Gordox solution 10000 KIE/ml 10 ml ampoules, 5 pcs.

Composition

One ampoule contains:Active ingredient: aprotinin 10,000 KIU. Auxiliary substances: sodium chloride, benzyl alcohol, water for injection.

Pharmacological action

Pharmacotherapeutic group:

proteolysis inhibitor.

ATX code: B 02 AB 01

Pharmacological properties

Pharmacodynamics

Aprotinin is a broad-spectrum proteolytic enzyme inhibitor with antifibrinolytic properties. Forming reversible stoichiometric complexes-enzyme inhibitors, aprotinin suppresses the activity of plasma and tissue kallikrein, trypsin, plasmin, reducing the fibrinolytic activity of blood.

Aprotinin inhibits the contact phase of clotting activation, which initiates coagulation with simultaneous activation of fibrinolysis. Under conditions of using an artificial circulatory system (AIC) and activation of coagulation caused by blood contact with foreign surfaces, additional inhibition of plasma kallikrein will help minimize disorders in the coagulation and fibrinolysis systems.

Aprotinin modulates the systemic inflammatory response that occurs during operations using AIC. The systemic inflammatory response leads to an interconnected activation of the hemostasis, fibrinolysis, and cellular and humoral response systems. Aprotinin, by inhibiting numerous mediators (kallikrein, plasmin, trypsin, etc. ), weakens the inflammatory response, reduces fibrinolysis and thrombin formation.

Aprotinin inhibits the release of inflammatory cytokines and supports glycoprotein homeostasis. Aprotinin reduces the loss of glycoproteins (GP Ib, GP IIb, GP IIIa) by platelets and interferes with the expression of anti-inflammatory adhesive glycoproteins (C IIb) by granulocytes.

The use of aprotinin in surgery during operations using AIC reduces the inflammatory response, which is expressed in a decrease in the volume of blood loss and the need for blood transfusion, a decrease in the frequency of repeated mediastinal revisions to search for the source of bleeding.

Pharmacokinetics

Distribution

After intravenous administration, the concentration of aprotinin in blood plasma decreases rapidly due to distribution in the intercellular space with an initial half-life of 0.3-0.7 hours. The final half-life is 5-10 hours. The average steady-state intraoperative plasma concentrations of the drug are 175-281 KIU/ml in patients treated with aprotinin during surgery in the following mode: an intravenous loading dose of 2 million IU / ml. KIE,2 million rubles. CI for the primary infusion volume,500 thousand rubles. It is administered hourly during the entire duration of the operation as a continuous intravenous infusion. When using half doses, the average steady-state intraoperative plasma concentrations of aprotinin are 110-164 KIU/ml.

Comparison of the pharmacokinetic parameters of aprotinin in healthy volunteers, in patients with cardiological pathology when using AIC and in women during Comfrey Woundwort showed linear pharmacokinetics of aprotinin at doses from 50 thousand to 2 million KIU.

80% of aprotinin binds to plasma proteins,20% of aprotinin is in free form and causes antifibrinolytic activity. The steady-state volume of distribution is approximately 20 l, and the total clearance of aprotinin is approximately 40 ml / min. Aprotinin accumulates in the kidneys and, to a lesser extent, in the cartilage tissue. Accumulation in the kidneys occurs due to binding to the brush border of epithelial cells of the proximal renal tubules and accumulation in the phagolysosomes of these cells. Accumulation in the cartilage tissue occurs due to the affinity of aprotinin, which is the base, to acidic proteoglycans of the cartilage tissue. Aprotinin concentrations in other organs are comparable to those in blood plasma. The lowest concentration of aprotinin 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 elimination

Aprotinin is metabolized by lysosomal enzymes in the kidneys to inactive metabolites – short peptide chains and amino acids. Active aprotinin is detected in the urine in a small amount (less than 5% of the administered dose). Within 48 hours,25-40% of aprotinin is detected as inactive metabolites in the urine.

Pharmacokinetics in special patient groups

Patients with renal insufficiency

The pharmacokinetics of aprotinin have not been studied in patients with end-stage renal insufficiency. In the study of patients with impaired renal function, changes in the pharmacokinetic parameters of aprotinin were not detected, and no dosage adjustment is required.

Indications

To prevent intraoperative blood loss and reduce the volume of blood transfusion during coronary artery bypass grafting operations using an artificial circulatory system (AIC) in adult patients who are at an increased risk of bleeding or the need for blood transfusion.

Use during pregnancy and lactation

Pregnancy

Studies on the use of Gordox® in pregnant women have not been conducted.

Use during pregnancy is possible only in cases where the intended benefit to the mother exceeds the potential risk to the fetus. When assessing the benefit/risk ratio, one should take into account the negative impact on the fetus of severe adverse reactions possible with the use of the drug, such as anaphylactic reactions, cardiac arrest, etc., as well as therapeutic measures taken to eliminate these reactions.

Breast-feeding period

The use of Gordox® during breastfeeding has not been studied. The drug is potentially safe when ingested in breast milk, as it does not have bioavailability when taken orally.

Contraindications

-Hypersensitivity to aprotinin or any of the excipients. – Age up to 18 years (efficacy and safety have not been established). – In patients who test positive for specific IgG antibodies to aprotinin (see section “Special instructions”).

If testing for specific IgG antibodies to aprotinin is not possible before starting treatment, but it is assumed that the patient has been treated with aprotinin or “fibrin sealants” for the previous 12 months, the introduction of aprotinin is contraindicated.

With caution

– Previous use of aprotinin

Side effects

Allergic / anaphylactic reactions 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 can increase up to 5%, especially with repeated use of aprotinin for 6 months. If aprotinin is used again after more than 6 months, the risk of allergic / anaphylactic reactions is 0.9%. The risk of developing severe allergic / anaphylactic reactions increases if aprotinin has been used more than twice within 6 months. Even if the repeated use of aprotinin did not cause any symptoms of allergic reactions, subsequent use of the drug can lead to the development of severe allergic reactions or anaphylactic shock, in rare cases with a fatal outcome.

Symptoms of allergic / anaphylactic reactions, manifested by violations:

from the blood vessels: hypotension; from the gastrointestinal tract: nausea;from the respiratory system, chest and mediastinal organs: bronchial asthma (bronchospasm); from the skin and subcutaneous tissues: pruritus, urticaria, skin rash.

If hypersensitivity reactions develop when using aprotinin, the drug should be stopped immediately and standard emergency measures should be provided – infusion therapy, administration of epinephrine (epinephrine), glucocorticosteroids.

Adverse drug reactions (NLR) associated with aprotinin use are presented by organ-system classes according to the MedDRA classification and by frequency of occurrence:

Infrequent: ≥1/1000 to <1/100 Rare: ≥1/10 000 to <1/1000 Very rare: <1/10 000.

* Information about these adverse reactions was obtained with post-marketing use of the drug.

Interaction

Gordox® should not be mixed with other medications. Gordox® is compatible with 20% glucose solution, hydroxyethylated starch solution, and Ringer’s lactate solution. Concomitant use of the drug Gordox® with streptokinase, urokinase, alteplase decreases the activity of these drugs.

How to take, course of administration and dosage

Before prescribing Gordox®, each patient is recommended to perform an antibody (IgG) test for aprotinin (see sections “Contraindications”, “Special instructions”). Gordox® is administered intravenously, slowly. The maximum rate of administration is 5-10 ml/min. When the drug is administered, the patient should be in a supine position. Gordox® should be administered through the main veins, which should not be used for the administration of other drugs.

Due to the high risk of allergic / anaphylactic reactions, all patients should receive a trial dose of 1 ml (10 thousand mg) 10 minutes before the main dose of Gordox®. CUE cards). In the absence of negative reactions, a therapeutic dose of the drug is administered. It is possible to use histamine H1 – and H2-receptor blockers 15 minutes before the administration of Gordox®. In any case, standard emergency measures aimed at treating an allergic / anaphylactic reaction should be provided.

Adult patients receive an initial dose of 1-2 million mg. These drugs are administered intravenously slowly for 15-20 minutes after the start of anesthesia and before sternotomy. The next 1-2 million. CIE is added to the primary volume of AIC “heart-lungs”. Aprotinin should be added to the primary volume during the recirculation period to ensure sufficient dilution of the drug and prevent interaction with heparin.

After the end of bolus administration, a constant infusion is established with an injection rate of 250-500 thousand rubles. KIU/hr until the end of the operation.

The total amount of aprotinin administered during the entire operation should not exceed 7 million KIU.

Special patient groups Patients with renal insufficiency No dosage adjustment is required in patients with impaired renal function.

Elderly patients (over 65 years of age)There is no need to change the dosage regimen in elderly patients.

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

Overdose

Currently, no cases of aprotinin overdose have been reported. There is no antidote.

Special instructions

When using 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 main dose of Gordox* is administered, a trial dose of 1 ml (10 thousand mg) is administered. CUE cards). Histamine H1 – and H2-receptor blockers may be used 15 minutes before the introduction of the therapeutic dose of Gordox®. However, allergic / anaphylactic reactions may also occur with the introduction of a therapeutic dose of the drug, even if no adverse reactions were observed during the administration of the trial dose.

If hypersensitivity reactions occur with the use of aprotinin, the drug should be discontinued immediately and standard emergency measures should be taken to treat allergic / anaphylactic reactions.

Patients who develop antibodies (IgG) to aprotinin have a high risk of developing anaphylactic reactions when using aprotinin. Therefore, the use of Gordox® in such patients is contraindicated. Before prescribing Gordox®, each patient is recommended to perform an antibody (IgG) test for aprotinin. If the determination of antibodies (IgG) to aprotinin is not possible, then in patients in whom the use of aprotinin cannot be excluded during the previous 12 months, the use of Gordox® is contraindicated.

Despite the fact that anaphylactic reactions most often develop with repeated administration of aprotinin for 12 months, there are reports of the development of anaphylactic shock at a later time (when repeated administration was performed later than 12 months after the first administration).

When performing thoracic aortic surgery using AIC and deep cold cardioplegia, Gordox® should be used with extreme caution against the background of adequate heparin therapy.

Determining the time of activated clotting is not a standardized test for determining the coagulation capacity of blood, and the use of aprotinin may affect different test methods. The Coagulation Measurement Test (ACT) is subject to various dilution and temperature effects. The ACT test with kaolin does not increase to the same extent in the presence of aprotinin as the ACT test with celitis. Due to the difference in 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 administered prior to cardiac canulation and the amount of heparin added to the primary volume in the AIC should be at least 350 IU / kg. The additional dose of heparin is determined by the patient’s body weight and the duration of extracorporeal circulation.

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

In patients treated with Gordox®, neutralization of heparin with protamine should be performed only after interruption of extracorporeal circulation, based on a fixed amount of heparin administered, or under the control of the protamine titration method.

The total amount of aprotinin administered during the treatment cycle should not exceed 7 million KIU.

Aprotinin is not a substitute for heparin.

Preparations for parenteral administration should be visually monitored immediately before use. Do not use the remaining solution for subsequent use.

Excipients This preparation contains benzyl alcohol. The daily dosage of benzyl alcohol should not exceed 90 mg per kilogram of body weight. Benzyl alcohol can cause anaphylactoid reactions.

Influence on the ability to drive vehicles and mechanisms

There are no data on any effect of the drug Gordox® on the ability to drive vehicles and work with mechanisms.

Storage conditions

In a dark place at a temperature not exceeding 30 °C. Keep out of reach of children.

Shelf

life is 5 years. Do not use after the expiration date.

Active ingredient

Aprotinin

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Weight

Weight: 99 gr.