Cytoseiv®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYTOSEYV® (CITOSAVE)

Composition:

Active substance: meldonium (meldonium);

1 vial of 5 ml contains 0.5 g of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate;

Excipient: water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Other cardiac preparations. Meldonium. ATC code C01EB22.

Pharmacological Properties.

Pharmacodynamics.

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

1. Effect on Carnitine Biosynthesis

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis and consequently preventing the transport of long-chain fatty acids across cellular membranes. This prevents the accumulation within cells of a strong detergent—activated forms of non-oxidized fatty acids—and thus protects cellular membranes from damage.

Under ischemic conditions, reduced carnitine concentration leads to inhibition of fatty acid β-oxidation, 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 supplied with nutrients and oxygen, and the utilization of these substances is optimized.

When biosynthesis of the carnitine precursor—GBB—increases, nitric oxide (NO) synthase is activated, 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 efficacy of meldonium is primarily based on 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 transmission system—the GBB-ergic system—exists in the body, responsible for transmitting nerve impulses between cells. The mediator of this system is the final carnitine precursor—GBB ester. Under the action of GBB esterase, the mediator donates an electron to the cell, thereby transferring an electrical impulse, and is converted 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 concentration of GBB ester.

As previously mentioned, 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 induces a 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. It exhibits myocardial protective 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 of stable angina pectoris with meldonium has shown that the drug reduces the frequency and intensity of angina attacks, as well as the need for glyceryl trinitrate. The drug exerts a pronounced antiarrhythmic effect 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.

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 the treatment of chronic heart failure due to IHD, noting its ability to increase tolerance to physical exertion 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, increases tolerance to physical exertion, and enhances 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 increases neuronal resistance under hypoxic conditions.

The drug 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, 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 in the complex therapy of acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulatory insufficiency). Meldonium normalizes the tone and resistance of cerebral capillaries and arterioles 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.

Results of evaluating meldonium’s therapeutic activity indicate its dose-dependent positive effect on physical endurance and restoration of functional independence during recovery.

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 meldonium improves convalescent quality of life (primarily by restoring physical function) and eliminates psychological disturbances.

Meldonium has a positive effect on nervous system function, reducing neurological deficits during recovery.

Overall neurological status improves (reduced 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 plasma 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 maternal 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, and the terminal elimination half-life is 15.34 hours.

Special Patient Groups

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

Renal Impairment. In patients with impaired kidney function, where bioavailability may be increased, the dose of meldonium should be reduced. 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. Meldonium, GBB, and the combination of meldonium/GBB have no direct effect on the renin-angiotensin-aldosterone system.

Hepatic Impairment. In patients with impaired liver function, where bioavailability may be increased, the dose of meldonium 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 administration of high meldonium doses (400 mg/kg and 1600 mg/kg) revealed lipid accumulation in liver cells. No changes in liver function parameters were observed in humans after administration of high doses (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 disorders:

• diseases of the heart and vascular system: stable exertional angina, chronic heart failure (NYHA functional class I–III), cardiomyopathy, functional disorders of heart and vascular system activity;
• acute and chronic ischemic disorders of cerebral circulation;
• reduced work capacity, physical and psychoemotional overstrain;
• during convalescence after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

Hypersensitivity to the components of the medicinal product, 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 types of interactions.

Meldonium can be used in combination with prolonged-action nitrates and other antianginal agents (for stable exertional angina), cardiac glycosides, and diuretics (for heart failure). It can also be combined with anticoagulants, antiplatelet agents, antiarrhythmic agents, and other drugs improving microcirculation.

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

Simultaneous administration of iron-containing drugs and meldonium in patients with iron-deficiency anemia improved the fatty acid composition in erythrocytes.

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 pathological 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 zidovudine or other drugs for AIDS treatment has a positive impact in the treatment of AIDS.

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazole, a pronounced anticonvulsant effect of meldonium was established. In turn, pretreatment with 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 completely blocks the anticonvulsant effect of meldonium.

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 products containing meldonium, as the risk of adverse reactions may increase.

Special precautions for use.

Caution should be exercised when administering the medicinal product to patients with a history of mild to moderate hepatic 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 for 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, parturition, and postnatal development. The potential risk to humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding.

Available animal studies indicate that meldonium passes into maternal milk. It is unknown whether meldonium passes into human breast milk. A risk to newborns/infants cannot be ruled out; therefore, meldonium is contraindicated during breastfeeding.

Ability to affect reaction rate while driving or operating machinery.

Studies to assess the impact on the ability to drive or operate machinery have not been conducted.

Method of administration and dosage.

Intravenous. The drug does not require special preparation prior to administration. Due to the possible stimulating effect, the drug is recommended to be administered in the first half of the day.

Adults.

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

The total course duration is 4–6 weeks. The treatment course 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 renal impairment.

Since the drug is eliminated via the kidneys, patients with mild to moderate renal impairment should receive a lower dose of meldonium.

Patients with hepatic impairment.

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

Children.

There is a lack of data on the safety and efficacy of meldonium in children (under 18 years of age); therefore, meldonium is contraindicated in this patient population.

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 blood pressure, headache, dizziness, tachycardia, and general weakness may occur. Treatment is symptomatic.

In case of severe overdose, liver and kidney functions should be monitored.

Hemodialysis is not significantly effective in meldonium overdose due to extensive protein binding in the blood.

Adverse Reactions

Adverse effects are classified by organ systems and frequency of occurrence according to MedDRA (Medical Dictionary for Regulatory Activities): common (≥ 1/100 to < 1/10), rare (≥ 1/10,000 to < 1/1,000).

Adverse effects observed in clinical studies and during the post-marketing period:

Immune system disorders: common — allergic reactions*; rare — hypersensitivity, including allergic dermatitis, urticaria, angioedema, anaphylactic reactions up to shock.

Psychiatric disorders: rare — agitation, fear, obsessive thoughts, sleep disturbances.

Nervous system disorders: common — headache*; rare — paresthesia, tremor, hypesthesia, tinnitus, vertigo, dizziness, gait disturbance, pre-syncope, syncope.

Cardiac disorders: rare — heart rhythm changes, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/pain.

Vascular disorders: rare — increased/decreased blood pressure, hypertensive crisis, hyperemia, pallor.

Respiratory, thoracic and mediastinal disorders: common — respiratory tract infections; rare — pharyngitis, cough, dyspnea, apnea.

Gastrointestinal disorders: common — dyspepsia*; rare — dysgeusia (metallic taste in mouth), loss of appetite, nausea, vomiting, flatulence, diarrhea, abdominal pain, dry mouth or hypersalivation.

Skin and subcutaneous tissue disorders: rare — rash, generalized/maculopapular/papular eruptions, pruritus.

Musculoskeletal and connective tissue disorders: rare — back pain, muscle weakness, muscle spasms.

Renal and urinary disorders: rare — pollakiuria.

General disorders and administration site conditions: rare — general weakness, chills, asthenia, swelling, facial edema, leg edema, hot flushes, cold sensation, cold sweat, injection site reactions, including pain at injection site.

Investigations: common — dyslipidemia, increased C-reactive protein level; rare — electrocardiogram (ECG) abnormalities, increased heart rate, eosinophilia*.

* Adverse effects observed in previously conducted uncontrolled clinical trials.

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

Shelf life.

5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging.

5 ml in ampoules, 10 ampoules (5×2) in a cardboard pack or 10 ampoules (10×1) in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhim-Kharkiv" (responsible for manufacturing and batch control/testing, excluding batch release).

LLC Scientific and Production Firm "MIKROKHIM" (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of operations.

Ukraine, 61115, Kharkiv region, Kharkiv, Severina Pototskogo St., 36 (Private Joint-Stock Company "Lekhim-Kharkiv").

Ukraine, 01013, Kyiv, Budynstustriyi St., 5 (LLC Scientific and Production Firm "MIKROKHIM").

Marketing Authorization Holder.

LLC Scientific and Production Firm "MIKROKHIM".

Address of the Marketing Authorization Holder.

Ukraine, 01013, Kyiv, Budynstustriyi St., 5.

You can report an adverse event associated with the use of this medicinal product by calling: +38 (050) 309-83-54 (24/7).