active substance: meldonium;
1 hard capsule contains 250 mg Meldonium;
auxiliary substances: potato starch, silicon dioxide, calcium stearate
capsule (body and cap) of titanium dioxide (E 171), gelatin.
Dosage form. Capsules hard.
Basic physico-chemical properties: white solid gelatin capsules. The contents of capsules - white crystalline powder with a mild odor. The powder is hygroscopic.
Other cardiac drugs. Code ATH S01E B22.
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. The effect on the biosynthesis of carnitine.
Meldonium, reversible inhibiting gamma butyrobetaine, reduces the biosynthesis of carnitine and therefore prevents the transport of long chain fatty acids through membranes of cells, thus preventing the accumulation in cells of a strong detergent - activated forms of oxidized fatty acids. Thus, damage of membrane cells 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 ATP transport from the places of its biosynthesis (mitochondria) to the places of consumption (cytosol) is restored. In fact, the cells are provided with nutrients and oxygen, and the consumption of these substances is optimized.
In turn, with an increase in the biosynthesis of the predecessor of carnitine, that is, GBB, no-synthetase is activated, as a result of which the rheological properties of the blood are improved and the peripheral resistance of the vessels decreases.
When the concentration of Meldonium decreases, the biosynthesis of carnitine increases again and the number of fatty acids in the cells gradually increases.
It is believed that the effectiveness of Meldonium is based on increased tolerance to cell load (when changing the amount of fatty acids).
2. The function of mediator in hypothetical GBB-aricescu system.
The hypothesis is put forward that there is a system of neuronal signal transfer in the body - GBB-ergic system, which provides the transfer of nerve impulse between cells. The mediator of this system is the last predecessor of carnitine - GBB-ether. As a result of GBB-esterase action, the mediator gives the cell an electron, thus transferring an electric pulse, turns into GBB. Further, the hydrolyzed form of HBB is actively transported to the liver, kidneys and ovaries, where it turns into carnitine. In somatic cells, new HBB molecules are synthesized again in response to irritation, ensuring signal propagation.
With a decrease in the concentration of carnitine, GBB synthesis is stimulated, resulting in an increase in the concentration of GBB ether.
Meldonium, as indicated earlier, is a structural analogue of GBB and can serve as a"mediator". In contrast, HBB hydroxylase "does not recognize" Meldonium, so the concentration of carnitine does not increase, but decreases. Thus, Meldonium itself, replacing the "mediator", and contributing to the increase in the concentration of HBB, leads to the development of an appropriate reaction of the body. As a result, overall metabolic activity also increases in other systems, such as the Central nervous system (CNS).
Influence on the cardiovascular system.
In animal studies found that Meldonium positively affects the contractile activity of the myocardium, it is inherent myocardioprotective effect (including against catecholamines and alcohol), it is able to prevent heart rhythm disorders, reduce the area of myocardial infarction.
Ischemic heart disease (stable angina of exertion).
Analysis of clinical data on the course use of Meldonium in the treatment of stable angina stress showed that the drug reduces the frequency and intensity of angina attacks, as well as the amount of glyceryltrinitrate that is used. The drug has a pronounced antiarrhythmic effect in patients with coronary heart disease (CHD) and ventricular extrasystoles, less action is observed in patients with supraventricular extrasystoles.
Especially important is the ability of the drug to reduce oxygen consumption at rest, considered an effective criterion for antianginal therapy IHD.
Meldonium has a positive effect on the atherosclerotic process in the coronary and perepilichny vessels by reducing the cholesterol level in blood serum and atherogenic index.
Chronic heart failure.
For many clinical studies the role of Meldonium in the treatment of chronic heart failure as a result of IHD was analyzed and its ability to increase tolerance to physical activity, as well as to the amount of performed work by patients with heart failure was noted.
In a separate study in the heart institutes of Latvia and Tomsk tested the effectiveness of Meldonium in the case of heart failure NYHA I-III functional class of moderate severity. Under the influence of Meldonium therapy, 59-78% of patients who were initially diagnosed with functional class II heart failure were included in the group and functional class. It was found that the use of Meldonium improves myocardial inotropic function and increases exercise tolerance, improves the quality of life of patients without causing severe side effects. However, it is noted that Meldonium can cause minor hypotension. Other possible side effects of Meldonium-allergic skin reactions, headaches, discomfort in the epigastric.
In case of severe heart failure Meldonium should be used in combination with other traditional means of therapy of heart failure.
Effect on the CNS.
In experiments on animals established antihypoxic action Meldonium and action, promotes brain blood circulation. The drug improves the volume redistribution of the cerebral blood flow in favor of ischemic lesions increases the strength of neurons to hypoxia.
The drug has a stimulating effect on the Central nervous system - increase of motor activity and physical endurance, stimulation of behavioral reactions, as well as anti - stress action-stimulation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, protection of internal organs against changes caused by stress.
Effectiveness in neurological diseases.
It is proved that Meldonium is an effective agent 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 the capillaries and arterioles of the brain and restores their reactivity.
The process of rehabilitation of patients with neurological disorders (after blood vessel diseases of the brain, brain operations, injuries, tick-borne encephalitis) was studied.
The results of the test of therapeutic activity of Meldonium indicate its dose-dependent positive effect on physical endurance and restoration of functional independence during recovery.
In the analysis of changes in individual and total intellectual functions after the use of the drug found a positive effect on the recoverable process of intellectual functions during recovery.
Meldonium has been found to improve the reconvalescent quality of life (mainly by updating the physical function of the body), in addition, it eliminates psychological disorders.
Meldonium has a positive effect on the function of the nervous system - reducing disorders in patients with neurological deficit during recovery.
Improves the General neurological status of patients (reduction of damage to the nerves of the brain and the pathology of reflexes, regression of pareses and improvement of coordination of movements and autonomic functions).
After a single oral dose of the maximum concentration in plasma (C max ) is 2,23-of 2.43 µg/ml, and after the application of repeated doses of 2.77 ?g/ml, the Time to maximum concentration in blood plasma (t max ) is 1-3 hours. The bioavailability after oral administration is 78%. The food slightly delays the suction.
Meldonium from the bloodstream is rapidly distributed in the tissues. The volume of distribution is 88.07 ± 8.56 liters due to plasma proteins is 78%. Meldonium and its metabolites partially pass through the placental barrier.
In the study of metabolism in experimental animals found that Meldonium is mainly metabolized in the liver.
In the withdrawal of Meldonium and its metabolites from the body important renal excretion. After oral administration of a single dose, the early withdrawal half life of Meldonium (t 1/2 ) is approximately 3.5-4 hours. When applying repeated doses, the half-life period is different. These results indicate a possible accumulation of Meldonium in blood plasma.
Special groups of patients
Elderly patients with impaired liver or kidney function, which increases bioavailability, should reduce the dose of Meldonium.
Violation of kidney function
Patients with impaired renal function, which increases bioavailability, 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, HBB and Meldonium/HBB combinations on the renin-angiotensin-aldosterone system.
Impaired liver function
Patients with impaired liver function, which increases bioavailability, should reduce the dose of Meldonium. In the study of toxicity in rats using Meldonium at a dose of 100 mg/kg established the color of the liver in yellow and denaturation of fats. When histopathological studies in animals after the use of high doses of Meldonium (400 mg/kg and 1600 mg/kg) found the accumulation of lipids in liver cells. Changes in liver function in humans after the use of high doses of 400-800 mg was not observed. It is impossible to exclude possible infiltration of fats into liver cells.
There is no data on the safety and efficacy of Meldonium in children under the age of 18 years, so the use of the drug in this category of patients is contraindicated.
In complex therapy in the following cases:
diseases of the heart and vascular system: stable angina load, chronic heart failure (NYHA I-II and 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 stress;
in the period of recovery after cerebrovascular disorders, head injuries and encephalitis.
Hypersensitivity to Meldonium and/or any auxiliary substance of the preparation
increase of intracranial pressure (in violation of venous outflow, intracranial tumors)
severe hepatic and/or renal insufficiency (no adequate data on the safety of use).
Interaction with other medicinal products and other forms of interaction
Meldonium may be used together with nitrates of prolonged action and other anti-anginal drugs (stable angina of exertion), cardiac glycosides and diuretic drugs (heart failure). It can also be combined with anticoagulants, antiplatelet agents, antiarrhythmic drugs and other drugs that improve the microcirculation. Meldonium can enhance the effect of drugs containing glyceryltrinitrate, nifedipine, beta-blockers and other antihypertensive agents and peripheral vasodilators.
As a result of simultaneous use of iron and Meldonium preparations in patients with anemia caused by iron deficiency, the composition of fatty acids in erythrocytes was improved.
When applying Meldonium in combination with Orotic acid to eliminate damage caused by ischemia/reperfusion, there is an additional pharmacological effect.
Meldonium helps to eliminate pathological changes in the heart caused by azidotimidine (AZT), and indirectly affects the oxidative stress reactions caused by AZT, which lead to mitochondrial dysfunction. Application melidoniou in combination with AZT or other drugs for the treatment of AIDS has a positive effect in the treatment of acquired immunodeficiency (AIDS). In the test of loss of reflex equilibrium caused by ethanol, Meldonium reduced sleep duration. During the trial, caused by pentylenetetrazole installed pronounced anticonvulsant effect melidoniou. In turn, when used before therapy with Meldonium alpha 2-adrenoblokator yohimbine at a dose of 2 mg/kg and nitric oxide synthase inhibitor (SOA) N- (G) -nitro-l-arginine at a dose of 10 mg/kg, completely blocked anticonvulsant action Meldonium.
Overdose melidoniou may enhance the cardiotoxicity induced by cyclophosphamide.
Carnitine deficiency, which is formed when using Meldonium, may increase cardiotoxicity caused by ifosfamide.
Meldonium has a protective effect with cardiotoxicity caused by indinavir, and neurotoxicity caused by efavirenz.
Do not use Meldonium capsules in conjunction with other Meldonium-containing preparations as the risk of adverse reactions may increase.
Patients with impaired liver and/or kidney function of mild or moderate severity in the anamnesis in the application of the drug should be careful (should be monitored liver and/or kidney function).
Many years of experience in the treatment of acute myocardial infarction and unstable angina in cardiac departments shows that Meldonium is not a first-line drug in acute coronary syndrome.
The possible development of exciting effect it is recommended to apply in the first half of the day.
Use during pregnancy or breast-feeding.
Pregnancy. To assess the impact of Meldonium on pregnancy, embryo/fetus development, childbirth and postpartum development studies in animals is not enough. The potential risk to people is unknown, so Meldonium during pregnancy is contraindicated.
Lactation. Available data on animals indicate Meldonium penetration into mother's milk. Unknown, Meldonium penetrates into breast milk. You can not exclude the risk for newborns/infants, so during breastfeeding Meldonium is contraindicated.
The ability to influence the reaction rate when driving motor transport or operating other mechanisms.
Studies to evaluate the effects on ability to drive and use machines was not performed.
Method of application and doses
For oral administration. Due to the possible stimulating effect, the drug is recommended to be used in the morning.
Adult diseases of the heart and vascular system, disorders of cerebral circulation
The dose is 500 mg to 1000 mg per day. The daily dose can be used all at once or divided into 2 admission. The maximum daily dose is 1000 mg.
Reduced performance, over voltage and recovery period
The dose is 500 mg per day. The daily dose can be applied all at once or divided into two single doses. The maximum daily dose is 500 mg.
The duration of treatment is 4-6 weeks. The course of treatment can be repeated 2-3 times a year.
For elderly patients with impaired liver and/or kidney function may be necessary to reduce the dose of Meldonium.
Patients with impaired renal function
Since the drug is excreted from the body through the kidneys, patients with impaired renal function of mild and moderate severity should use a lower dose of Meldonium.
Patients with impaired liver function
Patients with impaired hepatic function of mild to moderate severity should use a lower dose of Meldonium.
Children. There is no data on the safety and efficacy of Meldonium in children under the age of 18 years, so the use of Meldonium in this category of patients is contraindicated.
No cases of overdose on Meldonium have been reported. The drug is low toxic and does not cause harmful side effects.
With low blood pressure, headaches, dizziness, tachycardia, General weakness are possible. Treatment is symptomatic.
In the case of severe overdose it is necessary to control the functions of the liver and kidneys.
Hemodialysis is not significant in case of overdose melidoniou in connection with the expressed binding protein in the blood.
Side effects are classified by organ systems and frequency of occurrence MedDRA: often (?1/100 to <1/10), rarely (?1/10000 to <1/1000), very rarely (<1/10000).
Side effects observed in clinical trials and post-marketing period:
From the immune system
rare allergic reactions *
Hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions to shock
legkovozvodimyh, anxiety, obsessive thoughts, sleep disturbances
From the nervous system
redcoruna pain * Paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, lightheadedness, fainting
From the heart
heart rate change, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain
From the circulatory system
recopilada/low blood pressure, hypertensive crisis, flushing, pallor
Side respiratory, thoracic and mediastinal
rare respiratory infections
Inflammation in the throat, cough, shortness of breath, apnea
The gastro-intestinal tract
Rectiphase * dysgeusia (metallic taste in the mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation
The skin and subcutaneous tissue
regcuisine, General/maculusso/papular rash, itching
From the musculoskeletal and associated systems
redoble in the back, muscle weakness, muscle spasms
From the kidneys and urinary system
General disorders and reactions at the injection site
rare weakness, chills, asthenia, swelling, swelling of the face, swelling of the legs, a feeling of heat, a feeling of cold, cold sweat
rectiligne, increased levels of C-reactive protein
Deviation in electrocardiogram (ECG), acceleration of the heart, eosinophilia *
* Side effects observed in previously uncontrolled clinical trials.
Do not use after the expiry date.
Store at a temperature not exceeding 25 ° C.
Store in the original package to protect from moisture.
Keep out of reach of children.
10 capsules in a blister, 4 blisters in a pack of cardboard.
Category home away from home.
JSC "Grindeks", Latvia.
The manufacturer's location and address of the place of business.
Ul. Krustpils, 53, Riga, LV-1057, Latvia.
Tel/Fax: +371 67083205/+371 67083505
Email: [email protected]
Location of the applicant and/or the applicant's representative
Ul. Krustpils, 53, Riga, LV-1057, Latvia.
MILDRONATE CAPSULES 250MG №40
Metabolic LS complex action, able to restore balance between oxygen demand and its delivery to cellular structures. The drug improves metabolism, stimulates motor activity, increases physical endurance and mental performance. Eliminates accumulation of toxic substances in cells products metabolism slows down necrotic changes, reduces the rehabilitation period. The main active ingredient is Meldonium dihydrate.
Indications for use
The medication is prescribed for the treatment of angina pectoris, chronic sleep, dishormonal, cerebral circulation disorders (as a component of complex therapy). Effective in hemorrhages in the retina, thrombosis of Central veins, hemophthalmus, muscle strain. The remedy is contraindicated in:
Hypersensitivity to Meldonium or other components.
The medical product is taken orally. Daily dosage for adults is 500 mg.The duration of administration is determined by the specialist on the basis of clinical indications and anamnesis of the patient.