Gordoks - instructions for use, dose, side effects, contraindications

Aprotinin is an inhibitor of broad-spectrum proteolytic enzymes, which has antifibrinolytic properties. Forming reversible stoichiometric complexes - inhibitors of enzymes, aprotinin suppresses the activity of plasma and tissue kallikrein, trypsin, plasmin, which reduces the fibrinolytic activity of the blood.

Aprotinin activates the contact phase of clotting activation, which initiates coagulation with simultaneous activation of fibrinolysis. In conditions of the use of the apparatus of artificial circulation and the activation of clotting caused by the contact of blood with foreign surfaces, the additional inhibition of plasma kallikrein will help minimize disorders in clotting and fibrinolysis systems. Aprotinin modulates the systemic inflammatory reaction that occurs during operations of artificial circulation. Systemic inflammatory reaction leads to interconnected activation, hemostasis systems, fibrinolysis, activation of cellular and humoral response. Aprotinin, inhibiting numerous mediators (kallikrein, plasmin, trypsin , etc.), weakens the inflammatory reaction, reduces fibrinolysis and the formation of thrombin.

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

The use of aprotinin in surgery with the use of an artificial circulatory system (AIC) reduces the inflammatory response, which is reflected in a decrease in the volume of blood loss and the need for blood transfusion, a reduction in the frequency of repeated revisions of the mediastinum to find the source of bleeding.

Pharmacokinetics:

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

Comparison of pharmacodynamic parameters of aprotinin in healthy volunteers, in patients with cardiac pathology with the use of an artificial blood circulation in women during hysterectomy showed a linear pharmacokinetics of the drug when doses ranging from 50 thousand to 2 million KIE. 80% of aprotinin binds to plasma proteins and 20% of antifibrinolytic activity carries out the preparation, which is in free form. The equilibrium volume of distribution is about 20 liters and the total clearance of the drug is approximately 40 ml / min.

Aprotinin accumulates in the kidneys, and,to a lesser degree, in the cartilaginous tissue. Accumulation in the kidneys occurs due to binding to the brush border of epithelial cells proximal renal tubules and accumulation in phagolysosomes of these cells. Accumulation in the cartilaginous tissue occurs due to the affinity of aprotinin, which is the base, and acid proteoglycans of the cartilaginous tissue. Concentrations of aprotinin in other organs are comparable with the concentration of the drug in plasma. The low concentration of the drug itself is determined in the brain, aprotinin practically does not penetrate into the liquor.

A very limited amount of aprotinin penetrates the placental barrier.

Aprotinin is metabolized by lysosomal enzymes in the kidneys to inactive metabolites - short peptide chains and amino acids. Active aprotinin is revealed inurine 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.

In patients with terminal renal failure pharmacokinetics of aprotinin has not been studied. In the study of patients with impaired function kidneys change pharmacokinetic parameters of aprotinin are not revealed, correction of the dosing regimen is not required.

Indications:

The drug GORDOX® is used to prevent intraoperative blood loss and reduce the volume of blood transfusion during aortocoronary surgerybypass with the use of an artificial circulatory system (AIC) in adult patients.

Contraindications:

Hypersensitivity to aprotinin or any of the excipients.

Age to 18 years (effectiveness and safety not established).

Pregnancy and lactation:

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

Use during pregnancy is only possible when the intended The benefit to the mother exceeds the potential risk to the fetus.In assessing the benefit / risk relationship, one should take into account the adverse 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.

The use of the drug GORDOX® during lactation has not been studied. The drug is potentially safe when ingested with a baby with breast milk, because it does not have bioavailability when taken orally.

Dosing and Administration:

A drug GORDOX® introduce intravenously slowly.

The maximum rate of administration is 5-10 ml / min. When the drug is administered, the patient should be in the supine position. Introduce the drug GORDOX® through the trunk veins, do not use them for the administration of other drugs.

Due to the high risk development of allergic / anaphylactic reactions, all patients 10 minutes before the introduction of the main dose of the drug GORDOX ® should be administered a trial dose of 1 ml (10 thousand KIE). In the absence of negative reactions, a therapeutic dose of the drug is administered. Possible use of histamine blockers H1 and H2 receptors 15 minutes before the administration of the drug GORDOX®. In any case, standard emergency measures aimed at treatment should be provided allergic / anaphylactic reaction.

Adult patients the following dosing regimen is recommended:

the initial dose is 1-2 million. KANDE is administered iv slowly for 15-20 min after the onset of anesthesia and before sternotomy. The next 1-2 million KIEs are added to the primary volume, the heart-lung device. Aprotinin should be added to the primary volume during the recycling period to ensure sufficient dilution of the preparations to prevent interaction with heparin.

After the end of the bolus injection, a constant infusion is established at a rate of 250-500 thousand KIU / h until the end of the operation. Total number of entered aprotinin throughout the course should not exceed 7 million KIE.

Patients with impaired renal function

Patients with impaired renal function do not need to perform a mode correction dosing.

Children

The drug is contraindicated at the age of 18 years (efficacy and safety not established).

Elderly patients

A change in the dosing regimen in elderly patients is not required.

Side effects:

Have patients receiving aprotinin for the first time, the development of allergic or anaphylactic reactions is unlikely. If you re-introduce the frequency of development Allergic (anaphylactic) reactions can increase to 5%, especially when. repeated use of aprotinin for 6 months. With repeated use of aprotinin, more than in 6 months, the risk of allergic / anaphylactic reactions is 0.9%. The risk of severe allergic / anaphylactic reactions increases if, within 6 months aprotinin was applied more than twice. Even in that If, with repeated use of aprotinin, no symptoms of allergic reactions were observed, subsequent use of the drug may lead to the development of heavy allergic reactions or anaphylactic shock, in rare cases with lethal outcome.

Symptoms of allergic / anaphylactic reactions from:

Cardiovascular system: hypotension;

The digestive system: nausea;

Respiratory system: asthma (bronchospasm);

Skin: itching, hives, rash.

If hypersensitivity reactions develop with aprotinin, discontinue the drug immediately and provide standard urgent measures - infusion therapy, the introduction of epinephrine / epinephrine, corticosteroids.

Data on the side effects of aprotinin:

Frequent - the frequency of development: ≥1% and <10%
Not frequent - the frequency of development: ≥0,1% and <1% -	Cardiovascular system: myocardial ischemia, thrombosis / occlusion of the coronary arteries, infarction myocardium, pericardial effusion, thrombosis. Urinary system: violation of kidney function, kidney failure.
Rare - the frequency of development: ≥0.01% and <0.1%	Cardiovascular system: arterial thrombosis (with a possible manifestation of impaired function of vital, important organs, such as the kidneys, lungs, brain). Allergic / anaphylactic, anaphylactoid reactions.
Very rare frequency of development: <0.01%	Local reactions: Reactions in the field of injection / infusion; thrombophlebitis. Cardiovascular system: thromboembolism of the pulmonary artery Blood and hematopoiesis system: Syndrome of disseminated intravascular coagulation; coagulopathy. Anaphylactic shock, (potentially life-threatening).

Overdose:

At present, no cases of drug overdose have been reported. Antidote to the drug does not exist.

Interaction:

The drug GORDOX® Do not mix with other drugs.

The drug GORDOX® is compatible with 20% glucose solution, hydroxyethylated solution starch, lactated Ringer's solution.

With the simultaneous use of the drug GORDOX® with streptokinase, urokinase, alteplase decreases activity of these drugs.

Special instructions:

When using aprotinin, especially with repeated use of the drug, it is possible to develop allergic / anaphylactic reactions. Therefore, before using the drug it is necessary to carefully evaluate the benefit / risk ratio. 10 minutes before the introduction of the main a dose of GORDOX® is given a trial dose of 1 ml (10 thousand KIE). 15 minutes before the administration of the therapeutic dose of GORDOX®, the use of histamine blockers H₁- and H₂receptors. However, allergic / anaphylactic reactions may also develop with the administration of a therapeutic dose, even if during the administration of a trial dose of no reactions were noted. If hypersensitivity reactions develop with aprotinin, discontinue the drug immediately and provide standard urgent measures aimed at the treatment of allergic / anaphylactic reactions.

When carrying out an operation on the thoracic aorta using AIC and using deep cold cardioplegia, GORDOX® should be used very carefully with adequate heparin therapy.

The determination of the activated clotting time is not a standardized test for determining the coagulation ability of the blood, and the use of aprotinin can influence the different test methods. The measurement of the degree of coagulation (ACT) is influenced by various effects during dilution and exposure to temperature. ACT The test with kaolin does not increase to such an extent in the presence of aprotinin, as ACT test and Celite. Because of the difference in protocols, it is recommended to take minimal meanings ACT test - 750 seconds and ACT test with kaolin - 480 sec with presence aprotinin, regardless of the effects of hemodilution and hypothermia.The standard dose of heparin, administered prior to cardiac cannulation and the amount of heparin added to the primary volume in the circulatory system, should be at least 350 IU / kg. The additional dose of heparin is determined by the body weight patient and the duration of the extracorporeal circulation period. The method of titration of protamine is not influenced 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 prior to the use of aprotinin.

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

This preparation contains benzyl alcohol. The daily dosage of benzyl alcohol is not should exceed 90 mg per kilogram of body weight.

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

Aprotinin is not a substitute for heparin.

Preparations for parenteral administration should undergo visual control immediately before use. Do not use remnants of solution for later use.

Effect on the ability to drive transp. cf. and fur:Data on any influence of the drug GORDOX® on the ability to drive and work with mechanisms are absent.

Form release / dosage:

Solution for intravenous administration, 10 000 KIE / ml.

Packaging:For 10 ml of the preparation in a colorless glass ampoule I of hydrolytic class with a point for breakage. 5 ampoules in a plastic pallet, 5 pallets with ampoules and two additional pallets in a cardboard box with instructions for use.

Storage conditions:

Store in a dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N013656 / 01

Date of registration:14.10.2011

Expiration Date:Unlimited

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER, Plc. Hungary

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp06.05.2017

Illustrated instructions

Instructions

Gordox® (Gordox®)