Metonat®
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METONAT® (METONAT)
Composition:
Active substance: metonat (3-(2,2,2-trimethylhydrazinium) propionate dihydrate);
1 capsule contains 250 mg of metonat (3-(2,2,2-trimethylhydrazinium) propionate dihydrate);
Excipients: potato starch, colloidal anhydrous silicon dioxide, calcium stearate;
Capsule shell contains: gelatin, titanium dioxide (E 171).
Pharmaceutical form. Capsules.
Main physicochemical properties: hard gelatin capsules of white color containing a white or white with a yellowish tint crystalline powder with a specific odor.
Pharmacotherapeutic group. Agents affecting the cardiovascular system. Other cardiac preparations. ATC code C01EB22.
Pharmacological properties.
Pharmacodynamics.
Meldonium (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) is a carnitine precursor and a structural analogue of gamma-butyrobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom. Its effects on the body can be explained in two ways.
- Influence on carnitine biosynthesis.
Meldonium (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis. As a result, it impedes the transport of long-chain fatty acids across cellular membranes, thus preventing the accumulation of strong detergents—activated forms of non-oxidized fatty acids—within cells. Consequently, damage to cellular membranes is prevented.
Under ischemic conditions, reduced carnitine concentration slows down fatty acid beta-oxidation, optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores the transport of adenosine triphosphate (ATP) from its biosynthesis sites (mitochondria) to sites of utilization (cytosol). Essentially, cells are supplied with nutrients and oxygen, and the utilization of these substances is optimized.
Conversely, when biosynthesis of the carnitine precursor—i.e., GBB—increases, NO-synthase 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 intensifies again, and the amount of fatty acids gradually increases within cells.
It is believed that the efficacy of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is based on increased tolerance to cellular stress (due to changes in fatty acid levels).
- Mediator function in the hypothetical GBB-ergic system.
A hypothesis has been proposed that a neuronal signal transmission system—the GBB-ergic system—exists in the body, responsible for transferring nerve impulses between cells. The mediator of this system is the last carnitine precursor—GBB ether. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transmitting an electrical impulse and transforming into GBB. The hydrolyzed form of GBB is then actively transported to the liver, kidneys, and ovaries, where it is converted into carnitine. In somatic cells, new GBB molecules are synthesized in response to stimulation, ensuring signal propagation.
When carnitine concentration decreases, GBB synthesis is stimulated, leading to increased concentration of GBB ether.
Meldonium (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), as previously noted, is a structural analogue of GBB and can perform the function of a "mediator." In contrast, GBB hydroxylase does not recognize 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, so carnitine concentration does not increase but decreases. Thus, 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, both by replacing the "mediator" and by promoting increased GBB concentration, induces a corresponding physiological response. As a result, overall metabolic activity increases, including in other systems such as the central nervous system (CNS).
Effects on the cardiovascular system.
Animal studies have shown that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate positively affects myocardial contractile activity, exhibits cardioprotective properties (including protection against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces the size of myocardial infarction.
Ischemic heart disease (stable angina pectoris).
Analysis of clinical data on the course treatment with 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in patients with stable exertional angina has shown that the drug reduces the frequency and intensity of angina attacks and decreases the need for glyceryl trinitrate. The drug demonstrates pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while a lesser effect is observed in patients with supraventricular extrasystoles.
Particularly important is the drug’s ability to reduce oxygen consumption at rest, which is considered an effective criterion for antianginal therapy in IHD.
3-(2,2,2-trimethylhydrazinium) propionate dihydrate favorably influences atherosclerotic processes in coronary and peripheral vessels, reducing total serum cholesterol levels and the atherogenic index.
Chronic heart failure.
In a number of clinical studies, the role of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in the treatment of chronic heart failure due to IHD has been evaluated, and its ability to increase tolerance to physical exertion and improve work capacity in heart failure patients has been noted.
The efficacy of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate has been confirmed in cases of NYHA functional class I–III heart failure of moderate severity. Under treatment with 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, 59–78% of patients initially diagnosed with functional class II heart failure were reclassified into functional class I. It has been established that the use of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate improves myocardial inotropic function, increases tolerance to physical exertion, and enhances patients’ quality of life, without causing severe adverse effects. However, it has been noted that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate may cause mild hypotension.
In cases 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.
Animal experiments have demonstrated the antihypoxic effects of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and its beneficial effects on cerebral circulation. The compound optimizes redistribution of cerebral blood flow in favor of ischemic areas and increases neuronal resistance under hypoxic conditions.
3-(2,2,2-trimethylhydrazinium) propionate dihydrate has a stimulating effect on the CNS—increasing motor activity and physical endurance, stimulating behavioral responses, and exerting anti-stress effects—by stimulating the sympathoadrenal system, accumulating catecholamines in the brain and adrenal glands, and protecting internal organs from stress-induced changes.
Efficacy in neurological disorders.
It has been proven that meldonium (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 brain capillaries and arterioles and restores their reactivity.
The rehabilitation process in patients with neurological impairments (after cerebrovascular diseases, brain surgery, trauma, or tick-borne encephalitis) has been studied.
Results of evaluating the therapeutic activity of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate indicate its dose-dependent positive effect on physical endurance and recovery of functional independence during convalescence.
Analysis of changes in individual and overall intellectual functions after drug administration revealed a positive effect on the recovery of intellectual functions during convalescence.
It has been established that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate improves convalescent quality of life (mainly due to restoration of physical function) and helps eliminate psychological disturbances.
3-(2,2,2-trimethylhydrazinium) propionate dihydrate has a positive effect on nervous system function—reducing neurological deficits during recovery.
The overall neurological status of patients improves (reduced brain nerve damage and reflex pathology, regression of paresis, improved motor coordination, and autonomic functions).
Pharmacokinetics.
Absorption
After a single oral dose, maximum plasma concentration (Cmax) ranges from 2.23 to 2.43 µg/mL, and after repeated dosing, it reaches 2.77 µg/mL. Time to reach maximum plasma concentration (tmax) is 1–3 hours. Oral bioavailability is 78%. Food slightly delays absorption.
Distribution
3-(2,2,2-trimethylhydrazinium) propionate dihydrate rapidly distributes from the bloodstream into tissues. The volume of distribution is 88.07±8.56 L. Plasma protein binding is 78%. 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and its metabolites partially cross the placental barrier.
Biotransformation
Metabolism studies in experimental animals have shown that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is primarily metabolized in the liver.
Elimination
Renal excretion plays a significant role in the 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 dosing, the elimination half-life differs, suggesting possible accumulation of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in plasma.
Special patient groups
Elderly patients
In elderly patients with impaired liver or kidney function, where bioavailability may be increased, the dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate should be reduced.
Renal impairment
In patients with impaired renal function, where bioavailability may be increased, the dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate should be reduced. There is an interaction between 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, or the combination of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate/GBB on the renin-angiotensin-aldosterone system.
Hepatic impairment
In patients with impaired liver function, where bioavailability may be increased, the dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate should be reduced. Toxicity studies in rats administered doses exceeding 100 mg/kg showed yellow discoloration of the liver and fat denaturation. Histopathological studies in animals after high doses (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. However, no changes in liver function parameters were observed in humans after administration of high doses (400–800 mg). Nevertheless, possible fat infiltration into liver cells cannot be ruled out.
Children
There are no data on the safety and efficacy of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in children under 18 years of age; therefore, its use in this patient group is contraindicated.
Clinical characteristics.
Indications.
In complex therapy in the following cases:
- diseases of the heart and vascular system: stable exertional angina, chronic heart failure (NYHA functional class I–III), cardiomyopathy, functional disorders of the heart and vascular system;
- acute and chronic ischemic disorders of cerebral circulation;
- reduced work capacity, physical and psycho-emotional overstrain;
- during convalescence period after cerebrovascular disorders, head injuries, and encephalitis.
Contraindications.
Hypersensitivity to 3-(2,2,2-trimethylhydrazinium) propionate dihydrate and/or to any excipient of the drug;
increased intracranial pressure (in case of impaired venous outflow, intracranial tumors);
severe hepatic and/or renal insufficiency (insufficient safety data available).
Interaction with other medicinal products and other forms of interactions.
Metonat (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) can be used concomitantly with prolonged-action nitrates and other antianginal agents (stable exertional angina), cardiac glycosides, and diuretics (heart failure). It can also be combined with anticoagulants, antiplatelet agents, antiarrhythmic drugs, and other agents improving microcirculation. 3-(2,2,2-trimethylhydrazinium) propionate dihydrate may enhance the effects of drugs containing glyceryl trinitrate, nifedipine, beta-adrenoblockers, and 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 symptom manifestations, a positive effect of combined therapy has been observed (vasodilation of major arteries, improved peripheral circulation and quality of life, reduction of mental and physical stress).
In patients with iron-deficiency anemia, co-administration of iron-containing drugs and 3-(2,2,2-trimethylhydrazinium) propionate dihydrate improved the fatty acid composition in erythrocytes.
When 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is used in combination with orotic acid to eliminate ischemia/reperfusion-induced injuries, an additional pharmacological effect is observed.
3-(2,2,2-trimethylhydrazinium) propionate dihydrate helps eliminate cardiac pathological changes caused by zidovudine (AZT) and indirectly affects oxidative stress reactions induced by AZT, which lead to mitochondrial dysfunction. The use of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate in combination with AZT or other drugs for AIDS treatment has a positive impact on AIDS therapy. In the test of ethanol-induced loss of righting reflex, 3-(2,2,2-trimethylhydrazinium) propionate dihydrate reduced sleep duration. In seizures induced by pentetrazole, pronounced anticonvulsant action of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate was demonstrated. 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 administered prior to 3-(2,2,2-trimethylhydrazinium) propionate dihydrate therapy, the anticonvulsant effect of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate was completely blocked.
Overdose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate may enhance cardiotoxicity caused by cyclophosphamide.
Carnitine deficiency induced by administration of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate may enhance cardiotoxicity caused by ifosfamide.
3-(2,2,2-trimethylhydrazinium) propionate dihydrate exerts protective action against cardiotoxicity induced by indinavir and neurotoxicity induced by efavirenz.
Do not use metonat capsules (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) concomitantly with other drugs containing 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, as the risk of adverse reactions may increase.
Special precautions for use
Caution should be exercised when administering the drug to patients with mild to moderate liver and/or kidney dysfunction in their medical history (monitoring of liver and/or kidney function is recommended).
Long-term experience in treating 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 an excitatory effect, the drug is recommended to be administered in the first half of the day.
Use during pregnancy or breastfeeding
Pregnancy. Animal studies are insufficient to assess the impact of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate on pregnancy, embryonic/fetal development, labor, and postnatal development. The potential risk to humans is unknown; therefore, Metonat (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) is contraindicated during pregnancy.
Breastfeeding period. Available animal data indicate that 3-(2,2,2-trimethylhydrazinium) propionate dihydrate is excreted into maternal milk. It is unknown whether 3-(2,2,2-trimethylhydrazinium) propionate dihydrate passes into human breast milk. A risk to newborns/infants cannot be ruled out; therefore, Metonat (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) is contraindicated during breastfeeding.
Ability to influence reaction rate when driving or operating machinery
Studies evaluating the effect on the ability to drive vehicles or operate machinery have not been conducted.
Method of Administration and Dosage.
For oral use. Due to the possible stimulating effect, the drug is recommended to be taken in the first half of the day.
Adults
Cardiovascular diseases, cerebrovascular disorders
The dose is 500–1000 mg per day. The daily dose may be taken all at once or divided into two doses. The maximum daily dose is 1000 mg.
Reduced work capacity, overexertion, and recovery period
The dose is 500 mg per day. The daily dose may be taken all at once or divided into two doses. The maximum daily dose is 500 mg.
The duration of treatment is 4–6 weeks. The treatment course may be repeated 2–3 times per year.
Elderly patients
In elderly patients with impaired liver and/or kidney function, a dose reduction of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate may be necessary.
Patients with impaired kidney function
Since the drug is excreted through the kidneys, patients with mild to moderate renal impairment should receive a reduced dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate.
Patients with impaired liver function
Patients with mild to moderate hepatic impairment should receive a reduced dose of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate.
Children.
There are no data on the safety and efficacy of Metonat® (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) in children (under 18 years of age); therefore, the use of the drug in this patient group is contraindicated.
Overdose.
Cases of Metonat® (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) overdose have not been reported. The drug is low in toxicity and does not cause life-threatening adverse effects.
In cases of hypotension, headache, dizziness, tachycardia, and general weakness may occur. Treatment is symptomatic.
In the event of severe overdose, liver and kidney functions should be monitored.
Hemodialysis is not significantly effective in removing 3-(2,2,2-trimethylhydrazinium) propionate dihydrate due to its high plasma protein binding.
Adverse reactions.
Methonat (3-(2,2,2-trimethylhydrazinium) propionate dihydrate) is generally well tolerated.
Adverse reactions are classified by organ systems and frequency of occurrence according to MedDRA: common (≥1/100, <1/10), rare (≥1/10,000, <1/1,000).
Adverse reactions observed in clinical trials and during the post-marketing period:
Immune system disorders: allergic reactions; hypersensitivity, including allergic dermatitis; urticaria; angioedema; anaphylactic reactions up to shock.
Psychiatric disorders: excitement, fear, obsessive thoughts, sleep disturbances.
Nervous system disorders: headache, paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, syncope.
Cardiac disorders: change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain.
Vascular disorders: increased/decreased blood pressure, hypertensive crisis, hyperemia, pallor of the skin.
Respiratory, thoracic and mediastinal disorders: respiratory tract infections, sore throat, cough, dyspnea, apnea.
Gastrointestinal disorders: dyspepsia, dysgeusia (metallic taste in mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation.
Skin and subcutaneous tissue disorders: rash, generalized/maculopapular/papular rash, pruritus.
Musculoskeletal and connective tissue disorders: back pain, muscle weakness, muscle spasms.
Renal and urinary disorders: pollakiuria.
General disorders and administration site conditions: general weakness, chills, asthenia, edema, facial swelling, leg swelling, feeling of warmth, feeling of cold, cold sweat.
Investigations: dyslipidemia, elevated C-reactive protein levels, electrocardiogram (ECG) abnormalities, increased heart rate, eosinophilia.
Abdominal pain in the upper part of the abdomen and migraine have been reported in connection with the use of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate.
Shelf life.
4 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging.
10 capsules in a blister pack, 5 blisters in a carton.
Prescription status.
Prescription only.
Manufacturer.
JSC "Monfarm" (responsible for manufacturing, primary and secondary packaging, batch control and testing, excluding batch release).
PJSC "Technolog" (responsible for manufacturing, primary and secondary packaging, batch control and testing, excluding batch release).
LLC "FC "SALUTARIS" (responsible for batch release, excluding batch control and testing).
Manufacturer's address and location of operations.
JSC "Monfarm": Ukraine, 19161, Cherkasy region, Uman district, village Avramivka, Zavodska Street, 8.
PJSC "Technolog": Ukraine, 20300, Cherkasy region, city of Uman, Staroproryzna Street, 8.
LLC "FC "SALUTARIS": Ukraine, 04071, Kyiv, Verkhniy Val Street, 66-B.
Marketing Authorization Holder: LLC "FC "SALUTARIS".
Address of the Marketing Authorization Holder: Ukraine, 01042, Kyiv, Mykhnovskoho Mykola Boulevard, 9.