Aprotinin

Pharmacological properties

Aprotinin is a broad-spectrum protease inhibitor molecule, has antifibrinolytic activity. forming a reversible stoichiometric enzyme-inhibitor complex, human aprotinin inhibits trypsin, plasmin, kallikrein in blood plasma and tissues, which leads to inhibition of fibrinolysis. in addition, it inhibits the contact phase of activation of blood coagulation, is a factor in triggering the process of coagulation and stimulation of fibrinolysis.

Aprotinin is used in operations under extracorporeal circulation because it attenuates inflammatory reactions, which reduces the need for transfusion of allogeneic blood and reduces blood loss, as well as reduces the need for re-examination of the mediastinum for bleeding.

In patients who underwent coronary artery bypass surgery, the frequency of an increase in the level of creatinine in blood plasma by 0.5 mg / dl compared with the initial level was significantly higher in those who received a full dose of aprotinin compared with the placebo group. In most cases, postoperative renal dysfunction was reversible and not serious, the frequency of increasing plasma creatinine relative to baseline ≥2 mg / dl was the same in the group receiving the full dose of aprotinin and placebo.

Pharmacokinetics After iv administration, aprotinin is rapidly distributed throughout the extracellular space, which is accompanied by a rapid decrease in the concentration of aprotinin in blood plasma, T_½ is 0.3–0.7 hours. Later, in particular 5 hours after administration, the terminal elimination phase occurs, at which T_½ 5-10 hours

The placenta is probably not completely impermeable to aprotinin, however, penetration, obviously, is extremely slow.

Metabolism, elimination and excretion. The aprotinin molecule in the kidney is split into shorter peptides or amino acids by lysosomal enzymes. In a person with urine, less than 5% of the administered dose of aprotinin is excreted. Following iv administration of aprotinin with a label to healthy volunteers ¹³¹I 25–40% of the labeled substance is excreted within 48 hours with urine in the form of metabolites. These metabolites do not have fermenting activity.

There are no data on the use of the drug in patients with end-stage renal failure, however, in patients with impaired renal function, no clinically significant pharmacokinetic changes or obvious side effects were noted. In this regard, special dose adjustment in such cases is not required.

Indications

Aprotinin is indicated for prophylaxis in order to reduce postoperative blood loss and the need for blood transfusion in adult patients with a high risk of large blood loss during isolated cardiopulmonary bypass surgery (i.e. coronary artery bypass grafting, which is not combined with other cardiovascular interventions).

Aprotinin should be used only after a thorough study of the benefits and risks, and also pay attention that alternative treatments are available.

Application

Before administering the drug, all patients should be tested for igg antibodies specific for aprotinin (see contraindications).

Unless the nature of the prescriptions is different, the following doses of the drug are recommended for adult patients.

Test dose. Due to the risk of developing an allergic (anaphylactic) reaction, all patients should be given iv 10,000 KIED aprotinin (1 ml) at least 10 minutes before the initial dose. If the initial dose of 1 ml did not cause an allergic reaction, a therapeutic dose can be administered.

Antagonists H₁- and H₂receptors can be administered 15 minutes before the aprotinin test.Equipment must be available for standard emergency treatment of anaphylactic and allergic reactions.

Dosage during open heart surgery (with a cardiopulmonary bypass) to reduce blood loss and the need for blood transfusion. After anesthesia (but before sternotomy), it is recommended to introduce a loading dose of 1 000 000–2 000 000 KIED by slow intravenous injection or infusion for 20-30 minutes. The next dose of 1 000 000–2 000 000 KIED should be administered after turning on the heart-lung machine. In order to avoid the physical incompatibility of aprotinin and heparin, which is added to the primary filling solution of the pump, each preparation should be added to the primary filling solution of the pump during recycling, in order to ensure sufficient dilution of both drugs before mixing them with each other. After the initial bolus infusion at a high dose, 250,000–500,000 KIED / h should be administered by continuous infusion until the end of the operation.

In general, the total amount of aprotinin administered during the treatment cycle should not exceed 6,000,000 KIED, which is associated with the content of benzyl alcohol in the injection solution (see SPECIAL INSTRUCTIONS).

Aprotinin for iv administration should be administered via a central venous catheter, which should not be used to administer any other drug.

The drug can be administered only to patients who are in a prone position, administration should be carried out slowly (maximum speed - 5-10 ml / min) by intravenous injection or short-term infusion.

In patients with impaired renal function, dose adjustment is not required according to the clinical experience accumulated to date.

When used in elderly patients in accordance with current clinical experience, there is no need to change the dosage regimen.

Contraindications

Hypersensitivity to the active substance or any of the excipients. in patients with igg antibodies specific for aprotinin, there is an increased risk of anaphylaxis with aprotinin treatment. in this regard, aprotinin therapy is contraindicated in such patients.

In the event that testing for specific IgG antibodies to aprotinin before starting treatment is impossible, but it is assumed that the patient received treatment with aprotinin within the previous 12 months, administration of aprotinin is contraindicated.

Side effects

Security Profile Summary. the safety of aprotinin was evaluated in more than 45 studies of the II – III phase involving more than 3800 patients receiving aprotinin. in general, 11% of patients treated with aprotinin developed adverse reactions. the most serious adverse reaction was myocardial infarction. adverse reactions should be evaluated in the context of surgical interventions.

Allergic / anaphylactic reactions. In patients receiving aprotinin for the first time, the development of allergic or anaphylactic reactions is unlikely. In the case of repeated administration, the frequency of development of allergic (anaphylactic) reactions can reach 5%. In a retrospective analysis of allergic (anaphylactic) reactions, it was found that their frequency increases if repeated administration is noted within 6 months after the initial treatment (frequency is 5% with repeated exposure for 6 months and 0.9% with repeated exposure after completion 6 months). In addition, a retrospective analysis revealed that the frequency of severe anaphylactic reactions is further increased in patients who received aprotinin more than 2 times over 6 months. Even if the patient tolerated the aprotinin treatment well, subsequent administration can cause a severe allergic reaction or, in extremely rare cases, anaphylactic shock with a fatal outcome.

Symptoms of allergic or anaphylactic reactions:

from the cardiovascular system: arterial hypotension;

from the digestive system: nausea;

from the respiratory system: AD (bronchospasm);

on the part of the skin and its appendages: itching, urticaria, rash.

If an allergic reaction develops with an injection or infusion, drug administration should be stopped immediately. Standard emergency measures should be used, including the administration of epinephrine, corticosteroids, and infusion therapy.

The cardiovascular system. In patients who underwent coronary artery bypass surgery, it was not possible to demonstrate significant differences in the number of cases of myocardial infarction compared with placebo. Some studies have shown a tendency to increase the frequency of myocardial infarction with the introduction of aprotinin, while in other studies, on the contrary, there has been a decrease in the number of cases of this pathology.

Since the tasks of the above studies did not include the identification of differences in the incidence of myocardial infarction, an increase in the likelihood of developing clinically significant side effects cannot be statistically significantly excluded.

Undesirable effects identified during post-marketing use are indicated in italics.

Within individual frequency categories, adverse reactions are listed in decreasing order of severity.

special instructions

Aprotinin should not be used during coronary artery bypass grafting (ASC) in combination with other cardiovascular operations, since the benefit / risk ratio of aprotinin in other cardiovascular operations has not been established.

Aprotinin treatment may be associated with impaired renal function, especially in patients with kidney damage. In patients who underwent coronary artery bypass surgery, when using aprotinin, an increase in plasma creatinine levels of 0.5 mg / dl was noted compared to the normal value (see PHARMACOLOGICAL PROPERTIES). Accordingly, before prescribing aprotinin in patients with impaired renal function or at risk of kidney damage (with simultaneous treatment with aminoglycosides), a careful assessment of the benefit-risk ratio is necessary.

Patients treated with aprotinin showed an increase in the incidence of renal failure and mortality compared with a comparable age group, which had a similar medical history and in which operations were performed on the thoracic aorta under cardiopulmonary bypass and cardiopulmonary arrest with deep hypothermia. In such cases, aprotinin can only be prescribed with extreme caution. It is necessary to carry out appropriate anticoagulant therapy with heparin.

This drug contains benzyl alcohol, which can cause anaphylactoid reactions.

When using aprotinin, a careful assessment of the benefit-risk ratio is necessary, especially in patients who have already used aprotinin (including fibrin filling material containing aprotinin), since they may develop an allergic reaction (see ADVERSE EFFECTS). Although in most cases, anaphylaxis develops after the introduction of the permitted dose for 12 months; There are separate reports of cases where anaphylactic reactions occurred during repeated exposure after 12 months. When carrying out aprotinin therapy, it is necessary to have emergency means available for the treatment of allergic and anaphylactic reactions.

All patients receiving aprotinin treatment need