Vasonat®

INSTRUCTIONS for medical use of the medicinal product VAZONAT® (VAZONAT®)

Composition:

Active substance: meldonium dihydrate (meldonium);

1 capsule contains meldonium dihydrate 500 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 white/white gelatin capsules size 00, containing a 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 the biosynthesis of carnitine. 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 the utilization of these substances is optimized.

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

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

It is believed that the efficacy of meldonium is based on enhanced 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, responsible for transmitting nerve impulses between cells. The mediator of this system is the final precursor of carnitine—GBB ester. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transmitting an electrical impulse, and itself converts 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, leading to increased GBB ester concentration.

As previously mentioned, meldonium is a structural analogue of GBB and can act as a "mediator." However, GBB hydroxylase does not recognize meldonium, so carnitine concentration does not increase but rather decreases. Thus, meldonium, both by replacing the "mediator" and promoting increased GBB concentration, triggers a corresponding physiological response. As a result, overall metabolic activity increases in other systems as well, such as the central nervous system (CNS).

Effects on the CNS

In animal studies, meldonium has demonstrated anti-hypoxic effects and improved cerebral circulation. It optimizes redistribution of cerebral blood flow in favor of ischemic areas and enhances neuronal resistance under hypoxic conditions.

Meldonium has stimulatory effects on the CNS, including increased motor activity and physical endurance, stimulation of behavioral responses, and anti-stress effects—activation 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

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

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

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

It has been established that meldonium improves convalescent quality of life (primarily due to restoration of physical function) and helps eliminate psychological disturbances.

Meldonium exerts a positive influence on nervous system function—reducing neurological deficits during recovery.

Overall neurological status improves in patients (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 inflammatory activity in the liver and the severity of cytolytic and cholestatic syndromes. It exhibits reparative properties, manifested 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 dose of meldonium at 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. Accumulation of meldonium in plasma is possible. Food slightly delays absorption but does not alter Cmax or AUC values.

Distribution

Meldonium rapidly distributes from the bloodstream into tissues. Plasma protein binding increases over time after dosing. Meldonium and its metabolites partially cross the placental barrier. Animal studies have confirmed 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. The elimination half-life (t1/2) of meldonium is approximately 4 hours. The half-life may differ with repeated dosing.

Special Patient Groups

Elderly Patients

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

Renal Impairment

In patients with renal impairment and increased bioavailability, the dose of meldonium 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, the dose of meldonium should be reduced. Toxicity studies in animals showed yellow discoloration of the liver and fat denaturation 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 high doses (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 exertional angina, chronic heart failure (NYHA functional class I–III), cardiomyopathy, functional disorders of heart and vascular system activity;
• acute and chronic ischemic disorders of cerebral circulation;
• during convalescence 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 psychoemotional overstrain.

Contraindications.

Hypersensitivity to meldonium or to excipients of the drug.

Increased intracranial pressure (in case of impaired venous outflow, intracranial tumors).

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

Pregnancy or breastfeeding period.

Children and adolescents (under 18 years of age).

Interaction with other medicinal products and other forms of interaction.

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.

The drug may enhance the effect of agents 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 damage, an additional pharmacological effect is observed.

As a result of concomitant administration of iron-containing drugs and meldonium in patients with iron-deficiency anemia, improvement in fatty acid composition in erythrocytes was observed.

Meldonium helps eliminate cardiac abnormalities 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 the treatment of AIDS has a positive effect in the management of acquired immunodeficiency syndrome (AIDS).

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazole, pronounced anticonvulsant action of meldonium was established. In turn, when 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 were administered prior to meldonium therapy, the anticonvulsant effect of meldonium was completely blocked.

Meldonium overdose may enhance cardiotoxicity caused by cyclophosphamide.

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

Meldonium exerts protective effects 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 the treatment of 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 evaluate 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. Animal data indicate that meldonium passes into maternal milk. It is unknown whether meldonium is excreted in human breast milk. A risk to newborns/infants cannot be ruled out; therefore, meldonium is contraindicated during breastfeeding.

Ability to influence reaction rate while driving or operating machinery.

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

Method of Administration and Dosage

For oral use in adults. The capsule should be swallowed whole with water. Due to the possible stimulating effect, the drug is recommended to be taken in the first half of the day.

Adults

The dose is 500 mg–1000 mg per day. The total daily dose may be administered once or divided into two doses.

The 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 by 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.

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

The treatment course lasts 30 days.

Children.

Experience with the use of the drug in children is lacking; therefore, its use in children (under 18 years of age) 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 hypotension, headache, dizziness, tachycardia, and general weakness may occur. Symptomatic therapy is recommended.

In case of overdose, renal and hepatic 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 (≥1/100 to <1/10), rare (≥1/10,000 to <1/100), very rare (<1/10,000).

* Adverse effects observed in previously conducted uncontrolled clinical trials.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

6 capsules per blister pack.

5 or 10 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.