International non-proprietary name:Meldonium

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Composition 
Active ingredient:1 ampoule contains 500 mg of meldonium dihydrate.
Auxiliary substance:  water for injection.

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Description
It is a clear, colorless liquid.

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Pharmacotherapeutic group
Other means for the treatment of heart diseases. Metabolic agent.

ATC code:C01EB22.

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Pharmacological properties
Pharmacodynamics 
Meldonium is a drug with psychostimulant, cardioprotective, antihypoxant, metabolic properties. It is the predecessor of carnitine, and according to its chemical structure, it is a structural analog of gamma-butyrobetaine (GBB), which is present in every cell of the human body; differs from the gamma-butyrobetaine molecule in that one carbon atom is replaced by a nitrogen atom. 
Meldonium reversibly inactivates the enzyme γ-butyrobetaine hydroxylase, prevents the synthesis of carnitine and therefore the transport of long-chain fatty acids from the cell membrane, thus preventing the accumulation of activated forms of unoxidized fatty acids, acylcarnitine and acylcoenzyme A derivatives, and their harmful effects. Thus, damage to cell membranes is prevented. Meldonium has a positive effect on the body's energy metabolism. Moderately stimulates the central nervous system and increases resistance to stress. 
In cases of ischemia (lack of oxygen or nutrients, insufficient removal of end products of metabolism), it restores the balance between oxygen delivery and demand in cells, activates metabolic processes that do not require additional oxygen consumption for energy production, eliminates the accumulation of toxic metabolic products in cells and protects against damage; at the same time it has a toning effect. 
Due to these properties, meldonium is used in the treatment of various disorders of the cardiovascular system, as well as to increase blood supply to the brain, physical and mental performance. 
As a result of the decrease in the concentration of carnitine, the synthesis of gamma-butyrobetaine, which has vasodilation properties, increases, the expansion of vessels and thus the blood supply to the tissues improves. 
The mechanism of action of Meldonium determines the diversity of its pharmacological effects: it increases physical work capacity, reduces symptoms of mental and physical stress, activates tissue and humoral resistance, has a cardioprotective effect.  
Effects on the cardiovascular system
Meldonium has a positive effect on myocardial contractility, it has a myocardioprotective effect. It slows down the formation of necrotic area in tissues during acute myocardial infarction, shortens the rehabilitation period. During heart failure, it improves the inotropic function of the myocardium and increases resistance to physical stress, improves the quality of life of patients. It reduces the frequency and intensity of angina attacks in patients with stable tension angina (severe pain in the heart area), as well as reduces the amount of glyceryl trinitrate used.
Effectiveness in disorders of cerebral circulation and neurological diseases
Meldonium normalizes the tone and resistance of cerebral capillaries and arterioles, restores their reactivity in the complex treatment of acute and chronic ischemic disorders of cerebral circulation. The antihypoxic effect of meldonium and its effect on cerebral blood circulation were determined in animal experiments. It improves blood supply by optimizing the distribution of blood circulation volume in ischemic zones, increases the endurance of neurons in hypoxia conditions. It has a tonic effect on the central nervous system - improves memory, accelerates thinking, increases motor activity, stimulates behavioral reactions, increases mental and physical endurance. It also has an anti-stress effect - it stimulates the sympathoadrenal system, ensures the accumulation of catecholamines in the brain and adrenal glands, and strengthens the defense against changes caused by stress in the internal organs.
It has a positive effect on rehabilitation processes in patients with neurological disorders (after brain blood vessel diseases, brain surgery, trauma, tick-borne encephalitis).
Meldonium eliminates functional disorders of the nervous system during abstinence syndrome in patients suffering from chronic alcoholism. 
Pharmacokinetics
When administered intravenously, bioabsorption is 100%. 
The drug is collected in the blood plasma in maximum concentration immediately after injection. 
After intravenous administration of repeated doses, the Cmax of meldonium in blood plasma reached 25.50±3.63 μg/ml. It undergoes metabolism in the liver and is excreted through the kidneys in the form of two main metabolites. The elimination half-life (t1/2) is 3-6 hours depending on the dose. 
Trace concentrations of meldonium remain in the systemic circulation and blood cells for a long time. Meldonium and its metabolites partially pass through the placental barrier and are excreted in breast milk.
Pharmacokinetics in a special group of patients
Patients with liver failure
After the use of Meldonium in doses of 400-800 mg, no changes were observed in the functional indicators of the liver. However, taking into account the high bioavailability of meldonium, the dose of the drug should be adjusted in patients with liver failure.
Patients with renal failure 
Renal reabsorption of meldonium or its metabolites (eg, 3-hydroxymeldonium) and carnitine interact, resulting in increased renal clearance of carnitine. Taking into account the high bioavailability of Meldonium, the dose of the drug should be adjusted in patients with renal failure.
Elderly patients
The dose of the drug should be adjusted in elderly patients with impaired liver and/or kidney function.

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Instructions for use
It is used in complex treatment in the following cases:

• Cardiovascular diseases: ischemic heart disease (IHD) (constant tension angina pectoris, myocardial infarction), chronic heart failure (CHF), cardialgia on the background of dyshormonal cardiomyopathy; 

•  Acute and chronic disorders of cerebral circulation (ischemic stroke, cerebrovascular insufficiency);

•  Hemophthalmos, retinal hemorrhages of various etiologies, thrombosis of the central vein of the retina and its branches, retinopathies of various etiologies (diabetic, hypertensive);

• Impairment of working capacity; psychoemotional and physical stress (including in athletes);

• Abstinence syndrome in patients suffering from chronic alcoholism (combined with specific treatment).

 

Contraindications
Hypersensitivity to the components of the drug.
Organic damage to the central nervous system.
Increased intracranial pressure (when venous flow is disturbed, in intracranial tumors).
 

Pregnancy and lactation period.
Children under 18 years of age (the safety and effectiveness of the drug have not been established). 
Be careful
Severe kidney and/or liver failure (there is insufficient information on the safety of the drug).

Special instructions and precautions
The drug should be used with caution in patients with chronic diseases of the liver and/or kidneys (liver and kidney functions should be checked regularly).
The long-term experience of treatment of acute myocardial infarction and unstable angina in cardiology departments shows that meldonium does not belong to the first-line drugs for the treatment of acute coronary syndrome, and its use should only be based on the doctor's advice. 

 

Interaction with other drugs 
The drug enhances the effect of some hypotensive drugs and cardiac glycosides. 
Meldonium can be used together with antianginal, anticoagulant, antiaggregant, antiarrhythmic, diuretic, broncholytic drugs. The drug can cause arterial hypotension and mild tachycardia. Meldonium can enhance the effect of nitroglycerin, nifedipine, α-adrenoblockers, peripheral vasodilators and other hypotensive agents.

 

Use during pregnancy and lactation 
Pregnancy
There is insufficient data on the use and safety of meldonium in pregnant women. The use of the drug during pregnancy is contraindicated in order to prevent possible negative effects on the development of the embryo and fetus.
Lactation period
The excretion of Meldonium in breast milk and the effect on the health of the baby have not been studied. If it is necessary to use the drug during lactation, breastfeeding should be temporarily stopped.

Effects on the ability to drive vehicles and other potentially dangerous mechanisms
The effect of Meldonium on the ability to drive vehicles and engage in other potentially dangerous activities that require the ability to concentrate and copy psychomotor reactions has not been studied. 

Method of use and dosage
It is recommended to use in the first half of the day (no later than 5:00 PM) due to possible stimulating effect. 
Intravenous, intramuscular, parabulbar injection. 
The dose, method of administration and duration of treatment are selected depending on the indication, the severity of the disease, as well as the general condition of the patient.
Cardiovascular diseases
Ischemic heart disease (myocardial infarction): 0.5-1.0 g per day (5-10 ml solution for injection) is injected intravenously directly (by syringe method). The daily dose is divided into 1 or 2 times. 
Ischemic heart disease (constant tension angina), chronic heart failure and dyshormonal cardiomyopathy: 0.5-1.0 g (solution for injection 5-10 ml) once a day intravenously directly (by syringe) or intramuscularly 0.5 q is injected 1-2 times a day. 
In the complex treatment of cardiovascular diseases, the duration of injection treatment is 10-14 days, then the treatment is continued with internal forms of meldonium. The total course of treatment is 4-6 weeks. If necessary, the treatment can be repeated 2-3 times a year. 
Disorder of cerebral blood circulation
In the acute stage, 0.5 g (5 ml of solution) is injected once a day for 10 days by intravenous injection, then it is continued internally (in the form of oral medicine) from 0.5-1.0 g.
In case of chronic insufficiency of cerebral blood circulation (discirculatory encephalopathy), 0.5 g (5 ml of solution) intramuscularly or intravenously once a day for 10 days, then continued at a dose of 0.5 g in the form of oral medication. The general course of treatment is 4-6 weeks. 
Repeat courses (usually 2-3 times a year) are possible after consulting a doctor.
Impairment of working capacity; psychoemotional and physical stress 
It is prescribed intramuscularly or intravenously at a dose of 0.5 g (5 ml of solution) once a day. 
The duration of treatment is 10-14 days. If necessary, the treatment can be repeated after 2-3 weeks.
Ophthalmopathology (hemophthalmos and retinal hemorrhages of various etiologies, thrombosis of the central vein of the retina, retinopathies of various etiologies (diabetic, hypertensive)): parabulbar injection at a dose of 0.05 g (0.5 ml of solution) for 10 days._cc781905-5cde-3194 -bb3b-136bad5cf58d_
Abstinence syndrome during chronic alcoholism 
A dose of 0.5 g (5 ml of solution) is prescribed 2 times a day orally or intravenously. The course of treatment is 7-10 days.  
Pediatric patients 
The safety and efficacy of meldonium in children younger than 18 years have not been established. For this reason, the use of the drug is not recommended for patients of this age group.
Elderly patients
A dose reduction may be required in elderly patients with liver and/or kidney disease. 
In patients with kidney and/or liver diseases 
The dose of meldonium should be reduced in patients with mild to moderate renal and/or hepatic impairment.

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Side Effects 
Meldonium is less toxic and usually well tolerated by the body. Serious adverse reactions are not observed. Side effects are usually mild and transient. Observed additional reactions are classified according to organ systems and frequency of occurrence as follows: very often (≥1/10); often (≥1/100 to <1/10); sometimes (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10000); with an unknown frequency (the available data are insufficient to determine the frequency of occurrence).
To the cardiovascular system
Rare: vasodilatation; tachycardia, increase or decrease in blood pressure.
To the immune system
Rare: skin rash, angioneurotic edema.
To the nervous system  
Rare: psychomotor alertness.
To the digestive system
Rare: dyspepsia.
To the skin and subcutaneous tissues  
Rare: itching, redness of the skin.
Laboratory and instrumental examinations
Rare: eosinophilia.
General disorders and local reactions
Very rare: general weakness.
Consult a doctor if unwanted effects occur. 

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Overdose 
Symptoms: headache, tachycardia, dizziness and general weakness accompanied by hypotension (lowering of blood pressure).
Treatment: symptomatic treatment should be carried out. 

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Release form   
Solution for injection, 100 mg/ml.  
5 ml solution in an ampoule. 5 ampoules in a contour-slotted package. 2-contour-slot packaging is packed in a cardboard box with an insert. A knife or scarifier can be packed in the box to open the bulb.

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Storage conditions    
It should be stored at a temperature not higher than 25°С, protected from light and out of the reach of children. Do not freeze.

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Expiry date  
3 years. 
Do not use after the expiration date.

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Pharmacy release condition 
It is released on the basis of a prescription.

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Manufacturer 
Biosintez PJSC, Russian Federation.
440033, Drijba Street, Penza, Russian Federation.

Holder of registration card
Biosintez PJSC, Russian Federation.
440033, Drijba Street, Penza, Russian Federation.