Vasonat

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VAZONAT® (VAZONAT)

Composition:

Active substance: mildronate dihydrate (mildronate)

1 ampoule (5 ml of injection solution) contains 500 mg of mildronate dihydrate;

Excipients: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Other cardiac preparations. ATC code C01EB22.

Pharmacological Properties.

Pharmacodynamics.

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

1. Effect on carnitine biosynthesis.

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis and preventing the transport of long-chain fatty acids across cell membranes, thus avoiding the accumulation of strong detergents—unoxidized fatty acids—within cells. As a result, meldonium prevents damage to cellular membranes.

Under conditions of ischemia, reduced carnitine concentration delays beta-oxidation of fatty acids, optimizes oxygen consumption in cells, stimulates glucose oxidation, and restores adenosine triphosphate (ATP) transport from its biosynthesis sites (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, and the utilization of these substances is optimized.

In turn, increased biosynthesis of the carnitine precursor—i.e., GBB—activates NO-synthase, thereby improving blood rheological properties and reducing peripheral vascular resistance.

When meldonium concentration decreases, carnitine biosynthesis resumes and gradually increases the amount of fatty acids in cells.

It is believed that the efficacy of meldonium is based on increased tolerance to cellular stress (due to changes in fatty acid levels).

1. Mediator function in the hypothetical GBB-ergic system.

A hypothesis has been proposed that a neuronal signal transmission system—the GBB-ergic system—exists in the body, responsible for transferring nerve impulses between cells. The mediator of this system is the final precursor of carnitine—GBB-ether. Under the action of GBB-esterase, the mediator donates an electron to the cell, thereby transmitting an electrical impulse, and itself is converted into GBB. The hydrolyzed form of GBB is then actively transported to the liver, kidneys, and ovaries, where it is converted into carnitine. In somatic cells, in response to stimulation, new GBB molecules are synthesized, ensuring signal propagation.

When carnitine concentration decreases, GBB synthesis is stimulated, resulting in increased GBB-ether concentration.

As previously mentioned, meldonium is a structural analogue of GBB and can perform the function of a "mediator." In contrast, GBB-hydroxylase does not recognize meldonium, so carnitine concentration does not increase but decreases. Thus, meldonium, acting as a "mediator" and promoting increased GBB concentration, triggers the corresponding physiological response. As a result, overall metabolic activity increases, including in other systems such as the central nervous system (CNS).

Effect on the cardiovascular system.

Animal studies have demonstrated that meldonium positively affects myocardial contractility, possesses cardioprotective properties (including protection against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces the size of myocardial infarction.

Ischemic heart disease (stable exertional angina).

Analysis of clinical data on the course treatment of stable exertional angina with meldonium has shown that the drug reduces the frequency and intensity of angina attacks, as well as the amount of glyceryl trinitrate used. The drug exhibits pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while its effect is less pronounced in patients with supraventricular extrasystoles.

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

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

Chronic heart failure.

A considerable number of clinical studies have analyzed the role of meldonium in treating chronic heart failure due to IHD, demonstrating its ability to increase tolerance to physical exertion and the amount of work performed by patients with heart failure.

In a separate study conducted at cardiology institutes in Latvia and Tomsk, the efficacy of meldonium in heart failure according to NYHA (New York Heart Association) functional classes I–III of moderate severity was evaluated. Under meldonium therapy, 59–78% of patients initially diagnosed with functional class II heart failure were reclassified to functional class I. It has been established that meldonium improves myocardial inotropic function and increases tolerance to physical exertion, thereby improving patients' quality of life without causing severe adverse effects.

In cases of severe heart failure, meldonium should be used in combination with other conventional heart failure therapies.

Effect on the CNS.

Animal experiments have demonstrated the anti-hypoxic effects of meldonium and its influence on cerebral circulation. Meldonium optimizes redistribution of cerebral blood flow in favor of ischemic areas and increases neuronal resistance under hypoxic conditions.

Meldonium has stimulant effects on the CNS: increased motor activity and physical endurance, stimulation of behavioral responses, as well as anti-stress effects: stimulation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, and protection of internal organs from stress-induced changes.

Efficacy in neurological disorders.

It has been proven that meldonium is an effective agent in the complex therapy of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulatory insufficiency). Meldonium normalizes the tone and resistance of cerebral capillaries and arterioles and restores their reactivity.

The effect of meldonium on the rehabilitation process in patients with neurological impairments (after cerebrovascular diseases, brain surgery, trauma, or tick-borne encephalitis) has been studied.

Results of evaluating meldonium's therapeutic activity indicate its dose-dependent positive effect on physical endurance and restoration of functional independence during recovery.

Analysis of changes in individual and overall intellectual functions after drug administration revealed a positive effect on the recovery process of intellectual functions during convalescence.

It has been established that meldonium improves convalescent quality of life (mainly due to restoration of physical function) and contributes to the elimination of mental disorders.

Meldonium has a positive effect on nervous system function in patients with neurological deficits during recovery.

Overall neurological status improves (reduction of brain nerve damage and reflex pathology, regression of paresis, improved motor coordination, and autonomic functions).

Pharmacokinetics.

Pharmacokinetics were studied in healthy volunteers after intravenous and oral administration of meldonium.

Absorption

Bioavailability is 100%. Maximum plasma concentration (Cmax) is achieved 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) differs after single and repeated doses of meldonium, indicating possible accumulation of meldonium in plasma.

Distribution

Meldonium rapidly distributes from the bloodstream into tissues with high cardiac affinity. Meldonium and its metabolites partially cross the placental barrier. Animal studies have shown that meldonium penetrates into breast milk.

Biotransformation

Metabolism studies in experimental animals have shown that meldonium is primarily metabolized in the liver.

Excretion

Renal excretion plays a significant role in the elimination of meldonium and its metabolites. After single intravenous doses of meldonium (250 mg, 500 mg, and 1000 mg), the initial early elimination half-life ranges from 5.56 to 6.55 hours, and the terminal elimination half-life is 15.34 hours.

Special patient groups

Elderly patients

For elderly patients with impaired liver or kidney function, in whom bioavailability is increased, the dose of meldonium should be reduced.

Renal impairment

For patients with impaired kidney function and increased bioavailability, meldonium dosage should be reduced. There is an interaction between renal reabsorption of meldonium or its metabolites (e.g., 3-hydroxymeldonium) and carnitine, resulting in increased renal clearance of carnitine. Meldonium, GBB, and the combination of meldonium and GBB have no direct effect on the renin-angiotensin-aldosterone system.

Hepatic impairment

For patients with impaired liver function and increased bioavailability, meldonium dosage should be reduced. Toxicity studies in animals showed yellow discoloration of the liver and fat denaturation when meldonium was administered at doses exceeding 100 mg/kg. Histopathological studies in animals after high doses of meldonium (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. No changes in liver function parameters were observed in humans after administration of high doses (400–800 mg). However, fat infiltration into liver cells cannot be ruled out.

Clinical characteristics.

Indications.

As part of combination therapy for the following conditions:

• Heart and vascular diseases: stable exertional angina, chronic heart failure (NYHA functional class I–III), cardiomyopathy, functional disorders of the heart and vascular system;
• Acute and chronic ischemic cerebrovascular disorders;
• Reduced work capacity, physical and psychoemotional overstrain;
• During convalescence after cerebrovascular events, head injuries, and encephalitis.

Contraindications.

Hypersensitivity to meldonium or to excipients of the medicinal product.

Increased intracranial pressure (due to impaired venous outflow, intracranial tumors).

Severe hepatic and/or renal insufficiency (insufficient safety data available).

Pregnancy or breastfeeding period.

Pediatric use (under 18 years of age).

Interaction with other medicinal products and other forms of interaction.

Meldonium may be used in combination with long-acting nitrates and other antianginal agents (for stable exertional angina), cardiac glycosides, and diuretics (for heart failure).

It may also be combined with anticoagulants, antiplatelet agents, antiarrhythmic drugs, and other agents improving microcirculation.

Meldonium may enhance the effects of drugs containing glyceryl trinitrate, nifedipine, beta-adrenoblockers, and other antihypertensive agents and peripheral vasodilators.

In patients with iron-deficiency anemia, co-administration of iron preparations and meldonium improved fatty acid composition in erythrocytes.

When meldonium is used in combination with orotic acid to counteract ischemia/reperfusion injury, an additional pharmacological effect is observed.

Meldonium helps eliminate cardiac damage caused by zidovudine (AZT) and indirectly affects oxidative stress reactions induced by AZT, which lead to mitochondrial dysfunction. The use of meldonium in combination with zidovudine or other drugs for AIDS treatment has a beneficial effect in the treatment of acquired immunodeficiency syndrome (AIDS).

In a test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazol, a pronounced anticonvulsant effect of meldonium was observed. However, when the alpha2-adrenoblocker yohimbine at a dose of 2 mg/kg and the nitric oxide synthase (NOS) inhibitor N-(G)-nitro-L-arginine at a dose of 10 mg/kg were administered prior to meldonium therapy, the anticonvulsant effect of meldonium was completely blocked.

Overdose of meldonium may enhance cardiotoxicity caused by cyclophosphamide.

Carnitine deficiency induced by meldonium may enhance cardiotoxicity caused by ifosfamide.

Meldonium exerts a protective effect against cardiotoxicity caused by indinavir and against neurotoxicity caused by efavirenz.

Do not use in combination with other products containing meldonium, as this increases the risk of adverse reactions.

Special precautions for use

Patients with mild to moderate hepatic and/or renal impairment in their medical history should use the medicinal product with caution (liver and/or kidney function should be monitored).

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

Use during pregnancy or breastfeeding

Pregnancy. Animal studies are insufficient to assess the effects of meldonium on pregnancy, embryonic/fetal development, childbirth, and postnatal development. The potential risk in humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding. Available animal study data indicate that meldonium passes into maternal milk. It is unknown whether meldonium passes into human breast milk. Risk to newborns/infants cannot be excluded; therefore, meldonium is contraindicated during breastfeeding.

Ability to influence reaction speed when driving or operating machinery

There are no data indicating a negative effect of the drug on reaction speed when driving or operating machinery.

Method of Administration and Dosage

The drug is intended for intravenous use in adults. No special preparation is required prior to administration.

Due to the possible stimulatory effect, the drug is recommended to be administered in the first half of the day.

Adults

The daily intravenous dose is 500 mg–1000 mg (5–10 mL) administered in one or two doses. The treatment duration is usually 10–14 days, after which therapy should be continued with oral dosage forms.

The total treatment course lasts 4–6 weeks. The course may be repeated 2–3 times per year.

Geriatric Patients

For elderly patients with impaired liver and/or kidney function, a reduced dose of meldonium may be required.

Patients with Renal Impairment

Since the drug is excreted via the kidneys, patients with mild to moderate renal impairment should receive a lower dose of meldonium.

Patients with Hepatic Impairment

Patients with mild to moderate hepatic impairment should receive a lower dose of meldonium.

Children

There are no data on the safety and efficacy of meldonium in children (under 18 years of age); therefore, the use of the drug in this patient population is contraindicated.

Overdose

Cases of overdose have not been reported. The drug is low in toxicity and does not cause life-threatening adverse effects.

In cases of reduced arterial pressure, headache, dizziness, tachycardia, and general weakness may occur. Symptomatic therapy is recommended.

In the event of overdose, renal and hepatic functions should be monitored.

Hemodialysis is not significantly effective in overdose due to the drug's pronounced binding to blood proteins.

Adverse reactions.

Classification of adverse reactions by frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000).

Adverse effects observed in clinical studies and during the post-marketing period:

*Adverse reactions observed in previously conducted uncontrolled clinical trials.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

5 ml of injection solution in 1 ampoule.

10 ampoules in a blister pack contained in a cardboard box.

Prescription status.

By prescription only.

Manufacturer.

JSC "Olainfarm".

Manufacturer's name and address of the place of business.

5 Rupnicu street, Olaine, LV-2114, Latvia / 5 Rupnicu street, Olaine, LV-2114, Latvia.