Instructions for use Mitra solution for injection 100 mg/ml ampoule 5 ml No. 10
Composition
active ingredient: meldonium dihydrate;
5 ml of solution (1 ampoule) contain meldonium dihydrate 0.5 g;
excipients: water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: transparent colorless solution, practically free from visible particles.
Pharmacotherapeutic group
Other cardiological drugs. ATC code C01E B22.
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, damage to cell membranes is prevented.
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 the development of a corresponding reaction in the body. As a result, the overall metabolic activity also increases in other systems, 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 (including against catecholamines and alcohol), and 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 drug's ability to reduce resting oxygen consumption, which is considered an effective criterion for antianginal therapy in 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.
In a separate study at the cardiology institutes of Latvia and Tomsk, the effectiveness of meldonium was tested in cases of heart failure of functional class I–III according to the New York Heart Association (NYHA) classification of moderate severity. Under the influence of meldonium therapy, 59–78% of patients initially diagnosed with functional class II heart failure were included in the functional class I group. 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.
In animal experiments, the antihypoxic effect of meldonium and its effect on cerebral blood flow have been established. The drug optimizes the redistribution of cerebral blood flow volume in favor of ischemic foci, and 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 suffering from diseases of the blood vessels of the brain, 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 convalescent quality of life (mainly by restoring the physical function of the body), and in addition, it 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 cranial nerves and reflex pathology, regression of paresis, improvement of coordination of movements and autonomic functions).
Pharmacokinetics.
Pharmacokinetics were studied in healthy volunteers when meldonium was administered intravenously and orally.
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 initial 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 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
Children
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
Use in complex therapy:
diseases of the heart and vascular system: stable angina pectoris, chronic heart failure (NYHA functional class I–III), cardiomyopathy, functional disorders of the heart and vascular system;
acute and chronic ischemic cerebrovascular disorders;
reduced working capacity, physical and psycho-emotional overstrain;
during the recovery period after cerebrovascular disorders, head injuries and encephalitis.
Contraindication
Hypersensitivity to meldonium or to any of the excipients of the drug;
increased intracranial pressure (in case of impaired venous outflow, intracranial tumors);
severe hepatic or renal failure (there is insufficient data on the safety of use);
pregnancy or breastfeeding;
childhood (up to 18 years old).
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, beta-blockers and other antihypertensive agents and peripheral vasodilators.
As a result of the simultaneous use of iron and meldonium preparations in patients with iron deficiency anemia, 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 caused by azidothymidine (AZT) and indirectly affects the oxidative stress reactions caused by AZT, which 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 treatment 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 together with other drugs containing meldonium, as the risk of adverse reactions increases.
Application features
In patients with a history of mild or moderate liver 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 postnatal development. 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
No studies have been conducted to assess the effects on the ability to drive and use machines.
Method of administration and doses
Intravenously. The use of the medicinal product does not require 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), given intravenously as a single dose or in two divided doses. The duration of treatment is usually 10–14 days, after which treatment is continued with an oral dosage form.
The duration of the treatment course is 4–6 weeks. The treatment course can be repeated 2–3 times a year.
Elderly patients
Patients with renal impairment
Since the drug is excreted from the body by the kidneys, patients with mild to moderate renal impairment should use a lower dose of meldonium.
Patients with liver dysfunction
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 by system organ class and frequency according to MedDRA [Medical Dictionary for Regulatory Activities]: common (≥ 1/100 - < 1/10), rare (≥ 1/10,000 - < 1/1,000).
Side effects observed in clinical trials and in the post-marketing period:
| On the part of the immune system |
Often Rarely | Allergic reactions* Hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions up to shock |
| From the psyche |
| Rarely | Agitation, feelings of fear, intrusive thoughts, sleep disturbances |
| From the nervous system |
Often Rarely | Headaches* Paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, presyncope, syncope |
| From the heart |
| Rarely | Heart rhythm changes, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain |
| From the circulatory system |
| Rarely | Increase/decrease in blood pressure, hypertensive crisis, flushing, pallor |
| Respiratory, thoracic and mediastinal disorders |
Often Rarely | Respiratory tract infections Sore throat, cough, dyspnea, apnea |
| Gastrointestinal tract |
Often Rarely | Dyspepsia* Dysgeusia (metallic taste in the mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation |
| Skin and subcutaneous tissue disorders |
| Rarely | Rash, generalized/macular/papular rash, pruritus |
| Musculoskeletal and related systems |
| Rarely | Back pain, muscle weakness, muscle spasms |
| Renal and urinary system disorders |
| Rarely | Pollakiuria |
| 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 |
| Research |
Often Rarely | Dyslipidemia, increased C-reactive protein Electrocardiogram (ECG) abnormalities, tachycardia, eosinophilia* |
* Adverse effects observed in previously conducted uncontrolled clinical trials.
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C. Keep out of the reach of children. Do not freeze.
Incompatibility
Unknown. The drug should not be mixed in the same syringe with other drugs.
Packaging
5 ampoules in a contour blister pack, 2 contour blister packs in a cardboard pack.
Vacation category
According to the recipe.
Producer
K.T. Rompharm Company S.R.L.
Location of the manufacturer and its business address.
Eroilor St. No. 1A, Otopeni, 075100, Ilfov County, Romania - Romfarm 1 and Romfarm 2 buildings.
Applicant.
"FORCE-PHARMA DISTRIBUTION" LLC.
Location of the applicant.
Ukraine, 03127, Kyiv, Holosiivskyi Avenue, 132.
