Gordox ampoules

Mechanism of action

Inhibitor of proteolytic enzymes of a wide spectrum of action, possesses antifibrinolytic properties. Forming reversible stoichiometric complexes - enzyme inhibitors, aprotinin inhibits the activity of plasma and tissue kallikrein, trypsin, plasmin, as a result of which lowers the fibrinolytic activity of the blood.

Aprotinin activates the contact phase of coagulation activation, which initiates coagulation with simultaneous activation of fibrinolysis. Under the conditions of using the heart-lung machine (AIC) and activation of coagulation caused by contact of blood with foreign surfaces, additional inhibition of plasma kallikrein will help minimize disturbances in the coagulation and fibrinolysis systems. Aprotinin modulates the systemic inflammatory response that occurs during operations in cardiopulmonary bypass. Systemic inflammatory response leads to the interrelated activation of hemostasis, fibrinolysis, activation of cellular and humoral response. Aprotinin, inhibiting numerous mediators (including kallikrein, plasmin, trypsin), weakens the inflammatory response, reduces fibrinolysis and the formation of thrombin.

Aprotinin inhibits the release of inflammatory cytokines and maintains glycoprotein homeostasis. Aprotinin reduces the loss of glycoproteins (GPIb, GPIIb, GPIIIa) by platelets and inhibits the expression of anti-inflammatory adhesive glycoproteins (GPIIb) by granulocytes.

The use of aprotinin in surgery with the use of AIK reduces the inflammatory response, which is expressed in reducing the volume of blood loss and the need for blood transfusion, reducing the frequency of repeated revisions of the mediastinum to find the source of bleeding.

Pharmacokinetics

Distribution

After iv administration, the concentration of aprotinin in the plasma rapidly decreases due to distribution in the intercellular space with initial T_1/2 0.3-0.7 h. Final T_1/2 is 5-10 hours. The average equilibrium intraoperative plasma concentrations of the drug are 175-281 KIE / ml in patients receiving aprotinin treatment during the operation in the following mode: IV dose of 2 million KIE, 2 million.KIE for the primary volume of infusion, 500,000 KIE hourly for the entire duration of the operation as a continuous IV infusion. When using half doses, the average equilibrium intraoperative concentrations of the drug in plasma are 110-164 KIE / ml.

Comparison of the pharmacodynamic parameters of aprotinin in healthy volunteers, in patients with cardiac pathology when using the cardiopulmonary bypass, and in women with hysterectomy, showed the linear pharmacokinetics of the drug at doses from 50 thousand to 2 million KIE.

80% of aprotinin binds to plasma proteins and 20% of antifibrinolytic activity is carried out by the drug, which is in a free form.

V_d in equilibrium state is about 20 l. The total clearance of the drug is about 40 ml / min.

Aprotinin accumulates in the kidneys, and, to a lesser extent, in cartilage tissue. The accumulation in the kidneys occurs due to the binding of the epithelial cells of the proximal renal tubules to the brush border and the accumulation of these cells in the phagolysosomes. The accumulation in the cartilage is due to the affinity of aprotinin, which is the base, and the acidic proteoglycans of the cartilage tissue. Concentrations of aprotinin in other organs are comparable with the concentration of the drug in plasma. The lowest concentration of the drug is determined in the brain, aprotinin practically does not penetrate into the cerebrospinal fluid. A very limited amount of aprotinin penetrates the placental barrier.

Metabolism and excretion

Aprotinin is metabolized by lysosomal enzymes in the kidney to inactive metabolites - short peptide chains and amino acids.

Active aprotinin is detected with urine in a small amount (less than 5% of the administered dose). Within 48 hours, 25-40% aprotinin is defined as inactive metabolites in the urine.

Pharmacokinetics in special clinical situations

In patients with end-stage renal disease, the pharmacokinetics of aprotinin has not been studied. In the study of patients with impaired renal function, no changes in the pharmacokinetic parameters of aprotinin were detected; correction of the dosing regimen is not required.

Indications

- to prevent intraoperative blood loss and reduce blood transfusion during coronary artery bypass surgery using AIC in adult patients.

Dosage and administration

Gordox^® administered in / in, slowly. The maximum rate of administration is 5-10 ml / min. With the introduction of the drug, the patient should be in the supine position. Gordox^® should be administered through the main veins, do not use them for the introduction of other drugs.

Due to the high risk of allergic / Anaphylactic reactions, all patients 10 minutes before the administration of the main dose of the drug Gordox^® a test dose of 1 ml (10 thousand KIE) should be administered. In the absence of negative reactions, a therapeutic dose of the drug is administered. Perhaps the use of histamine H blockers₁- and H₂-receptors 15 minutes before administration of the drug Gordox^®. In any case, standard emergency measures aimed at treating an allergic / anaphylactic reaction should be provided.

For adultsthe drug is recommended to be administered in the initial dose of 1-2 million KIE; Injected into / in slowly for 15-20 minutes after the start of anesthesia and before the sternotomy. The next 1-2 million KIE are added to the primary volume of the heart-lung apparatus. Aprotinin should be added to the primary volume during the recycling period to ensure adequate dilution of the drug and prevent interaction with Heparin.

After the end of the bolus, a continuous infusion is established at an injection rate of 250-500 thousand KIE / h until the end of the operation. The total amount of injected aprotinin during the entire course should not exceed 7 million KIE.

Patients with impaired renal function dose adjustment is not required.

Change in dosing regimenelderly patients not required.

Side effect

Allergic reactions: rarely (≥0.01% and <0.1%) - allergic, anaphylactic, anaphylactoid reactions; very rarely (<0.01%) - anaphylactic shock (potentially life-threatening).

In patients receiving aprotinin for the first time, the development of allergic or anaphylactic reactions is unlikely. With repeated administration, the incidence of allergic (anaphylactic) reactions may increase to 5%, especially with repeated use of aprotinin for 6 months. With repeated use of aprotinin after more than 6 months, the risk of allergic / anaphylactic reactions is 0.9%. The risk of severe allergic / anaphylactic reactions increases if aprotinin has been used more than 2 times for 6 months.Even if the symptoms of allergic reactions were not observed with repeated use of aprotinin, the subsequent use of the drug can lead to severe allergic reactions or anaphylactic shock, in rare cases with a fatal outcome. Symptoms of allergic / anaphylactic reactions are manifested by disorders of the cardiovascular system (arterial hypotension), the digestive system (nausea), the respiratory system (asthma / bronchospasm), and the skin (itching, urticaria, rash). In the case of the development of hypersensitivity reactions with the use of aprotinin, it is necessary to immediately stop the introduction of the drug and ensure that standard emergency measures are taken - infusion therapy, the introduction of adrenaline / epinephrine, corticosteroids.

Cardiovascular: infrequently (≥0.1% and <1%) - myocardial ischemia, thrombosis / occlusion of the coronary arteries, myocardial infarction, pericardial effusion, thrombosis; rarely (≥0.01% and <0.1%) - arterial thrombosis (with possible manifestation of dysfunction of vital organs such as the kidneys, lungs, brain); very rarely (<0.01%) - pulmonary embolism.

From the hemopoietic system: very rarely (<0.01%) - coagulopathy, incl. DIC syndrome.

From the urinary system: infrequently (≥0.1% and <1%) - a renal failure, a renal failure.

Local reactions:very rarely (<0.01%) - reactions in the area of ​​injection / infusion, thrombophlebitis.

Contraindications

- age up to 18 years (efficacy and safety have not been established);

- Hypersensitivity to aprotinin or any of the excipients.

Use during pregnancy and lactation

Studies on the use of the drug Gordox^® in pregnant women were not performed. In pregnancy, use is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus. When assessing the benefit / risk ratio, the adverse effects on the fetus of severe adverse reactions that may occur when using the drug, such as anaphylactic reactions, cardiac arrest, etc., as well as therapeutic measures taken to eliminate these reactions should be considered.

Use of the drug Gordox^® during lactation has not been studied.The drug is potentially safe when ingested with breast milk because it does not have bioavailability when taken orally.

Application for violations of kidney function

Patients with impaired renal function dose adjustment is not required.

Use in children

Use in children and adolescents under the age of 18 years is contraindicated (efficacy and safety have not been established).

Use in elderly patients

Elderly patients dose adjustment is not required.

special instructions

With the use of aprotinin, especially with repeated use of the drug, allergic / anaphylactic reactions may develop. Therefore, before using the drug, it is necessary to carefully evaluate the benefit / risk ratio. 10 minutes before the introduction of the main dose of the drug Gordox^® A test dose of 1 ml is administered (10 thousand KIE). 15 minutes before the introduction of a therapeutic dose of the drug Gordox^® perhaps the use of histamine H blockers₁- and H₂-receptors. However, allergic / anaphylactic reactions may develop with the introduction of a therapeutic dose of the drug, even if during the administration of a test dose, no adverse reactions were noted. In the case of the development of hypersensitivity reactions with the use of aprotinin, it is necessary to immediately stop the introduction of the drug and ensure that standard emergency measures are taken to treat allergic / anaphylactic reactions.

When performing operations on the thoracic aorta using AIK and the use of deep cold cardioplegia Gordox^® It should be used very carefully against the background of adequate heparin therapy.

Determining the time of activated coagulation is not a standardized test for determining the coagulation ability of the blood, and the use of aprotinin can affect various test procedures. The coagulation degree test (ACT) is affected by various effects upon dilution and exposure to temperature. The ACT test with kaolin does not increase to the same extent with aprotinin, as the ACT test with telitis. Due to the difference in the protocols, it is recommended to take the minimum values ​​of the ACT test - 750 seconds and the ACT test with kaolin - 480 seconds in the presence of aprotinin, regardless of the effects of hemodilution and hypothermia.

The standard dose of heparin given before cardiac conduction and the amount of heparin added to the primary volume in AIC should be at least 350 IU / kg. The extra dose of heparin is determined by the patient’s body weight and the duration of the extracorporeal circulation period.

The protamine titration method is not affected by aprotinin. Additional doses of heparin are determined based on the concentration of heparin calculated by this method. The concentration of heparin during shunting should not fall below 2.7 U / ml (0.2 mg / kg) or below the level determined before the use of aprotinin.

In patients receiving the drug Gordox^®Neutralization of heparin with protamine should be carried out only after interruption of the extracorporeal circulation, on the basis of a fixed amount of heparin injected or under the control of the protamine titration method.

Gordox^® contains benzyl alcohol. The daily dose of benzyl alcohol should not exceed 90 mg / kg body weight.

During the treatment cycle, the maximum dose of aprotinin can not exceed 6 million KIE.

Aprotinin is not a substitute for heparin.

Preparations for parenteral administration should be subject to visual inspection immediately prior to use. Do not use residual solution for later use.

Use in pediatrics

Do not use forchildren and adolescents under the age of 18(efficacy and safety have not been established).

Influence on ability to drive vehicles and mechanisms

Data on the effect of the drug Gordox^® on the ability to drive vehicles and work with the mechanisms are missing.

Overdose

Currently, no cases of overdose have been reported.

There is no antidote to the drug.

Drug interaction

Gordox^® should not be mixed with other drugs.

With simultaneous use of the drug Gordox^® with streptokinase, urokinase, alteplazy decreases the activity of these drugs.

Gordox^® compatible with 20% glucose solution, hydroxyethylated starch solution, Ringer's lactate solution.

Terms and conditions of storage

The drug should be stored out of the reach of children, protected from light at a temperature not higher than 30 ° C. Shelf life - 5 years. Do not use after expiration date.

Pharmacy sales terms

The drug is available on prescription.