Instructions for use Metonat capsules 250 mg blister No. 50
Composition
active ingredient: metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate);
1 capsule contains 250 mg of metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate);
excipients: potato starch, colloidal anhydrous silicon dioxide, calcium stearate;
The capsule shell contains: gelatin, titanium dioxide (E 171).
Dosage form
Capsules.
Main physicochemical properties: white hard gelatin capsules containing white or white with a yellowish tinge powder with a specific odor.
Pharmacotherapeutic group
Drugs affecting the cardiovascular system. Other cardiological drugs. ATC 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 across 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 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.
On the other hand, 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 3-(2,2,2-trimethylhydrazinium) propionate dihydrate decreases, carnitine biosynthesis increases again and the amount of fatty acids in the cells gradually increases.
It is believed that the effectiveness of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is based on increasing 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 transfer 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, it 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 (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), as mentioned earlier, is a structural analogue of GBB and can perform the functions of a “mediator”. In contrast, GBB hydroxylase “does not recognize” 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, so the concentration of carnitine does not increase, but decreases. Thus, 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, both by itself, replacing the “mediator”, and by contributing to the increase in the concentration of GBB, leads to the development of the corresponding reaction of 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 3-(2,2,2-trimethylhydrazinium) propionate dihydrate 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 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in the treatment of stable exercise-induced 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.
3-(2,2,2-trimethylhydrazinium) propionate dihydrate has a beneficial effect on atherosclerotic processes in coronary and peripheral vessels, reducing total serum cholesterol levels and the atherogenic index.
A relatively large number of clinical studies have analyzed the role of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in the treatment of chronic heart failure resulting from coronary artery disease and noted its ability to increase exercise tolerance and the amount of work performed by patients with heart failure.
The studies tested the effectiveness of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in heart failure of NYHA I-III functional class of moderate severity. Under the influence of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate 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 3-(2,2,2-trimethylhydrazinium) propionate dihydrate 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. However, it was noted that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate can cause slight hypotension.
In case of severe heart failure, 3-(2,2,2-trimethylhydrazinium) propionate dihydrate should be used in combination with other conventional heart failure therapies.
Effects on the CNS.
In animal experiments, the antihypoxic effect of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and the effect that promotes cerebral blood circulation have been established. 3-(2,2,2-trimethylhydrazinium) propionate dihydrate optimizes the redistribution of cerebral blood circulation volume in favor of ischemic foci, increases the strength of neurons in conditions of hypoxia.
3-(2,2,2-trimethylhydrazinium) propionate dihydrate has an inherent 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 against changes caused by stress.
Effectiveness in neurological diseases.
It has been proven that metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) is an effective agent in the complex therapy of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulatory insufficiency). 3-(2,2,2-trimethylhydrazinium) propionate dihydrate normalizes the tone and resistance of capillaries and arterioles of the brain, restores their reactivity.
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 3-(2,2,2-trimethylhydrazinium) propionate dihydrate 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 3-(2,2,2-trimethylhydrazinium) propionate dihydrate improves the convalescent quality of life (mainly due to the renewal of the physical function of the body), and it also contributes to the elimination of mental disorders.
3-(2,2,2-trimethylhydrazinium) propionate dihydrate 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
Absorption
After a single oral dose, the maximum plasma concentration (Cmax) is 2.23-2.43 μg/ml, and after repeated doses - 2.77 μg/ml. The time to reach maximum plasma concentration (tmax) is 1-3 hours. Bioavailability after oral administration is 78%. Food slightly delays absorption.
Distribution
3-(2,2,2-trimethylhydrazinium) propionate dihydrate from the bloodstream is rapidly distributed in tissues. The volume of distribution is 88.07±8.56 l, and the plasma protein binding is 78%. 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and its metabolites partially cross the placental barrier.
Biotransformation
In a study of metabolism in experimental animals, it was found that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is mainly metabolized in the liver.
Breeding
Renal excretion is the major route of elimination of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and its metabolites from the body. After a single oral dose, the early elimination half-life (t1/2) is approximately 3.5-4 hours. With repeated doses, the elimination half-life varies. These results indicate a possible accumulation of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in the blood plasma.
Special patient groups
Elderly patients
Elderly patients with impaired liver or kidney function, in whom bioavailability is increased, should have their dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate reduced.
Patients with impaired renal function, in whom bioavailability is increased, should reduce the dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate. There is an interaction between the renal reabsorption of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate or its metabolites (e.g. 3-hydroxymeldonium) and carnitine, resulting in increased renal clearance of carnitine. There is no direct effect of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, GBB, and the combination of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate/GBB on the renin-angiotensin-aldosterone system.
Liver dysfunction
Patients with impaired liver function, in whom bioavailability is increased, should reduce the dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate. In a toxicity study in rats, yellow liver coloration and fat denaturation were observed when 3-(2,2,2-trimethylhydrazinium) propionate dihydrate was administered at a dose of more than 100 mg/kg. In histopathological studies in animals, lipid accumulation in liver cells was observed after administration of large doses of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate (400 mg/kg and 1600 mg/kg). No changes in liver function parameters were observed in humans after administration of large doses of 400-800 mg. The possible infiltration of fat into liver cells cannot be excluded.
Children
There is no data on the safety and efficacy of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in children under 18 years of age, therefore the use of the drug in this category of patients is contraindicated.
Indication
In complex therapy in the following cases:
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 cerebrovascular disorders;
reduced working capacity, physical and psycho-emotional overstrain;
during the recovery period after cerebrovascular disorders, head injuries and encephalitis.
Contraindication
Hypersensitivity to 3-(2,2,2-trimethylhydrazinium) propionate dihydrate 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 (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) 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. 3-(2,2,2-trimethylhydrazinium) propionate dihydrate can enhance the effect of drugs containing glyceryl trinitrate, nifedipine, beta-blockers and the effect of other antihypertensive agents and peripheral vasodilators. In patients with chronic heart failure, who use 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and lisinopril to reduce symptoms, a positive effect of combination therapy was found (vasodilation of the main arteries, improvement of peripheral circulation and quality of life, reduction of mental and physical stress).
As a result of the simultaneous use of iron preparations and 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in patients with iron deficiency anemia, the composition of fatty acids in erythrocytes improved.
When 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is used in combination with orotic acid to reverse ischemia/reperfusion injury, an additive pharmacological effect is observed.
3-(2,2,2-Trimethylhydrazinium) propionate dihydrate 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 3-(2,2,2-Trimethylhydrazinium) propionate dihydrate in combination with AZT or with other drugs for the treatment of AIDS has a positive effect in the treatment of AIDS. In the ethanol-induced loss of balance reflex test, 3-(2,2,2-Trimethylhydrazinium) propionate dihydrate reduced the duration of sleep. During seizures caused by pentylenetetrazole, a pronounced anticonvulsant effect of 3-(2,2,2-Trimethylhydrazinium) propionate dihydrate was established. In turn, when used before therapy with 3-(2,2,2-trimethylhydrazinium) propionate dihydrate with 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, the anticonvulsant effect of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is completely blocked.
Overdose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate may potentiate cyclophosphamide-induced cardiotoxicity.
Carnitine deficiency resulting from the use of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate may enhance ifosfamide-induced cardiotoxicity.
Do not use Metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) capsules with other medications containing 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, as the risk of adverse reactions may increase.
Application features
Patients with a history of mild or moderate hepatic and/or renal impairment should be treated with caution (liver and/or renal function should be monitored).
Many years of experience in the treatment of acute myocardial infarction and unstable angina in cardiology departments shows that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is not a first-line drug for acute coronary syndrome.
Due to the possible development of a stimulating effect, the drug is recommended to be used in the morning.
Use during pregnancy or breastfeeding
Pregnancy: Animal studies are insufficient to evaluate the effects of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate on pregnancy, embryonal/fetal development, parturition, and postnatal development. The potential risk to humans is unknown, therefore, metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) is contraindicated during pregnancy.
Breast-feeding. Available animal data indicate that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is excreted in human milk. It is not known whether 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is excreted in human milk. A risk to the newborn/infants cannot be excluded, therefore metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) 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
For internal use. Due to the possible stimulating effect, the drug is recommended to be used in the morning.
Adults Diseases of the heart and vascular system, cerebrovascular disorders
The dose is 500 - 1000 mg per day. The daily dose can be taken all at once or divided into 2 doses. The maximum daily dose is 1000 mg.
Reduced performance, overexertion and recovery period
The dose is 500 mg per day. The daily dose can be taken all at once or divided into two single doses. 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
Elderly patients with impaired liver and/or kidney function may require a reduction in the dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate.
Patients with renal impairment
Since the drug is excreted from the body via the kidneys, patients with mild to moderate renal impairment should use a lower dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate.
Patients with liver dysfunction
Patients with mild to moderate hepatic impairment should be given a lower dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate.
Children
There are no data on the safety and efficacy of Metonat® in children (under 18 years of age), therefore the use of the drug in this category of patients is contraindicated.
Overdose
There have been no reports of overdose with Metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate). The drug is of low toxicity and does not cause any dangerous side effects.
With low blood pressure, headaches, 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 overdose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate due to the pronounced binding to blood proteins.
Side effects
Metonate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) is generally well tolerated.
Adverse reactions are classified by system organ class and frequency according to MedDRA: common (≥1/100, <1/10), rare (≥1/10,000, <1/1,000).
Adverse reactions observed in clinical trials and in the post-marketing period:
Immune system disorders: 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.
From the nervous system: headache, paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, fainting.
Cardiac: change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain.
On the part of the circulatory system: increase/decrease in blood pressure, hypertensive crisis, hyperemia, pallor of the skin.
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.
Investigations: dyslipidemia, increased C-reactive protein, electrocardiogram (ECG) abnormalities, tachycardia, eosinophilia.
Upper abdominal pain and migraine have been reported in association with the use of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate.
Expiration date
4 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of the reach of children.
Packaging
10 capsules in a blister, 5 blisters in a pack.
Vacation category
According to the recipe.
Producer
PJSC "Monpharm".
Technolog PJSC.
Location of the manufacturer and its address of place of business.
PJSC "Monpharm": Ukraine, 19161, Cherkasy region, Uman district, Avramivka village, Zavodska st., 8.
PrJSC "Technolog": Ukraine, 20300, Cherkasy region, Uman city, Stara Prorizna street, building 8.
Applicant
LLC "FC "SALUTARIS".
Location of the applicant. Ukraine, 01042, Kyiv city, Mikhnovsky Mykola blvd., building 9.
