Ml-card

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ML-CARD

Composition:

Active substance:

1 ml of solution contains meldonium dihydrate (meldonium) – 100 mg;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physico-chemical 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. As a result, it hinders the transport of long-chain fatty acids across cell membranes, thus preventing the accumulation of a strong detergent—activated forms of non-oxidized fatty acids—within cells. This mechanism helps prevent damage to cellular membranes.

Under ischemic conditions, reduced carnitine concentration leads to inhibition of fatty acid beta-oxidation, which optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores adenosine triphosphate (ATP) transport from its site of biosynthesis (mitochondria) to its site of utilization (cytosol). Essentially, cells are better supplied with nutrients and oxygen, and 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 the amount of fatty acids gradually increases within cells.

It is believed that the basis of meldonium’s efficacy lies in increasing cellular tolerance to metabolic 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 the electrical impulse, and is converted into GBB. The hydrolyzed form of GBB is then 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 concentration of GBB ester.

As previously mentioned, meldonium is a structural analogue of GBB and can perform the mediator function. 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 other systems as well, including the central nervous system (CNS).

Effect on the cardiovascular system.

Animal studies have demonstrated that meldonium positively affects myocardial contractility. It exhibits cardioprotective properties (including 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 shows that the drug reduces the frequency and intensity of angina attacks, as well as the amount of nitroglycerin used. The drug exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while a milder 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.

In numerous clinical studies, the role of meldonium in the treatment of chronic heart failure due to IHD has been analyzed, and its ability to increase tolerance to physical exertion and the amount of work performed by patients with heart failure has been noted.

A separate study conducted at cardiology institutes in Latvia and Tomsk evaluated the efficacy of meldonium in heart failure of functional classes I–III according to the New York Heart Association (NYHA) classification, with moderate severity. Under meldonium therapy, 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified into NYHA 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 antihypoxic effect of meldonium 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 stimulating effect on the CNS—increasing motor activity and physical endurance, stimulating behavioral responses, and exerting an anti-stress effect—by stimulating the sympathoadrenal system, increasing catecholamine accumulation in the brain and adrenal glands, and protecting 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 capillary and arteriolar tone and resistance in the brain 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 therapeutic activity assessments indicate a dose-dependent positive effect 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 (primarily due to restoration of physical function) and eliminates psychological disturbances.

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

The overall neurological status of patients improves (reduced 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 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 maternal 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. After single intravenous doses of meldonium at 250 mg, 500 mg, and 1000 mg, the initial elimination half-life ranges from 5.56 to 6.55 hours, while the terminal half-life is 15.34 hours.

Special patient groups

Elderly patients

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

Renal impairment

In patients with impaired renal function 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, leading to 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 rats administered meldonium at doses exceeding 100 mg/kg showed yellow discoloration of the liver and fat denaturation. Histopathological studies in animals after administration of high meldonium doses (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. Changes in liver function parameters were not observed in humans after administration of high doses (400–800 mg). However, 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, use of the drug in this patient group is contraindicated.

Clinical characteristics.

Indications.

In complex therapy of the following conditions:

• cardiovascular 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 disorders of cerebral circulation;
• reduced work capacity, physical and psychoemotional overstrain;
• during convalescence period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium and/or to any of the 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).

Interaction with other medicinal products and other forms of interactions.

Meldonium may be used concomitantly with prolonged-action 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-adrenergic blockers, 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-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 that lead to mitochondrial dysfunction. The use of meldonium in combination with AZT or other drugs for treatment of acquired immunodeficiency syndrome (AIDS) has a positive impact in the management of 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, 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.

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 induced by indinavir and neurotoxic effects induced by efavirenz.

Do not use the drug concomitantly 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 a history of mild to moderate hepatic and/or renal impairment (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 meldonium on pregnancy, embryo/fetal development, parturition, and postnatal development. The potential risk to humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding period

Available animal data indicate that meldonium passes into maternal 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 affect reaction rate while driving or operating machinery.

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

Method of Administration and Dosage

Administered intravenously. No special preparation of the drug is required prior to administration.

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) administered intravenously either as a single dose or divided into two doses. The duration of treatment is usually 10–14 days, after which treatment 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 lower dose of meldonium.

Children

There is a lack of safety and efficacy data regarding the use of meldonium in children (under 18 years of age); therefore, meldonium is contraindicated in this patient population.

Overdose

No cases of meldonium overdose have been reported. The drug is low in toxicity and does not produce life-threatening adverse effects.

In cases of lowered 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 meldonium overdose due to the drug's pronounced protein binding.

Adverse reactions

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

2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach of children.

Packaging.

5 ml in ampoules made of colorless transparent glass.

5 or 10 ampoules per pack; 5 ampoules in a blister, 1 or 2 blisters per pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "BIOLIK PHARMA".

Manufacturer's location and address of its business activity.

Legal entity location:

70 Pomyrky, Kharkiv, Kharkiv region, 61070, Ukraine.

Address of the place of business activity:

Pomyrky-70, building b/n, Kharkiv, Kharkiv region, 61070, Ukraine.

Date of last review.