MILDROCARD-N

MILDROCARD-N

Solution for injection 100 mg/ml 5 ml in ampoules No.10

1 ml of the solution contains 100 mg of 3-(2,2,2- trimethylhydrazinium) propionate dihydrate.

Antihypoxic and cytoprotective product which increases cell load tolerance.

Marketing Authorization No. UA/10376/01/01

Composition

Active ingredient: 3-(2,2,2-trimethylhydrazinium) propionate  dehydrate (meldonium);

1 ml of the solution contains  100 mg of 3-(2,2,2- trimethylhydrazinium) propionate dehydrate (meldonium);

Excipients: water for injections.

Pharmaceutical form

Solution for injection.

Physical and chemical properties: clear colorless liquid.

Pharmacotherapeutic group

Cardiovascular medicinal products. Other cardiac products. ATC Code С01Е В22.

Pharmacological properties

Pharmacodynamics.

Meldonium is the carnitine precursor and the structural analogue of gamma-butyrobetaine (GBB) which has one carbon atom substituted with nitrogen atom. Its effect on human organism may be interpreted in two ways.

  1. Effect on carnitine biosynthesis.

By inhibiting gamma-butyrobetainehydroxylase, meldonium reduces the carnitine biosynthesis and hence inhibits the transportation of longchain fatty acids through cell membranes, so that a heavy detergent – activated non-oxidized fatty acids – is not accumulated in the cells. As the result, it helps to avoid cell membranes damage.

If carnitine concentration is decreased during ischemia, beta-oxidation of fatty acids is restrained and oxygen consumption in cells is optimized; we can see the stimulation of glucose oxidation and re-transportation of ATP from the point of its biosynthesis (mitochondria) to its consumption area (cytosol). As the matter of fact, the cells are supplied with nutritional agents and oxygen and consumption of these agents is optimized as well.

On the other hand, if biosynthesis of carnitine precursor (i.e. GBB) is increased, NO-synthetase is activated which in its turn results in increase of blood rheological properties and decrease of vascular peripheral resistance.

If concentration of meldonium is reduced, the carnitine biosynthesis becomes more intensive and the concentration of fatty acids in cells increases gradually.

It is believed that meldonium efficiency lies in the fact that it increases the tolerance to cell overload (if number of fatty acids is changed).

  1. The role of mediator in hypothetic GBB system.

There is a hypothesis that human organism has the system of neuronal signals transmission – a GBB system which ensures the transmission of nerve impulses between the cells. A GBB ether is the last carnitine precursor which acts as mediator of GBB system. As the result of GBB-esterase effect, mediator gives an electron to the cell, so that it transmits an electric impulse and turns into GBB. Then a GBB hydrolyzed form is actively transported into the liver, kidneys and ovaries where it turns into carnitine. As the reaction to irritation, new GBB molecules are synthesized once again in somatic cells and ensure the signal distribution.

If carnitine concentration is decreased, GBB synthesis is stimulated, which results in increase of GBB ether concentration.

As it has been mentioned above, meldonium is the structural analogue of GBB and may play the role of mediator. By contrast to this, meldonium cannot be detected by GBB-hydroxylase, so carnitine concentration is not increased, but decreased.  Therefore, by replacing the mediator and ensuring the increase of GBB concentration, meldonium causes the relevant organism reaction. As the result, the general metabolic activity increases on other systems, for example, in the central nervous system.

Effect on cardiovascular system.

Based on animal studies, meldonium has positive effect on myocardium contractive activity, it is characterized by myocardium protective effect (including protection against catecholamines and alcohol) and can also avoid the heart rhythm   disorder and reduce the area of myocardial infarction.

Ischemic heart diseases (stable effort angina).

The clinical data on course treatment with meldonium against stable effort angina show that the product reduces the frequency and intensity of angina attacks and the quantity of glyceryl trinitrate intake as well.  The product demonstrates apparent anti-arrhythmic effect among the patients with ischemic heart diseases (IHD) and  ventricular extrasystoles, the lesser effect is observed among the patients with supraventricular extrasystoles.

One of the most significant properties of the product is that it can reduce the oxygen consumption at rest, which in its turn is believed to be the efficient criterion of anti-angina therapy against IHD.

Meldonium has positive effect on atherosclerotic processes in coronary and peripheral vessels which results in decrease of the general cholesterol level in blood serum and atherogenic index as well.

Chronic cardiac failure.

A lot of clinical trials dealt with the function of meldonium for treatment of the chronic cardiac failure being resulted from IHD. It has been reported about its ability to increase the tolerance to physical overload and ability to increase the working capacity among the patients with cardiac failure.

In the event of severe cardiac failure, meldonium should be used in combination with other traditional means for cardiac failure therapy.

Effect on central nervous system.

The animal tests show that meldonium has antihypoxic effect and effect on cerebral blood circulation either. The product optimizes distribution of the blood circulation volumes in favor of ischemic sites. It also increases the neurons’ resistance during hypoxia.

The product is characterized by its stimulating effect on central nervous system which includes the following: increase of physical activity and stamina, behavior reaction stimulation and anti-stress effect (sympathoadrenal system stimulation, accumulation of catecholamines in cerebrum and adrenal glands, protection of internals against the changes caused by stress).

Efficiency during neurological diseases.

It was proved that meldonium is the efficient product used in complex therapy against the acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulatory insufficiency). Meldonium normalizes the tonus and resistance of cerebral capillaries and arteriolas and restores their reactivity.

There were the studies regarding medlonium’s effect on rehabilitation of patients having neurological diseases (after cerebral blood vessels disorders, cerebral surgery, injuries and tick-borne encephalitis).

Results received in connection with meldonium’s therapeutic activity show that the product has dose-dependent positive effect on physical stamina and renovation of functional independence in the process of rehabilitation.

While analyzing the changes of separate and total intellectual functions after the product intake, it was found out that product has positive effect on renovation of the intellectual functions during rehabilitation period. It was proved that meldonium improves the convalescent life quality (mainly due to the renovation of physical function) and eliminates psychological disturbances.

Meldonium has positive effect on nervous system functions: it decreases disturbances among the patients with neurological deficit during their rehabilitation period.

The product helps to improve the general neurological condition of patients (decrease of cerebral nerves injury and reflex pathology, paresis regression, improvement of motor coordination and vegetative functions).

Pharmacokinetics.

The product’s pharmacokinetics was analyzed among the healthy volunteers who took meldonium both intravenously and orally.

Absorption

100% biological availability. The highest concentration in blood plasma (Сmax) appears immediately upon the product’s administration. After intravenous administration of several doses, Сmax becomes  25.5 ± 3.63 mkg/ml.

During the intravenous administration, there is a difference between the areas under concentration-time curve (AUC) due to the single and repeated meldonium doses which may evidence about meldonium accumulation in blood plasma.

Distribution

Meldonioum is rapidly distributed from the blood to the high cardiac affinity tissues. Meldonium and its metabolites  partially go through the placenta barrier. The data on animal studies show that meldonium penetrates into breast milk.

Biological transformation

The studies on experimental animals show that meldonium is mostly metabolized in liver.

Clearance

To clear the organism from meldonium and its metabolites, renal excretion plays an important role. After a single dose of meldonium of 250 mg, 500 mg and 1000 mg, excretion half-life is 5.56-6.55 hours and the final excretion period is 15.34 hours.

Special groups of patients

Elderly patients

Meldonium dose should be reduced among the elderly patients having liver and renal dysfunction and high biological availability.

Renal dysfunction

Meldonium dose should be reduced among the patients having renal dysfunction and high biological availability. There is a correlation between renal re-absorption of meldonium and its metabolites (for example, 3-hydroxymeldonium) and carnitine which leads to the increase of carnitine renal clearance. There is no direct impact of meldonium, GBB and meldonium/GBB combinations on renin-angiotensin-aldosterone system.

Liver dysfunction

Meldonium dose should be reduced among the patients having liver dysfunction and high biological availability. Toxicity studies on rats, where more than 100 mg/kg of meldonium were administered, show that liver acquires yellow color and fats denaturation occur. Histopathological animal studies, where large meldonium doses (400 mg/kg and 1600 mg/kg) were administered, show that lipids are accumulated in liver cells. No changes in liver function were detected during human intake of the large doses (400-80 mg).  The possible fat infiltration in liver cells should not be ruled out.

Children.

Since there is no safety and efficiency data on usage of meldonium by children (under 18 years old), this category of product is contraindicated for such patients group.

Clinical performance

Indications.

As the complex therapy against the following diseases:

- cardiac and vascular diseases: stable effort angina, chronic cardiac failure,  (NYHA, I-III functional class), cardiac myopathy, cardiac and vascular functional deficiency;

- acute and chronic ischemic deficiency of cerebral blood circulation;

- reduced working capacity, physical and psychoemotional overload;

- rehabilitation period after cerebral and vascular events, head injuries and encephalitis.

Contraindications

Hypersensitivity to meldonium, high intracranial pressure (venous drainage disorders, intracranial tumors), severe liver and/or renal failure (no sufficient safety data). Pediatric use. Pregnancy and lactation.

Interaction with other medicinal products and other forms of interaction

Meldonium may be used along with the nitrates of durable effect and other anti-angina products  (stable effort angina), cardiac glycosides and diuretics (cardiac failure). It can also be used in combination with anticoagulants, antiaggregants, antiarrhythmic products and other medicines which improve microcirculation.

Meldonium may intensify the effect of the products containing glyceryl trinitrate, nifedipine, beta-adrenergic blocking agents and other hypotensive products and peripheral vasodilators.

As the result of the simultaneous intake of meldonium and iron, the patients having iron deficiency anemia have better content of fatty acids in erythrocytes.

Additional pharmacological effect can be seen during the intake of meldoniumn along with orotic acid aimed at elimination of the damages caused by ischemia/reperfusion.

Meldonium helps to eliminate pathological cardiac changes caused by azidothymidine (AZT) and indirectly influences upon oxidative stress reactions caused by AZT and which also result in mitochondria dysfunction. When used in combination with azidothymine and other anti AIDS drugs, the product demonstrates positive effect during the treatment of acquired immune deficiency syndrome (AIDS).

Meldonium decreases sleep duration during the statotonic reflex loss test. The product demonstrates apparent anticonvulsant effect during the convulsions caused by pentylenetetrazole. In its turn, when the product is administered after the intake of α2-adrenoreceptor blocking agent yohimbine of 2 mg/kg strength and inhibitor of nitrogen oxide synthase N-(G)-nitroо-L-arginine of 10 mg/kg strength, its antoconvulsant abilities are blocked completely.

The overdose with meldonium may increase the cardiac toxicity caused by cyclophosphamide.

Carnitine deficit caused by meldonium intake may increase the cardiac toxicity caused by iphosphamide.

Meldonium demonstrates protective effect in the case of cardiac toxicity caused by indinavir and neurotoxic effect caused by efavirenz.

The product should not be used along with other drugs containing meldonium, since adverse reactions may appear.

Precautions for use

If product is administered by the patients having slight and moderate liver and/or renal dysfunction in their medical history, such patients should be treated with due care (control over liver and/or renal functions is recommended).

Long-term experience of treatment of the acute myocardium infarction and  unstable angina shows that meldonium is not the first-line drug to treat the acute coronary syndrome.

Pregnancy and lactation.

Pregnancy

There is no sufficient animal studies data  to evaluate the impact of meldonium on pregnancy, embryo/foetus development, labors and postnatal development. Since there is no data on potential risk for humans, the product is contraindicated during the pregnancy.

Breastfeeding.

The animal study data available show that meldonium can penetrate into the breast milk. There is no data on meldonium penetration into human breast milk. The risk for the new-borns and infants should not be excluded, hence the product is contraindicated during the breastfeeding.

Effects on ability to drive and use machines.

No studies available.

Posology and method of administration

Intravenous administration. The product does not require a special preparation before its intake. Due to its agitating effect, the product should be administered before noon.

Adults

Cardiovascular disorders; cerebral blood circulation disorders

500-1000 mg (5-10 ml) per day, the dose should be administered at once or divided into two administrations. The maximum daily dose is 1000 mg.

Reduced working capacity, physical and psychoemotional overload; rehabilitation period after cerebrovascular events, head injuries and encephalitis

500 mg (5 ml) per day. The maximum daily dose is 500 mg.

The treatment course lasts 4-6 weeks. The course may be repeated 2-3 times per year.

Elderly patients

Meldonium dose should be reduced among the elderly patients having liver and renal dysfunction and high biological availability.

Patients with renal dysfunction

Since the product is excreted through kidneys, meldonium dose should be reduced for the patients having slight and moderate renal dysfunction.

Patients with liver dysfunction

Meldonium dose should be reduced for the patients having slight and moderate liver  dysfunction.

Children.

Since there is no safety and efficiency data on usage of meldonium by children (under 18 years old), this category of product is contraindicated for such patients group.

Overdose

There is no data on Mildrocard-N overdose. The product is low-toxic and do not cause critical adverse reactions.

In case of low arterial pressure, there can be headache, dizziness, tachycardia, general weakness. Apply symptomatic treatment.

In case of severe overdose perform the control over renal and liver function.

Hemodialysis is not of great importance during meldonium overdose due to apparent blood protein binding

Adverse reactions

Adverse reactions are classified according to the organs system and  MedDRA frequency of occurrence: often (≥ 1/100 to < 1/10), seldom (≥ 1/10 000 to < 1/1000).

Immune system disorders: often – allergic reactions; seldom –hypersensitivity, including allergic dermatitis, hives, angioedema, anaphylactic reactions extending to shock.

Psychological disorders: seldom–agitation, fear, obsession, sleep disorders.

Nervous system disorders: often –headache; seldom – paresthesia, tremor, hypoesthesia, tinnitus, vertigo, dizziness, gait impairment, presyncope, faint.

Cardiac disorders: seldom – changes of heart rhythm, tachycardia/ sinus tachycardia, auricle fibrillation, arrhythmia, sense of discomfort in chest/chest pain.

Blood circulation disorders: seldom – increse/decrease of arterial tension, hypertensive crisis, hyperemia, pallor.

Respiratory organs, thoracic organs and mediastinum disorders: often – respiratory tract infections; seldom– throat inflammation, cough, dyspnea, apnea.

Gastrointestinal disorders: often – dyspepsia; seldom – dysgeusia (metallic taste), appetite loss, nausea, vomiting, bloat, diarrhea, stomachache, dry mouth, hypersalivation.

Dermal and sub-dermal disorders: seldom – rash, general/macular/popular rash, itching.

Skeletal and muscular and associated system disorders: seldom –backache, muscle weakness, muscle spasm.

Renal and urinary system: seldom– pollakiuria.

General disorders in the site of administration: seldom– general weakness, chills, asthenia, edema, face edema, leg edema, fever, feeling of cold, cold sweat, reactions in the administration site, including pain in the site of administration.

Studies: often – dyslipidemia,  increase of C-reactive protein; seldom– deviations in cardiogram (ECG), acceleration of cardiac performance, eosinophilia.

Shelf life

3 years

Storage conditions

Store in original package at the temperature not above 25 °С. Do not freeze. Keep away from children.

Incompatibility

No data available. The product should not be mixed with other products in one syringe

Package

5 ml in polyethylene ampoules  No. 10 in carton folding boxes.

Prescription category

Following the doctor’s prescription.

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Materials on the medicine

«Медикаментозная реабилитация больных хроническим обструктивным заболеванием легких»

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