Meldex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MELDEX (MELDEX)

Composition:

Active substance: mildronate;

1 ml of solution contains mildronate dihydrate 100 mg;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear colorless liquid.

Pharmacotherapeutic group. Agents acting on the cardiovascular system. Other cardiac preparations. Mildronate. ATC code C01EB22.

Pharmacological properties.

Pharmacodynamics.

Meldonium is a carnitine precursor 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 cellular membranes, thus preventing the accumulation of a potent detergent—activated forms of non-oxidized fatty acids—within cells. This mechanism helps prevent damage to cellular membranes.

Under ischemic conditions, reduced carnitine concentration delays beta-oxidation of fatty acids, optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores adenosine triphosphate (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 is optimized.

Conversely, when biosynthesis of the carnitine precursor—i.e., GBB—increases, nitric oxide (NO) synthase is activated, leading to improved blood rheological properties and reduced peripheral vascular resistance.

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

It is believed that the basis of meldonium’s efficacy lies in enhancing 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 signal transmission system—termed the GBB-ergic system—exists in the body, responsible for transmitting nerve impulses between cells. The mediator of this system is the final carnitine precursor—GBB ester. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring an electrical impulse and converting 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, resulting in increased GBB ester concentration.

As noted earlier, 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 other systems as well, for example, in the central nervous system (CNS).

Effect on the cardiovascular system

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

Ischemic heart disease (IHD) (stable exertional angina)

Analysis of clinical data on the course-based use of meldonium in the treatment of stable exertional angina has shown that the drug reduces the frequency and intensity of angina attacks, as well as the amount of glyceryl trinitrate used. The drug exerts a pronounced antiarrhythmic effect in patients with IHD and ventricular extrasystoles, while a lesser 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

The role of meldonium in the treatment of chronic heart failure due to IHD has been analyzed in several clinical studies, which have demonstrated its ability to increase tolerance to physical exertion and 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 evaluated in patients with mild to moderate heart failure classified as functional class I–III according to the New York Heart Association (NYHA) classification. Under meldonium therapy, 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified to class I. It has been established that meldonium improves myocardial inotropic function, increases tolerance to physical exertion, 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 heart failure therapies.

Effect 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.

The drug has a stimulating effect on the CNS—increasing motor activity and physical endurance, stimulating behavioral responses, and exerting anti-stress effects—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 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 meldonium’s therapeutic activity 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 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 also alleviates psychological disturbances.

Meldonium exerts a positive effect on nervous system function by reducing neurological deficits during recovery.

Overall neurological status improves in patients (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.

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.

Excretion

Renal excretion plays a significant role in the elimination of meldonium and its metabolites. After single intravenous doses of meldonium (250 mg, 500 mg, and 1000 mg), the initial elimination half-life 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 administration of high doses (400–800 mg). Fat infiltration into liver cells cannot be ruled out.

Children

There are no data on the safety and efficacy of meldonium use in children under 18 years of age; therefore, the use of the drug 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 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 types 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, antiarrhythmics, and other drugs improving microcirculation.

Meldonium may enhance the effects of agents containing glyceryl trinitrate, nifedipine, beta-adrenoblockers, and other antihypertensive agents and peripheral vasodilators.

In patients with iron-deficiency anemia, concomitant use 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, 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. During seizures induced by pentamethylenetetrazole, a pronounced anticonvulsant effect of meldonium was observed. However, when the alpha2-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 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 together with other medicinal 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 hepatic and/or renal impairment in medical history (monitoring of liver and/or kidney function is recommended). 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, labor, 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 excluded; therefore, meldonium is contraindicated during breastfeeding.

Ability to influence reaction rate while driving or operating machinery.

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

Method of Administration and Dosage

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

Due to its potential 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 as a single dose or divided into two doses. The treatment duration is usually 10–14 days, after which therapy should be continued with the 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 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

No cases of meldonium overdose have 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 the event of severe overdose, liver and kidney function should be monitored.

Hemodialysis is not significantly effective in meldonium overdose due to the drug's pronounced binding to blood proteins.

Side effects

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

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

Immune system disorders: common – allergic reactions*; rare – hypersensitivity, including allergic dermatitis, urticaria, angioneurotic edema, anaphylactic reactions up to shock.

Psychiatric disorders: rare – agitation, fear, obsessive thoughts, sleep disturbances.

Nervous system disorders: common – headache*; rare – paresthesia, tremor, hypesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, syncope.

Cardiac disorders: rare – heart rhythm changes, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain.

Vascular system 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 or 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 – polyuria.

General disorders and administration site conditions: rare – general weakness, chills, asthenia, swelling, 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*.

* Adverse reactions observed in previously conducted uncontrolled clinical trials.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Packaging. 5 mL in glass vials; 5 vials in a blister pack; 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and location of business activity.

84A Nemirivske Highway, Vinnytski Khutory Village, Vinnytsia District, Vinnytsia Oblast, 23219, Ukraine.