Mildralex-Z 500 mg capsule №60

Mildralex-Z user manual

Composition

active substance: meldonium (trimethylhydrazinium propionate) 1 capsule contains meldonium dihydrate 250 mg or 500 mg
auxiliary substances: potato starch, calcium stearate, silicon dioxide colloid capsule shell contains titanium dioxide (E 171), gelatin.

Dosage form

Capsules are solid.

Basic physical and chemical properties:

hard gelatin capsules in white. Contents of capsules - a mixture containing granules and white powder with a weak odor.The presence of agglomerates is allowed. On the capsule, it is allowed to apply the trademark of the enterprise - ZT.

Pharmacological group

Other cardiac preparations . ATX Code C01E B22.

Pharmacological properties

Pharmacodynamics. Meldonium is a precursor of carnitine, a structural analogue of gamma-butyrobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom. Its effect on the body can be explained in two ways.

1. Effect on the biosynthesis of carnitine.

Meldonium, reversibly inhibiting gamma-butyrobetaine hydroxylase, decreases the biosynthesis of carnitine and therefore prevents the transport of long chain fatty acids through the cell membranes, thus preventing the accumulation of strong detergent in the cells-activated forms of unoxidized fatty acids. Thus, damage to cell membranes is prevented.

With a decrease in carnitine concentration under conditions of ischemia, beta-oxidation of fatty acids is delayed and oxygen consumption in cells is optimized, glucose oxidation is stimulated, and transport of ATP from the sites of its biosynthesis (mitochondria) to places of consumption (cytosol) is restored. In fact, cells are provided with nutrients and oxygen, and the consumption of these substances is optimized.

In turn, with increasing biosynthesis of the carnitine precursor, that is, GBB, NO-synthetases are activated, as a result of which the rheological properties of the blood improve and the peripheral resistance of the vessels decreases.

With a decrease in the concentration of meconium, the biosynthesis of carnitine again increases and the number of fatty acids gradually increases in the cells.

It is believed that the basis for the effectiveness of action meldoniya is an increase in tolerance to the cellular load (with a change in the amount of fatty acids).

2. Function of the mediator in the hypothetical GBB-ergic system.

A hypothesis has been put forward that in the body there is a system for the transfer of neuronal signals - the GBB-ergic system, which ensures the transfer of a nerve impulse between the cells. The mediator of this system is the last precursor of carnitine - GBB-ether. As a result of the action of GBB-esterase, the mediator gives the electron to the cell, thus transferring the electrical impulse, turns into GBB. Further hydrolyzed form of GBB is actively transported to the liver, kidneys and ovaries, where it is converted into carnitine. In somatic cells, in response to stimulation, new HBB molecules are newly synthesized, providing signal propagation.

With a decrease in the concentration of carnitine, synthesis of GBB is stimulated, as a result of which the concentration of the GBB ether increases.

Meldonium, as indicated earlier, is a structural analogue of GBB and can serve as a "mediator". In contrast, HBB hydroxylase "does not recognize" meldonia, so the concentration of carnitine does not increase, but decreases. Thus, meldonium itself, replacing the "mediator", and contributing to the increase in the concentration of GBB, leads to the development of a corresponding reaction of the organism. As a result, the overall metabolic activity increases in other systems, for example, in the central nervous system (CNS).

Influence on the cardiovascular system. It has been established that meldonium positively influences the contractile activity of the myocardium, it has myocardioprotective action (including C. Against catecholamines and alcohol), it is able to prevent cardiac arrhythmias, to reduce the zone of myocardial infarction.

Ischemic heart disease (stable angina pectoris load). Analysis of clinical data on the course of the use of meldonium in the treatment of stable angina pectoris load showed that the drug reduces the frequency and intensity of angina attacks, as well as the amount of glyceryl trinitrate that is applied. The drug has a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, less effect is observed in patients with supraventricular extrasystoles.

Particularly important is the ability of the drug to reduce oxygen consumption at rest, is considered an effective criterion for antianginal therapy of ischemic heart disease.

Meldonium favorably affects the atherosclerotic processes in the coronary and peripheral vessels, reducing the overall serum cholesterol level and the atherogenic index.

Chronic heart failure. The ability of meldonia to increase tolerance to physical activity, as well as the volume of work performed by patients with heart failure is noted.

The effectiveness of meconium in the case of heart failure NYHA I-III functional class of moderate severity. Under the influence of milling therapy, 59-78% of patients who initially had cardiac insufficiency II functional class were included in the group and functional class. It was found that the use of meldonia improves the inotropic function of the myocardium and increases tolerance to physical activity, improves the quality of life of patients without causing serious side effects.However, it is noted that meldonia can cause minor hypotension. Other possible side effects meldonia - allergic skin reactions, headaches, a feeling of discomfort in the epigastrium.

In case of severe heart failure, meldonia should be used in combination with other traditional means of therapy for heart failure.

Influence on the central nervous system. The established antihypoxic effect meldonia and action, promotes cerebral circulation. The drug improves the redistribution of the volume of cerebral circulation in favor of ischemic foci, increases the strength of neurons in hypoxic conditions.

The drug has a stimulating effect on the central nervous system - increased motor activity and physical endurance, stimulation of behavioral reactions, as well as anti-stress action - stimulation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, protection of internal organs against changes caused by stress.

Efficacy in neurological diseases. It is proved that meldonium is an effective agent in the complex therapy of acute and chronic disorders of cerebral circulation (ischemic stroke, chronic cerebral circulatory failure). Meldonium normalizes the tone and resistance of the capillaries and arterioles of the brain, restores their reactivity.

The process of rehabilitation of patients with neurological disorders (after the diseases of the blood vessels of the brain, brain operations, injuries, tick-borne encephalitis) has been studied.

The results of testing the therapeutic activity of meldonia indicate its dose-dependent positive effect on physical endurance and restoration of functional independence during the recovery period.

When analyzing changes in individual and total intellectual functions after application of the drug, a positive effect on the restored process of intellectual functions during the recovery period was established.

It is established that meldonia improves the convalescent quality of life (mainly due to the renewal of the body's physical function), besides, it eliminates psychological disturbances.

Meldonium has a positive effect on the function of the nervous system - a reduction in impairment in patients with neurologic deficits during recovery.

Improves the overall neurological state of patients (reduction of damage to the brain nerves and pathology of reflexes, regression of paresis, improvement of coordination of movements and autonomic functions).

Pharmacokinetics.

Suction. After a single dose, Cmax is 2.23-2.43 μg / ml, and after repeated doses of 2.77 μg / ml. T max is 1-3 hours.Bioavailability with oral administration is 78%. Food slightly delays absorption.

Distribution. Meldonium from the bloodstream is quickly distributed in tissues. The volume of distribution is 88.07 ± 8.56 L, the connection with plasma proteins is 78%. Meldonium and its metabolites partially pass through the placental barrier.

Metabolism. It has been established that meldonia is mainly metabolized in the liver.

Conclusion. In the derivation of meldonium and its metabolites from the body, renal excretion is important. After ingestion of a single dose, the half-period of early withdrawal of meldonia is approximately 3.5-4 hours. When applying repeated doses, the half-life period is different. These results indicate a possible accumulation of meldonia in the blood plasma.

Special groups of patients.

Patients of advanced age. Older patients with impaired liver or kidney function, in which bioavailability increases, should reduce the dose of meldonia.

Impaired renal function. Patients with impaired renal function, in which bioavailability increases, should reduce the dose of meldonia. There is an interaction of renal reabsorption of meldonia or its metabolites (eg, 3-hydroxymeledonium) and carnitine, which increases the renal clearance of carnitine. There is no direct effect of meldonia, GBB and membonium / GBB combinations on the renin-angiotensin-aldosterone system.

Violation of the function of the liver. Patients with impaired liver function, in which bioavailability increases, should reduce the dose of meldonia. When applying meldonium in a dose of 100 mg / kg, the color of the liver is set to yellow and the denaturation of fats. After application of large doses of meldonia (400 mg / kg and 1600 mg / kg), accumulation of lipids in liver cells is established. Changes in liver function in humans after using large doses of 400-800 mg were not observed. It is impossible to exclude the possible infiltration of fats into liver cells.

Children. There is no data on the safety and efficacy of meldonium in children under the age of 18, so the use of a drug in this category of patients is contraindicated.

Indications

In complex therapy in the following cases:

• heart disease and vascular system: stable angina pectoris, chronic heart failure (NYHA I-II and functional class), cardiomyopathy, functional disorders of the heart and vascular system;
• acute and chronic ischemic impairment of cerebral circulation
• decreased performance, physical and psycho-emotional overstrain;
• in the recovery period after cerebrovascular disorders, head injuries and encephalitis.

Contraindications

Hypersensitivity to meldonia and / or any excipient of the drug
increased intracranial pressure (with violation of venous outflow, intracranial tumors)
severe hepatic and / or renal failure (there is insufficient evidence of safety of use).

Interaction with other drugs and other interactions

Meldonium can be used together with long-acting nitrates and other anti-anginal agents (stable angina of the load), cardiac glycosides and diuretic drugs (heart failure). It can also be combined with anticoagulants, antiaggregants, antiarrhythmics and other drugs that improve microcirculation. Meldonium can enhance the action of drugs containing glyceryl trinitrate, nifedipine, beta-adrenoblockers and other antihypertensives and peripheral vasodilators.

As a result of simultaneous application of iron preparations and meldonium in patients with anemia caused by iron deficiency, the composition of fatty acids in erythrocytes was improved.

When using meldonium in combination with orotic acid to eliminate damage caused by ischemia / reperfusion, an additional pharmacological effect is observed.

Meldonium helps to eliminate pathological changes in the heart caused by azidothymidine (AZT), and indirectly affects the oxidative stress reactions caused by AZT, which lead to mitochondrial dysfunction. The use of meldonium in combination with azidothymidine or other drugs for the treatment of AIDS has a positive effect in the treatment of acquired immunodeficiency (AIDS). In the loss test of the equilibrium reflex caused by ethanol, meldonium reduced the duration of sleep. During the trial, caused by pentylenetetrazole, pronounced anticonvulsant action of meldonia is established. In turn, when anticonvulsant action is completely blocked in the dose of 10 mg / kg before treatment with meconium alpha-2-adrenoblocker yohimbine at a dose of 2 mg / kg and an inhibitor of nitric oxide synthase (COA) N- (G) -nitro-L-arginine mulled stone.

An overdose of mecedonia can exacerbate the cardiotoxicity caused by cyclophosphamide.

Deficiency of carnitine, which is formed by the use of meldonia, can enhance the cardiotoxicity caused by Ifosfamide.

Meldonium has a protective effect in case of cardiotoxicity caused by indinavir and neurotoxicity caused by efavirenz.

Do not use together with other preparations containing meldonia, since the risk of adverse reactions may increase.

Application features

Patients with violations of the liver and / or kidneys of mild or moderate severity in the history of the drug should be used with caution (liver and / or kidney function should be monitored).

Many years of experience in the management of acute myocardial infarction and unstable angina in cardiac units shows that meldonium is not a first-line drug in acute coronary syndrome.

For the possible development of an exciting effect, the drug is recommended for use in the first half of the day.

Use during pregnancy or lactation

Pregnancy. To assess the impact of meldonium on pregnancy, the development of the embryo / fetus, childbirth and the postnatal development of animal studies is not enough. The potential risk for humans is unknown, so meldonium is contraindicated during pregnancy.

Breastfeeding. The available data on animals indicate the penetration of meldonia into the mother's milk. It is unknown, penetrates the meldonia into breast milk. It is impossible to exclude the risk for newborns / infants, so during breastfeeding meldoon is contraindicated.

The ability to influence the reaction rate when driving vehicles or other mechanisms

Studies to assess the impact on the ability to manage transport and work with mechanisms have not been conducted.

Dosing and Administration

For oral administration. In connection with the possible exciting effect of the drug is recommended to use in the morning.

Adults. Diseases of the heart and vascular system, cerebral circulation disorders. A dose of 500-1000 mg per day. The daily dose can be applied all at once or divided into 2 doses. The maximum daily dose is 1000 mg.

Reduced performance, overexertion and recovery period. A dose of 500 mg per day. The daily dose can be used all at once or divided into two single doses. The maximum daily dose is 500 mg.

The duration of treatment is 4-6 weeks. The course of treatment can be repeated 2-3 times a year.

Patients of advanced age. For elderly patients with impaired liver and / or kidney function, there may be a need to reduce the dose of meconium.

Patients with impaired renal function. Since the drug is excreted from the body through the kidneys, patients with mild to moderate renal dysfunction should take a smaller dose of meldonia.

Patients with impaired hepatic function. Patients with impaired liver function of mild to moderate severity should be treated with a smaller dose of meldonia.

Children

There are no data on the safety and efficacy of meldonium in children under the age of 18 years, so the use of mondonia in this category of patients is contraindicated.

Overdose

No cases of an overdose of meldonia have been reported. The drug is low in toxicity and does not cause dangerous side effects.

With lowered arterial pressure, headaches, dizziness, tachycardia, general weakness are possible. Treatment is symptomatic.

In case of severe overdose, it is necessary to monitor the liver and kidney function.

Hemodialysis does not have a significant effect in overdose meldonia due to pronounced binding to blood proteins.

Adverse Reactions

On the part of the immune system: allergic reactions, hypersensitivity, including allergic dermatitis, hives, angioedema, anaphylactic reactions in shock.

From the side of the psyche: arousal, a sense of fear, obsessive thoughts, sleep disturbance.

On the part of the nervous system: headaches, paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, fainting.

From the heart: a change in the rhythm of the heart, palpitations, tachycardia / sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort / chest pain.

On the part of the circulatory system: increase / decrease in blood pressure, hypertensive crisis, redness, pale skin.

On the part of the respiratory, thoracic and mediastinal disorders: respiratory tract infection, sore throat, cough, shortness of breath, sleep apnea.

On the part of the gastrointestinal tract: dyspepsia, dysgeusia (metallic taste in the mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation.

Skin and subcutaneous tissue: skin rashes, joint / makulezno / papular rash, itching.

On the part of the musculoskeletal system and connective tissue disorders: back pain, muscle weakness, muscle cramps.

The kidneys and urinary system: pollakiuria.

General disorders: general weakness, chills, fatigue, edema, facial edema, swelling of the legs, feeling hot, feeling cold, cold sweat.

Study: dyslipidemia, elevated levels of C-reactive protein abnormalities in ECG, acceleration of the heart, eosinophilia.

Shelf life

2 years.

Storage conditions

Stored in original package at a temperature not higher than 25 ° C.Hranit the reach of children.

Packaging

Capsules 250 mg № 10x4 in blisters in a box or 500 mg 10x6 № in blisters in a box.

Category of leave

On prescription.