INSTRUCTIONS
on the medical use of the medicinal product
MILDRONAT®
(MILDRONATE®)
Composition:
active substance: meldonium;
5 ml of solution (1 ampoule) contain 0.5 g of meldonium dihydrate;
excipients: water for injection.
Dosage form. Injection.
Basic physical and chemical properties: clear, colorless liquid.
Pharmacotherapeutic group.
Other cardiac medications.
ATX code C01E B22.
Pharmacological properties.
Pharmacodynamics.
Meldonium is a precursor to 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.
1. Influence on carnitine biosynthesis.
Meldonium, by reversibly inhibiting gamma-butyrobetaine hydroxylase, reduces the biosynthesis of carnitine and therefore prevents the transport of long-chain fatty acids through the cell membranes, thus preventing the accumulation of a strong detergent in the cells - activated forms of unoxidized fatty acids. Thus, damage to cell membranes is prevented.
With a decrease in the concentration of carnitine under ischemic conditions, beta oxidation of fatty acids is delayed and oxygen consumption in cells is optimized, glucose oxidation is stimulated and the transport of adenosine triphosphate (ATP) from the sites of its biosynthesis (mitochondria) to the sites of consumption (cytosol) is resumed. Essentially, the cells are supplied with nutrients and oxygen, and the use of these substances is optimized.
In turn, with an increase in the biosynthesis of the precursor of carnitine, i.e., GBB, NO-synthetase is activated, as a result of which the rheological properties of blood improve, and peripheral vascular resistance decreases.
With a decrease in the concentration of meldonium, the biosynthesis of carnitine increases again and the amount of fatty acids in the cells gradually increases.
It is believed that the effectiveness of meldonium action is based on an increase in tolerance to cell load (with a change in the amount of fatty acids).
2. Function of a mediator in a hypothetical GBB-ergic system.
A hypothesis has been put forward that there is a system for the transfer of neuronal signals in the body - the GBB-ergic system, which ensures the transfer of nerve impulses between cells. The mediator of this system is the latest precursor of carnitine, GBB ether. As a result of the action of GBB-esterase, the mediator donates an electron to the cell, thus, transferring an electrical impulse, it turns into GBB. Further, the hydrolyzed form of GBB is actively transported to the liver, kidneys and ovaries, where it is converted into carnitine. In response to stimulation, somatic cells again synthesize new GBB molecules, providing signal propagation.
With a decrease in the concentration of carnitine, GBB synthesis is stimulated, as a result of which the concentration of GBB ether increases.
Meldonium, as indicated earlier, is a structural analogue of GBB and can act as a "mediator". In contrast, GBB hydroxylase “does not recognize” meldonium, so the carnitine concentration does not increase, but decreases. Thus, meldonium, both by replacing the "mediator" and by promoting an increase in GBB concentration, leads to the development of a response in the body.
As a result, the overall metabolic activity also increases in other systems, for example, in the central nervous system (CNS).
Effects on the cardiovascular system.
In animal studies, it was found that meldonium has a positive effect on the contractile activity of the myocardium, it has a myocardioprotective effect (including against catecholamines and alcohol), it is able to prevent heart rhythm disturbances, and reduce the zone of myocardial infarction.
Ischemic heart disease (stable exertional angina).
Analysis of clinical data on the course use of meldonium in the treatment of stable exertional angina 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 the drug to reduce oxygen consumption at rest, which is considered an effective criterion for antianginal therapy for coronary artery disease.
Meldonium has a beneficial effect on atherosclerotic processes in the coronary and peripheral vessels, reducing the total serum cholesterol level and the atherogenic index.
Chronic heart failure.
Relatively numerous clinical studies have analyzed the role of meldonium in the treatment of chronic heart failure as a result of coronary artery disease and noted its ability to increase exercise tolerance, as well as the volume of work performed by patients with heart failure.
In a separate study at the cardiological institutes of Latvia and Tomsk, the efficacy of meldonium in the case of NYHA (New York Heart Association) functional class I – III heart failure of moderate severity was tested. Under the influence of meldonium therapy, 59–78% of patients who were initially diagnosed with heart failure of functional class II were included in group I of functional class. It was found that the use of meldonium improves the inotropic function of the myocardium and increases exercise tolerance, improves the quality of life of patients without causing severe side effects. In the case of severe heart failure, meldonium should be used in combination with other traditional therapy for heart failure.
Effect on the central nervous system.
In experiments on animals, the antihypoxic effect of meldonium and the effect on cerebral circulation were established. The drug optimizes the redistribution of the volume of cerebral circulation in favor of ischemic foci, increases the strength of neurons under conditions of hypoxia.
The drug has a stimulating effect on the central nervous system - an increase in physical activity and physical endurance, stimulation of behavioral reactions, as well as an anti-stress effect - stimulation of the sympathoadrenal system, the 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 agent in the complex therapy of acute and chronic disorders of cerebral circulation (ischemic stroke, chronic cerebrovascular insufficiency). Meldonium normalizes the tone and resistance of the capillaries and arterioles of the brain, restores their reactivity.
The influence of meldonium on the process of rehabilitation of patients with neurological disorders (after suffering diseases of the blood vessels of the brain, operations on the brain, trauma, and suffering from 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 period of recovery was established.
It has been established that meldonium improves the convalescent quality of life (mainly due to the renewal of the physical function of the body), moreover, it eliminates mental disorders.
Meldonia has a positive effect on the function of the nervous system - a decrease in impairments in patients with neurological deficit during the recovery period. The general neurological condition of patients improves (reduction of damage to the nerves of the brain and pathology of reflexes, regression of paresis, improvement of coordination of movements and autonomic functions).
Pharmacokinetics.
Pharmacokinetics was studied in healthy volunteers when using meldonium intravenously and orally.
Suction
Bioavailability is 100%. The maximum concentration in 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 a single and repeated administration of doses of meldonium is different, which indicates a possible accumulation of meldonium in the blood plasma.
Distribution
Meldonium from the bloodstream is rapidly distributed in tissues, with a high cardiac affinity. Meldonium and its metabolites partially pass through the placental barrier. In animal studies, it was found that meldonium penetrates into mother's milk.
Biotransformation
In studies of metabolism in experimental animals, it was found that meldonium is mainly metabolized in the liver.
Withdrawal
In the elimination of meldonium and its metabolites from the body, renal excretion is important. After a single intravenous administration of doses of meldonium of 250 mg, 500 mg and 1000 mg, the initial early half-life of meldonium is 5.56–6.55 hours, and the final half-life is 15.34 hours.
Special patient groups
Elderly patients
Elderly patients with impaired liver or kidney function in whom bioavailability increases, the dose of meldonium should be reduced.
Renal dysfunction
Patients with impaired renal function, in whom bioavailability increases, should reduce the dose of meldonium. There is an interaction between renal reabsorption of meldonium or its metabolites (for example, 3-hydroxymeldonium) and carnitine, as a result of which the renal clearance of carnitine increases. 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 increases, should reduce the dose of meldonium. In the study of toxicity in rats with the use of meldonium at a dose of more than 100 mg / kg, the liver was stained yellow and the fat was denatured. Histopathological studies in animals after the use of large doses of meldonium (400 mg / kg and 1600 mg / kg) showed the accumulation of lipids in liver cells. Changes in liver activity indicators in humans after the use of large doses of 400-800 mg were not observed. The possible infiltration of fats into liver cells cannot be ruled out.
Children
There is no data on the safety and effectiveness of the use of meldonium in children under the age of 18, therefore the use of the drug in this category of patients is contraindicated.
Clinical characteristics.
Indications.
In the complex therapy of the following diseases:
- diseases of the heart and vascular system: stable exertional angina, chronic heart failure (NYHA I – IIІ functional class), cardiomyopathy, functional disorders of the heart and vascular system;
- acute and chronic ischemic disorders of cerebral circulation;
- decreased performance, physical and psycho-emotional overstrain;
- during the recovery period after cerebrovascular disorders, head trauma and encephalitis.
Contraindications.
- Hypersensitivity to meldonium and / or to any excipient of the drug;
- increased intracranial pressure (in violation of venous outflow, intracranial tumors);
- severe hepatic and / or renal impairment (insufficient data on the safety of use).
Interaction with other medicinal products and other types of interactions.
Meldonium can be used together with long-acting nitrates and other antianginal drugs (stable angina pectoris), cardiac glycosides and diuretic drugs (heart failure). It can also be combined with anticoagulants, antiplatelet agents, antiarrhythmics and other drugs that improve microcirculation.
Meldonium can enhance the effect of drugs containing glyceryl trinitrate, nifedipine, beta-blockers and other antihypertensive drugs, 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 eliminate damage caused by ischemia / reperfusion, an additional pharmacological effect is observed.
Meldonium helps to eliminate pathological changes in the heart caused by azidothymidine (AZT), and indirectly affects the reactions of oxidative stress caused by AZT, leading 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 treatment of acquired immunodeficiency disorders (AIDS).
In the ethanol-induced loss of equilibrium reflex test, meldonium decreased sleep duration. During convulsions caused by pentylenetetrazole, a pronounced anticonvulsant effect of meldonium was established. In turn, when the alpha2-adrenergic blocker yohimbine at a dose of 2 mg / kg and the nitric oxide synthase (COA) inhibitor N- (G) -nitro-L-arginine at a dose of 10 mg / kg are used before therapy with meldonium, the anticonvulsant effect of meldonium is completely blocked ...
An overdose of meldonium can increase the cardiotoxicity caused by cyclophosphamide.
A carnitine deficiency resulting from the use of meldonium can increase the cardiotoxicity caused by ifosfamide.
Meldonium is protective against indinavir-induced cardiotoxicity and efavirenz-induced neurotoxicity.
Do not use meldonium injections together with other drugs containing meldonium, as the risk of adverse reactions may increase.
Features of the application.
If the patient has a mild or moderate severity of liver and / or kidney dysfunctions in the anamnesis, use the drug with caution (it is necessary to monitor liver and / or kidney functions).
Long-term experience in the treatment of acute myocardial infarction and unstable angina pectoris in cardiology departments shows that meldonium is not a first-line drug for acute coronary syndrome.
Application during pregnancy or lactation.
Pregnancy
Animal studies are insufficient to assess the effects of meldonium on pregnancy, embryo / fetal development, childbirth and postpartum development. The potential risk to humans is unknown, so meldonium is contraindicated during pregnancy.
Lactation
The available animal data indicate the penetration of meldonium into mother's milk. It is not known whether Meldonium passes into human breast milk. The risk to newborns / babies cannot be ruled out, therefore Meldonium is contraindicated during breastfeeding.
The ability to influence the reaction rate when driving or driving other mechanisms.
No studies have been conducted to assess the impact on the ability to drive and maintain vehicles.
Method of administration and dosage.
Intravenously. The use of the drug does not provide for special preparation before administration.
Due to the possible stimulating effect, the drug is recommended to be used in the morning.
Adults
The dose is 500-1000 mg (5-10 ml) into a vein, it is administered at one time or divided into two doses. The duration of treatment is usually 10-14 days, after which treatment is continued with an oral dosage form.
The duration of the course of treatment is 4-6 weeks. The course of treatment can be repeated 2-3 times a year.
Elderly patients
Elderly patients with impaired liver and / or kidney function may need to reduce the dose of meldonium.
Patients with impaired renal function
Since the drug is excreted by the body through the kidneys, a lower dose of meldonium should be used in patients with mild to moderate renal impairment.
Patients with impaired liver function
Patients with mild to moderate hepatic impairment should take a lower dose of meldonium.
Children.
There is no data on the safety and efficacy of using meldonium in children (under the age of 18), therefore the use of meldonium in this category of patients is contraindicated.
Overdose.
No cases of meldonium overdose have been reported. The drug is low-toxic and does not cause threatening side effects.
With low blood pressure, headaches, dizziness, tachycardia, and general weakness are possible. Treatment is symptomatic.
In case of severe overdose, it is necessary to monitor liver and kidney function.
Hemodialysis is not essential in case of an overdose of meldonium due to the pronounced binding to blood proteins.
Adverse reactions.
Side effects are classified by organ system and frequency of occurrence according to MedDRA: often (? 1/100 to <1/10), rarely (? 1/10 000 to <1/1000).
Side effects that were observed in clinical trials and in the post-registration period:
From the immune system
Often - Allergic reactions *
Rare - Hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions to shock
From the psyche
Rarely Excitement, fear, obsessive thoughts, sleep disturbances
From the nervous system
Often - Headaches *
Rarely - Paresthesias, tremors, hypesthesia, tinnitus, vertigo, dizziness, gait disturbances, light-headedness, fainting
From the side of the heart
Rarely Changes in heart rate, palpitations, tachycardia / sinus tachycardia, atrial fibrillation, arrhythmias, chest discomfort / chest pain
From the circulatory system
Rare Increase / decrease in blood pressure, hypertensive crisis, hyperemia, pallor
On the part of the respiratory system, chest and mediastinum
Often - Respiratory tract infections
Rarely - Sore throat, cough, dyspnea, apnea
From the gastrointestinal tract
Often - Dyspepsia *
Rare - Dysgeusia (metallic taste in the mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth, or hypersalivation
From the skin and subcutaneous tissues
Rare Rash, general / macular / papular rash, pruritus
On the part of the musculoskeletal and accompanying system
Rare Back pain, muscle weakness, muscle cramps
From the kidneys and urinary system
Rarely Pollakiuria
General disorders and reactions at the injection site
Rarely General weakness, chills, asthenia, edema, edema of the face, edema of the legs, sensation of heat, sensation of coldness, cold sweat, reactions at the injection site, including pain at the injection site
Research
Often - Dyslipidemia, increased C-reactive protein levels
Rare - Electrocardiogram (ECG) abnormalities, accelerated heart rate, eosinophilia *
***
* Side effects that were observed in previous uncontrolled clinical trials.
Shelf life.
5 years.
Do not use after the expiration date printed on the package.
Storage conditions.
Store at a temperature not exceeding 25 ° C. Do not freeze.
Keep out of the reach of children.
Packaging.
5 ml each in a colorless glass ampoule, hydrolytic class I with a break line or break point.
5 ampoules in a blister strip packaging (pallet) made of polyvinyl chloride film.
2 or 4 blister packs (pallets) are placed in a cardboard box.
Vacation category.
On prescription.
Manufacturer.
Manufacturer responsible for batch release, including batch control / testing.
JSC "Grindeks".
Manufacturer's location and address of the place of business.
St. Krustpils 53, Riga, LV-1057, Latvia.
Applicant.
JSC "Grindeks".
Applicant's location.
St. Krustpils 53, Riga, LV-1057, Latvia.
