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

Excipients: sugar spheres¹⁾ (710-850 microns) 36.68 mg, hypromellose 6.40 mg.Film sheath: ethyl cellulose 8.00 mg, tributylacetyl citrate 1.20 mg, talc 12.00 mg. Blend for pelletizing the pellets: talc 0.43 mg, magnesium stearate 0.14 mg.

Hard gelatin capsule №2 with a white casing and an orange-red lid. On cover printed logo of the company and the inscription "80" of white color²⁾: 61,000 mg.

Capsule case: titanium dioxide (E 171) 0.732 mg, gelatin³⁾ 35.868 mg.

Capsule cover: titanium dioxide (E 171) 0.122 mg, iron oxide red (E 172) 0.366 mg, gelatin³⁾ 23.912 mg.

1) The composition of sugar spheres: sucrose - no more than 92% (in terms of dry matter), corn starch. May also contain starch hydrolysis products and colorants.

2) The seal of the logo and the inscription on the capsule is applied in white ink, which includes shellac, titanium dioxide, simethicone, propylene glycol, ammonium hydroxide. The total amount of ink per capsule is approximately 0.15 mg.

3) Contains an average of 14.5% water (loss in mass when dried).

Description:

Hard gelatin capsules No. 2 with a white casing and an orange-red lid. The logo of the company and the inscription "80" of white color are printed on the cover. Content capsules: granules of a spherical shape of white or almost white color.

Pharmacotherapeutic group:antianginal

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 the oxidation of fatty acids by selective inhibition of the 3-ketoacyl-CoA-thiolase (3-CAT) enzyme of the mitochondrial long chain fatty acid isoform, which leads to increased glucose oxidation and glycolysis acceleration with glucose oxidation, which determines myocardial protection from ischemia. Switching energy metabolism from the oxidation of fatty acids 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 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 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 the inadequate effect of other antianginal drugs.

In a study of 426 patients with stable angina,the addition of 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 with placebo: the total duration of the stress tests was +20, 1 s, p = 0.023, the total time of the load +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 angina 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 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 time to development of ischemic depression in the segment ST by 1 mm (+34.4 s, p = 0.03) when carrying out load tests in a subgroup of patientsn= 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 groups for other secondary endpoints (total duration of stress tests,total load time and clinical end points).

In a study involving 1962 patients with stable angina, trimetazidine 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 subgroup of patients with symptoms of angina pectoris (n=1574), trimetazidine (140 mg) significantly improved the overall time of the stress test (+23.8 seconds compared with +13.1 seconds for placebo, p = 0.001) and the time until the onset of an angina attack (+46.3 seconds compared with +32.5 for placebo, p = 0.005).

Pharmacokinetics:

Absorption

After oral administration of the Preductal® OD capsule, trimetazidine has a linear pharmacokinetic profile and reaches a maximum plasma concentration approximately 14 hours after ingestion. In the intervals between doses of the drug (i.e.within 24 hours) concentration of trimetazidine in the blood plasma for 15 hours after taking the drug remains at a level of at least 75% of the maximum concentration.

The equilibrium state is achieved after taking the 3rd dose (after 3 days). Eating does not affect the bioavailability of trimetazidine when taking Premedtal® OD 80 mg.

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.

Renal clearance of trimetazidine directly correlates with creatinine clearance (CC), the hepatic clearance decreases with the age of the 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 failure (QC less than 30 mL / min) compared with 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-grade renal insufficiency (CK 30-60 ml / min), and on average 4-fold - in patients with severe renal insufficiency (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 heart disease: prevention of attacks of stable angina in the mono-or combination therapy.

Contraindications:

Hypersensitivity to any of the components of the drug.

Parkinson's disease, symptoms of parkinsonism, tremor, restless legs syndrome and other associated motor disorders.

Severe renal insufficiency (creatinine clearance less than 30 ml / min).

Intolerance to fructose / sucrose, the presence of glucose-galactose malabsorption syndrome, sucrose-isomaltase deficiency and other fermentopathies associated with intolerance to sucrose, which is part of the drug.

Due to the lack of sufficient clinical data, patients under 18 years of age are not recommended.

Carefully:

Patients with hepatic insufficiency of severe severity (from 10 to 15 points on the Child-Pugh scale).

Patients with moderate-level renal insufficiency (creatinine clearance 30-60 ml / min).

Patients older than 75 years (see the section "Dosing and Administration" and "Special instructions").

Pregnancy and lactation:

There are no data on the use of Preductal ® OD 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, do not use Preductal ® OD during pregnancy.

Data on the release of trimetazidine or its metabolites in breast milk are not available. The risk to a newborn / child can not be ruled out. If it is necessary to use Preductal® OD during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, 1 capsule 1 time per day, in the morning, during breakfast.

Capsules should be taken whole, not liquid, squeezed with water.

Assessment of the benefits of treatment can be carried out after three months of taking the drug. The drug Preductal® OD should be discontinued if no improvement has occurred during this time.

The duration of treatment is determined by the doctor.

Special Groups

Patients with renal insufficiency

In patients with moderate-grade renal insufficiency (CK 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.

Patients with hepatic impairment

Caution should be exercised in the treatment of patients with severe hepatic insufficiency (see section "Special instructions"), because the available data are limited and do not completely exclude the absence of the effect of liver function abnormalities on the metabolism of trimetazidine.

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 renal function (see section "Pharmacokinetics"). In patients with moderate-grade renal failure (CK 30-60 ml / min), a dose reduction is recommended, i.e. 1 tablet containing 35 mg of trimetazidine per day.

The choice of dose in patients older than 75 years should be done with caution (see section "Special instructions").

Patients under 18 years of age

The safety and efficacy of trimetazidine in patients younger than 18 years of age have not been established. No data available.

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 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: Parkinsonism symptoms (tremor, akinesia, tone increase), gait unsteadiness, restless legs syndrome, 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: heart palpitations, extrasystole, tachycardia, 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.

On the part of the hematopoiesis and lymphatic system

Unspecified frequency: agranulocytosis, thrombocytopenia, thrombocytopenic purpura.

From the liver and biliary tract

Unspecified frequency: hepatitis.

Overdose:

There is only very limited information on the overdose of trimetazidine.

In case of an overdose, symptomatic therapy should be given.

Interaction:

Not observed.

The patient should inform the doctor about all medications taken.

Special instructions:

Preductal® OD is not intended for arresting 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® OD can cause or worsen symptoms of parkinsonism (tremor, akinesia, tone increase), therefore regular monitoring of patients, especially of 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, gait unsteadiness, Preductal® OD should be completely abolished.

Such cases are rare and symptoms usually pass 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 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® OD 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").

The composition of the drug is sucrose, so the drug is not recommended for patients with intolerance to fructose, glucose-galactose malabsorption syndrome and insufficiency of isomaltase sugarase.

Effect on the ability to drive transp.cf. and fur:

In the course of clinical trials, there was no evidence of the effects of trimetazidine on hemodynamic parameters, however, in the period of post-marketing use, cases of dizziness and drowsiness were observed (see the "Side effect" section), which could affect the ability to drive vehicles and perform jobs requiring increased physical and mental reactions.

Form release / dosage:

Capsules with sustained release, 80 mg.

Packaging:

10 capsules in a blister of PA / Al / PVC film and aluminum foil. For 3 or 6 blisters with instructions for medical use in a pack of cardboard.

For 9 capsules in a blister of PA / Al / PVC film and aluminum foil. For 3 blisters with instructions for medical use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003410

Date of registration:13.01.2016

Expiration Date:13.01.2021

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

Manufacturer: & nbsp

PHARMSTANDART-FORESTRY, OJSC Russia

Representation: & nbspServier Laboratories Servier Laboratories France

Information update date: & nbsp05.08.2016

Illustrated instructions

Instructions

Preductal® OD (Preductal® OD)