TIVORTIN

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

Composition:

Active substance: L-arginini hydrochloridum;

1 ml contains 42 mg of arginine hydrochloride (in 100 ml contains 20 mmol of arginine and 20 mmol of chlorides);

Excipient: water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly yellowish-brown solution; pH 5.0−6.5.

Pharmacotherapeutic group. Blood substitutes and perfusion solutions. Additional solutions for intravenous administration. Amino acids. Arginine hydrochloride.

ATC code B05X B01.

Pharmacological Properties.

Pharmacodynamics.

Arginine (α-amino-δ-guanidinovaleric acid) is an amino acid belonging to the class of conditionally essential amino acids. It acts as an active and versatile cellular regulator of numerous vital functions in the body and exhibits important protective effects under critical conditions.

Tivortin® demonstrates anti-hypoxic, membrane-stabilizing, cytoprotective, antioxidant, antiradical, and detoxifying activities. It functions as an active regulator of intermediate metabolism and energy supply processes, and plays a certain role in maintaining hormonal balance in the body. It is known that arginine increases blood levels of insulin, glucagon, growth hormone, and prolactin. It participates in the synthesis of proline, polyamines, and agmatine, is involved in fibrinogenolysis and spermatogenesis, and exerts membrane-depolarizing effects.

Arginine is one of the main substrates in the urea cycle for urea synthesis in the liver. The drug's hypoammonemic effect is achieved by enhancing the conversion of ammonia into urea. It exerts hepatoprotective action due to its antioxidant, anti-hypoxic, and membrane-stabilizing activities, and positively influences energy supply processes in hepatocytes.

Tivortin® serves as a substrate for NO-synthase, the enzyme catalyzing nitric oxide (NO) synthesis in endotheliocytes. The drug activates guanylate cyclase and increases the level of cyclic guanosine monophosphate (cGMP) in vascular endothelium. It reduces activation and adhesion of leukocytes and platelets to the vascular endothelium, suppresses the synthesis of adhesion proteins VCAM-1 and MCP-1, thereby preventing the formation and progression of atherosclerotic plaques. It also inhibits the synthesis of endothelin-1, a potent vasoconstrictor and stimulator of vascular smooth muscle cell proliferation and migration. Tivortin® additionally suppresses the synthesis of asymmetric dimethylarginine—a powerful endogenous stimulator of oxidative stress. The drug stimulates thymus gland activity, which produces T-cells, and regulates blood glucose levels during physical exertion. It exerts an acidifying effect and promotes correction of acid-base balance.

Pharmacokinetics.

During continuous intravenous infusion, maximum plasma concentration of arginine hydrochloride is observed 20–30 minutes after the start of administration. Tivortin® crosses the placental barrier, is filtered in the renal glomeruli, but is almost completely reabsorbed in the renal tubules.

Clinical characteristics.

Indications.

Metabolic alkalosis, hyperammonemia, atherosclerosis of the heart and cerebral vessels, peripheral vascular atherosclerosis including manifestations of intermittent claudication, diabetic angiopathy, arterial hypertension, chronic heart failure, hypercholesterolemia, chronic obstructive pulmonary diseases, pulmonary hypertension, fetal growth retardation, and preeclampsia – as part of complex therapy.

Contraindications.

Hypersensitivity to the drug. Severe impairment of kidney function, hyperchloremic acidosis; history of allergic reactions; use of potassium-sparing diuretics, as well as spironolactone. Myocardial infarction (including in medical history).

Interaction with other medicinal products and other types of interactions.

When using Tivortin®, it should be taken into account that it may cause pronounced and persistent hyperkalemia against the background of renal insufficiency in patients taking or having taken spironolactone. Prior use of potassium-sparing diuretics may also contribute to increased blood potassium concentration. Concurrent use with aminophylline may increase blood insulin levels.

Arginine is incompatible with thiopental.

Special precautions for use

In patients with renal insufficiency, urine output and plasma potassium levels should be checked before starting the infusion, as the medicinal product may promote the development of hyperkalemia.

The drug should be used with caution in patients with endocrine gland dysfunction. Tivortin® may stimulate insulin and growth hormone secretion.

If dry mouth occurs, blood glucose levels should be checked.

Caution is advised in patients with electrolyte metabolism disorders and kidney diseases. If symptoms of asthenia worsen during treatment, therapy should be discontinued.

The drug should be used with caution in patients with angina pectoris.

Use during pregnancy or breastfeeding

The drug crosses the placenta; therefore, during pregnancy it should be used only when the expected benefit for the mother outweighs the potential risk to the fetus.

There are no data available regarding the use of the medicinal product during breastfeeding.

Ability to affect reaction speed while driving or operating machinery

Caution should be exercised when driving or operating machinery, as the drug may cause dizziness.

Administration and Dosage

The drug is administered intravenously by drip infusion at a rate of 10 drops per minute for the first 10–15 minutes; thereafter, the infusion rate may be increased to 30 drops per minute.

The daily dose of the drug is 100 mL of solution.

In severe circulatory disturbances affecting central and peripheral vessels, pronounced signs of intoxication, hypoxia, or asthenic conditions, the dose may be increased up to 200 mL per day.

The maximum infusion rate of the solution should not exceed 20 mmol/hour.

For children under 12 years of age, the daily dose is 5–10 mL per kg of body weight.

For the treatment of metabolic alkalosis, the dose can be calculated as follows:

arginine hydrochloride (mmol)
______________________________________ × 0.3 × body weight (kg)
base excess (Be) (mmol/L)

Infusion should begin with half of the calculated dose. Any additional correction should be performed after obtaining updated acid-base balance test results.

Children

The drug is indicated for use in children aged 3 years and older.

Overdose

Symptoms: renal failure, hypoglycemia, metabolic acidosis.

Treatment: In case of overdose, infusion of the drug must be discontinued. Continuous monitoring of physiological responses and supportive therapy to maintain vital functions should be implemented. If necessary, administer alkalinizing agents, diuretics (saluretics), and electrolyte solutions (0.9% sodium chloride solution, 5% glucose solution). Treatment is symptomatic.

Adverse reactions.

General disorders: hyperthermia, hot flushes, malaise.

Musculoskeletal system: joint pain.

Gastrointestinal tract: dry mouth, nausea, vomiting.

Skin and subcutaneous tissue: injection site reactions, including hyperemia, itching sensation, skin pallor, up to acrocyanosis.

Immune system: anaphylactic shock, hypersensitivity reactions, including rash, urticaria, angioneurotic edema.

Respiratory system, thoracic organs and mediastinum: dyspnea.

Cardiovascular system: fluctuations in blood pressure, changes in heart rhythm, chest pain.

Nervous system: headache, dizziness, fear sensation, weakness, seizures, tremor, more frequently when the infusion rate is exceeded.

Laboratory findings: hyperkalemia.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility.

The drug is incompatible with thiopental.

Packaging.

100 ml or 200 ml in glass bottles. 100 ml or 200 ml in polymer bottles. One bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of business activity.

108, Kozbirska St., Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.