Trizipine®

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

Composition:

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

One tablet contains 250 mg of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate;

Excipients: potato starch, povidone, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, hydroxypropyl cellulose, talc, titanium dioxide (E 171), hydroxypropylmethylcellulose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties.

White or white with cream shade tablets with a biconvex smooth surface, possibly with a specific odor, coated with a film layer.

Pharmacotherapeutic group. ATC Code.

Other cardiac preparations. Mildronate. 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. Influence on carnitine biosynthesis.

Meldonium reversibly inhibits gamma-butyrobetaine hydroxylase, thereby reducing carnitine biosynthesis and consequently preventing the transport of long-chain fatty acids across cell 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 delays beta-oxidation of fatty acids, 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, 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 intensifies again, and the amount of fatty acids gradually increases within cells.

It is believed that the effectiveness of meldonium is based on increased tolerance to cellular stress (due to changes in fatty acid levels).

1. Function as a mediator in the hypothetical GBB-ergic system.

A hypothesis has been proposed that the organism contains a neuronal signal transmission system—the GBB-ergic system—which mediates nerve impulse transmission between cells. The mediator of this system is the final carnitine precursor—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 testes, 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, increasing the concentration of GBB ether.

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 decreases. Thus, meldonium itself, by replacing the "mediator," and by promoting increased GBB concentration, induces the 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 contractile activity, possesses 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 and decreases the need for glyceryl trinitrate. The drug exhibits pronounced antiarrhythmic effects in patients with ischemic heart disease (IHD) and ventricular extrasystoles, while a milder 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.

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

In a separate study, the efficacy of meldonium was evaluated in NYHA functional class I-III heart failure of moderate severity. Under meldonium therapy, 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, enhances quality of life, and does not cause severe adverse effects. However, mild hypotension may occur with meldonium. Other possible adverse effects include skin allergic reactions, headaches, and epigastric discomfort.

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 anti-hypoxic action of meldonium and its beneficial effect 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 CNS-stimulating properties—increased motor activity and physical endurance, stimulation of behavioral responses—and anti-stress effects—activation of the sympathoadrenal system, accumulation of catecholamines in the brain and adrenal glands, and protection of internal organs against 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 capillary and arteriolar tone and resistance in the brain and restores their reactivity.

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 assessment 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 (mainly due to restoration of physical function) and eliminates psychological disturbances.

Meldonium exerts a positive influence 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.

Absorption

After a single oral dose, maximum plasma concentration (Cmax) is 2.23–2.43 µg/mL, and after repeated dosing, 2.77 µg/mL. Time to reach maximum plasma concentration (tmax) is 1–3 hours. Oral bioavailability is 78%. Food slightly delays absorption.

Distribution

Meldonium rapidly distributes from the bloodstream into tissues. The volume of distribution is 88.07±8.56 L. Plasma protein binding is 78%. Meldonium and its metabolites partially cross the placental barrier.

Biotransformation

Studies on metabolism 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 a single oral dose, the early elimination half-life (t1/2) of meldonium is approximately 3.5–4 hours. With repeated dosing, the elimination half-life differs. These results suggest possible accumulation of meldonium in plasma.

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, 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.

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 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 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 in children; therefore, its use in this patient group is contraindicated.

Clinical characteristics.

Indications.

In complex therapy in the following cases:

• 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 psycho-emotional overstrain;
• during convalescence period after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium and/or to any excipient 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.

TRIZIPIN® can be used concomitantly with antianginal agents, anticoagulants, antiaggregants, antiarrhythmic agents, cardiac glycosides, diuretics, and other drugs.

TRIZIPIN® potentiates the effects of nitroglycerin, nifedipine, β-adrenoblockers, antihypertensive agents, and peripheral vasodilators.

Simultaneous administration 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 eliminate ischemia/reperfusion-induced injuries, an additional pharmacological effect is observed.

Meldonium helps eliminate pathological changes in the heart 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 treatment of acquired immunodeficiency syndrome (AIDS).

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazol, pronounced anticonvulsant action of meldonium was established. In turn, pretreatment with 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 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 induced by indinavir and neurotoxicity induced by efavirenz.

Do not take meldonium tablets together with other preparations containing meldonium, as this may increase the risk of adverse reactions.

Special precautions for use.

Use with caution in patients with chronic liver or kidney diseases.

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.

Due to the possible development of stimulating effects, it is recommended to administer TRIZIPIN® in the first half of the day.

Use during pregnancy or breastfeeding.

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

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

Ability to influence reaction speed when driving vehicles or operating machinery.

Patients should be warned to exercise caution when operating potentially hazardous machinery or driving vehicles, as psychomotor excitation and dizziness may occur.

Method of administration and dosage.

For oral use. Due to the possible stimulating effect, the drug is recommended to be taken in the first half of the day.

Adults

Heart and vascular diseases, cerebral circulation disorders.

The dose is 500–1000 mg per day. The daily dose may be taken all at once or divided into 2 doses. The maximum daily dose is 1000 mg.

Reduced work capacity, overstrain, and recovery period.

The dose is 500 mg per day. The daily dose may be taken all at once or divided into two individual doses. 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

In elderly patients with impaired liver and/or kidney function, a dose reduction of meldonium may be necessary.

Patients with impaired kidney function

Since the drug is excreted from the body through the kidneys, patients with mild to moderate kidney impairment should receive a reduced dose of meldonium.

Patients with impaired liver function

Patients with mild to moderate liver impairment should receive a reduced dose of meldonium.

Children.

There is no data on the safety and efficacy of meldonium in children; therefore, the use of meldonium in this patient group is contraindicated.

Overdose.

Cases of meldonium overdose have not been reported. The drug is low-toxic 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 its pronounced protein binding.

Adverse reactions.

Adverse reactions are classified by organ systems and frequency of occurrence according to MedDRA: common (≥ 1/100 to < 1/10), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000). Side effects observed in clinical trials and post-marketing period:

Immune system disorders: common – allergic reactions; rare – hypersensitivity, including allergic dermatitis, urticaria, rash, angioneurotic edema, anaphylactic shock.

Psychiatric disorders: rare – excitement, fear, obsessive thoughts, sleep disturbances.

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

Blood and lymphatic system disorders: common – dyslipidemia, increased C-reactive protein level; rare – eosinophilia.

Cardiac disorders: rare – change in heart rhythm, palpitations, tachycardia/sinus tachycardia, arrhythmia, changes in blood pressure, atrial fibrillation, chest discomfort/chest pain, hypertensive crisis, hyperemia, pallor of the skin, electrocardiogram (ECG) abnormalities, increased heart rate.

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

Gastrointestinal disorders: common – dyspeptic symptoms; rare – diarrhea, nausea, vomiting, abdominal pain, flatulence, metallic taste in mouth, loss of appetite, dry mouth or hypersalivation.

Skin and subcutaneous tissue disorders: rare – generalized/maculopapular/papular rash.

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 – chills, weakness, hyperthermia, increased sweating, asthenia, swelling, facial swelling, leg swelling, feeling of warmth, feeling of cold, cold sweat.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

40 tablets in a polymer bottle in a cardboard box.

Or 40 tablets (10×4) in blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

5, Budyndustrії Street, Kyiv, 01013, Ukraine.

INSTRUCTION

for medical use of medicinal product

TRIZIPIN®

(TRIZIPIN)

Composition:

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

One tablet contains 250 mg of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate;

Excipients: potato starch, povidone, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, hydroxypropyl cellulose, talc, titanium dioxide (E 171), hydroxypropyl methylcellulose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties.

White or almost white, biconvex smooth-surfaced tablets, which may have a specific odor, coated with a film coating.

Pharmacotherapeutic group. ATC code.

Other cardiac preparations. Mildronate. 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 effects on the body can be explained in two ways.

1. Influence on carnitine biosynthesis.

Meldonium reversibly inhibits gamma-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 beta-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 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, improving blood rheological properties and reducing peripheral vascular resistance.

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

It is believed that the effectiveness of meldonium is primarily based on enhanced 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 signal transmission system—the GBB-ergic system—exists in the body, responsible for transferring nerve impulses between cells. The mediator of this system is the final carnitine precursor—GBB-ether. Under the action of GBB-esterase, the mediator donates an electron to the cell, thereby transmitting the electrical impulse and converting into GBB. The hydrolyzed form of GBB is then actively transported to the liver, kidneys, and testes, 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-ether.

As previously mentioned, 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, both by replacing the "mediator" and promoting increased GBB concentration, induces 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, exhibits cardioprotective properties (including protection against catecholamines and alcohol), prevents cardiac arrhythmias, and reduces the size of myocardial infarction.

Ischemic heart disease (stable exertional angina).

Analysis of clinical data on the course treatment of stable exertional angina with meldonium 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, although a lesser effect is observed in patients with supraventricular extrasystoles.

Particularly important is the drug’s ability to reduce oxygen consumption at rest, 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.

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

In a separate study, the efficacy of meldonium was evaluated in NYHA functional class I–III heart failure of moderate severity. Under meldonium therapy, 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, increases tolerance to physical exertion, enhances patients’ quality of life, and does not cause severe adverse effects. However, mild hypotension may occur. Other possible adverse effects of meldonium include skin allergic reactions, headaches, and epigastric discomfort.

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 meldonium’s anti-hypoxic effects and its ability to improve cerebral blood flow. The drug optimizes redistribution of cerebral blood flow in favor of ischemic areas and increases neuronal resistance under hypoxic conditions.

The drug has stimulatory effects 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 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 impact on the recovery process of intellectual functions during convalescence.

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

Meldonium exerts a positive influence 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.

Absorption

After a single oral dose, maximum plasma concentration (Cmax) ranges from 2.23 to 2.43 µg/mL, and after repeated dosing, it reaches 2.77 µg/mL. Time to reach maximum plasma concentration (tmax) is 1–3 hours. Oral bioavailability is 78%. Food slightly delays absorption.

Distribution

Meldonium rapidly distributes from the bloodstream into tissues. The volume of distribution is 88.07 ± 8.56 L, and plasma protein binding is 78%. Meldonium and its metabolites partially cross the placental barrier.

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 a single oral dose, the early elimination half-life (t1/2) of meldonium is approximately 3.5–4 hours. With repeated dosing, the elimination half-life differs. These results suggest possible accumulation of meldonium in plasma.

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 renal 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 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 administration of high doses (400–800 mg). However, possible fat infiltration into liver cells cannot be excluded.

Children

There are no data on the safety and efficacy of meldonium in children; therefore, its use in this patient group is contraindicated.

Clinical characteristics.

Indications.

In complex therapy in the following cases:

• 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 psycho-emotional overstrain;
• during convalescence after cerebrovascular disorders, head injuries, and encephalitis.

Contraindications.

• Hypersensitivity to meldonium and/or to any excipient of the drug;
• 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 types of interactions.

TRIZIPIN® can be used concomitantly with antianginal agents, anticoagulants, antiaggregants, antiarrhythmics, cardiac glycosides, diuretics, and other drugs.

TRIZIPIN® potentiates the effects of nitroglycerin, nifedipine, β-adrenoblockers, antihypertensive agents, and peripheral vasodilators.

In patients with iron-deficiency anemia, combined use of iron-containing drugs and meldonium 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 pathological changes in the heart 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 the treatment of AIDS has a positive effect in the treatment of acquired immunodeficiency syndrome (AIDS).

In the test of ethanol-induced loss of righting reflex, meldonium reduced sleep duration. In seizures induced by pentetrazol, a pronounced anticonvulsant effect of meldonium was established. In turn, when α2-adrenoblocker yohimbine at a dose of 2 mg/kg and a nitric oxide synthase inhibitor (NOS) N-(G)-nitro-L-arginine at a dose of 10 mg/kg were administered before 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 has a protective effect against cardiotoxicity caused by indinavir and neurotoxicity caused by efavirenz.

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

Special precautions for use.

Use with caution in chronic liver and kidney diseases.

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.

Due to the possible development of stimulating effects, it is recommended to administer TRIZIPIN® in the first half of the day.

Use during pregnancy or breastfeeding.

Animal studies are insufficient to assess the effects of meldonium on pregnancy, embryo/fetal development, delivery, and postnatal development. The potential risk in humans is unknown; therefore, meldonium is contraindicated during pregnancy.

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

Ability to affect reaction speed when driving vehicles or operating machinery.

Patients should be warned to exercise caution when operating potentially hazardous machinery and when driving vehicles, as psychomotor excitation and dizziness may occur.

Method of Administration and Dosage

For oral use. Due to the possible stimulating effect, the drug is recommended to be taken in the first half of the day.

Adults

Cardiovascular diseases, cerebral circulation disorders.

The dose is 500–1000 mg per day. The daily dose may be taken all at once or divided into two doses. The maximum daily dose is 1000 mg.

Reduced work capacity, overexertion, and recovery period.

The dose is 500 mg per day. The daily dose may be taken all at once or divided into two doses. The maximum daily dose is 500 mg.

The duration of treatment course is 4–6 weeks. The course may be repeated 2–3 times per year.

Elderly patients

In elderly patients with impaired liver and/or kidney function, a dose reduction of meldonium may be necessary.

Patients with impaired kidney function

Since the drug is excreted from the body via the kidneys, patients with mild to moderate kidney impairment should receive a reduced dose of meldonium.

Patients with impaired liver function

Patients with mild to moderate liver impairment should receive a reduced dose of meldonium.

Children

There are no data on the safety and efficacy of meldonium in children; therefore, its use 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, 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 protein binding.

Adverse Reactions.

Adverse reactions are classified by organ systems and frequency of occurrence according to MedDRA: common (≥ 1/100 to < 1/10), rare (≥ 1/10,000 to < 1/100), very rare (< 1/10,000). Side effects observed in clinical trials and during the post-registration period:

Immune system disorders: common – allergic reactions; rare – hypersensitivity, including allergic dermatitis, urticaria, rash, angioneurotic edema, anaphylactic shock.

Psychiatric disorders: rare – excitement, fear, obsessive thoughts, sleep disturbances.

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

Blood and lymphatic system disorders: common – dyslipidemia, increased C-reactive protein level; rare – eosinophilia.

Cardiac disorders: rare – change in heart rhythm, palpitations, tachycardia/sinus tachycardia, arrhythmia, changes in blood pressure, atrial fibrillation, chest discomfort/chest pain, hypertensive crisis, hyperemia, pallor, electrocardiogram (ECG) abnormalities, increased heart rate.

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

Gastrointestinal disorders: common – dyspeptic symptoms; rare – diarrhea, nausea, vomiting, abdominal pain, flatulence, metallic taste in mouth, loss of appetite, dry mouth or hypersalivation.

Skin and subcutaneous tissue disorders: rare – generalized/maculopapular/papular rash.

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 – chills, weakness, hyperthermia, increased sweating, asthenia, edema, facial swelling, leg swelling, feeling of warmth, feeling of cold, cold sweat.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

40 tablets in a polymer bottle in a cardboard box.

Or 40 tablets (10×4) in blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

LLC NPF "MIKROKHEM".

Manufacturer's address and location of its business activity.

33, Lenina St., Rubizhne, Luhansk region, 93009, Ukraine.

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