Meldin

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

Composition:

Active substance: meldonium;

1 ml of solution contains meldonium dihydrate 100 mg;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Cardiovascular agents. Other cardiac preparations. Meldonium. 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 impedes 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 delays beta-oxidation of fatty acids and optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores adenosine triphosphate (ATP) transport from its site of biosynthesis (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, and the utilization of these substances is optimized.

Conversely, increased biosynthesis of the carnitine precursor, i.e., GBB, activates NO-synthase, leading to 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 basis of meldonium’s efficacy lies in increasing cellular tolerance to metabolic stress (through modulation of 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 immediate 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 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, resulting in increased GBB-ether concentration.

As previously mentioned, meldonium is a structural analogue of GBB and can perform "mediator" functions. 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 and exhibits cardioprotective properties (including protection against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces the size of myocardial infarction.

Ischemic heart disease (IHD) (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 required amount of glyceryl trinitrate. Meldonium exerts a pronounced antiarrhythmic effect in patients with 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 levels 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 evaluated, demonstrating its ability to increase tolerance to physical exertion and enhance the amount of work performed by patients with heart failure.

A separate study conducted at cardiology institutes in Latvia and Tomsk assessed the efficacy of meldonium in heart failure of functional classes I–III according to the New York Heart Association (NYHA) classification, of moderate severity. Under meldonium therapy, 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified to 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 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.

Meldonium has a stimulatory 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 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 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 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 alleviates psychological disturbances.

Meldonium has a positive impact on nervous system function, 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 maternal 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 250 mg, 500 mg, and 1000 mg, the initial elimination half-life of meldonium 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, 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.

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 revealed yellow discoloration of the liver and fat denaturation. Histopathological studies in animals after high doses of meldonium (400 mg/kg and 1600 mg/kg) showed lipid accumulation in liver cells. No changes in liver function parameters were observed in humans after administration of high doses (400–800 mg). However, 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 disorders:

• 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 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 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-adrenoblockers, and other antihypertensive agents and peripheral vasodilators.

In patients with iron-deficiency anemia, co-administration of iron-containing 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 managing acquired immunodeficiency syndrome (AIDS).

In a test assessing ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazole, meldonium demonstrated pronounced anticonvulsant activity. However, pretreatment with 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 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 in combination 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 impairment and/or history of renal dysfunction (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 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 excluded; therefore, meldonium is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted to assess the effect of meldonium on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Intravenous. The use of the drug does not require special preparation 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 as a single dose or divided into two doses. The treatment duration usually lasts 10–14 days, after which therapy should be continued with the oral dosage form.

The total course duration is 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 a lack of data on the safety and efficacy of meldonium in children (under 18 years of age); therefore, its use 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 low blood pressure, 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, < 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, 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 — 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, 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*.

* Adverse reactions observed in previously conducted uncontrolled clinical trials.

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 its business activity.

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