Instructions Ripronat solution for injection 100 mg/ml ampoule 5 ml No. 10
Composition
active ingredient: meldonium;
1 ml of solution contains meldonium dihydrate 100 mg;
excipient: water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: transparent colorless solution.
Pharmacotherapeutic group
Other cardiological drugs. ATC code C01E B22.
Pharmacological properties
Pharmacodynamics
Mechanism of action.
Meldonium is a precursor to carnitine, a structural analogue of gamma-butyrobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom.
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 - 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.
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, leads to the development of a 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 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 it reduces the frequency and intensity of angina attacks, as well as the amount of glyceryl trinitrate used. It 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 ability of meldonium to reduce resting oxygen consumption, which is considered an effective criterion for antianginal therapy of coronary heart disease.
Meldonium has a beneficial effect on atherosclerotic processes in coronary and peripheral vessels, reducing the total level of cholesterol in blood plasma and the atherogenic index.
Chronic heart failure.
Relatively many clinical studies have analyzed the role of meldonium 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.
In case of severe heart failure, meldonium should be used in combination with other traditional heart failure therapies.
Effects on the CNS.
Animal experiments have established the antihypoxic effect of meldonium and its effect on cerebral blood flow. It optimizes the redistribution of cerebral blood flow volume in favor of ischemic foci, and increases the strength of neurons in conditions of hypoxia.
Meldonium 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 meldonium is an effective remedy in the complex therapy of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulation insufficiency). It 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 the use of meldonium, 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), 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
The pharmacokinetics of meldonium were studied in healthy volunteers when meldonium was administered intravenously and orally.
Absorption.
After intravenous administration, the bioavailability of meldonium 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. It is unknown whether meldonium is excreted in human 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 early elimination half-life of meldonium is 5.56–6.55 hours, the terminal elimination period 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.
Patients with impaired liver function, in whom bioavailability is increased, should reduce the dose of meldonium. In toxicity studies on rats, yellow liver coloration and fat denaturation were observed when meldonium 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 meldonium (400 mg/kg and 1600 mg/kg). No changes in liver function parameters were observed in humans after administration of high doses of 400–800 mg. The possible infiltration of fat into liver cells cannot be ruled out.
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
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;
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 other components of the drug;
Increased intracranial pressure (in case of impaired venous outflow, intracranial tumors);
Severe hepatic and/or renal insufficiency (insufficient data on safety of use).
Pregnancy and/or breastfeeding.
Children's age (no data on safety of use).
Interaction with other medicinal products and other types of interactions
Meldonium can be used together with long-acting nitrates and other antianginal agents for the treatment of stable exercise-induced angina, cardiac glycosides and diuretics for the treatment of heart failure.
Meldonium can be combined with anticoagulants, antiplatelet agents, antiarrhythmic agents, and other agents that improve microcirculation.
Meldonium may enhance the effects of drugs containing glyceryl trinitrate, nifedipine, beta-blockers and other antihypertensive agents and peripheral vasodilators.
With the simultaneous use of meldonium with lisinopril, a positive effect of combination therapy was revealed (vasodilation of the main arteries, improvement of peripheral blood circulation and quality of life, reduction of mental and physical stress).
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 AZT 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 convulsions induced by pentylenetetrazol, 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 in the case of cardiotoxicity caused by indinavir and neurotoxicity caused by efavirenz.
The drug should not be used together with other drugs containing meldonium, as the risk of adverse reactions may increase.
Application features
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.
The drug should be used with caution in patients with a history of mild to moderate hepatic and/or renal impairment. During treatment, liver and/or renal function should be monitored in such patients.
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. The drug is contraindicated during pregnancy.
Breastfeeding period.
Available animal data indicate that meldonium is excreted in breast milk. It is not known whether meldonium is excreted in human breast milk. A risk to newborns/infants cannot be excluded, therefore the medicinal product is contraindicated during breast-feeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted to assess the effect on the ability to drive or use machines.
Method of administration and doses
The drug is intended for intravenous use. No special preparation of the solution is required before administration.
Due to the possible stimulating effect, the drug is recommended to be used in the morning.
Adults.
The drug should be administered at a dose of 500–1000 mg (5–10 ml) intravenously in 1 or 2 doses.
The duration of treatment is usually 10–14 days, after which treatment should be 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.
Elderly patients with impaired liver and/or kidney function may require a reduction in the dose of the drug.
Since meldonium is excreted by the kidneys, patients with mild to moderate renal impairment should use a lower dose of the drug.
Patients with liver dysfunction.
Patients with mild to moderate hepatic impairment should use a lower dose of the drug.
Children
There is no data on the safety and efficacy of meldonium in children under 18 years of age, therefore the drug is contraindicated in such patients.
Overdose
Symptoms.
There have been no reports of overdose. Meldonium is low-toxic and does not cause any dangerous side effects. With low blood pressure, headache, dizziness, tachycardia, and general weakness are possible.
Treatment.
Symptomatic therapy. In case of severe overdose, it is necessary to monitor liver and kidney function. Hemodialysis is of no significant importance in case of meldonium overdose due to the pronounced binding to blood proteins.
Side effects
Adverse reactions are classified according to MedDRA system organ class and frequency: common (≥1/100 to <1/10), rare (≥1/10,000 to <1/1,000).
On the part of the immune system:
often - allergic reactions*; rarely - hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions up to shock.
From the psyche:
rarely - agitation, feelings of fear, obsessive thoughts, sleep disturbances.
From the nervous system:
often - headache*, rarely - paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, fainting.
From the heart:
Rare: change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest pain.
From the vascular side:
rarely - increase/decrease in blood pressure, hypertensive crisis, hyperemia, pallor of the skin.
Respiratory, thoracic and mediastinal disorders:
often - respiratory tract infections; rarely - sore throat, cough, dyspnea, apnea.
From the digestive tract:
common – dyspepsia*; rare – dysgeusia (metallic taste in the mouth), loss of appetite, retching, nausea, vomiting, flatulence, diarrhoea, abdominal pain, dry mouth or hypersalivation.
Skin and subcutaneous tissue disorders:
Rare: rash, generalized/macular/papular rash, pruritus.
Musculoskeletal and connective tissue disorders:
rarely - back pain, muscle weakness, muscle spasms.
From the kidneys and urinary tract:
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:
common: dyslipidemia, increased C-reactive protein; rare: electrocardiogram (ECG) abnormalities, tachycardia, eosinophilia*.
* Adverse effects observed in previously conducted uncontrolled clinical trials.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions that occur after the marketing authorisation of a medicinal product is very important. This allows the benefit/risk balance of the medicinal product to be continuously monitored. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging and out of the reach of children.
Do not freeze.
Packaging
5 ml in an ampoule, 5 ampoules in a contour blister pack, 2 contour blister packs together with instructions for medical use in a cardboard box.
Vacation category
According to the recipe.
Producer
Mefar Ilach San. A.Sh./Mefar Ilac San. AS
Address
Ramazanoglu Mach. Ansar Jad. No. 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey/Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.
Applicant
WORLD MEDICINE LLC, Ukraine/WORLD MEDICINE, LLC, Ukraine.
