kinetic population method showed an average twofold increase in plasma exposure in patients with severe renal failure (CC less than 30 ml / min) compared with patients with CC more than 60 ml / min. No safety features were observed in patients over 75 years of age compared to the general population. Exposure of trimetazidine on average was increased by 2.4 times in patients with moderate renal failure (CK 30-60 ml / min), and on average 4 times in patients with severe renal insufficiency (CK less than 30 ml / min) compared to with healthy volunteers with normal kidney function. No safety features were found in this patient population compared to the general population. The pharmacokinetics of trimetazidine in children and adolescents under the age of 18 years has not been studied.
Indications
- long-term treatment of coronary artery disease: prevention of attacks of stable angina in the composition of mono-or combination therapy.
Contraindications
- severe renal failure (QC less than 30 ml / min) - Parkinson's disease, parkinsonism symptoms, tremor, restless legs syndrome and other related motor disorders - fructose / sucrose intolerance, glucose-galactose malabsorption syndrome, sucrase / isomaltase deficiency and other fermentopathies associated with intolerance to sucrose, which is part of the drug - up to 18 years of age (due to the lack of sufficient clinical data) - hypersensitivity to any of the components of the drug.With caution, the drug should be prescribed to patients with severe hepatic insufficiency (10 to 15 points on the Child-Pugh scale), moderate renal insufficiency (CC 30-60 ml / min), patients over 75 years old (see sections "Dosing regimen" and "Special Instructions").
Use during pregnancy and lactation
Data on the use of the drug Preductal OD in pregnant women are not available. Animal studies have not revealed direct or indirect reproductive toxicity. Reproductive toxicity studies did not show the effect of trimetazidine on reproductive function in rats of both sexes. As a precautionary measure, it is not recommended to use the drug Preductal OD in pregnancy. There are no data on the release of trimetazidine or its metabolites in breast milk. The risk for a newborn / child cannot be excluded. If necessary, the use of the drug Preductal OD in the period of lactation breastfeeding should be stopped.
Dosage and administration
The drug is taken orally, 1 capsule 1 time / day, in the morning during breakfast. Capsules should be taken whole, not liquid, squeezed water. Evaluation of the benefits of treatment can be carried out after 3 months of the drug. If during this time there is no improvement, the use of the drug Preductal OD should be discontinued. The duration of treatment is determined by the doctor. In patients with moderately severe renal failure (CC 30-60 ml / min) (see the sections “Pharmacokinetics” and “Special Instructions”), a dose reduction is recommended, i.e. 1 tablet containing 35 mg of trimetazidine, per day. Care should be taken when treating patients with severe liver failure (see section "Special Instructions") due to the fact that the available data are limited and do not completely eliminate the absence of the effect of impaired liver function on trimetazidine metabolism. In patients older than 75 years, increased exposure to trimetazidine may be observed due to age-related decline in renal function (see the Pharmacokinetics section). In patients with moderately severe renal failure (CK 30–60 ml / min), a dose reduction is recommended, i.e. 1 tablet containing 35 mg of trimetazidine, per day. Selection of the dose in patients older than 75 years should be done with caution (see section "Special instructions").The safety and efficacy of trimetazidine in patients under the age of 18 years have not been established. No data available.
Side effects
Adverse reactions, defined as adverse events, at least having a possible relationship to the treatment with trimetazidine, are given in the following gradation: very often (1/10); often (1/100, less than 1/10); infrequently (1/1000, less than 1/100); rarely (1/10 000, less than 1/100); very rarely (less than 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), "shaky" gait, restless legs syndrome, other motor disturbances associated with them, usually reversible after cessation of therapy. Sleep disturbances (insomnia, drowsiness). Since the cardiovascular system: rarely - palpitations, extrasystoles, tachycardia, marked reduction 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, "tides" of blood to the skin of the face. On the part of the digestive system: often - abdominal pain, diarrhea, dyspepsia, nausea, vomiting; unspecified frequency - constipation. On the part of the liver and biliary tract: unspecified frequency - hepatitis. On the part of the hematopoietic system: unspecified frequency - agranulocytosis, thrombocytopenia, thrombocytopenic purpura. On the part of the skin and subcutaneous fat: often - skin rash, itching, urticaria; unspecified frequency - angioedema, acute generalized exantmatous pustus. General disorders: often - asthenia.
Overdose
There is only very limited information on trimetazidine overdose. Treatment: in case of overdose, symptomatic therapy should be carried out.
Interaction with other drugs
Not observed. The patient should inform the doctor about all the drugs taken.
special instructions
Preductal OD is not intended to relieve angina attacks and is not indicated for the initial course of treatment of unstable angina or myocardial infarction in the prehospital or in the first days of hospitalization.In the event of an attack of angina, treatment should be reviewed and adapted (drug therapy or revascularization). Preductal OD can cause or worsen parkinsonism symptoms (tremor, akinesia, increased tone), therefore, patients should be regularly monitored, especially in the elderly. In doubtful cases, the patient should be referred to a neurologist for an appropriate examination. When motor disorders such as parkinsonism symptoms, restless legs syndrome, tremor, "shaky" gait, Preductal OD should be finally canceled. Such cases are rare and symptoms usually disappear 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 falling associated with instability in the Romberg position and "shaky" gait or a pronounced decrease in blood pressure, especially in patients taking antihypertensive drugs (see the section "Side effect"). Precautionary OD should be prescribed with caution in patients who may increase its exposure: - in case of moderate renal failure (see the sections "Pharmacological action" and "Dosage regimen"); - in elderly patients older than 75 years (see section "Dosage regimen"). The preparation 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 motor vehicles and control mechanisms During clinical studies, no effect of trimetazidine on hemodynamic parameters was detected, however, during the period of post-registration use, cases of dizziness and drowsiness were observed (see the section "Side Effects"). These symptoms can affect the ability to drive and perform work that requires an increased rate of physical and mental reactions.