Instructions for Tivorel aspartate oral solution, polymer bottle 100 ml
Composition
active ingredients: arginine aspartate (L-arginine L-aspartate), levocarnitine;
1 ml of solution contains 264 mg of arginine aspartate (L-arginine L-aspartate) in terms of arginine – 149.7 mg and 100 mg of levocarnitine;
excipients: methyl parahydroxybenzoate (E 218) – 0.8 mg; propyl parahydroxybenzoate (E 216) – 0.2 mg; malic acid (E 296); sodium saccharin (E 954); water for injections.
Dosage form
Oral solution.
Main physicochemical properties: transparent colorless or slightly yellowish viscous liquid.
Pharmacotherapeutic group
Medicinal products affecting the cardiovascular system. Other combined cardiac medicinal products.
ATX code C01E X.
Pharmacological properties
Pharmacodynamics.
The therapeutic effect of the drug Tivorel aspartate is due to the synergistic action of its components - arginine and levocarnitine.
Arginine (a-amino-d-guanidino-valeric acid) belongs to the class of conditionally essential amino acids, is an active cellular regulator of numerous vital functions of the body and exhibits protective effects in critical conditions of the body.
Arginine has antihypoxic, membrane-stabilizing, cytoprotective, antioxidant, antiradical, detoxifying effects, manifests itself as an active regulator of intermediate metabolism and energy supply processes, plays a certain role in maintaining hormonal balance in the body, improves placental blood flow, reduces the risk of fetal oxidative stress. It is known that arginine improves the sensitivity of peripheral tissues to insulin, glucagon, increases the content of somatotropic hormone and prolactin in the blood, regulates the content of glucose in the blood during physical exertion, participates in the synthesis of proline, polyamine, agmatine, is involved in the processes of fibrinogenolysis, spermatogenesis, has a membrane-stabilizing effect.
Arginine is the main supplier of nitric oxide, thereby affecting hemodynamics in the body. The pronounced cationic properties of the guanidine group of arginine contribute to the improvement of metabolic processes in tissues, causing a decrease in the content of membrane lipid peroxidation products, increasing the activity of the antioxidant defense system and energy supply of mitochondria by activating their redox system.
The antihypoxic effect of arginine is realized not only through an increase in nitric oxide (NO) production by endothelial NO synthase, but also through an indirect antioxidant effect caused by arginine, combined with a decrease in the concentration of superoxide anion radical released from the endothelium.
Arginine activates guanylate cyclase and increases the level of cyclic guanosine monophosphate (cGMP) in the vascular endothelium, reduces the activation and adhesion of leukocytes and platelets to the vascular endothelium, inhibits the synthesis of adhesion proteins, thus preventing the formation and development of atherosclerotic plaques, inhibits the synthesis of endothelin-1, which is a potent vasoconstrictor and stimulator of proliferation and migration of vascular smooth myocytes. Arginine also inhibits the synthesis of asymmetric dimethylarginine - a potent endogenous stimulator of oxidative stress.
The NO molecule inhibits mononuclear cell adhesion, platelet aggregation, vascular smooth muscle proliferation, and the generation of reactive oxygen species. Under physiological conditions, NO participates in the adaptation of the vascular system to increased metabolic demands caused by physical exertion.
Arginine is directly involved in the regulation of processes occurring inside blood vessels, including placental vessels, due to its effect on the endothelium.
Arginine plays an important role in the processes of ammonia neutralization in the ornithine cycle of urea synthesis, as well as binding this neurotoxin to non-toxic glutamine and stimulating the excretion of ammonia from the central nervous system (CNS) and the body as a whole. Thus, the hypoammonemic effect of the drug is realized.
Arginine stimulates the activity of the thymus gland, which produces T-cells. It has an acid-forming effect and helps correct acid-base balance.
Levocarnitine is a natural substance that participates in most energy processes, its presence is mandatory in the metabolism of fatty acids, amino acids, carbohydrates and ketone bodies. Only the L-isomer of carnitine is biologically active. The highest concentration of levocarnitine is determined in muscle tissue, in the myocardium and liver.
Levocarnitine plays an important role in cardiac metabolism, as fatty acid oxidation depends on the availability of sufficient amounts of this substance. The formation of adenosine triphosphate (ATP) from fatty acids is energetically more advantageous than the oxidation of glucose. Modulation of the glycolytic pathway for ATP formation with levocarnitine is optimal for cardioprotection, because, in addition to optimizing the glycolytic pathway for ATP formation in ischemic cells, it does not affect the use of fatty acids as the main source of ATP in non-ischemic cells.
Experimental studies have also shown that stress, acute ischemia, and myocarditis can lead to a decrease in levocarnitine levels in myocardial tissue. A large number of animal studies have been conducted, which have confirmed the positive effect of levocarnitine in various induced cardiac disorders: acute and chronic ischemia, cardiac decompensation, heart failure as a result of myocarditis, and drug cardiotoxicity (taxanes, adriamycin, etc.).
Levocarnitine, by ensuring the use of fatty acids as an energy substrate, helps increase endurance during physical exertion.
By releasing coenzyme-A from complex thioesters, levocarnitine also enhances the oxidation of carbohydrates in the Krebs tricarboxylic acid cycle, stimulates the activity of the key enzyme of glycolysis - pyruvate dehydrogenase, and in skeletal muscles - the oxidation of branched-chain amino acids. Thus, levocarnitine directly or indirectly participates in most energy processes, its presence is mandatory for the oxidation of fatty acids, amino acids, carbohydrates and ketone bodies.
By reducing the plasma concentration of free fatty acids, levocarnitine reduces tissue insulin resistance.
The results of a phase III clinical trial involving 137 patients demonstrate that the use of the drug Tivorel aspartate as part of complex therapy for ischemic heart disease is more effective than standard therapy, leads to an increase in the duration of physical activity, an increase in the power of the threshold load, and an improvement in the assessment of quality of life (according to the HeartQoL questionnaire).
The results of another phase III clinical study involving 106 patients demonstrate that the use of the drug Tivorel aspartate as part of complex therapy for acute ischemic stroke in the carotid artery basin is effective and has a satisfactory safety profile.
The experience of the combined use of L-arginine aspartate and levocarnitine in a clinical study indicates that their combination leads to an increase in general and special physical performance and an improvement in the psychophysiological state of athletes in various sports.
Pharmacokinetics.
Not studied.
Indication
- Tivorel aspartate is used as part of complex treatment:
- chronic ischemic heart disease;
- atherosclerosis of coronary, cerebral and peripheral vessels;
- acute ischemic type cerebral circulation disorders.
- Tivorel aspartate is used to increase tolerance to physical exertion, including in sports.
Contraindication
- Hypersensitivity to the active substances or to any of the excipients.
- History of allergic reactions.
- Severe renal dysfunction.
- Use of potassium-sparing diuretics, as well as spironolactone.
- Myocardial infarction (including history).
Interaction with other medicinal products and other types of interactions
When using the drug Tivorel aspartate, it should be taken into account that the drug can cause severe and persistent hyperkalemia against the background of renal failure in patients who are taking or have taken spironolactone. Previous use of potassium-sparing diuretics can also contribute to an increase in the level of potassium concentration in the blood.
When used simultaneously with aminophylline, an increase in insulin levels in the blood is possible.
Simultaneous use with glucocorticoids leads to the accumulation of levocarnitine in body tissues (except the liver). Other anabolic agents enhance the effect of the drug.
Very rare cases of increased international normalized ratio (INR) have been observed in patients receiving coumarin anticoagulants concomitantly with levocarnitine (see sections 4.4 and 4.8). INR or other appropriate coagulation test should be performed weekly until stable, and monthly thereafter in patients receiving such anticoagulants concomitantly with levocarnitine.
Concomitant use of levocarnitine with agents that induce hypocarnitineemia by increasing renal excretion of carnitine (e.g. valproic acid, prodrugs containing pivalonic acid, cephalosporins, cisplatin, carboplatin, ifosfamide) may reduce its levels.
The drug is incompatible with thiopental.
Application features
Arginine and levocarnitine enhance glucose metabolism, therefore, when using the drug Tivorel aspartate in patients with diabetes mellitus who are treated with hypoglycemic drugs, it is necessary to regularly monitor the level of glucose in the blood plasma for timely correction of therapy.
When using the drug, it is necessary to refrain from alcohol, nicotine, and psychostimulants.
If symptoms of asthenia develop while taking the drug, treatment should be discontinued.
The drug is used with caution in patients with angina pectoris.
Very rare cases of increased INR have been observed in patients who were simultaneously taking levocarnitine and coumarin anticoagulants (see sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions"). Appropriate monitoring is required when coumarin anticoagulants are used concomitantly.
Seizures have been reported in patients with a history of seizure activity, but it is not yet clear whether levocarnitine increases the frequency and/or severity of seizures. In cases where seizures are associated with levocarnitine, discontinuation of this drug should be considered.
Long-term oral administration of high doses of levocarnitine in patients with severe renal impairment or end-stage chronic renal disease (ESRD) is contraindicated (see Contraindications) as it may lead to accumulation in the blood of potentially toxic metabolites trimethylamine (TMA) and trimethylamine-N-oxide (TMAO) due to insufficient renal excretion. This accumulation leads to increased urinary TMA.
Do not exceed the recommended dose. If side effects occur, discontinue use. Sensitivity to the drug should be carefully assessed during the first week of use and after each dose increase.
The medicinal product contains excipients such as methyl parahydroxybenzoate (E 218) and propyl parahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed).
Tivorel aspartate contains:
0.0039 mmol (or less than 0.09 mg) of sodium in 1 ml of the medicinal product;
0.078 mmol (or 1.79 mg) sodium per 20 ml of the medicinal product, i.e. essentially sodium-free.
Use during pregnancy or breastfeeding
There are no data on the use of Tivorel aspartate in pregnant women. Data on the excretion of the drug into breast milk and its effect on the fetus are unknown. Therefore, during pregnancy or breastfeeding, the drug should be prescribed only if the expected benefit to the woman outweighs the potential risk to the fetus/child.
Ability to influence reaction speed when driving vehicles or other mechanisms
In some cases, some adverse reactions from the CNS may affect the ability to drive or operate complex mechanisms.
Method of administration and doses
Take orally before meals.
A single dose is 10–20 ml. The maximum daily dose is 40 ml. The daily dose of the drug can be divided into 2–4 doses.
| Indication | Dose | Treatment period |
| As part of the complex treatment: | | |
| chronic ischemic heart disease | 20 ml 2 times a day | 21 days |
| acute ischemic type cerebral circulation disorders | 20 ml 2 times a day | 21 days |
| atherosclerosis of coronary, cerebral and peripheral vessels | 10 ml 3–4 times a day | 21 days |
| To increase tolerance to physical exertion, including in sports | 15 ml 2 times a day | 21 days |
The course of use of the drug can be extended if necessary, as prescribed by a doctor.
Children.
There are no data on the use of the drug in children.
Overdose
Symptoms
Kidney failure, hypoglycemia, and large doses of the drug can cause diarrhea.
Treatment
If the above manifestations are present, it is necessary to stop taking the drug. It is necessary to monitor physiological reactions and maintain the vital functions of the body. Gastric lavage and sorbents are indicated. If necessary, alkalizing agents and agents for establishing diuresis (saluretics), electrolyte solutions (0.9% sodium chloride solution), 5% glucose solution are administered. It is necessary to conduct symptomatic and supportive therapy. There is no antidote.
Side effects
The adverse reactions listed below are classified by system organ class and frequency. The frequency of occurrence is classified as very common (≥ 1/10), common (≥ 1/100 - < 1/10), uncommon (≥ 1/1000 - <1/100), rare (≥ 1/10000 - <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).
| Organ systems | Frequency | Adverse reactions |
| Immune system disorders | Frequency unknown | Anaphylactic shock, hypersensitivity reactions including rash, urticaria, bronchospasm, angioedema |
| Neurological disorders | Frequency unknown | Headache, dizziness, feeling of fear, weakness, tremor, convulsions* |
| Cardiovascular system | Blood pressure fluctuations, heart rhythm changes, pain in the heart area |
| Respiratory, thoracic and mediastinal disorders | Frequency unknown | Dyspnea |
| Gastrointestinal disorders | Rarely | Feeling of mild discomfort in the stomach and intestines, nausea immediately after taking the medicine, which disappear on their own; vomiting, diarrhea |
| Frequency unknown | Dry mouth, abdominal pain | |
| Musculoskeletal and connective tissue disorders | Frequency unknown | Joint pain |
| General disorders | Frequency unknown | Hyperthermia, feeling hot, body aches |
| Research | Very rare | Increased INR, hyperkalemia |
| Others | Very rare | Specific body odor |
* Seizures have been reported in patients with and without prior seizure activity. In patients with prior seizure activity, the frequency and/or severity of seizures was increased.
Reporting of adverse reactions
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
2 years.
The shelf life after first opening the bottle is 14 days.
Storage conditions
Store at a temperature not exceeding 30 °C in the original packaging. Keep out of the reach of children.
Incompatibility
The drug is incompatible with thiopental.
Packaging
100 ml or 200 ml in a brown polymer bottle with a tamper-evident cap, 1 bottle with a measuring cup in a cardboard box.
Vacation category
According to the recipe.
Producer
LLC "Yuria-Pharm".
Location of the manufacturer and address of its place of business.
Ukraine, Cherkasy region, Cherkasy city, Kobzarska st., 108. Tel.: (044) 281-01-01.
