Cytocert

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYTOCERT (CYTOCERT)

Composition:

Active substance: 3-(2,2,2-trimethylhydrazinium) propionate dihydrate (meldonium);

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

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Other cardiac preparations. ATC code C01EB22.

Pharmacological Properties.

Pharmacodynamics. Meldonium is a carnitine precursor and a structural analogue of γ-butyrobetaine (GBB), in which one carbon atom is replaced by a nitrogen atom. Its effects on the body can be explained in two ways.

1. Effect on carnitine biosynthesis. Meldonium reversibly inhibits γ-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis and consequently interfering with the transport of long-chain fatty acids across cell membranes. This prevents the accumulation within cells of a potent detergent — activated forms of non-oxidized fatty acids — thus protecting cellular membranes from damage.

Under ischemic conditions, reduced carnitine concentration delays β-oxidation of fatty acids, optimizes cellular oxygen consumption, stimulates glucose oxidation, and restores adenosine triphosphate (ATP) transport from its site of biosynthesis (mitochondria) to its site of utilization (cytosol). Essentially, cells are better supplied with nutrients and oxygen, and utilization of these substances is optimized.

In turn, increased biosynthesis of the carnitine precursor, i.e., GBB, activates NO-synthase, resulting in improved blood rheological properties and reduced peripheral vascular resistance.

When meldonium concentration decreases, carnitine biosynthesis resumes and fatty acid levels gradually increase within cells.

It is believed that the primary basis for meldonium’s efficacy is increased tolerance to cellular stress (due to changes in fatty acid levels).

1. Mediator function in the hypothetical GBB-ergic system. A hypothesis has been proposed that a neuronal signaling system — the GBB-ergic system — exists in the body, responsible for transmitting nerve impulses between cells. The mediator of this system is the final precursor of carnitine — GBB-ether. Under the action of GBB-esterase, the mediator donates an electron to the cell, thereby transferring the electrical impulse and converting 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, in response to stimulation, new GBB molecules are synthesized, ensuring signal propagation.

When carnitine concentration decreases, GBB synthesis is stimulated, leading to increased GBB-ether concentration.

As previously noted, meldonium is a structural analogue of GBB and can perform the function of a "mediator." In contrast, GBB-hydroxylase does not recognize meldonium, so carnitine concentration does not increase but rather decreases. Thus, by replacing the "mediator" and promoting increased GBB concentration, meldonium triggers the corresponding physiological response. As a result, overall metabolic activity increases, including in other systems such as the central nervous system (CNS).

Effect on the cardiovascular system. Animal studies have shown that meldonium positively affects myocardial contractile activity and exhibits myocardial protective effects (including against catecholamines and alcohol). It can prevent cardiac arrhythmias and reduce the size of myocardial infarction.

Ischemic heart disease (stable exertional angina). Clinical data analysis of meldonium treatment in patients with stable exertional angina shows 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 the effect is less pronounced 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.

Meldonium favorably influences atherosclerotic processes in coronary and peripheral vessels by reducing total serum cholesterol and the atherogenic index.

Chronic heart failure. Numerous clinical studies have analyzed the role of meldonium in treating chronic heart failure due to IHD, demonstrating its ability to increase exercise tolerance and the amount of work performed by patients with heart failure.

A separate study conducted at cardiology institutes in Latvia and Tomsk evaluated the efficacy of meldonium in heart failure of functional classes I–III according to the New York Heart Association (NYHA) classification, with moderate severity. Under meldonium therapy, 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified to NYHA class I. It has been established that meldonium improves myocardial inotropic function and increases exercise tolerance, thereby enhancing patients’ quality of life without causing severe adverse effects.

In cases of severe heart failure, meldonium should be used in combination with other conventional heart failure therapies.

Effect on the CNS. Animal experiments have demonstrated meldonium’s anti-hypoxic effects and its influence on cerebral circulation. The drug optimizes redistribution of cerebral blood flow in favor of ischemic areas and enhances neuronal resistance under hypoxic conditions.

Meldonium has a stimulant effect on the CNS — increasing motor activity and physical endurance, stimulating behavioral responses, and exerting anti-stress effects — by stimulating the sympathoadrenal system, increasing catecholamine accumulation in the brain and adrenal glands, and protecting internal organs from stress-induced changes.

Efficacy in neurological disorders. Meldonium has been proven effective as part of combination therapy for acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulatory insufficiency). Meldonium normalizes capillary and arteriolar tone and resistance in the brain and restores their reactivity.

The effect of meldonium on the rehabilitation process in patients with neurological impairments (after cerebrovascular diseases, brain surgery, trauma, or tick-borne encephalitis) has been studied.

Therapeutic activity assessments indicate dose-dependent positive effects of meldonium 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 process of intellectual functions during recovery.

It has been established that meldonium improves convalescent quality of life (primarily by restoring physical function) and alleviates psychological disturbances. Meldonium positively affects nervous system function in patients with neurological deficits during recovery, improving overall neurological status (reducing brain nerve damage and reflex pathology, regression of paresis, improved motor coordination, and autonomic functions).

Pharmacokinetics. Pharmacokinetics were studied in healthy volunteers following intravenous and oral administration of meldonium.

Absorption. Bioavailability is 100%. Maximum plasma concentration (Cmax) is achieved immediately after administration. After intravenous administration of multiple doses, Cmax reaches 25.5±3.63 µg/mL.

Following intravenous administration, the area under the concentration-time curve (AUC) differs after single and repeated doses, indicating potential accumulation of meldonium in plasma.

Distribution. Meldonium rapidly distributes from the bloodstream into tissues with high cardiac affinity. Meldonium and its metabolites partially cross the placental barrier. Animal studies have shown that meldonium penetrates into breast milk.

Biotransformation. Metabolism studies in experimental animals have shown that meldonium is primarily metabolized in the liver.

Elimination. Renal excretion plays a significant role in the elimination of meldonium and its metabolites. After single intravenous doses of meldonium (250 mg, 500 mg, and 1000 mg), the initial elimination half-life ranges from 5.56 to 6.55 hours, while the terminal half-life is 15.34 hours.

Special patient groups.

Elderly patients. In elderly patients with impaired liver and kidney function, where bioavailability is increased, the dose of meldonium should be reduced.

Renal impairment. In patients with impaired renal function, where bioavailability is increased, the meldonium dose should be reduced. There is an interaction between renal reabsorption of meldonium or its metabolites (e.g., 3-hydroxymeldonium) and carnitine, leading to increased renal clearance of carnitine. Meldonium, GBB, and the combination of meldonium/GBB have no direct effect on the renin-angiotensin-aldosterone system (RAAS).

Hepatic impairment. In patients with impaired liver function, where bioavailability is increased, the meldonium dose should be reduced. Toxicity studies in rats administered meldonium at doses exceeding 100 mg/kg showed yellow discoloration of the liver and fat denaturation. Histopathological studies in animals after high-dose meldonium administration (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. No changes in liver function parameters were observed in humans after high-dose administration (400–800 mg). However, fat infiltration into liver cells cannot be ruled out.

Children. There are no data on the safety and efficacy of meldonium use in children (under 18 years of age); therefore, the use of this medicinal product in this patient group is contraindicated.

Clinical characteristics.

Indications. In complex therapy of the following conditions:

• 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 psychoemotional overstrain;
• during the recovery period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium and/or to any of the excipients of the medicinal product;
• increased intracranial pressure (due to impaired venous outflow, intracranial tumors);
• severe hepatic and/or renal insufficiency (there are insufficient data on safety of use).

Interaction with other medicinal products and other forms of interaction.

Meldonium can be used in combination 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.

Meldonium may enhance the effects of drugs containing glyceryl trinitrate, nifedipine, β-adrenoblockers, and other antihypertensive agents and peripheral vasodilators.

As a result of concomitant administration of iron-containing drugs and meldonium in patients with iron-deficiency anemia, improvement in the fatty acid composition of erythrocytes was observed.

When meldonium is used in combination with orotic acid to eliminate ischemia/reperfusion-induced injuries, an additional pharmacological effect is observed.

Meldonium helps eliminate cardiac changes caused by zidovudine (AZT) and indirectly affects oxidative stress reactions induced by AZT, which lead to mitochondrial dysfunction. The use of meldonium in combination with AZT or other drugs for the treatment of acquired immunodeficiency syndrome (AIDS) has a positive impact on AIDS treatment.

In the test of ethanol-induced loss of righting reflex, meldonium reduced the duration of sleep. During seizures induced by pentylentetrazol, a pronounced anticonvulsant effect of meldonium was established. Also, when α2-adrenoblocker yohimbine at a dose of 2 mg/kg and an inhibitor of nitric oxide synthase (NOS) N-(G)-nitro-L-arginine at a dose of 10 mg/kg were administered prior to meldonium therapy, the anticonvulsant effect of meldonium was completely blocked.

Overdose of meldonium may enhance cardiotoxicity caused by cyclophosphamide.

Carnitine deficiency induced by meldonium may enhance cardiotoxicity caused by ifosfamide.

Meldonium exerts protective effects against cardiotoxicity caused by indinavir and neurotoxic effects caused by efavirenz.

Do not use together with other medicinal products containing meldonium, as this may increase the risk of adverse reactions.

Special precautions for use.

Caution is required when administering the drug to patients with a history of mild to moderate hepatic impairment and/or renal impairment (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 meldonium is not a first-line drug in acute coronary syndrome.

Use during pregnancy or breastfeeding.

Pregnancy. There is insufficient animal data available to assess the effects of meldonium on pregnancy, embryonic/fetal development, labor, and postnatal development. The potential risk to humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding period. Available animal study data indicate that meldonium passes into maternal milk. It is unknown whether meldonium is excreted in human breast milk. Risk to newborns/infants cannot be ruled out; therefore, meldonium is contraindicated during breastfeeding.

Effects on ability to drive and use machines. Studies to assess the effect on the ability to drive vehicles or operate machinery have not been conducted.

Method of Administration and Dosage

Intravenous. The medicinal product does not require special preparation prior to administration.

Due to the possible stimulating effect of the drug, it is recommended to administer it in the first half of the day.

Adults. The dose is 500–1000 mg (5–10 mL) intravenously, administered as a single dose or divided into two doses. The treatment duration usually lasts 10–14 days, after which therapy should be continued orally with an oral dosage form.

The total course of treatment lasts 4–6 weeks. The course of treatment may be repeated 2−3 times per year.

Elderly patients. Elderly patients with impaired liver and/or kidney function may require a reduced dose of meldonium.

Patients with impaired kidney function. Since the drug is eliminated through the kidneys, patients with mild to moderate renal impairment should receive a lower dose of meldonium.

Patients with impaired liver function. Patients with mild to moderate hepatic impairment should receive a lower dose of meldonium.

Children. There are no data on the safety and efficacy of meldonium in children (under 18 years of age); therefore, the use of this medicinal product in this patient population is contraindicated.

Overdose.

Cases of meldonium overdose have not been reported. The drug is low in toxicity and does not cause life-threatening adverse effects.

In cases of low arterial pressure, symptoms such as 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 meldonium overdose due to the drug's pronounced binding to blood proteins.

Adverse reactions.

The frequency of adverse reactions was determined according to the classification of the World Health Organization (WHO): very common (≥10%); common (≥1%, but ≤10%); uncommon (≥0.1%, but ≤1%); rare (≥0.01%, but ≤0.1%); very rare (≤0.01%); frequency not known (cannot be estimated based on available data).

Reporting of adverse reactions. Reporting adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 5 ml in an ampoule, 5 ampoules in a blister, 2 blisters per pack.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and location of operations.
36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.