Metamax

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

Composition:

Active substance: meldonium dihydrate;

1 ml of solution contains meldonium dihydrate 100 mg;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

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.

Influence on carnitine biosynthesis.

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis and consequently preventing the transport of long-chain fatty acids across cell membranes. Thus, meldonium prevents the accumulation within cells of a strong detergent — activated forms of non-oxidized fatty acids. In this way, meldonium protects cellular membranes from damage.

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 sites of its biosynthesis (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, and utilization of these substances is optimized.

In turn, increased biosynthesis of the carnitine precursor, i.e. GBB, activates NO-synthase, resulting in improved blood rheological properties and reduced peripheral vascular resistance.

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

Function as a mediator 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 last carnitine precursor — 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 converted 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 mentioned, 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 rather decreases. Thus, meldonium, by replacing the "mediator" and promoting increased GBB concentration, triggers a corresponding response in the body. 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 positively affects myocardial contractility. It has cardioprotective properties (particularly 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 showed 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, 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 affects atherosclerotic processes in coronary and peripheral vessels by reducing total serum cholesterol and the atherogenic index.

Chronic heart failure.

Numerous clinical studies have analyzed the role of meldonium in the treatment of chronic heart failure due to IHD, noting its ability to increase tolerance to physical exertion and the amount of work performed by patients with heart failure.

A study conducted at cardiology institutes in Latvia and Tomsk evaluated the efficacy of meldonium in moderate-severity chronic heart failure classified as functional class I–III according to the New York Heart Association (NYHA) classification. 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified to NYHA class I after meldonium therapy. 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 action and positive 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 CNS-stimulating properties: increased motor activity and physical endurance, stimulation of behavioral responses, as well as anti-stress effects: 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 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 of intellectual functions during convalescence.

It has been established that meldonium improves the patient’s quality of life during the convalescent period (primarily due to restoration of physical function), and also eliminates psychological disturbances.

Meldonium has a positive effect on nervous system function: reduction of 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.

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 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 passes into maternal milk.

Metabolism

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 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 and/or kidney function, where bioavailability is increased, meldonium dosage should be reduced.

Renal impairment

In patients with impaired renal function, where bioavailability is increased, 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, where bioavailability is increased, meldonium dosage should be reduced. In toxicity studies in rats administered meldonium at doses exceeding 100 mg/kg, yellow discoloration of the liver and fat denaturation were observed. Histopathological studies in animals after high-dose meldonium administration (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. Changes in liver function parameters in humans after administration of high doses (400–800 mg) were not observed. However, the possibility of fat infiltration into liver cells cannot be excluded.

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:

• 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 cerebral circulation disorders;
• reduced work capacity, physical and psychoemotional 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).
• Pediatric use.
• Pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Meldonium can be used in combination with long-acting nitrates and other antianginal agents (for stable exertional angina), cardiac glycosides, and diuretic agents (for heart failure).

It can also be combined with anticoagulants, antiplatelet agents, antiarrhythmic agents, and other drugs improving microcirculation.

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

In patients with iron-deficiency anemia, co-administration of iron preparations and meldonium improved the fatty acid composition of 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 pathological changes and indirectly affects oxidative stress responses caused by azidothymidine, which lead to mitochondrial dysfunction. The use of meldonium in combination with azidothymidine or other drugs for AIDS treatment has a positive impact in the therapy of acquired immunodeficiency syndrome (AIDS).

In a 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-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 a protective effect against cardiotoxicity caused by indinavir and neurotoxicity caused by efavirenz.

Do not administer meldonium injections together with other medicinal products containing meldonium, as this increases the risk of adverse effects.

Special precautions.

If the patient has a history of hepatic and/or renal impairment, caution should be exercised when using the medicinal product (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. Animal studies are insufficient 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. 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 speed when driving or operating machinery.

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

Method of Administration and Dosage

Administer intravenously. The medicinal product does not require special preparation prior to administration. Due to the possible stimulating effect, the medicinal product is recommended to be administered in the first half of the day.

Adults.

Cardiovascular diseases; cerebrovascular disorders.

The dose is 500–1000 mg (5–10 mL) per day, administered once or divided into two doses. The maximum daily dose is 1000 mg.

Reduced work capacity, physical and psycho-emotional overstrain, and recovery period after cerebrovascular disorders, head injuries, and encephalitis.

The dose is 500 mg (5 mL) per day. The maximum daily dose is 500 mg.

The duration of treatment is usually 10–14 days, after which therapy should be continued in an oral dosage form.

Elderly patients.

Elderly patients with impaired liver and/or kidney function may require a reduced dose of meldonium.

Patients with impaired kidney function.

Since the medicinal product is eliminated from the body via the kidneys, patients with mild to moderate renal impairment should receive a lower dose of meldonium.

Patients with impaired liver function.

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 in this patient group is contraindicated.

Overdose.

There have been no reports of meldonium overdose. The medicinal product is low in toxicity and does not cause life-threatening adverse effects.

In cases of low 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 binding to blood proteins.

Adverse Reactions

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

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.

Renal and urinary disorders: rare – polyuria.

Metabolism and nutritional disorders: common – dyslipidemia, increased C-reactive protein.

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

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

Cardiac disorders: rare – palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/pain, change in heart rhythm, increased/decreased blood pressure, hypertensive crisis, hyperemia, pallor.

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

Skin and subcutaneous tissue disorders: rare – rash, generalized maculopapular rash, pruritus.

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

General disorders and administration site conditions: rare – general weakness, chills, asthenia, swelling, facial edema, leg edema, feeling of warmth, feeling of cold, cold sweat, injection site reactions, including injection site pain.

Investigations: rare – ECG abnormalities, eosinophilia.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach of children.

Incompatibilities.

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

Packaging.

5 ml in a vial; 5 vials in a blister pack; 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspylska Street, Kyiv, 02093, Ukraine.