Trizipine

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

Composition:

Active substance: meldonium;

1 ampoule 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 γ-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 γ-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis. As a result, it interferes with the transport of long-chain fatty acids across cell membranes, thus preventing the accumulation of strong detergents—activated forms of non-oxidized fatty acids—within cells. This mechanism helps prevent damage to cellular membranes.

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

When biosynthesis of the carnitine precursor—i.e., 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 gradually increases the amount of fatty acids in cells.

It is believed that the basis of meldonium's efficacy lies in increasing cellular tolerance to metabolic stress (associated with 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 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, new GBB molecules are synthesized in response to stimulation, ensuring signal propagation.

When carnitine concentration decreases, GBB synthesis is stimulated, leading to increased concentration of GBB ester.

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

Effect on the Cardiovascular System

Animal studies have demonstrated that meldonium positively influences myocardial contractile activity. It exhibits cardioprotective 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 amount of nitroglycerin used. The drug exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while a weaker 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 affects atherosclerotic processes in coronary and peripheral vessels by reducing total serum cholesterol and the atherogenic index.

Chronic Heart Failure

In a relatively large number of clinical studies, the role of meldonium in the treatment of chronic heart failure due to IHD has been analyzed, with noted ability to increase tolerance to physical exertion and the amount of work performed by patients with heart failure.

In a separate study conducted at cardiology institutes in Latvia and Tomsk, the efficacy of meldonium was evaluated in patients with NYHA functional class I–III moderate-severity heart failure. Under meldonium therapy, 59–78% of patients initially diagnosed with functional class II heart failure were reclassified into functional class I. It has been established that meldonium improves myocardial inotropic function and increases tolerance to physical exertion, thereby improving 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 increases neuronal resistance under hypoxic conditions.

Meldonium 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

It has been demonstrated that meldonium is an effective agent 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 therapeutic activity assessments indicate dose-dependent positive effects of meldonium 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 process of intellectual functions during convalescence.

It has been established that meldonium improves convalescent quality of life (primarily due to restoration of physical function) and eliminates psychological disturbances.

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

Overall neurological status improves (reduction in brain nerve damage and reflex pathology, regression of paresis, improved motor coordination, and autonomic functions).

Pharmacokinetics

Pharmacokinetics were studied in healthy volunteers after 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 250 mg, 500 mg, and 1000 mg, the early elimination half-life of meldonium 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 is increased, the dose of meldonium should be reduced.

Renal Impairment

In patients with impaired renal function, where bioavailability is 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 (RAAS).

Hepatic Impairment

In patients with impaired liver function, where bioavailability is increased, the dose of meldonium should be reduced. Toxicity studies in rats administered meldonium at doses exceeding 100 mg/kg revealed 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) showed lipid accumulation in liver cells. No changes in liver function parameters were observed in humans after administration of high doses (400–800 mg). However, possible fat infiltration of liver cells cannot be excluded.

Children

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

Clinical characteristics.

Indications.

As part of combination therapy for the following conditions:

• Cardiovascular diseases: stable exertional angina, chronic heart failure (NYHA functional class I–III), cardiomyopathy, functional disorders of heart and vascular system;
• Acute and chronic ischemic cerebrovascular disorders;
• Reduced work capacity, physical and psychoemotional overstrain;
• During convalescence period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

Hypersensitivity to the drug components, increased intracranial pressure (due to impaired venous outflow, intracranial tumors), severe hepatic and/or renal insufficiency (insufficient safety data available).

Interaction with other medicinal products and other forms of interaction.

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 may also be combined with anticoagulants, antiplatelet agents, antiarrhythmics, and other drugs improving microcirculation.

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

When administered concomitantly with iron preparations, meldonium improved fatty acid composition in erythrocytes in patients with iron-deficiency anemia.

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

Meldonium helps eliminate cardiac pathology 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 anti-AIDS drugs has a beneficial effect in the treatment of AIDS.

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentylentetrazole, meldonium demonstrated pronounced anticonvulsant activity. However, when α2-adrenoblocker yohimbine at a dose of 2 mg/kg and nitric oxide synthase (NOS) inhibitor 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 neurotoxicity caused by efavirenz.

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

Special precautions for use.

Caution should be exercised when administering the drug to patients with mild or moderate hepatic and/or renal impairment (liver and/or kidney function should be monitored). Long-term experience in treating acute myocardial infarction and unstable angina in cardiology departments shows that meldonium is not a first-line agent 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, parturition, and postnatal development. The potential risk in humans is unknown; therefore, meldonium is contraindicated during pregnancy.

Breastfeeding period.

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

Ability to affect reaction rate while driving or operating machinery.

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

Mode of Administration and Dosage

Intravenous. The use of 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. The daily dose may be administered once or divided into two doses. The duration of treatment is usually 10–14 days, after which therapy should be continued with an oral dosage form.

The total treatment course lasts 4–6 weeks. The 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 excreted 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 are no data on the safety and efficacy of meldonium in children under 18 years of age; therefore, the use of meldonium 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 reduced 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 protein binding.

Adverse reactions.

Adverse effects are classified by organ systems and MedDRA frequency categories: common (≥ 1/100, < 1/10), rare (≥ 1/10,000, < 1/1,000).

Adverse effects observed in clinical trials 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 – excitement, fear, obsessive thoughts, sleep disturbances.

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

Cardiac disorders: rare – change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest 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: fatigue, chills, asthenia, edema, facial swelling, leg swelling, feeling of warmth, feeling of cold, 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.

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) per cardboard pack.

Prescription category.

Prescription only.

Manufacturer.

MICROCHEM LLC (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of business activity.

5, Budyndustrії Street, Kyiv, 01013, Ukraine.

Marketing Authorization Holder.

MICROCHEM LLC.

Address of the Marketing Authorization Holder.

5, Budyndustrії Street, Kyiv, 01013, Ukraine.

To report adverse events during the use of this medicinal product, please call +38 (050) 309-83-54 (24/7).

INSTRUCTION

for medical use of the medicinal product

TRIZIPIN

(TRIZIPIN)

Composition:

Active ingredient: meldonium;

1 ampoule 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 precursor of carnitine 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. As a result, it interferes with the transport of long-chain fatty acids across cellular membranes, thus preventing the accumulation within cells of a potent detergent—activated forms of non-oxidized fatty acids. This mechanism helps prevent damage to cellular membranes.

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

When biosynthesis of carnitine precursor (i.e., GBB) increases, nitric oxide synthase (NO-synthase) is activated, improving blood rheological properties and reducing peripheral vascular resistance.

When meldonium concentration decreases, carnitine biosynthesis resumes and gradually increases the intracellular concentration of fatty acids.

It is believed that the efficacy of meldonium is primarily based on increasing cellular tolerance to metabolic stress (associated with 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 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-ether.

As previously mentioned, meldonium is a structural analogue of GBB and can perform mediator functions. However, 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 a corresponding physiological response. As a result, overall metabolic activity increases, including in other systems such as the central nervous system (CNS).

Effects on the Cardiovascular System

Animal studies have demonstrated that meldonium positively influences myocardial contractility and exhibits myocardial protective effects (including protection against catecholamines and alcohol). It can prevent cardiac arrhythmias and reduce the size of myocardial infarction.

Ischemic Heart Disease (Stable Angina Pectoris)

Analysis of clinical data on the course use of meldonium in the treatment of stable exertional angina shows that the drug reduces the frequency and intensity of angina attacks, as well as the need for glyceryl trinitrate. Meldonium exerts a pronounced antiarrhythmic effect in patients with ischemic heart disease (IHD) and ventricular extrasystoles, although the effect is less pronounced in patients with supraventricular extrasystoles.

Of particular importance is the drug’s ability to reduce oxygen consumption at rest, which is considered an effective criterion for antianginal therapy in IHD.

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

Chronic Heart Failure

In a number of clinical studies, the role of meldonium in the treatment of chronic heart failure due to IHD has been evaluated, with observed improvements in exercise tolerance and the amount of work performed by patients with heart failure.

In a separate study conducted at cardiology institutes in Latvia and Tomsk, the efficacy of meldonium was tested in patients with NYHA functional class I–III moderate-severity heart failure. Under meldonium therapy, 59–78% of patients initially diagnosed with NYHA class II heart failure were reclassified into NYHA class I. It has been established that meldonium improves myocardial inotropic function, increases exercise tolerance, 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.

Effects on the CNS

Animal experiments have demonstrated the antihypoxic effects of meldonium 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.

Meldonium has a stimulatory 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 complex therapy for acute and chronic cerebral circulation disorders (ischemic stroke, chronic cerebral circulatory insufficiency). It 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 therapeutic activity assessments indicate dose-dependent positive effects of meldonium on physical endurance and restoration of functional independence during recovery.

Analysis of changes in individual and overall intellectual functions after meldonium administration revealed a positive impact on the recovery of intellectual functions during convalescence.

It has been established that meldonium improves convalescent quality of life (primarily due to restoration of physical function) and eliminates psychological disturbances.

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

Overall neurological status improves (reduction in 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 (C_max) is achieved immediately after administration. After intravenous administration of multiple doses, C_max 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 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 250 mg, 500 mg, and 1000 mg, the early elimination half-life of meldonium ranges from 5.56 to 6.55 hours, and the terminal elimination half-life is 15.34 hours.

Special Patient Populations

Elderly Patients

In elderly patients with impaired liver and kidney function, where bioavailability may be increased, meldonium dosage should be reduced.

Renal Impairment

In patients with impaired renal function and increased bioavailability, meldonium dosage 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 (RAAS).

Hepatic Impairment

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

Children

There are no data on the safety and efficacy of meldonium in children under 18 years of age; therefore, its use 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 the heart and vascular system;
• acute and chronic ischemic disorders of cerebral circulation;
• reduced work capacity, physical and psychoemotional overstrain;
• during convalescence period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

Hypersensitivity to the components of the drug, increased intracranial pressure (due to 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 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.

Concomitant use of iron-containing preparations 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 counteract ischemia/reperfusion-induced injuries, an additional pharmacological effect is observed.

Meldonium helps eliminate cardiac damage 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 effect in the management 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 demonstrated. However, when the α2-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 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 in combination with other products containing meldonium, as this may increase the risk of adverse reactions.

Special precautions for use.

Caution should be exercised when administering the drug to patients with mild or moderately severe hepatic and/or renal impairment (liver and/or kidney function should be monitored). Long-term experience in treating acute myocardial infarction and unstable angina in cardiology departments shows that mildronate 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 mildronate on pregnancy, embryo/fetal development, parturition, and postnatal development. The potential risk in humans is unknown; therefore, mildronate is contraindicated during pregnancy.

Breastfeeding period.

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

Ability to affect reaction speed when driving or operating machinery.

Studies evaluating the effect on the ability to drive or operate machinery have not been conducted.

Method of Administration and Dosage.

Intravenous use. 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. The dose may be administered once or divided into 2 doses. The treatment duration is usually 10–14 days, after which therapy should be continued with an oral dosage form.

The total treatment course lasts 4–6 weeks. The 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 impaired kidney function.

Since the drug is excreted by the kidneys, patients with mild to moderate kidney impairment should receive a lower dose of meldonium.

Patients with impaired liver function.

Patients with mild to moderate liver 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, meldonium is contraindicated in this patient group.

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 reduced arterial 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 the drug's pronounced binding to blood proteins.

Side effects.

Adverse effects are classified by organ systems and MedDRA frequency terms: common (≥ 1/100, < 1/10), rare (≥ 1/10,000, < 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 – excitement, 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 – change in heart rhythm, palpitations, tachycardia/sinus tachycardia, atrial fibrillation, arrhythmia, chest discomfort/chest 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 rash, 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: general weakness, chills, asthenia, edema, facial edema, leg edema, feeling of heat, feeling of cold, cold sweat, injection site reactions including pain at injection site.

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

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.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM PHARMACEUTICAL COMPANY LTD.

Manufacturer's address and location.

33 Lenin St., Rubizhne, Luhansk region, 93000, Ukraine.

Marketing Authorization Holder.

MICROCHEM PHARMACEUTICAL COMPANY LTD.

Address of the Marketing Authorization Holder.

5 Budynstustriyi St., Kyiv, 01013, Ukraine.

You can report adverse events associated with the use of this medicinal product at +38 (050) 309-83-54 (24/7).