Mildrocard-n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MILDROCARD-N (MILDROCARD-N)

Composition:

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

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

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: transparent colourless 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 interferes with the transport of long-chain fatty acids across cell membranes, thus preventing the accumulation within cells of a potent detergent—activated forms of non-oxidized fatty acids. This helps prevent damage to cellular membranes.

Under ischemic conditions, reduced carnitine concentration leads to inhibition of fatty acid beta-oxidation, optimization of cellular oxygen consumption, stimulation of glucose oxidation, and restoration of ATP transport from its site of biosynthesis (mitochondria) to sites of utilization (cytosol). Essentially, cells are better supplied with nutrients and oxygen, and the utilization of these substances becomes more efficient.

Conversely, when biosynthesis of carnitine's precursor—i.e., GBB—increases, 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 fatty acid levels gradually increase within cells.

It is believed that the efficacy of meldonium is primarily 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 immediate precursor of carnitine—GBB ester. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring 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, 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 noted, 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, by replacing the "mediator" and promoting increased GBB concentration, meldonium triggers a 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 shown that meldonium positively affects 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 (stable angina pectoris).

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 and decreases the need for glyceryl trinitrate. Meldonium demonstrates pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, although its 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 levels and the atherogenic index.

Chronic heart failure.

In numerous clinical studies, meldonium has demonstrated its ability to increase exercise tolerance and the amount of physical work performed by patients with heart failure due to IHD.

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 enhances neuronal resistance under hypoxic conditions.

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

It has been established 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 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.

Assessment of meldonium’s therapeutic activity indicates 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 has revealed a positive impact on the recovery of intellectual functions during convalescence. Meldonium improves convalescent quality of life (primarily through restoration of physical function) and alleviates psychological disturbances.

Meldonium exerts a beneficial effect on nervous system function by 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 (C_max) is achieved immediately after administration. After intravenous administration of multiple doses, C_max reaches 25.5 ± 3.63 µg/mL.

Following intravenous administration, the area under the concentration-time curve (AUC) differs after 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.

Elimination

Renal excretion is the main route of elimination for 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 may be increased, meldonium dosage should be reduced.

Renal impairment

In patients with renal impairment and increased bioavailability, meldonium dosage 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 and increased bioavailability, meldonium dosage 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). 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 heart and vascular system activity;
• 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 available). Pediatric age. Pregnancy, breastfeeding period.

Interaction with other medicinal products and other types of interactions.

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

Meldonium may enhance the effects of drugs containing glyceryl trinitrate, nifedipine, beta-adrenoblockers, 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 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 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, a pronounced anticonvulsant effect of meldonium was observed. In turn, pretreatment with the α2-adrenoblocker 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 induced by indinavir and neurotoxic effects induced by efavirenz.

Do not use 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 mild to moderate liver and/or kidney dysfunction in their 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 is insufficient animal data available to assess the effects of meldonium on pregnancy, embryo/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. A risk to newborns/infants cannot be ruled out; therefore, meldonium is contraindicated during breastfeeding.

Ability to affect reaction rate while driving or operating machinery

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

Method of Administration and Dosage

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) intravenously per day. The dose may be administered once or divided into two doses. The usual duration of treatment is 10 – 14 days, after which therapy should be continued in 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 from the body 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 lack of data on the safety and efficacy of meldonium in children (under 18 years of age); therefore, the use of meldonium in this patient group is contraindicated.

Overdose

Cases of overdose with Mildrocard-N have not been reported. The drug is low in toxicity 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 protein binding in the blood.

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 – agitation, fear, obsessive thoughts, sleep disturbances.

Nervous system disorders: common – headache; rare – paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, presyncope, 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 – pharyngitis, 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 rash, pruritus.

Musculoskeletal and connective tissue disorders: rare – back pain, muscle weakness, muscle spasms.

Renal and urinary disorders: rare – polyuria.

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, increased heart rate, eosinophilia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Incompatibilities.

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

Packaging.

5 ml in polyethylene ampoules, pack of 10 in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "FARMASEL".

Manufacturer's address and location of its business activity.

3 Pryrizna St., Kvitneve, Brovary District, Kyiv Oblast, 07408, Ukraine