Miocard

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

Composition:

Active substance: meldonium;

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

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Agents affecting the cardiovascular system.

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 prevents the transport of long-chain fatty acids across cell membranes, thus avoiding the accumulation of a potent detergent—activated forms of non-oxidized fatty acids—within cells. Consequently, cellular membrane damage is prevented.

Under ischemic conditions, reduced carnitine concentration leads to delayed beta-oxidation of fatty acids, optimized cellular oxygen consumption, stimulation of glucose oxidation, and restoration of ATP transport from its site of biosynthesis (mitochondria) to its site of utilization (cytosol). Essentially, cells are provided with nutrients and oxygen, and the utilization of these substances is optimized.

In turn, when biosynthesis of the carnitine precursor—i.e., GBB—is increased, nitric oxide (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 within cells.

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

1. Mediator function in the hypothetical GBB-ergic system.

A hypothesis has been proposed that a neuronal signaling transmission system—the GBB-ergic system—exists in the body, responsible for transmitting nerve impulses between cells. The mediator of this system is the last precursor of carnitine—GBB ether. Under the action of GBB esterase, the mediator transfers an electron to the cell, thereby transmitting an 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, in response to stimulation, new GBB molecules are synthesized, ensuring signal propagation.

When carnitine concentration decreases, GBB synthesis is stimulated, leading to increased concentration of GBB ether.

As previously noted, meldonium is a structural analogue of GBB and can perform the function of a "mediator." In contrast, GBB hydroxylase does not recognize meldonium, so carnitine concentration does not increase but decreases. Thus, meldonium, by replacing the "mediator" and promoting increased GBB concentration, induces the corresponding physiological response. As a result, overall metabolic activity increases in other systems as well, for example, in the central nervous system (CNS).

Effect on the cardiovascular system.

Animal studies have shown that meldonium exerts a positive effect on myocardial contractility. It possesses cardioprotective properties (including protection 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 has shown that the drug reduces the frequency and intensity of angina attacks, as well as the amount of nitroglycerin used. The drug demonstrates pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, although the effect is less pronounced 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 a relatively large number of 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.

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.

The drug has a stimulatory effect on the CNS: increased motor activity and physical endurance, stimulation of behavioral responses, and anti-stress action—stimulation 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.

It has been demonstrated that meldonium is an effective agent 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 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 evaluating the therapeutic activity of meldonium indicate its dose-dependent positive effect on physical endurance and restoration of functional independence during recovery.

Analysis of changes in individual and overall intellectual functions after administration of the drug revealed a positive effect on the recovery process of intellectual functions during convalescence. Meldonium has been shown to improve convalescent quality of life (mainly due to restoration of physical function), and it also alleviates psychological disturbances.

Meldonium has a positive effect on nervous system function: it reduces neurological deficits during recovery.

The overall neurological status of patients 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 (Cmax) is achieved immediately after administration. After intravenous administration of multiple doses, Cmax reaches 25.5 ± 3.63 mcg/mL.

After intravenous administration, the area under the concentration-time curve (AUC) differs after single and repeated 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.

Biotransformation

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

Excretion

Renal excretion is important for elimination of meldonium and its metabolites. After single intravenous doses of meldonium (250 mg, 500 mg, and 1000 mg), the early elimination half-life ranges from 5.56 to 6.55 hours, and 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 is increased, the dose of meldonium should be reduced.

Renal impairment

In patients with impaired renal function, where bioavailability is 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 (RAAS).

Hepatic impairment

In patients with impaired liver function, where bioavailability is 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 administration of high doses of meldonium (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 administration of high doses (400–800 mg). Nevertheless, lipid 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:

• cardiovascular diseases: stable exertional angina, chronic heart failure (NYHA functional classes 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, increased intracranial pressure (due to impaired venous outflow, intracranial tumors), severe hepatic and/or renal insufficiency (insufficient safety data). Pediatric age. Pregnancy or lactation period.

Interaction with other medicinal products and other forms of interaction.

Meldonium may be used concomitantly with prolonged-action nitrates and other antianginal agents (for stable exertional angina), cardiac glycosides, and diuretics (in heart failure). It may also be combined with anticoagulants, antiplatelet agents, antiarrhythmic drugs, and other agents improving microcirculation.

Meldonium may enhance the effect 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-containing preparations 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 damage 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 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 pentetrazole, meldonium demonstrated pronounced anticonvulsant activity. However, when the α2-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 a protective effect against cardiotoxicity caused by indinavir and neurotoxicity caused by efavirenz.

Do not use together with other preparations containing meldonium, as this may increase 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.

Use during pregnancy or breastfeeding.

Pregnancy.

There is insufficient animal data available to assess the effects of meldonium on pregnancy, embryonic/fetal development, delivery, 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 breast 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 affect reaction rate while driving or operating machinery.

Studies on the influence of meldonium on the ability to drive vehicles or operate machinery have not been conducted.

Method of administration and dosage.

Administer intravenously. The preparation of the drug prior to administration does not require special procedures. 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. The dose may be 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 course of treatment lasts 4–6 weeks. The treatment course may be repeated 2–3 times per year.

Elderly patients

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

Patients with renal impairment

Since the drug is excreted through 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 are no data on the safety and efficacy of meldonium in children (under 18 years of age); therefore, the use of meldonium is contraindicated in this patient population.

Overdose.

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

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

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

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

Adverse reactions.

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

Immune system disorders:

common – allergic reactions;

rare – hypersensitivity, including allergic dermatitis, urticaria, angioedema; anaphylactic reactions up to shock.

Psychiatric disorders:

rare – excitement, fear, obsessive thoughts, sleep disturbances.

Nervous system disorders:

common – headache;

rare – paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, syncope.

Cardiac disorders:

rare – change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain.

Vascular disorders:

rare – increased/decreased blood pressure, hypertensive crisis, hyperemia, pallor.

Respiratory, thoracic and mediastinal disorders:

common – respiratory tract infections;

rare – throat inflammation, cough, dyspnea, apnea.

Gastrointestinal disorders:

common – dyspepsia;

rare – dysgeusia (metallic taste in mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth, hypersalivation.

Skin and subcutaneous tissue disorders:

rare – rash, generalized/maculopapular/papular eruptions, pruritus.

Musculoskeletal and connective tissue disorders:

rare – back pain, muscle weakness, muscle spasms.

Renal and urinary disorders:

rare – pollakiuria.

General disorders and administration site conditions:

rare – general weakness, chills, asthenia, edema, facial swelling, leg swelling, feeling of warmth, feeling of cold, cold sweat, injection site reactions, including pain at injection site.

Investigations:

common – dyslipidemia, increased C-reactive protein level;

rare – electrocardiogram (ECG) abnormalities, tachycardia, eosinophilia.

Shelf life. 3 years.

Storage conditions. Store in original packaging at temperature not exceeding 25 ºC.

Do not freeze. Keep out of reach of children.

Incompatibilities.

Unknown. The medicinal product should not be mixed in the same syringe with other medicinal products.

Packaging. 5 ml in glass ampoules No. 10 (5x2) in blisters in a cardboard pack.

Prescription category. Prescription only.

Manufacturer.

LLC "FARMASEL".

Manufacturer's address and place of business.

3, Prorizna Street, Kvitneve, Brovary District, Kyiv Region, 07408, Ukraine.