Gordox injection solution 10000KIE / 1ml, 10ml No. 5
Expiration Date: 05/2027
Russian Pharmacy name:
Гордокс раствор для инъекций 10000КИЕ/1мл, 10мл №5
Before prescribing the drug GordoxЃ, each patient is recommended to perform a test for the presence of antibodies (IgG) to aprotinin (see sections 'Contraindications', 'Special instructions').
GordoxЃ is administered intravenously, slowly. The maximum injection rate is 5-10 ml / min. When administering the drug, the patient should be in the supine position. GordoxЃ should be administered through the main veins, which should not be used for the administration of other drugs.
Due to the high risk of developing allergic / anaphylactic reactions, all patients should receive a trial dose of 1 ml (10 thousand KIE) 10 minutes before the administration of the main dose of GordoxЃ. In the absence of negative reactions, a therapeutic dose of the drug is administered. It is possible to use blockers of histamine H1 and H2 receptors 15 minutes before the administration of the drug GordoxЃ. In any event, standard emergency procedures should be provided to treat the allergic / anaphylactic reaction.
For adults, the drug is recommended to be administered at an initial dose of 1-2 million KIE; injected intravenously slowly within 15-20 minutes after the onset of anesthesia and before the sternotomy. The next 1-2 million CIUs are added to the primary heart-lung volume of the AIC. Aprotinin should be added to the primary volume during the recirculation period to ensure sufficient dilution of the drug and to prevent interactions with heparin. After the end of the bolus administration, 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. No dose adjustment is required in patients with impaired renal function. Changing the dosage regimen in elderly patients (over 65 years of age) is not required.
The use of the drug is contraindicated in children and adolescents under the age of 18 years (efficacy and safety have not been established).
aprotinin
hypersensitivity to aprotinin or any of the excipients; age up to 18 years (efficacy and safety have not been established);
in patients with a positive test for specific IgG antibodies to aprotinin (see section 'Special instructions').
If testing for specific IgG antibodies to aprotinin before starting treatment is not possible, but it is assumed that the patient has received treatment with aprotinin or 'fibrin sealants' within the previous 12 months, administration of aprotinin is contraindicated.
With care: previous use of aprotinin (see the section 'Special instructions').
pharmachologic effect
An inhibitor of proteolytic enzymes with a broad spectrum of action, has antifibrinolytic properties. Forming reversible stoichiometric complexes - enzyme inhibitors, aprotinin suppresses the activity of plasma and tissue kallikrein, trypsin, plasmin, as a result of which it reduces the fibrinolytic activity of the blood. Aprotinin activates the contact phase of coagulation activation, which initiates coagulation with simultaneous activation of fibrinolysis. Under conditions of using a heart-lung machine (AIC) and activation of coagulation caused by contact of blood with foreign surfaces, additional inhibition of plasma kallikrein will help to minimize disturbances in coagulation and fibrinolysis systems. Aprotinin modulates the systemic inflammatory response that occurs during AIK operations.The systemic inflammatory response leads to the interrelated activation of the hemostasis systems, fibrinolysis, activation of the cellular and humoral responses. Aprotinin, inhibiting numerous mediators (including kallikrein, plasmin, trypsin), weakens the inflammatory response, reduces fibrinolysis and thrombin formation. 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 during operations using AIK reduces the inflammatory response, which is reflected in a decrease in the volume of blood loss and the need for blood transfusion, and in a decrease in the frequency of repeated revisions of the mediastinum to find the source of bleeding.activation of cellular and humoral responses. Aprotinin, inhibiting numerous mediators (including kallikrein, plasmin, trypsin), weakens the inflammatory response, reduces fibrinolysis and thrombin formation. 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 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, and in a decrease in the frequency of repeated revisions of the mediastinum to find the source of bleeding.activation of cellular and humoral responses. Aprotinin, inhibiting numerous mediators (including kallikrein, plasmin, trypsin), weakens the inflammatory response, reduces fibrinolysis and thrombin formation. 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 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, and in a decrease in the frequency of repeated revisions of the mediastinum to find the source of bleeding.trypsin), weakens the inflammatory response, reduces fibrinolysis and thrombin formation. 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 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, and in a decrease in the frequency of repeated revisions of the mediastinum to find the source of bleeding.trypsin), weakens the inflammatory response, reduces fibrinolysis and thrombin formation. 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 during operations using AIK reduces the inflammatory response, which is reflected in a decrease in the volume of blood loss and the need for blood transfusion, and in a decrease in the frequency of repeated revisions of the mediastinum to find the source of bleeding.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 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, and in a decrease in the frequency of repeated revisions of the mediastinum to find the source of bleeding.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 during operations using AIK reduces the inflammatory response, which is reflected in a decrease in the volume of blood loss and the need for blood transfusion, and in a decrease in the frequency of repeated revisions of the mediastinum to find the source of bleeding.
Pharmacokinetics
Distribution
After intravenous administration, the concentration of aprotinin in plasma rapidly decreases due to distribution in the intercellular space with an initial T1 / 2 of 0.3-0.7 hours. The final T1 / 2 is 5-10 hours. The average equilibrium intraoperative plasma concentrations of the drug are 175-281 KIE / ml in patients receiving treatment with aprotinin during the operation in the following mode: intravenous loading dose of 2 million CIU, 2 million CIU for the initial volume of infusion, 500,000 CIU hourly during the entire operation as a continuous intravenous infusion ... When using half doses, the average equilibrium intraoperative plasma concentrations of the drug are 110-164 KIE / ml. Comparison of pharmacodynamic parameters of aprotinin in healthy volunteers, in patients with cardiac pathology when using AIC, and in women with hysterectomy,showed linear pharmacokinetics of the drug when administered in 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 in free form. Vd in equilibrium is about 20 liters. The total clearance of the drug 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 the binding of epithelial cells of the proximal renal tubules to the brush border and the accumulation of these cells in the phagolysosomes. Accumulation in cartilaginous tissue occurs due to the affinity of aprotinin, which is the base, and acidic proteoglycans of cartilage tissue. Concentrations of aprotinin in other organs are comparable to 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 crosses the placental barrier.
Metabolism and excretion
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 small amounts (less than 5% of the administered dose). Within 48 hours, 25-40% of aprotinin is determined as inactive metabolites in the urine.
Pharmacokinetics in special patient groups
In patients with end-stage renal failure, the pharmacokinetics of aprotinin have not been studied. In the study of patients with impaired renal function, changes in the pharmacokinetic parameters of aprotinin were not identified; no dosage adjustment is required.
Side effect
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 may increase up to 5%, especially with repeated administration of aprotinin for 6 months. With repeated use of aprotinin after more than 6 months, the risk of developing allergic / anaphylactic reactions is 0.9%. The risk of developing severe allergic / anaphylactic reactions increases if aprotinin has been used more than 2 times within 6 months. Even if no symptoms of allergic reactions were observed with repeated use of aprotinin, 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: from the vessels: arterial hypotension; from the gastrointestinal tract: nausea; from the respiratory system: bronchial asthma (bronchospasm); on the part of the skin and subcutaneous tissues: itching, urticaria, skin rash. If hypersensitivity reactions develop when using aprotinin, the drug should be discontinued immediately and the standard emergency measures should be ensured - infusion therapy, the introduction of epinephrine (adrenaline), GCS. Adverse drug reactions (ADRs) when using aprotinin are presented by systemic organ classes in accordance with the MedDRA classification and with a frequency of occurrence: infrequently (from? 1/1000 to <1/100), rarely (from? 1/10000 to <1 / 1000), very rare (<1/10000). From the immune system: rarely - allergic reactions,anaphylactic / anaphylactoid reactions; very rarely - anaphylactic shock (potentially life-threatening) *. From the hematopoietic system: very rarely - disseminated intravascular coagulation *, coagulopathy *. From the side of the cardiovascular system: infrequently - myocardial ischemia, thrombosis / occlusion of coronary arteries, myocardial infarction, pericardial effusion, thrombosis; rarely - arterial thrombosis (organ-specific clinical manifestations of dysfunction of vital organs: kidneys, lungs, brain); very rarely - pulmonary embolism *. From the urinary system: infrequently - oliguria, acute renal failure, tubular necrosis. Others: very rarely - reactions in the area of ??injection / infusion, thrombophlebitis / phlebitis at the infusion site.From the hematopoietic system: very rarely - disseminated intravascular coagulation *, coagulopathy *. From the side of the cardiovascular system: infrequently - myocardial ischemia, thrombosis / occlusion of coronary arteries, myocardial infarction, pericardial effusion, thrombosis; rarely - arterial thrombosis (organ-specific clinical manifestations of dysfunction of vital organs: kidneys, lungs, brain); very rarely - pulmonary embolism *. From the urinary system: infrequently - oliguria, acute renal failure, tubular necrosis. Others: very rarely - reactions in the area of ??injection / infusion, thrombophlebitis / phlebitis at the infusion site.From the hematopoietic system: very rarely - disseminated intravascular coagulation *, coagulopathy *. From the side of the cardiovascular system: infrequently - myocardial ischemia, thrombosis / occlusion of coronary arteries, myocardial infarction, pericardial effusion, thrombosis; rarely - arterial thrombosis (organ-specific clinical manifestations of dysfunction of vital organs: kidneys, lungs, brain); very rarely - pulmonary embolism *. From the urinary system: infrequently - oliguria, acute renal failure, tubular necrosis. Others: very rarely - reactions in the area of ??injection / infusion, thrombophlebitis / phlebitis at the infusion site.rarely - arterial thrombosis (organ-specific clinical manifestations of dysfunction of vital organs: kidneys, lungs, brain); very rarely - pulmonary embolism *. From the urinary system: infrequently - oliguria, acute renal failure, tubular necrosis. Others: very rarely - reactions in the area of ??injection / infusion, thrombophlebitis / phlebitis at the infusion site.rarely - arterial thrombosis (organ-specific clinical manifestations of dysfunction of vital organs: kidneys, lungs, brain); very rarely - pulmonary embolism *. From the urinary system: infrequently - oliguria, acute renal failure, tubular necrosis. Others: very rarely - reactions in the area of ??injection / infusion, thrombophlebitis / phlebitis at the infusion site.
Application during pregnancy and lactation
Pregnancy
Studies on the use of the drug GordoxЃ in pregnant women have not been conducted. During 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, one should take into account the negative effect on the fetus of severe adverse reactions possible with the use of the drug, such as anaphylactic reactions, cardiac arrest, etc., as well as the therapeutic measures taken to eliminate these reactions.
Breastfeeding period
The use of the drug GordoxЃ during lactation has not been studied. The drug is potentially safe when ingested in a child's body with breast milk, since it does not have oral bioavailability.
Application for impaired renal function
No dose adjustment is required in patients with impaired renal function.
Application in children
Contraindicated for use in children and adolescents under the age of 18 years (efficacy and safety have not been established).
Use in elderly patients
Elderly patients (over 65 years of age) do not need dose adjustment.
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 assess the benefit / risk ratio. 10 minutes before the administration of the main dose of GordoxЃ, a trial dose of 1 ml (10 thousand KIE) is administered. 15 minutes before the administration of a therapeutic dose of the drug GordoxЃ, it is possible to use blockers of histamine H1 and H2 receptors. However, allergic / anaphylactic reactions can develop with the introduction of a therapeutic dose of the drug, even if no adverse reactions were noted during the administration of the test dose. In case of development of hypersensitivity reactions when using aprotinin, you should immediately stop the administration of the drug and ensure that standard emergency measures are taken,aimed at the treatment of allergic / anaphylactic reactions. Patients in whom antibodies (IgG) to aprotinin are detected have a high risk of developing anaphylactic reactions when using aprotinin. In this regard, the use of the drug GordoxЃ in such patients is contraindicated. Before prescribing GordoxЃ, each patient is recommended to perform a test for the presence of antibodies (IgG) to aprotinin. If the determination of antibodies (IgG) to aprotinin is not possible, then in patients in whom the use of aprotinin during the previous 12 months cannot be excluded, the use of GordoxЃ is contraindicated. Despite the fact that anaphylactic reactions most often develop with repeated administration of aprotinin within 12 months,there are reports of the development of anaphylactic shock at a later date (when the repeated administration was performed later than 12 months after the first administration). When performing surgery on the thoracic aorta using AIK and using deep cold cardioplegia, GordoxЃ should be used with extreme caution against the background of adequate heparin therapy. Determination of the activated clotting time is not a standardized test for determining the coagulability of blood, and the use of aprotinin can influence various test methods. The Coagulation Measurement Test (ACT) is influenced by various dilution and temperature effects. The ACT kaolin test does not increase as much with aprotinin as the ACT test with celite.Due to the difference in protocols, it is recommended to take the minimum values ??of the ACT test - 750 sec and the ACT test with kaolin - 480 sec in the presence of aprotinin, regardless of the effects of hemodilution and hypothermia. The standard dose of heparin administered prior to canalization of the heart 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 the extracorporeal circulation period. The protamine titration method is not affected by aprotinin. Heparin supplements are based on the heparin concentration 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 using aprotinin. In patients who received the drug GordoxЃ,neutralization of heparin with protamine should be carried out only after interruption of extracorporeal circulation, on the basis of a fixed amount of injected heparin or under the control of the protamine titration method. The total amount of injected aprotinin during the treatment cycle should not exceed 7 million KIE. Aprotinin is not a substitute for heparin. Preparations for parenteral administration should be visually inspected immediately before use. Do not use the remains of the solution for subsequent use. GordoxЃ contains benzyl alcohol. The daily dose of benzyl alcohol should not exceed 90 mg / kg of body weight. Benzyl alcohol can cause anaphylactoid reactions.Influence on the ability to drive vehicles and mechanisms There are no data on the effect of GordoxЃ on the ability to drive vehicles and work with mechanisms.
Overdose
Currently, no cases of drug overdose have been reported. There is no antidote to the drug.
Drug interactions
GordoxЃ should not be mixed with other drugs. With the simultaneous use of the drug GordoxЃ with streptokinase, urokinase, alteplase, the activity of these drugs decreases. GordoxЃ is compatible with 20% glucose solution, hydroxyethylated starch solution, Ringer's lactate solution.