Vazonat

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VASONAT® (VAZONAT)

Composition:

Active substance: meldonium dihydrate (meldonium);

1 capsule contains meldonium dihydrate 250 mg;

Excipients: potato starch, colloidal anhydrous silicon dioxide, calcium stearate; capsule shell: titanium dioxide (E 171), gelatin.

Pharmaceutical form. Capsules.

Main physico-chemical properties: hard gelatin capsules size №1, white/white, containing white or almost white powder.

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 effects on the body can be explained in two ways.

1. Influence on Carnitine Biosynthesis

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis. As a result, it interferes with the transport of long-chain fatty acids across cell membranes, thus preventing the accumulation of strong detergents — activated forms of non-oxidized fatty acids — within cells. This mechanism helps prevent damage to cellular membranes.

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

Conversely, increased biosynthesis of carnitine’s precursor — GBB — activates nitric oxide (NO) synthase, improving blood rheological properties and reducing peripheral vascular resistance.

When meldonium concentration decreases, carnitine biosynthesis resumes and gradually increases fatty acid levels within cells.

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

2. Mediator Function in the Hypothetical GBB-ergic System

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

When carnitine concentration decreases, GBB synthesis is stimulated, increasing GBB ester concentration.

As previously mentioned, meldonium is a structural analogue of GBB and can act as a "mediator." In contrast, GBB hydroxylase does not recognize meldonium, so carnitine concentration does not increase but decreases. Thus, meldonium — both by replacing the "mediator" and by increasing 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).

Effects on the CNS

Animal studies have demonstrated meldonium’s anti-hypoxic effects and its ability to improve cerebral blood flow. Meldonium optimizes redistribution of cerebral blood flow in favor of ischemic areas and enhances neuronal resistance under hypoxic conditions.

Meldonium exerts a stimulatory effect on the CNS — increasing motor activity and physical endurance, stimulating behavioral responses, and demonstrating anti-stress activity — by activating the sympathoadrenal system, increasing catecholamine accumulation in the brain and adrenal glands, and protecting internal organs from stress-induced changes.

Efficacy in Neurological Disorders

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

Therapeutic activity studies of meldonium indicate its dose-dependent positive effects on physical endurance and restoration of functional independence during recovery.

Analysis of individual and overall intellectual functions after meldonium administration revealed a positive impact on the recovery of intellectual functions during convalescence.

Meldonium has been shown to improve convalescent quality of life (mainly by restoring physical function) and helps eliminate psychological disturbances.

Meldonium exerts a beneficial effect on nervous system function — reducing neurological deficits during recovery.

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

When added to the basic therapy of non-alcoholic steatohepatitis and toxic hepatitis, meldonium reduces gamma-glutamyltransferase levels by more than 1.5 times. It reduces hepatic inflammatory activity and the severity of cytolytic and cholestatic syndromes. Meldonium demonstrates reparative properties, evidenced by a rapid reduction in liver size. Additionally, meldonium exerts a metabolic effect, leading to normalization of fasting glycemia.

Pharmacokinetics

Absorption

After a single oral administration of meldonium at doses of 25, 50, 100, 200, 400, 800, or 150 mg, maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) increase proportionally to the administered dose. Time to reach maximum plasma concentration (tmax) is 1–2 hours. With repeated dosing, steady-state plasma concentration is achieved within 72–96 hours after the first dose. Meldonium accumulation in plasma is possible. Food slightly delays absorption but does not alter Cmax and AUC values.

Distribution

Meldonium rapidly distributes from the bloodstream into tissues. Plasma protein binding increases over time after dose administration. Meldonium and its metabolites partially cross the placental barrier. Animal studies have confirmed that meldonium passes into breast milk.

Biotransformation

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

Elimination

Renal excretion plays a significant role in the elimination of meldonium and its metabolites. The elimination half-life (t1/2) of meldonium is approximately 4 hours. With repeated dosing, the half-life may differ.

Special Patient Groups

Elderly Patients

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

Renal Impairment

In patients with renal impairment and increased bioavailability, meldonium dosage should be reduced. Non-clinical studies showed that oral administration of meldonium to animals at doses of 20, 100, and 500 mg/kg is low in toxicity and does not affect kidney function. 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/GBB have no direct effect on the renin-angiotensin-aldosterone system.

Hepatic Impairment

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

Clinical characteristics.

Indications.

In complex therapy in the following cases:

• diseases of the heart and vascular system: stable angina pectoris, chronic heart failure (NYHA functional class I–III), cardiomyopathy, functional disorders of the heart and vascular system;
• acute and chronic ischemic disorders of cerebral circulation;
• during the recovery period after cerebrovascular disorders, head injuries, and encephalitis;
• as part of complex therapy for non-alcoholic steatohepatitis and toxic hepatitis;
• reduced work capacity, physical and psycho-emotional overstrain.

Contraindications.

Hypersensitivity to meldonium or to any of the excipients of the drug.

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

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

Pregnancy or breastfeeding period.

Children under 18 years of age.

Interaction with other medicinal products and other types of interactions.

The drug can be combined with prolonged-action nitrates and other antianginal agents, cardiac glycosides and diuretics, anticoagulants, antiplatelet agents, antiarrhythmic drugs, and other agents improving microcirculation.

Meldonium may enhance the effect of drugs containing glyceryl trinitrate, nifedipine, adrenergic blockers, other antihypertensive agents, and peripheral vasodilators.

When meldonium is used in combination with orotic acid to eliminate ischemia/reperfusion-induced injuries, an additional pharmacological effect is observed.

Simultaneous use of iron-containing drugs and meldonium in patients with iron-deficiency anemia improves the fatty acid composition in erythrocytes.

Meldonium helps eliminate pathological changes in the heart 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 positive effect in the treatment of acquired immunodeficiency syndrome (AIDS).

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentylentetrazole, pronounced anticonvulsant action of meldonium was demonstrated. In turn, pretreatment with the alpha2-adrenergic blocker 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 completely blocks the anticonvulsant effect of meldonium.

Overdose of meldonium may enhance cardiotoxicity caused by cyclophosphamide.

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

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

Do not use the drug together 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 should use the drug with caution (monitoring of liver and/or kidney function is recommended).

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

Due to the possible development of stimulating effects, the drug is recommended to be administered in the first half of the day.

Use during pregnancy or breastfeeding

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

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

Ability to influence reaction speed while driving or operating machinery

There are no data regarding negative effects of the drug on reaction speed while driving or operating machinery.

Method of administration and dosage.

For oral use in adults. Swallow the capsules whole with water. The drug can be taken independently of food intake.

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

Adults

The dose is 500 mg per day (2 capsules of 250 mg). The daily dose may be taken all at once or divided into two single doses. The maximum daily dose is 500 mg.

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

Elderly patients

In elderly patients with impaired liver and/or kidney function, dose reduction of meldonium may be required.

Patients with impaired kidney function

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

Patients with impaired liver function

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

For the treatment of non-alcoholic steatohepatitis and toxic hepatitis – 500 mg per day.

The treatment course lasts 30 days.

Children.

There is no experience with the use of the drug in children; therefore, its use in children (under 18 years of age) is contraindicated.

Overdose.

Cases of overdose are unknown. The drug is low in toxicity and does not cause life-threatening adverse effects.

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

In the event of overdose, kidney and liver functions should be monitored.

Hemodialysis is not significantly effective in overdose due to the pronounced protein binding of the drug.

Adverse reactions.

Adverse effects are classified by organ systems and MedDRA frequency terms: common (≥ 1/10); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000).

*Adverse effects observed in previously conducted non-controlled clinical trials.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 capsules per blister; 4 or 6 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer

JSC «Olainfarm».

Manufacturer's address and place of business.

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