Metonat

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

Composition:

Active substance: metonat (3-(2,2,2-trimethylhydrazinium) propionate dihydrate);

5 ml of solution (1 ampoule) contains 500 mg of metonat (3-(2,2,2-trimethylhydrazinium) propionate dihydrate);

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Other cardiac preparations. ATC code C01EB22.

Pharmacological Properties.

Pharmacodynamics.

Meldonium (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) 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. Effect on Carnitine Biosynthesis

Meldonium (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis. As a result, it interferes with the transport of long-chain fatty acids across cellular 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 slows down fatty acid beta-oxidation, optimizes oxygen consumption in cells, stimulates glucose oxidation, and restores 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 becomes more efficient.

On the other hand, increased biosynthesis of the carnitine precursor, i.e., GBB, activates NO-synthase, leading to improved blood rheological properties and reduced peripheral vascular resistance.

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

It is believed that the efficacy of meldonium is primarily based on increasing cellular tolerance to metabolic stress (associated with changes in fatty acid levels).

1. 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 immediate precursor of carnitine—GBB ether. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring an electrical impulse and transforming 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, new GBB molecules are synthesized in response to stimulation, ensuring signal propagation.

When carnitine concentration decreases, GBB synthesis is stimulated, increasing the concentration of GBB ether.

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

Effects on the Cardiovascular System

Animal studies have demonstrated that meldonium positively influences myocardial contractility and exhibits cardioprotective properties (including protection against catecholamines and alcohol). It can prevent cardiac arrhythmias and reduce the size of myocardial infarction.

Ischemic Heart Disease (IHD) (Stable Angina Pectoris)

Analysis of clinical data on the course treatment of meldonium in patients with stable exertional angina shows that the drug reduces the frequency and intensity of angina attacks, as well as the need for glyceryl trinitrate. The drug exerts a pronounced antiarrhythmic effect in patients with IHD and ventricular extrasystoles, while a weaker effect is observed 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 by reducing total serum cholesterol and the atherogenic index.

Chronic Heart Failure

In a number of clinical studies, the role of meldonium in treating chronic heart failure due to IHD has been evaluated, demonstrating its ability to increase tolerance to physical exertion and improve 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 was tested in patients with NYHA functional class I-III heart failure of moderate severity. Under meldonium therapy, 59–78% of patients initially diagnosed with functional class II heart failure were reclassified into functional class I. It has been established that meldonium improves myocardial inotropic function, increases tolerance to physical exertion, enhances quality of life, and does not cause severe adverse effects.

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

Effects on the CNS

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

Meldonium has a stimulatory effect on the CNS—increasing motor activity and physical endurance, stimulating behavioral responses, and exerting anti-stress effects—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

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

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

Results of therapeutic activity assessments indicate dose-dependent positive effects of meldonium 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 alleviates psychological disturbances.

Meldonium has a positive effect on nervous system function, reducing neurological deficits during recovery.

Overall neurological status improves (reduction in 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.

Following intravenous administration, the area under the concentration-time curve (AUC) differs between single and repeated doses, indicating potential 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 250 mg, 500 mg, and 1000 mg, the early elimination half-life of meldonium ranges from 5.56 to 6.55 hours, while the terminal elimination half-life is 15.34 hours.

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 impaired renal function, where bioavailability may be increased, the dose of meldonium 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/GBB have no direct effect on the renin-angiotensin-aldosterone system.

Hepatic Impairment

In patients with impaired liver function, where bioavailability may be increased, the dose of meldonium should be reduced. Toxicity studies in rats administered meldonium at doses exceeding 100 mg/kg showed 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 liver cells. However, no changes in liver function parameters were observed in humans after high-dose administration (400–800 mg). Nevertheless, possible fat infiltration into liver cells cannot be ruled out.

Children

There are no data on the safety and efficacy of Meldonium**®** in children under 18 years of age; therefore, its use in this patient group is contraindicated.

Clinical characteristics.

Indications.

In complex therapy of the following conditions:

• diseases of the heart and vascular system: stable exertional angina, 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;
• reduced work capacity, physical and psycho-emotional overstrain;
• during convalescence period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to Metonat**®** and/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).

Interaction with other medicinal products and other types of interactions.

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

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

Metonat may enhance the effect of drugs containing glyceryl trinitrate, nifedipine, beta-blockers, and other antihypertensive agents and peripheral vasodilators.

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

When Metonat is used in combination with orotic acid to counteract ischemia/reperfusion-induced damage, an additional pharmacological effect is observed.

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

In the test of ethanol-induced loss of righting reflex, Metonat reduced sleep duration. In seizures induced by pentylentetrazole, a pronounced anticonvulsant effect of Metonat was observed. However, 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 Metonat therapy, the anticonvulsant effect of Metonat was completely blocked.

Overdose of Metonat may enhance cardiotoxicity caused by cyclophosphamide.

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

Metonat exerts a protective effect against cardiotoxicity caused by indinavir and neurotoxic effects caused by efavirenz.

Metonat should not be used concomitantly with other medicinal products containing meldonium, as this may increase the risk of adverse reactions.

Special precautions.

Patients with mild to moderate hepatic impairment and/or a history of renal dysfunction should use the drug with caution (liver and/or kidney function should be monitored). 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.

Use during pregnancy or breastfeeding.

Pregnancy

There is insufficient animal data available to assess the effects of metonate on pregnancy, embryo/fetal development, labor, and postnatal development. The potential risk to humans is unknown; therefore, metonate is contraindicated during pregnancy.

Breastfeeding period

Available animal data indicate that metonate is excreted into maternal milk. It is unknown whether metonate passes into human breast milk. A risk to newborns/infants cannot be ruled out; therefore, metonate is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Studies evaluating the effect of metonate on the ability to drive or operate machinery have not been conducted.

Method of Administration and Dosage

Intravenous use. The preparation of the drug prior to administration is not required.

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

Adults

The dose is 500–1000 mg (5–10 mL), administered intravenously either as a single dose or divided into two doses. The treatment duration is usually 10–14 days, after which therapy should be continued with an oral dosage form.

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

Elderly Patients

Elderly patients with impaired liver and/or kidney function may require a reduced dose of metonate.

Patients with Renal Impairment

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

Patients with Hepatic Impairment

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

Children

There is a lack of data on the safety and efficacy of metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) in children under 18 years of age; therefore, the use of metonate in this patient population is contraindicated.

Overdose

There have been no reported cases of metonate overdose. The drug is low in toxicity and does not cause life-threatening adverse effects.

In cases of reduced arterial pressure, symptoms such as headache, dizziness, tachycardia, and general weakness may occur. Treatment is symptomatic.

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

Hemodialysis is not significantly effective in metonate overdose due to its pronounced binding to blood proteins.

Adverse reactions.

Adverse reactions are classified by organ systems and MedDRA frequency: common (≥1/100, <1/10), rare (≥1/10,000, <1/1,000).

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

* Adverse reactions observed in previously conducted uncontrolled clinical trials.

Shelf life.

4 years.

Storage conditions.

Store at a temperature not exceeding 25 °C, in a place inaccessible to children.

Do not freeze.

Incompatibility. Metonat® solution should not be mixed in the same syringe with other drugs.

Packaging.

5 ml in vials, 5 vials in a single-sided blister pack, 2 blisters per cardboard box.

Prescription status.

By prescription only.

Manufacturer.

JSC "Lekhym-Kharkiv" (responsible for manufacturing, primary and secondary packaging, batch control and testing, excluding batch release)

LLC "FC "SALYUTARIS" (responsible for batch release, excluding batch control and testing)

Manufacturer's address and location of operations.

JSC "Lekhym-Kharkiv": Ukraine, 61115, Kharkiv region, city of Kharkiv, Severina Pototskogo Street, 36.

LLC "FC "SALYUTARIS": Ukraine, 04071, Kyiv, Verkhniy Val Street, 66-B.

Marketing Authorization Holder.

LLC "FC "SALYUTARIS".

Address of the Marketing Authorization Holder.

Ukraine, 57453, Mykolaiv region, Mykolaiv district, Koblevе village, Odeska Street, 4.