Instructions Metonat solution 100 mg/ml ampoule 5 ml No. 10
Composition
active ingredient: metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate);
5 ml of solution (1 ampoule) contains 500 mg of metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate);
excipient: water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: clear colorless liquid.
Pharmacotherapeutic group
Drugs affecting the cardiovascular system. Other cardiological drugs.
ATX code C01E B22.
Pharmacological properties
Pharmacodynamics
Metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) 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.
1. Effect on carnitine biosynthesis.
Metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), 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 - activated forms of unoxidized fatty acids - in cells. 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 ATP transport 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.
When the concentration of metonate 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 metonate is increased tolerance to cellular stress (when changing the amount of fatty acids).
2. 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.
Metonate, as mentioned earlier, is a structural analogue of GBB and can perform the functions of a “mediator”. In contrast, GBB hydroxylase “does not recognize” metonate, so the concentration of carnitine does not increase, but decreases. Thus, metonate, replacing the “mediator” and contributing to the increase in GBB concentration, leads to 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 metonate 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 metonate 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.
Metonate 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 metonate in heart failure of NYHA I-III functional class of moderate severity was tested. Under the influence of metonate therapy, 59-78% of patients who were initially diagnosed with heart failure of functional class II were included in the group of functional class I. It was found that the use of metonate 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, metonate should be used in combination with other traditional heart failure therapies.
Effects on the CNS.
In animal experiments, the antihypoxic effect of metonate 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 - increasing motor activity and physical endurance, stimulating behavioral reactions, as well as an anti-stress effect - stimulating the sympathoadrenal system, accumulating catecholamines in the brain and adrenal glands, protecting internal organs from changes caused by stress.
Effectiveness in neurological diseases.
It has been proven that metonate is an effective agent in the complex therapy of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulation insufficiency). Metonate normalizes the tone and resistance of capillaries and arterioles of the brain, restores their reactivity.
The effect of metonate 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 metonate 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 metonate improves the convalescent quality of life (mainly by restoring the physical function of the body), and in addition, it eliminates psychological disorders.
Metonate has an inherent positive effect on nervous system function, reducing impairment 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 metonate 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 metonate differs, indicating possible accumulation of metonate in blood plasma.
Distribution
Metonate is rapidly distributed from the bloodstream to tissues with high cardiac affinity. Metonate and its metabolites partially cross the placental barrier. Animal studies have shown that metonate is excreted in breast milk.
Biotransformation
Metabolism studies in experimental animals have shown that metonate is primarily metabolized in the liver.
Breeding
Renal excretion is important in the elimination of metonate and its metabolites from the body. After single intravenous administration of metonate doses of 250 mg, 500 mg and 1000 mg, the early elimination half-life of metonate is 5.56-6.55 hours, the terminal elimination 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 metonate.
Kidney dysfunction
Patients with impaired renal function, in whom bioavailability is increased, should reduce the dose of metonate. There is an interaction between renal reabsorption of metonate 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 metonate. In toxicity studies on rats, yellow liver coloration and fat denaturation were observed when metonate 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 metonate (400 mg/kg and 1600 mg/kg). Changes in liver function parameters in humans after administration of high doses
400 - 800 mg was not observed. Possible infiltration of fats into liver cells cannot be excluded.
There is no data on the safety and effectiveness of metonate in children, so the use of the drug in this category of patients is contraindicated.
Indication
In the complex therapy of the following diseases:
- 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 metonate and/or to any of the excipients of the drug;
- increased intracranial pressure (in case of impaired venous outflow, intracranial tumors);
- severe hepatic and/or renal failure (there is insufficient data on the safety of use).
Interaction with other medicinal products and other types of interactions
Metonate 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, antiarrhythmic agents and other drugs that improve microcirculation.
Metonate 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 preparations and metonate in patients with iron deficiency anemia, the composition of fatty acids in erythrocytes improved.
When metonate is used in combination with orotic acid to reverse ischemia/reperfusion injury, an additive pharmacological effect is observed.
Metonate helps to reverse the 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 metonate 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, metonate reduced sleep duration. During pentylenetetrazole-induced seizures, a pronounced anticonvulsant effect of metonate 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 metonate therapy, the anticonvulsant effect of metonate was completely blocked.
Overdose of metonate may potentiate cardiotoxicity caused by cyclophosphamide.
Carnitine deficiency, which occurs with the use of metonate, may enhance cardiotoxicity caused by ifosfamide.
Metonate 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 may increase.
Application features
Patients with a history of mild or moderate liver and/or kidney dysfunction should be cautious 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 metonate on pregnancy, embryonal/fetal development, parturition, and postnatal development. The potential risk to humans is unknown, therefore metonate is contraindicated during pregnancy.
Breast-feeding.
Available animal data indicate that metonate is excreted in human milk. It is not known whether metonate is excreted in human milk. A risk to the newborn/infants cannot be excluded, therefore metonate 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
Administer intravenously. The use of the drug does not require special preparation before administration. Due to the possible stimulating effect, it is recommended to administer the drug 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 dose is 500 mg (5 ml) per day. The maximum daily dose is 500 mg.
The duration of the treatment course is 4-6 weeks. The treatment course can be repeated 2-3 times a year.
Elderly patients with impaired liver and/or kidney function may require a reduction in the dose of metonate.
Patients with impaired renal function
Since the drug is excreted by the body through the kidneys, patients with mild to moderate renal impairment should use a lower dose of metonate.
Patients with liver dysfunction
Patients with mild to moderate hepatic impairment should be given a lower dose of metonate.
Children.
There are no data on the safety and efficacy of metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) in children, therefore the use of metonate in this category of patients is contraindicated.
Overdose
No cases of overdose with metonate have been reported. The drug is low-toxic and does not cause any dangerous side effects.
With low blood pressure, headache, dizziness, tachycardia, and general weakness are possible. Treatment is symptomatic.
In case of severe overdose, liver and kidney function should be monitored.
Hemodialysis is of no significant value in case of metonate overdose due to the pronounced binding to blood proteins.
Adverse reactions
On the part of the immune system: allergic reactions, hypersensitivity, including allergic dermatitis; urticaria, angioedema, anaphylactic reactions up to shock.
On the part of the psyche: excitement, feelings of fear, obsessive thoughts, sleep disturbances.
Nervous system: headache, paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, fainting.
Cardiac disorders: change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain.
From the circulatory system: increase/decrease in blood pressure, hypertensive crisis, hyperemia, pallor of the skin.
Respiratory, thoracic and mediastinal disorders: respiratory tract infections, sore throat, cough, dyspnea, apnea.
Gastrointestinal: 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: rash, generalized/macular/papular rash, pruritus.
Musculoskeletal and related systems: back pain, muscle weakness, muscle spasms.
From the kidneys and urinary system: pollakiuria.
General disorders and administration site conditions: general weakness, chills, asthenia, edema, facial edema, leg edema, feeling hot, feeling cold, cold sweat, injection site reactions including injection site pain.
Investigations: dyslipidemia, increased C-reactive protein, electrocardiogram (ECG) abnormalities, tachycardia, eosinophilia.
Expiration date
4 years.
Storage conditions
Store at a temperature not exceeding 25 °C out of the reach of children.
Do not freeze.
Incompatibility: Metonat solution should not be mixed in the same syringe with other drugs.
Packaging
5 ml in ampoules, 10 ampoules in cardboard packs.
Vacation category
According to the recipe.
Producer
OJSC "Lubnyfarm".
Location of the manufacturer and its business address
Ukraine, 37500, Lubny, Poltava region, Petrovsky str., 16.
or
Producer
PJSC "Lekhim-Kharkiv".
Location of the manufacturer and its business address
Ukraine, 61115, Kharkiv, 17-Partzyezda St., 36.
Applicant
LLC "Pharmaceutical Company "Salutaris".
Applicant's location
01042, Kyiv, 9 Druzhby Narodiv Blvd.
