Use of the drug Gordox
Adults - the initial dose is 500,000 CIU of aprotinin IV slowly (maximum rate 5 ml/min) with the patient lying down. To maintain the achieved level in the blood, administration continues with a long-term drip infusion (200,000 CIED every 4–6 hours). The daily dose is at least 1,000,000 CIED. After improvement of the clinical picture and laboratory parameters, the daily dose can be gradually reduced to 500,000 CIED. For children - the daily dose is 20,000 CIED of aprotinin per 1 kg of body weight per day.
Special instructions for the drug Gordox
The active substance has a protein nature and a polypeptide structure, therefore it can act as an antigen. In order to establish hypersensitivity, before administering the initial dose, it is necessary to administer 1 ml of a test dose from a 10,000-fold dilution intravenously. If an allergic reaction to the test dose occurs, the use of the drug is contraindicated. If hypersensitivity reactions occur during administration of the drug, the infusion must be stopped immediately. In the second and third trimester of pregnancy, the drug can be prescribed only after a thorough assessment of the benefit/risk ratio.
Instructions for use GORDOX
Recent observational studies suggest that treatment with aprotinin may be associated with renal impairment, particularly in patients with pre-existing renal impairment. When analyzing the results of placebo-controlled studies carried out in patients undergoing coronary artery bypass surgery, it was shown that in the group receiving aprotinin, there was an increase in serum creatinine levels by 0.5 mg/dl compared with the normal value. Accordingly, before prescribing aprotinin to patients with impaired renal function or at risk of renal damage (for example, during concomitant treatment with aminoglycosides), a careful assessment of the benefit-risk ratio is necessary.
During pregnancy, aprotinin should only be prescribed if the potential benefits outweigh the expected risks.
This medicine contains benzyl alcohol. According to European guidelines, the daily dose of benzyl alcohol should not exceed 90 mg/kg body weight. Thus, during the treatment cycle, the maximum dose of aprotinin cannot exceed 6 million KIU.
When using aprotinin, a careful benefit-risk assessment is necessary, especially in patients who have previously used aprotinin (including fibrin filling material containing aprotinin), as they may develop an allergic reaction. Although most cases of anaphylaxis develop after the resolving dose is administered within 12 months, there are isolated case reports of anaphylactic reactions occurring upon reexposure after 12 months. When conducting aprotinin therapy, it is necessary to have emergency supplies available to treat allergic and anaphylactic reactions.
All patients receiving treatment with aprotinin should first be administered a test dose in order to assess the presence of a tendency to allergic reactions. The test dose should be administered to the patient in the operating room.
H1- and H2-histamine receptor blockers can be administered 15 minutes before the aprotinin test.
The test dose of aprotinin in all patients should be 1 ml (10,000 KIU), after which the patient should be observed for at least 10 minutes before administering the loading dose.
However, even despite the absence of complications in the period after the initial dose of 1 ml, a therapeutic dose of aprotinin can cause an anaphylactic reaction. If an anaphylactic reaction develops, the aprotinin infusion should be stopped and the necessary emergency measures taken.
Due to the possibility of developing hypersensitivity reactions, before starting the use of Gordox, it is necessary to carefully evaluate the benefit-risk ratio in each patient who has already received treatment with aprotinin.
If it is known that the patient has already received or may have received re-treatment with aprotinin, the following precautions are recommended. As indicated in the "Dosage Regimen" section, all patients should be administered a test dose of Gordox in a volume of 1 ml (10,000 KIU) at least 10 minutes before the initial dose. In addition, an H1-histamine receptor blocker (eg, clemastine) and an H2-histamine receptor blocker (eg, cimetidine) may be administered 15 minutes before administering the test dose of Gordox. If necessary, standard emergency measures should be used to treat an allergic (anaphylactic) reaction.
It should not be forgotten, however, that a therapeutic dose can cause an allergic reaction, even if the patient tolerated the initial test dose of 1 ml well without experiencing any undesirable symptoms. If this occurs, the aprotinin infusion should be stopped immediately and standard emergency management measures to treat anaphylactic reactions should be initiated.
Patients receiving Gordox had an increased incidence of renal failure and mortality compared with an age-matched control group, which had a similar medical history and also underwent surgery on the thoracic aorta under cardiopulmonary bypass with circulatory arrest during deep hypothermia . In such cases, Gordox can be prescribed only with extreme caution. Appropriate anticoagulant treatment with heparin is necessary.
Impact on the ability to drive vehicles and machinery
Given the scope of use of the drug, consideration of these effects is irrelevant.
Additional notes on the use of the drug under conditions of artificial circulation
To maintain adequate anticoagulant activity during cardiopulmonary bypass while using Gordox, it is recommended to use any of the following methods:
- 1. Activated clotting time (ACT)
- ABC cannot be considered a standard coagulation test;
- interpretation of the results of this test depends on the presence of aprotinin. In addition, the test results are influenced by differences due to dilution and the temperature used under cardiopulmonary bypass conditions. It has been shown that the effect of aprotinin is expressed to a lesser extent in relation to kaolin ABC, in comparison with ABC using diatomaceous earth (celite). Despite the variety of protocols, it is recommended to perform the 750-second ABC test using diatomaceous earth or the 480-second ABC test using kaolin in the presence of aprotinin, regardless of the degree of hemodilution and hypothermia. Consult the manufacturer of the ABC test reagents for advice regarding the interpretation of test results in the presence of Gordox.
:
2. Administration of heparin in constant doses:
The standard loading dose of heparin that is administered before cardiac catheterization, as well as the amount of heparin that is added to the primary filling solution of the heart-lung machine, should be at least 350 IU/kg. The additional dose of heparin is determined taking into account the patient's body weight and the duration of the intervention under artificial circulation.
3. Heparin/protamine titration:
The results of this method are not affected by the presence of aprotinin and are therefore acceptable for measuring heparin levels. The relationship between heparin dose and response should be assessed by titrating protamine before administering aprotinin (to determine the heparin loading dose).
Additional heparin can be administered based on the heparin concentration measured by titration with protamine. Heparin concentrations during cardiopulmonary bypass should not fall below 2.7 U/mL (2.0 mg/kg) or below the dose determined in the heparin dose-response test performed prior to administration of aprotinin.
After completion of cardiopulmonary bypass, if the patient received Gordox injections, heparin should be neutralized by administering protamine. The amount of protamine should be calculated based on a fixed ratio, which is determined from the amount of heparin administered or calculated using the protamine titration method.
Important:
using Gordox does not mean that the need for heparin is reduced.
Results of preclinical safety studies
Acute toxicity
In rats, guinea pigs, rabbits and dogs, rapid administration of a large amount (over 150,000 KIU/kg body weight) of the active substance was accompanied by the development of arterial hypotension of varying severity, which quickly resolved.
Approximate values of 50% lethal dose (LD50) for intravenous administration were:
- Mice:
- from 2.5 to 6.5 million KIU per kg of body weight.
- from 2.5 to 5.0 million KIU per kg of body weight.
Rats:
Dogs:
- over 1.36 million KIU per kg of body weight.
Rabbits:
- over 0.5 million KIU per kg of body weight.
In the study, which was designed to simulate intended use in humans, dogs received a daily dose of 340,000 KIU/kg body weight as a 4-hour infusion or a dose of 1,360,000 KIU/kg body weight daily as an 8-hour infusion. hourly infusion. These doses are 3-10 times higher than recommended doses for humans. The following deviations from the norm were observed:
- pseudoallergic reactions and mild or moderate hyaline changes in the cytoplasm of epithelial cells of the renal tubules. The morphological changes observed in the kidneys did not affect the glomeruli, but were not completely reversible after a 10-day period without treatment.
In rats, guinea pigs, rabbits and dogs, rapid administration of large amounts (over 150,000 KIU/kg body weight) of the active substance was accompanied by the development of rapidly resolving hypotension of varying severity.
Chronic toxicity
Rats received aprotinin at a daily dose of 10,000 to 300,000 KIU/kg body weight for 13 weeks intraperitoneally. When administered in high doses, a slowdown in the rate of weight gain was observed, which was not accompanied by a deterioration in renal function. At autopsy, an increase in the relative weight of the kidneys was revealed, and histological examination revealed hyaline drops and casts in the renal tubules, especially in the two groups receiving the highest doses of the drug (150,000 and 300,000 KIU per kg of body weight). Changes in the tubules were not permanent and were not accompanied by damage to the glomeruli.
In another study in rats, there were no pathological changes (including biochemical abnormalities, macro- and microscopic changes) in the kidneys after a 35-day recovery period. The only exception was the relative weight of the kidneys, which was slightly higher in males and females receiving the maximum dose of the drug. Subsequently, all morphological and functional changes that occurred in the renal tubules were completely reversible within 35 days after the end of treatment.
Numerous studies have been conducted on dogs; Doses ranging from 5000 to 500,000 KIU/kg body weight have been used, administered intravenously or intraperitoneally over a maximum period of 16 weeks. As in rats, the most significant target of toxicity in dogs was also the renal tubular epithelium. In some studies that included a period without treatment, these morphological and functional abnormalities were shown to be reversible.
Reproductive toxicity
In rats, intravenous administration of aprotinin at a daily dose of 80,000 KIU per kg/body weight did not have a toxic effect on the mother and was not accompanied by embryotoxicity or fetotoxicity. Daily administration of the drug at a dose of up to 100,000 KIU/kg body weight was not accompanied by an effect on the growth and development of the offspring; IV administration at a dose of 200,000 KIU/kg/day did not have a teratogenic effect. In rabbits, intravenous administration of aprotinin at a daily dose of up to 100,000 KIU/kg body weight did not have a toxic effect on the mother and was not accompanied by embryotoxicity, fetotoxicity or teratogenic effects.
Mutagenicity
Aprotinin did not exhibit mutagenic properties in Salmonella
/microsomal test (Ames) and B. subtilis DNA damage test
.
