Preductal MB - instructions for use, dose, side effects, contraindications

Excipients: calcium hydrophosphate dihydrate, povidone, hypromellose, magnesium stearate, silicon dioxide colloid, macrogol-6000; sheath: dry premix for pink shell N5361, consisting of titanium dioxide, iron dye oxide red, glycerol, hypromellose, magnesium stearate, macrogol-6000.

Description:Round, biconvex tablets, covered with a film membrane, pink. Color of the tablet on the break: white.

Pharmacotherapeutic group:antihypoxic agent

ATX: & nbsp

C.01.E.B Other drugs for the treatment of heart disease

C.01.E.B.15 Trimetazidine

Pharmacodynamics:Mechanism of action

Trimetazidine prevents the reduction of 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 preservation of cellular homeostasis. Trimetazidine inhibits oxidation of fatty acids due to selective inhibition of the enzyme 3-ketoacyl-CoA thiolase (3-KAT) mitochondrial isoform long chain fatty acids, which leads to increased oxidation of glucose and acceleration of glycolysis to glucose oxidation, which is responsible for protecting the myocardium from ischemia. Switching energy metabolism with oxidation of fatty acids on the oxidation of glucose underlies the pharmacological properties of trimetazidine.

It is experimentally confirmed that trimetazidine has the following properties:

- supports energy metabolism of the heart and neurosensory tissues during ischemia;

- reduces severity 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 reperfused heart tissues;

- 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 onset of ischemia caused by physical exertion, starting from 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 for short-acting nitroglycerin;

- improves left ventricular contractility patients with ischemic dysfunction.

The results of clinical trials confirmed the efficacy and safety of trimetazidine in patients with stable angina, both in monotherapy and in combination of therapy at inadequate effect other antianginal drugs.

In a randomized, double-blind, placebo-controlled study involving 426 patients with stable angina (TRIMPOL-II), the addition of trimetazidine (60 mg / day) to metoprolol therapy 100 mg / day (50 mg twice daily) for 12 weeks statistically significantly improved the results of exercise tests and clinical symptoms compared with placebo: the total duration of the stress tests was +20.1 s, p = 0.023, the total loading time is +0.54 METs, p = 0.001, time to development of segment depression ST at 1 mm +33.4 s, p = 0.003, time until the development of an attack of angina pectoris +33.9 s, p <0.001, the number of attacks of stenocardia per week -0.73, p = 0.014 and 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 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 to an increase in time to development ischemic depression of the segment ST on 1 mm (+34.4 s, p = 0.03) when performing load tests in a subgroup of patients (n = 173), compared with placebo, after 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 groups for other secondary endpoints (total duration of stress tests, total load time and clinical endpoints).

In a three-month, randomized, double-blind study involving 1962 patients with stable angina (Vasco), trimetazinDin in two dosages (70 mg / day and 140 mg / day) in comparison with placebo was added to the therapy with atenolol 50 mg / day. In the general population, including patients, both without symptoms and with symptoms of angina pectoris, trimetazidine did not demonstrate the benefits of ergometric (total duration of exercise tests, time to onset of ischemic depression of the segment ST at 1 mm and the time until the onset of an attack of angina pectoris) 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 the time until the onset of an attack of angina (+46.3 s compared with +32.5 for placebo, p = 0.005).

Pharmacokinetics: Absorption

After oral administration trimetazidine quickly absorbed and reaches a maximum concentration 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. Eating does not affect the bioavailability of trimetazidine.

Distribution

The volume of distribution is 4.8 l / kg, which indicates a good distribution of trimetazidine in tissues (the degree of binding to blood plasma proteins is quite low, about 16 % in vitro).

Excretion

Trimetazidine is excreted mainly by the kidneys, mainly in unchanged form. Half-life in young healthy volunteers is about 7 hours, in patients older than 65 years - about 12 hours.

The renal clearance of trimetazidine directly correlates with creatinine clearance (CC), the hepatic clearance decreases with age patient.

Special Groups

Patients older than 75 years

In patients older than 75 years, there may be an increased exposure of trimetazidine due to age-related decline in kidney function. A special study was conducted in a population of patients older than 75 years with the administration of 35 mg of trimetazidine tablets twice a day. An analysis of the kinetic population method showed, on average, a twofold increase in plasma exposure in patients with severe renal insufficiency (QC less than 30 ml / min) compared to patients with QC greater than 60 ml / min.

There were no safety features in patients older than 75 years compared with the general population.

Patients with renal insufficiency

Exposure of trimetazidine on average was increased by 2.4 times in patients with moderate-level renal insufficiency (CK 30-60 ml / min), and on average 4-fold in patients with renal insufficiency of severe severity (CC less than 30 ml / min) compared with healthy volunteers with normal renal function.

No safety features were found in this patient population in comparison with the general population.

Application in children and adolescents

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

Indications:Long-term therapy of ischemic disease heart: prevention of attacks stable angina in the mono- or combination therapy.

Contraindications:- Hypersensitivity to any of the components of the preparation.

- Parkinson's disease, symptoms Parkinsonism, tremor, syndrome "restless legs" and others associated with them motor disorders.

- Severe renal insufficiency (creatinine clearance less than 36 ml / min).

Due to the lack of sufficient clinical data for patients under 18 years of age, the use of the drug is not recommended.

Carefully:Patients with renal inadequacy of severe severity (SC less than 30 ml / min) (clinical data limited), patients with renal insufficiency of moderate severity (CK 30-60 ml / min), use in patients older than 75 years.

Pregnancy and lactation:There are no data on the use of Preductal® MB in pregnant women. Studies in animals have not revealed the presence of direct or indirect reproductive toxicity. Reproductive toxicity studies did not show influences trimetazidine on reproductive function in rats of both sex. As a precaution, it is not recommended to use Preductal® MB during pregnancy. Data on the release of trimetazidine or its metabolites into breast milk are absent. The risk to a newborn / child can not be ruled out. Do not use Preductal® MB during breastfeeding.

Dosing and Administration:

Tablets should be taken whole, not chewing, washing with water.

Inside, 1 tablet 2 times a day, in the morning and in the evening, while eating.

The duration of treatment is determined doctor.

The maximum daily dose is 70 mg.

Special Groups

Patients with renal insufficiency

Have patients with moderate-level renal insufficiency (KK 30-60 ml / min) daily dose is 35 mg (1 tablet), in the morning during breakfast.

Patients older than 75 years

Have patients older than 75 years may experience increased exposure to trimetazidine due to age-related decline kidney function (see section "Pharmacokinetics"). In patients with moderate-grade renal failure (CK 30-60 mL / min), the recommended daily dose is 35 mg (1 tablet) in the morning during breakfast. The choice of dose in patients older than 75 years should be done with caution (see.section "Special instructions").

Side effects:Undesirable reactions, defined as undesirable events, at least with possible relevance 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 / 10000, <1/1000); very rarely (<1/10000), unspecified frequency (frequency can not be calculated from the available data).

From the digestive system

Often: abdominal pain, diarrhea, indigestion, nausea, vomiting.

Unspecified frequency: constipation.

General disorders

Often: asthenia.

From the central nervous system

Often: dizziness, headache.

Unspecified frequency: symptoms Parkinsonism (tremor, akinesia, tone increase), instability in the Romberg position and the "unsteadiness" of the gait, the syndrome of restless legs, and other associated motor disorders, usually reversible after cessation of therapy. Sleep disturbances (insomnia, drowsiness).

From the skin and subcutaneous fat

Often: skin rash, itching, hives.

Unspecified frequency: acute generalized exanthematous pustulosis, angioedema.

From the side of the cardiovascular system

Rarely: a feeling of palpitations, extrasystole, tachycardia, pronounced decrease AD, orthostatic hypotension, which may be accompanied by general weakness, dizziness, or loss of balance, especially when simultaneous admission of antihypertensive drugs, "hot flashes" of blood to the skin of the face.

From the side of the blood and lymphatic system

Unspecified frequency: agranulocytosis, thrombocytopenia, thrombocytopenic purpura.

From the liver and bile excretory ways

Unspecified frequency: hepatitis.

Overdose:There is only limited information about an overdose of trimetazidine. In case of an overdose, symptomatic therapy should be given.

Interaction:

Not observed.

Special instructions:Preductal® MB is not designed for relief of angina attacks and not is indicated for the initial course of therapy unstable angina or infarction myocardial pre-hospital stage or the first days of hospitalization.

In case of an attack of angina pectoris The treatment should be reviewed and adapted (drug therapy or procedures revascularization).

Preductal® MB may cause or worsen symptoms of parkinsonism (tremor, akinesia, increased tonus), so conduct regular monitoring of patients, especially the elderly. In questionable patients should be referred to neurologist for the appropriate survey.

When there are motor disorders, such as symptoms of parkinsonism, syndrome "restless legs," tremor, instability in Romberg's pose and "shaky" gait, Preductal® MB should be finalized cancel.

Such cases are rare and symptoms usually go away after discontinuation of therapy: the 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 pose and the "shakiness" of the gait or a pronounced decrease in blood pressure, especially in patients taking antihypertensive drugs (see the "Side effect" section).

Caution should be used to prescribe Preductal® MV to patients who may have an increase in exposure:

-With moderate renal failure (see sections "Pharmacological properties" and "Method of administration and dose").

- In elderly patients older than 75 years (see section "Method of administration and dose").

Effect on the ability to drive transp. cf. and fur:In the course of clinical studies, the effect of Preductal® MB on the indices hemodynamics, however during the post-registration period applications there were cases of dizziness and drowsiness (see section "Side effect"), which can affect the ability to drive vehicles and perform work that requires an increased speed of physical and mental reactions.

Form release / dosage:

Tablets with modified release, film-coated, 35 mg.

Packaging:

30 tablets per blister (PVC / Al). 2 blisters with instruction on

medical use in a pack of cardboard.

When packaging (packaging) / production at a Russian company LLC "Serdiks":

30 tablets per blister (PVC / Al). 2 blisters with instruction on

medical use in a pack of cardboard.

Packing for hospitals:

30 tablets per blister (PVC / Al). For 3 or 6 blisters with instructions for medical use in a pack of cardboard.

For 10 blisters of 30 tablets in a blister pack in a pack of cardboard (the pack is not labeled).3 packs of cardboard with instructions for medical use in a cardboard box with the control of the first autopsy.

Storage conditions:

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.

Terms of leave from pharmacies:On prescription

Registration number:П N013215 / 01

Date of registration:29.12.2010

The owner of the registration certificate:SERVICE, CJSC SERVICE, CJSC Russia

Manufacturer: & nbsp

SERDIK, LLC Russia

Pharmaceutical Joint-Stock Company ANPHARM, S.A. Poland

Information update date: & nbsp25.10.2015

Illustrated instructions

Instructions

Preductal® MB (Preductal® MR)