Instructions Metamax solution for injection 10% ampoule 5 ml No. 10
Composition
active ingredient: meldonium dihydrate;
1 ml of solution contains meldonium dihydrate 100 mg;
excipient: water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: clear colorless liquid.
Pharmacotherapeutic group
Other cardiological drugs. Meldonium. ATC code C01EB22.
Pharmacological properties
Pharmacodynamics.
Meldonium is a precursor of carnitine, a structural analogue of gamma-butyrobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom. Its effect on the body can be explained in two ways.
Effect on carnitine biosynthesis.
Meldonium, by reversibly inhibiting gamma-butyrobetaine hydroxylase, reduces carnitine biosynthesis and therefore prevents the transport of long-chain fatty acids through cell membranes, thus preventing the accumulation of a strong detergent in cells - activated forms of unoxidized fatty acids. Thus, meldonium prevents damage to cell membranes.
When carnitine concentration decreases under ischemic conditions, beta-oxidation of fatty acids is inhibited and oxygen consumption in cells is optimized, glucose oxidation is stimulated and the transport of adenosine triphosphate (ATP) from its biosynthesis sites (mitochondria) to its consumption sites (cytosol) is restored. In essence, cells are supplied with nutrients and oxygen, and their consumption is optimized.
In turn, with an increase in the biosynthesis of the carnitine precursor, i.e., GBB, NO synthetase is activated, resulting in improved blood rheological properties and reduced peripheral vascular resistance.
As the concentration of meldonium decreases, carnitine biosynthesis increases again, and the amount of fatty acids in the cells gradually increases.
It is believed that the basis of the effectiveness of meldonium is increased tolerance to cellular stress (when changing the amount of fatty acids).
The function of the mediator in the hypothetical GBB-ergic system.
It is hypothesized that there is a system of neuronal signal transmission in the body – the GBB-ergic system, which ensures the transmission of nerve impulses between cells. The mediator of this system is the last precursor of carnitine – GBB-ester. As a result of the action of GBB-esterase, the mediator gives an electron to the cell, thus transferring an electrical impulse, and is converted into GBB. Then the hydrolyzed form of GBB is actively transported to the liver, kidneys and ovaries, where it is converted into carnitine. In somatic cells, in response to irritation, new GBB molecules are again synthesized, ensuring the propagation of the signal.
When the concentration of carnitine decreases, the synthesis of GBB is stimulated, resulting in an increase in the concentration of GBB ester.
Meldonium, as mentioned earlier, is a structural analogue of GBB and can perform the functions of a “mediator”. In contrast, GBB hydroxylase “does not recognize” meldonium, so the concentration of carnitine does not increase, but decreases. Thus, meldonium, replacing the “mediator” and contributing to the increase in the concentration of GBB, causes an appropriate reaction in the body. As a result, the overall metabolic activity in other systems increases, for example, in the central nervous system (CNS).
Effect on the cardiovascular system.
Animal studies have shown that meldonium has a positive effect on myocardial contractile activity, has an inherent myocardial protective effect (in particular against catecholamines and alcohol), is able to prevent heart rhythm disturbances, and reduce the area of myocardial infarction.
Ischemic heart disease (stable angina pectoris).
Analysis of clinical data on the course use of meldonium in the treatment of stable angina pectoris showed that the drug reduces the frequency and intensity of angina attacks, as well as the amount of glyceryl trinitrate used. The drug exhibits a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, a lesser effect is observed in patients with supraventricular extrasystoles.
Of particular importance is the ability of a drug to reduce resting oxygen consumption, which is considered an effective criterion for antianginal therapy of coronary artery disease.
Meldonium has a beneficial effect on atherosclerotic processes in coronary and peripheral vessels, reducing total serum cholesterol levels and the atherogenic index.
Chronic heart failure.
A study conducted at the cardiology institutes of Latvia and Tomsk studied the effectiveness of meldonium in heart failure of I-III functional class of moderate severity according to the New York Heart Association (NYHA) classification. 59-78% of patients initially diagnosed with heart failure of II functional class were transferred to the I functional class group under the influence of meldonium therapy. It was found that the use of meldonium improves the inotropic function of the myocardium and increases tolerance to physical exertion, improves the quality of life of patients, without causing severe side effects.
In case of severe heart failure, meldonium should be used in combination with other traditional heart failure therapies.
Effects on the CNS.
Animal experiments have established the antihypoxic effect of meldonium and its positive effect on cerebral blood flow. The drug optimizes the redistribution of cerebral blood flow volume in favor of the ischemic area, increases the strength of neurons in conditions of hypoxia.
The drug has a stimulating effect on the CNS: increased motor activity and physical endurance, stimulation of behavioral reactions, as well as an anti-stress effect: stimulation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, protection of internal organs from changes caused by stress.
Effectiveness in neurological diseases.
It has been proven that meldonium is an effective remedy in the complex therapy of acute and chronic disorders of cerebral circulation (ischemic stroke, chronic cerebral circulatory insufficiency). Meldonium normalizes the tone and resistance of capillaries and arterioles of the brain, restores their reactivity.
The effect of meldonium on the rehabilitation process of patients with neurological disorders (after cerebrovascular diseases, brain surgery, injuries, and tick-borne encephalitis) was studied.
The results of testing the therapeutic activity of meldonium indicate its dose-dependent positive effect on physical endurance and restoration of functional independence during the recovery period.
When analyzing changes in individual and total intellectual functions after using the drug, a positive effect on the recovery process of intellectual functions during the recovery period was established.
It has been established that meldonium improves the patient's quality of life during the convalescent period (mainly by restoring the body's physical function), and it also eliminates psychological disorders.
Meldonium has an inherent positive effect on the function of the nervous system: reducing disorders in patients with neurological deficits during the recovery period.
The general neurological condition of patients improves (reduction of damage to the nerves of the brain and reflex pathology, regression of paresis, improvement of coordination of movements and autonomic functions).
Pharmacokinetics.
Absorption
Bioavailability is 100%. The maximum concentration in the blood plasma (Cmax) is reached immediately after administration. After intravenous administration of multiple doses, Cmax reaches 25.5 ± 3.63 μg/ml.
When administered intravenously, the area under the concentration-time curve (AUC) after single and repeated doses of meldonium differs, indicating a possible accumulation of meldonium in blood plasma.
Distribution
Meldonium is rapidly distributed from the bloodstream to tissues with high cardiac affinity. Meldonium and its metabolites partially cross the placental barrier. Animal studies have shown that meldonium is excreted in breast milk.
Biotransformation
Metabolism studies in experimental animals have shown that meldonium is mainly metabolized in the liver.
Breeding
Renal excretion is important in the elimination of meldonium and its metabolites from the body. After a single intravenous administration of meldonium doses of 250 mg, 500 mg and 1000 mg, the early half-life of meldonium is 5.56−6.55 hours, the terminal half-life is 15.34 hours.
Special patient groups
Elderly patients
Elderly patients with impaired liver and/or kidney function, in whom bioavailability is increased, need to reduce the dose of meldonium.
Kidney dysfunction
Patients with impaired renal function, in whom bioavailability is increased, should reduce the dose of meldonium. 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. There is no direct effect of meldonium, GBB and the combination of meldonium/GBB on the renin-angiotensin-aldosterone system.
Liver dysfunction
Patients with impaired liver function, in whom bioavailability is increased, should reduce the dose of meldonium. In a toxicity study on rats, yellow liver coloration and fat denaturation were observed when meldonium was administered at a dose of more than 100 mg/kg. In histopathological studies on animals, lipid accumulation in liver cells was observed after administration of high doses of meldonium (400 mg/kg and 1600 mg/kg). No changes in liver function parameters were observed in humans after administration of high doses of 400-800 mg. The possibility of fat infiltration into liver cells cannot be excluded.
There is no data on the safety and effectiveness of meldonium in children (under 18 years of age), therefore the use of the drug in this category of patients is contraindicated.
Indication
In complex therapy:
- diseases of the heart and vascular system: stable angina pectoris, chronic heart failure (NYHA I−III functional class), cardiomyopathy, functional disorders of the heart and vascular system;
- acute and chronic ischemic disorders of cerebral circulation;
- reduced working capacity, physical and psycho-emotional overstrain;
- during the recovery period after cerebrovascular disorders, head injuries and encephalitis.
Contraindication
- Hypersensitivity to meldonium and/or to any of the excipients of the medicinal product.
- Increased intracranial pressure (with impaired venous outflow, intracranial tumors).
- Severe hepatic and/or renal insufficiency (insufficient data on safety of use).
- Childhood.
- Pregnancy, breastfeeding period.
Interaction with other medicinal products and other types of interactions
Meldonium can be used together with long-acting nitrates and other antianginal agents (stable exercise angina), cardiac glycosides and diuretics (heart failure).
It can also be combined with anticoagulants, antiplatelet agents, antiarrhythmics, and other drugs that improve microcirculation.
Meldonium may enhance the effects of drugs containing glyceryl trinitrate, nifedipine, β-blockers, other antihypertensives, and peripheral vasodilators.
As a result of the simultaneous use of iron and meldonium preparations in patients with anemia caused by iron deficiency, the composition of fatty acids in erythrocytes improved.
When meldonium is used in combination with orotic acid to repair damage caused by ischemia/reperfusion, an additional pharmacological effect is observed.
Meldonium helps to eliminate pathological changes in the heart and indirectly affects oxidative stress reactions that are caused by azidothymidine and lead to mitochondrial dysfunction. The use of meldonium in combination with azidothymidine or other drugs for the treatment of AIDS has a positive effect in the therapy of acquired immunodeficiency (AIDS).
In the ethanol-induced loss of balance reflex test, meldonium reduced sleep duration. During pentylenetetrazole-induced seizures, a pronounced anticonvulsant effect of meldonium was established. 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 used before meldonium therapy, the anticonvulsant effect of meldonium was completely blocked.
Meldonium overdose may enhance cardiotoxicity caused by cyclophosphamide.
Carnitine deficiency, which occurs with the use of meldonium, may increase cardiotoxicity caused by ifosfamide.
Meldonium has a protective effect against indinavir-induced cardiotoxicity and efavirenz-induced neurotoxicity.
Do not use meldonium injections together with other medications containing meldonium, as the risk of side effects increases.
Application features
If the patient has a history of liver and/or kidney dysfunction, caution should be exercised when using the drug (liver and/or kidney function should be monitored).
Many years of 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. Animal studies are insufficient to assess the effects of meldonium on pregnancy, embryonal/fetal development, parturition and subsequent development of the child. The potential risk to humans is unknown, therefore meldonium is contraindicated during pregnancy.
Breastfeeding. Available animal data indicate that meldonium is excreted in human milk. It is not known whether meldonium is excreted in human milk. A risk to the newborn/infants cannot be excluded, therefore meldonium is contraindicated during breast-feeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies to assess the effect on the ability to drive and use machines have not been conducted.
Method of administration and doses
Administer intravenously. The use of the drug does not require special preparation before administration. Due to the possible stimulating effect, the drug is recommended to be administered in the morning.
Adults.
Diseases of the heart and vascular system; cerebrovascular disorders.
The dose is 500-1000 mg (5-10 ml) per day, administered as a single dose or divided into 2 doses. The maximum daily dose is 1000 mg.
Reduced performance, physical and psycho-emotional overstrain and recovery period after cerebrovascular disorders, head injuries and encephalitis.
The duration of treatment is usually 10–14 days, after which treatment should be continued in oral dosage form.
Elderly patients.
Elderly patients with impaired liver and/or kidney function may require a reduced dose of meldonium.
Patients with impaired renal function.
Since the drug is excreted from the body through the kidneys, patients with mild to moderate renal impairment should use a lower dose of meldonium.
Patients with impaired liver function.
Patients with mild to moderate liver impairment should use a lower dose of meldonium.
Children.
There is no data on the safety and effectiveness of meldonium in children (under 18 years of age), therefore the use of meldonium in this category of patients is contraindicated.
Overdose
There have been no reports of overdose with meldonium. The drug is low-toxic and does not cause any dangerous side effects.
Low blood pressure may cause headaches, dizziness, tachycardia, and general weakness. Treatment is symptomatic.
In case of severe overdose, liver and kidney function should be monitored.
Hemodialysis is of no significant importance in case of meldonium overdose due to its pronounced binding to blood proteins.
Adverse reactions
Adverse reactions are classified according to MedDRA system organ class and frequency: common (≥ 1/100 to < 1/10), rare (≥ 1/10,000 to < 1/1,000).
Respiratory, thoracic and mediastinal disorders: often - respiratory tract infections; rarely - sore throat, cough, dyspnea, apnea.
Gastrointestinal: often - dyspepsia; rarely - dysgeusia (metallic taste in the mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation.
On the part of the kidneys and urinary system: rarely - pollakiuria.
Metabolism: often - dyslipidemia, increased C-reactive protein.
From the nervous system: often - headaches; rarely - paresthesias, tremor, hypoesthesia, tinnitus, dizziness, gait disturbance, pre-syncope, fainting, vertigo.
On the part of the psyche: rarely - excitement, feelings of fear, obsessive thoughts, sleep disturbances.
Cardiovascular system: rarely - palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain, change in heart rhythm, increase/decrease in blood pressure, hypertensive crisis, flushing, pallor.
On the part of the immune system: often - allergic reactions, hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions up to shock.
Skin and subcutaneous tissue disorders: rarely - rash, generalized macular/papular rash, itching.
Musculoskeletal and connective tissue disorders: rarely - back pain, muscle weakness, muscle spasms.
General disorders and administration site conditions: rarely - general weakness, chills, asthenia, edema, facial edema, leg edema, feeling hot, feeling cold, cold sweat, injection site reactions including injection site pain.
Laboratory indicators: rarely - abnormalities on the electrocardiogram, eosinophilia.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.
Expiration date
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.
Incompatibility.
Unknown. The drug should not be mixed in the same syringe with other drugs.
Packaging
5 ml in an ampoule; 5 ampoules in a contour blister pack; 2 contour blister packs in a pack.
Vacation category
According to the recipe.
Producer
PrJSC "Pharmaceutical Company "Darnitsa".
Location of the manufacturer and address of its place of business.
Ukraine, 02093, Kyiv, Boryspilska St., 13.
