When using aprotinin, especially with repeated use of the drug may develop allergic / anaphylactic reactions. Therefore, before using the drug, you should carefully evaluate the benefit / risk ratio.
Despite the fact that the anaphylactic reaction most often develops after repeated administration of the drug for 12 months, there are some reports of the development of anaphylactic shock and at later times, when the drug was re-injected later than 12 months later. When using aprotinin, it is necessary to have emergency preparations ready for an allergic / anaphylactic reaction. Before administering aprotinin, each patient should perform a test-sample to identify a possible allergic reaction (see "Method of administration and dose"). Before the test-sample is performed, the patient must be intubated and the means for emergency cannulation should be ready in case of necessity to transfer the patient to the extracorporeal circulation. The test sample must be performed only under operating conditions.
10 minutes before the loading dose of Trisilol, a trial dose of 1 ml (10 thousand KIE) is introduced.15 minutes before the administration of the therapeutic dose of Trisolol, the use of blockers of histamine H1 and H2 receptors is possible. However, allergic / anaphylactic reactions may also develop with the administration of a therapeutic dose of the drug, even if no adverse reactions were noted during the administration of the trial dose. If hypersensitivity reactions occur during the use of the drug, the drug should be discontinued immediately and standard measures taken to treat the allergic / anaphylactic reaction should be carried out.
The results of recent studies have shown that aprotinin can cause renal dysfunction, especially in patients with renal insufficiency. A meta-analysis of placebo-controlled studies of patients undergoing CABG revealed an increase in serum creatinine by more than 0.5 mg / dl from the baseline in patients who received aprotinin (see "Pharmacodynamics"). Thus, before assigning aprotinin to patients with chronic renal failure or at risk (for example, concurrent use of aminoglycosides), it is recommended that the risk / benefit ratio be carefully analyzed.
When performing an operation on the thoracic aorta using AIC and the use of deep cold cardioplegia, Trisinol should be used with extreme caution when accompanied by adequate therapy with heparin.
Determination of the activated clotting time is not a standardized test for determining the coagulation ability of the blood, and the use of aprotinin may influence various test methods. The measurement of the degree of coagulation (ACT) is influenced by various effects during dilution and exposure to temperature. The result of the ACT test with kaolin increases to a lesser extent in the presence of aprotinin than the result of the ACT test with Celite. Because of the difference in protocols, it is recommended to take minimum ACT test values with Celite - 750 seconds and ACT test with kaolin - 480 seconds in the presence of aprotinin, regardless of the effects of hemodilution and hypothermia. The standard loading dose of heparin administered prior to cardiac cannulation 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 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 receiving Trachylin, 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. Trachylol is not a substitute for heparin. Preparations for parenteral administration should undergo visual control immediately before use. Do not use remnants of the solution for later use.
Safety data from preclinical studies
Acute toxicity: With intravenous administration, the LD50 is 2.5-6.5 million KIE / kg for mice, 2.5-5 million KIE / kg for rats, more than 1.36 million KIE / kg for dogs and 500,000 KIE / kg for rabbits. In studies with the administration of the drug to dogs in a dose corresponding to 3-10 highest recommended doses for a human, pseudoallergic reactions were observed,as well as changes in the type of hyaline transformation in the cells of the epithelium of the kidneys, unaccompanied by damage to the glomerular epithelium. The use of the drug in high doses (> 150,000 KIU / kg) in rats, guinea pigs, rabbits and dogs with rapid administration caused a short-term decrease in blood pressure of varying degrees of severity.
Toxicity with prolonged use: Daily intraperitoneal administration of aprotinin in rats at a dose of 10,000 to 300,000 KIE / kg / day for 13 weeks caused a decrease in body weight in animals receiving a high dose of the drug, with no changes in renal function, in animals receiving aprotinin in doses greater than 150,000 KIU / kg / day, changes in the epithelium of the renal tubules were observed that did not affect the glomerular epithelium and were completely reversible after discontinuation of the drug. Changes in the epithelium of the kidneys in dogs in a similar study were also completely reversible and did not affect the glomerular epithelium.
Toxic effect on reproductive function: with intravenous administration of rats to a daily dose of up to 80,000 KIU / kg, there was no toxic effect on the adult, embryotoxicity and fetotoxicity.With the introduction of a daily dose of 100,000 KIU / kg, no negative effect on the growth and development of offspring was found. When a daily dose of 200,000 KIU / kg was administered, there was no teratogenic effect. When intravenously administered to rabbits a daily dose of up to 100,000 KIU / kg, there was no toxic effect on the adult, embryotoxicity, fetotoxicity and teratogenic effect.
There was no mutagenic effect of aprotinin when tested on microbiological models.