LEVOFOLIK

INSTRUCTIONS for medical use of the medicinal product VASOPRO^®(VASOPRO^®)

Composition

active substance: mildronate; 1 ml of solution contains 100 mg of mildronate (in the form of methionate); excipient: water for injections.

Pharmaceutical form

Solution for injection.

Main physical and chemical properties

Clear colorless liquid.

Pharmacotherapeutic group

Cardiological preparations. ATC code C01E B22.

Pharmacological properties

Pharmacodynamics

Mildronate is a precursor of carnitine, a structural analog of gamma-butyrobetaine (GABA), 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 carnitine biosynthesis

Mildronate, by reversibly inhibiting gamma-butyrobetaine hydroxylase, reduces carnitine biosynthesis and thereby prevents the transport of long-chain fatty acids through cell membranes, thus preventing the accumulation of strong detergents - activated forms of unoxidized fatty acids in cells. This prevents damage to cell membranes.

When the concentration of carnitine decreases under ischemic conditions, beta-oxidation of fatty acids is slowed down, and oxygen consumption in cells is optimized, glucose oxidation is stimulated, and ATP transport from the site of its biosynthesis (mitochondria) to the site of consumption (cytosol) is restored. In essence, cells are provided with nutrients and oxygen, and the consumption of these substances is optimized.

In turn, with an increase in the biosynthesis of the carnitine precursor, i.e., GABA, NO-synthase is activated, resulting in improved rheological properties of blood and decreased peripheral vascular resistance.

When the concentration of mildronate decreases, carnitine biosynthesis is again enhanced, and the amount of fatty acids in cells gradually increases.

It is believed that the basis of the effectiveness of mildronate is the increased tolerance of cells to loading (with a change in the amount of fatty acids).

2. Function of a mediator in the hypothetical GABA-ergic system

A hypothesis has been put forward that in the body there is a system of neuronal signal transmission - the GABA-ergic system, which ensures the transmission of a nerve impulse between cells. The mediator of this system is the last precursor of carnitine - GABA ester. As a result of the action of GABA esterase, the mediator donates an electron to the cell, thereby carrying an electric impulse, and is converted into GABA. Further, the hydrolyzed form of GABA is actively transported to the liver, kidneys, and ovaries, where it is converted into carnitine. In somatic cells, in response to stimulation, new GABA molecules are synthesized, ensuring the spread of the signal.

When the concentration of carnitine decreases, GABA synthesis is stimulated, resulting in an increased concentration of GABA ester.

Mildronate, as mentioned earlier, is a structural analog of GABA and can perform the functions of a "mediator". On the other hand, GABA hydroxylase "does not recognize" mildronate, so the concentration of carnitine does not increase, but decreases. Thus, mildronate, replacing the "mediator" and contributing to the increase in GABA concentration, leads to the development of a corresponding reaction of the body. As a result, the overall metabolic activity also increases in other systems, such as the central nervous system (CNS).

Effect on the cardiovascular system

In animal studies, it has been found that mildronate has a positive effect on the contractile activity of the myocardium, has a cardioprotective effect (including against catecholamines and alcohol), and is able to prevent rhythm disturbances, reduce the area of myocardial infarction. Ischemic heart disease (stable exertional angina).

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

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

Mildronate has a beneficial effect on atherosclerotic processes in coronary and peripheral vessels, reducing the total cholesterol level in blood serum and the atherogenic index.

Chronic heart failure

In many clinical studies, the role of mildronate in the treatment of chronic heart failure due to IHD has been analyzed, and its ability to increase tolerance to physical exertion, as well as the volume of work performed by patients with heart failure, has been noted.

The effectiveness of mildronate has been tested in cases of heart failure of NYHA I-III functional class of moderate severity. Under the influence of mildronate therapy, 59-78% of patients who were initially diagnosed with heart failure of II functional class were included in the group of I functional class. It has been established that the use of mildronate improves the inotropic function of the myocardium and increases tolerance to physical exertion, improves the quality of life of patients, without causing severe side effects.

In cases of severe heart failure, mildronate should be used in combination with other traditional means of treating heart failure.

Effect on the CNS

In experiments on animals, the antihypoxic effect of mildronate and its effect on cerebral blood flow have been established. The drug optimizes the redistribution of cerebral blood flow in favor of ischemic foci, increases the strength of neurons under hypoxia.

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

Efficacy in neurological diseases

It has been proven that mildronate is an effective remedy in the complex therapy of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulation insufficiency). Mildronate normalizes the tone and resistance of capillaries and arterioles of the brain, restoring their reactivity.

The effect of mildronate on the process of rehabilitation of patients with neurological disorders (after cerebrovascular disorders, brain operations, injuries, and tick-borne encephalitis) has been studied.

The results of checking the therapeutic activity of mildronate 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 taking the drug, a positive effect on the recovery process of intellectual functions during the recovery period has been established.

It has been established that mildronate improves the quality of life during rehabilitation (mainly due to the renewal of physical function of the body), and also eliminates psychological disorders.

Mildronate has a positive effect on the function of the nervous system, reducing disorders in patients with neurological deficiency during the recovery period.

The overall neurological condition of patients improves (reduction of brain damage and reflex pathology, regression of paresis, improvement of movement coordination and autonomic functions).

Pharmacokinetics

Pharmacokinetics were studied in healthy volunteers when using mildronate intravenously and orally.

Absorption

Bioavailability is 100%. The maximum concentration in plasma (Cmax) is reached immediately after administration. After intravenous administration of multiple doses, Cmax reaches 25.5 ± 3.63 μg / ml.

After intravenous administration, the area under the concentration-time curve (AUC) after single and repeated administration of mildronate doses differs, indicating possible accumulation of mildronate in plasma.

Distribution

Mildronate is rapidly distributed from the bloodstream to tissues with high cardiac affinity. Mildronate and its metabolites partially cross the placental barrier. In animal studies, it has been found that mildronate penetrates into breast milk.

Metabolism

In metabolism studies on experimental animals, it has been found that mildronate is mainly metabolized in the liver.

Excretion

In the excretion of mildronate and its metabolites from the body, renal excretion plays a role. After a single intravenous administration of a dose of mildronate at 250 mg, 500 mg, and 1000 mg, the half-period of early excretion of mildronate is 5.56-6.55 hours, and the final excretion period is 15.34 hours.

Special patient groups

Elderly patients

Elderly patients with impaired liver and/or kidney function, in whom bioavailability increases, should have their mildronate dose reduced.

Impaired renal function

Patients with impaired renal function, in whom bioavailability increases, should have their mildronate dose reduced. There is an interaction between renal reabsorption of mildronate or its metabolites (e.g., 3-hydroxymildronate) and carnitine, resulting in increased renal clearance of carnitine. There is no direct effect of mildronate, GABA, or the combination of mildronate/GABA on the renin-angiotensin-aldosterone system.

Impaired liver function

Patients with impaired liver function, in whom bioavailability increases, should have their mildronate dose reduced. In toxicity studies on rats when using mildronate at a dose of more than 100 mg/kg, yellowing of the liver and denaturation of fats were found. In histopathological studies on animals after administration of large doses of mildronate (400 mg/kg and 1600 mg/kg), accumulation of lipids in liver cells was found. Changes in liver function tests in humans after administration of large doses of 400-800 mg were not observed. Infiltration of fats into liver cells cannot be ruled out.

Clinical characteristics

Indications

In the complex therapy of the following diseases:

• heart and vascular diseases: stable exertional angina, chronic heart failure (NYHA I-III functional class), cardiomyopathy, functional disorders of heart and vascular activity;
• acute and chronic ischemic cerebral circulation disorders;
• reduced performance, physical and psychoemotional overload;
• during the recovery period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications

- Hypersensitivity to mildronate and/or any of the excipients of the drug;

- increased intracranial pressure (with impaired venous outflow, intracranial tumors);

- severe liver and/or kidney failure (there is no sufficient data on the safety of use).

Interaction with other medicinal products and other types of interactions

Mildronate can be used in combination with nitrates of prolonged action and other antianginal agents (stable exertional angina), cardiac glycosides, and diuretic agents (heart failure).

It can also be combined with anticoagulants, antiaggregants, antiarrhythmic agents, and other agents that improve microcirculation.

Mildronate may enhance the effect of drugs containing glyceryl trinitrate, nifedipine, beta-adrenoblockers, other hypotensive agents, and peripheral vasodilators.

As a result of the simultaneous use of iron preparations and mildronate in patients with iron deficiency anemia, the fatty acid composition in erythrocytes improved.

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

Mildronate helps to eliminate pathological changes in the heart caused by azidothymidine (AZT) and indirectly affects the reactions of oxidative stress caused by AZT, which lead to mitochondrial dysfunction. The use of mildronate in combination with azidothymidine or other drugs for the treatment of AIDS has a positive effect on the treatment of acquired immunodeficiency syndrome (AIDS).

In a test of loss of balance reflex caused by ethanol, mildronate reduced sleep duration.

During seizures caused by pentylenetetrazole, a pronounced anticonvulsant effect of mildronate was found. In turn, when using the alpha2-adrenoblocker yohimbine at a dose of 2 mg/kg and the nitric oxide synthase inhibitor (NOS) N-(G)-nitro-L-arginine at a dose of 10 mg/kg before mildronate therapy, the anticonvulsant effect of mildronate is completely blocked.

Overdose of mildronate may increase cardiotoxicity caused by cyclophosphamide.

The carnitine deficiency that occurs when using mildronate may increase cardiotoxicity caused by ifosfamide.

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

Do not use with other drugs containing mildronate, as this may increase the risk of adverse reactions.

Special instructions

Patients with impaired liver and/or kidney function of mild or moderate severity in history should be cautious when using the drug (liver and/or kidney function monitoring should be performed).

Long-term experience in treating acute myocardial infarction and unstable angina in cardiology departments shows that mildronate is not a first-line drug for acute coronary syndrome.

Use during pregnancy or breastfeeding

Pregnancy

There is insufficient data on the effect of mildronate on pregnancy, embryonic/fetal development, childbirth, and postpartum development. The potential risk to humans is unknown, so mildronate is contraindicated during pregnancy.

Breastfeeding

Data from animals indicate that mildronate penetrates into breast milk. It is unknown whether mildronate penetrates into human breast milk. The risk to newborns/infants cannot be ruled out, so mildronate is contraindicated during breastfeeding.

Ability to affect reaction speed when driving vehicles or using mechanisms

Studies to assess the impact on the ability to drive vehicles and operate mechanisms have not been conducted.

Method of application and doses

Administer intravenously. The use of the drug does not require special preparation before administration.

In connection with the possible stimulating effect of the drug, it is recommended to use it in the first half of the day.

Adults

The dose is 500-1000 mg (5-10 ml) per day, the dose is administered once or divided into 2 doses. The duration of treatment is usually 10-14 days, after which treatment is continued with an oral medicinal form.

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

Elderly patients

Elderly patients with impaired liver and/or kidney function may have their mildronate dose reduced.

Patients with impaired renal function

Since the drug is excreted by the body through the kidneys, patients with impaired renal function of mild to moderate severity should use a smaller dose of mildronate.

Patients with impaired liver function

Patients with impaired liver function of mild to moderate severity should use a smaller dose of mildronate.

Children

There is no data on the safety and efficacy of using mildronate in children, so the use of mildronate in this category of patients is contraindicated.

Overdose

There have been no reports of mildronate overdose. The drug is low-toxic and does not cause life-threatening side effects.

In case of decreased arterial pressure, possible headaches, dizziness, tachycardia, general weakness. Treatment is symptomatic.

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

Hemodialysis is not significant in case of mildronate overdose due to pronounced binding to blood proteins.

Side effects

Side effects are classified according to the MedDRA system of organs and frequency of occurrence: often (≥1/100 to <1/10), rarely (≥1/10000 to <1/1000).

Side effects observed in clinical trials and in the post-marketing period:

* Side effects that were observed in previously conducted uncontrolled clinical trials of mildronate.

Shelf life

2 years.

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

Storage conditions

Store in the original packaging at a temperature not exceeding 25°C. Do not freeze. Store in a place inaccessible to children.

Packaging

5 ml in an ampoule. 10 ampoules in a pack. 5 ml in an ampoule. 5 ampoules in a blister pack. 2 blister packs in a pack.

Release category

By prescription.

Manufacturer

Pharmaceutical company "Pharmak".

Location of the manufacturer and its address

Ukraine, 04080, Kyiv, Kyrylivska Street, 74.