Meldonium

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MELDONIUM (MELDONIUM)

Composition:

Active substance: meldonium;

1 ml of solution contains meldonium (3 -(2 ,2 ,2 -trimethylhydrazinium ) propionate dihydrate)
100 mg;

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

Excipients: sodium hydroxide, hydrochloric acid diluted, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Cardiology drugs. 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 prevents the transport of long-chain fatty acids across cellular membranes, thus avoiding the accumulation within cells of a strong detergent—activated forms of non-oxidized fatty acids. Consequently, damage to cellular membranes is prevented.

Under ischemic conditions, reduced carnitine concentration leads to delayed beta-oxidation of fatty acids, optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores 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, when biosynthesis of the carnitine precursor (i.e., GBB) increases, nitric oxide synthase (NO-synthase) is activated, resulting in improved blood rheological properties and reduced peripheral vascular resistance.

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

It is believed that the basis of meldonium’s efficacy lies in increasing cellular tolerance to metabolic stress (via modulation of 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 ether. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring an electrical impulse, and is converted into its hydrolyzed form, GBB. GBB is actively transported to the liver, kidneys, and ovaries, where it is transformed 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 ether 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 rather decreases. Thus, meldonium, by replacing the "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).

Effects on the Cardiovascular System

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

Ischemic Heart Disease (Stable Angina Pectoris)

Analysis of clinical trial data on the use of meldonium in the treatment of stable angina pectoris shows that the drug reduces the frequency and intensity of angina attacks and decreases the required dosage of glyceryl trinitrate. Meldonium exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (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 influences atherosclerotic processes in coronary and peripheral vessels by reducing total serum cholesterol and the atherogenic index.

Chronic Heart Failure

It has been established that meldonium improves myocardial inotropic function, increases exercise tolerance, and enhances patients’ quality of life, without causing severe adverse effects. In cases of severe heart failure, meldonium should be used in combination with other conventional therapeutic agents.

Effects on the CNS

Animal experiments have demonstrated meldonium’s antihypoxic 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.

The drug has CNS-stimulating properties—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 circulatory insufficiency). Meldonium normalizes capillary and arteriolar tone and resistance in the brain 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.

Therapeutic activity studies 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 of intellectual functions during convalescence.

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

Meldonium has a positive effect on nervous system function, reducing 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 (C_max) is achieved immediately after administration. After intravenous administration, C_max reaches 25.5 ± 3.63 µg/mL. The area under the plasma concentration-time curve (AUC) differs after single and repeated intravenous doses, 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.

Biological Transformation

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. After single intravenous doses of 250 mg, 500 mg, and 1000 mg, the elimination half-life ranges from 5.56 to 6.55 hours, and the terminal elimination period 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 renal impairment and increased bioavailability, 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 (RAAS).

Hepatic Impairment

In patients with impaired liver function and increased bioavailability, 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 hepatocytes. No changes in liver function parameters have been observed in humans after administration of high doses (400–800 mg). However, fat infiltration of 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 after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium 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);
• pregnancy or breastfeeding;
• pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interaction.

Meldonium can be used concomitantly with prolonged-action nitrates and other antianginal agents (for stable exertional angina), cardiac glycosides, and diuretics (for heart failure). It can 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-blockers, and other hypotensive agents and peripheral vasodilators.

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

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

Meldonium helps eliminate cardiac alterations 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 AZT or other drugs for AIDS treatment has a beneficial 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 pentetrazol, a pronounced anticonvulsant effect of meldonium was observed. 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 exerts protective effects against cardiotoxicity caused by indinavir and neurotoxic effects caused by efavirenz.

Do not use together with other products containing meldonium, as this may increase the risk of adverse reactions.

Special precautions for use.

Caution should be exercised when administering the drug to patients with mild or moderate severity hepatic and/or renal dysfunction in medical history (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 are insufficient animal studies 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 study data indicate that meldonium passes into breast milk. It is unknown whether meldonium passes into human breast milk. Risk to newborns/infants cannot be ruled out; therefore, meldonium is contraindicated during breastfeeding.

Ability to influence reaction rate while driving or operating machinery.

No studies on the effect on the ability to drive or operate machinery have been conducted.

Dosage and Administration

Administer intravenously. No special preparation of the drug prior to administration is required. Due to the possible stimulating effect, the drug is recommended to be administered in the first half of the day.

Adults

The dose is 500–1000 mg (5–10 ml) per day, administered once 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 treatment course 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 meldonium.

Patients with Renal Impairment

Since the drug is eliminated 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 reduced dose of meldonium.

Children

There is no safety and efficacy data available for the use of meldonium in children (under 18 years of age). Therefore, meldonium is contraindicated in this patient population.

Overdose

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

In cases of low blood pressure, headache, dizziness, tachycardia, and general weakness may occur. Treatment is symptomatic.

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

Hemodialysis is not significantly effective in meldonium overdose due to extensive protein binding in the blood.

Adverse reactions.

Adverse effects are classified according to system organ classes and MedDRA frequency terms: common (> 1/100 to < 1/10), rare (> 1/10000 to < 1/1000).

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

* Adverse effects observed in previously conducted uncontrolled clinical trials.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 ºС in the original packaging. Do not freeze. Keep out of reach of children.

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of its business activities.

108, Kobzarska St., Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.