GORDOKS

Active material: Aprotinin
When ATH: B02AB01
CCF: Hemostatic drug. An inhibitor of fibrinolysis – polyvalent proteinase inhibitor plasma
ICD-10 codes (testimony): i26, K85, R57.1, R57.8, R58, T79.1, T79.4
When CSF: 11.17.01
Manufacturer: GEDEON RICHTER Ltd. (Hungary)

Pharmaceutical form, composition and packaging

Concentrate for solution for i / v administration colorless or slightly colored, net.

Excipients: sodium chloride, benzyl alcohol, water d / and.

10 ml – colorless glass vials (5) – packings Valium plastic (5) – packs cardboard.

Pharmacological action

Polyvalent protease inhibitor. Aprotinin – polypeptide, which is obtained from the lungs of cattle. It has antiproteoliticheskoe, antifibrinolytic and haemostatic effect.

Forming reversible stoichiometric enzyme-inhibiting complex, inactivates important protease: trypsin, plasmin, plasma and tissue kallikrein, ximotripsin, kininogenases (incl. activating fibrinolysis). It stops as the total proteolytic activity, and the activity of certain proteolytic enzymes.

Due antiproteaznoy activity of aprotinin is effective in patients with lesions of the pancreas and other conditions, involving high kallikrein and other proteases in plasma and tissues.

Lowers blood fibrinolytic activity, inhibits fibrinolysis and provide haemostatic effect in coagulopathies.

The inhibition of kallikrein-kinin system determines the effectiveness of the drug for the prevention and treatment of various types of states of shock.

The efficacy is expressed in kallikrein-inactivating units (KIE). 1 KIE matches 140 ng of aprotinin, 100 000 KIE – 14 mg of aprotinin, 500 000 KIE – 70 mg of aprotinin.

Pharmacokinetics

Distribution

Aprotinin binds to epithelial cells in the proximal renal tubule and cartilage (but less) by reaction of its molecules, possessing alkaline properties, with kislыmi glikoproteinami.

Metabolism

As a result of the activity of lysosomal cell renal tissue aprotinin molecule are hydrolyzed to shorter peptides and amino acids.

Deduction

T_1/2 is 150 m, terminal T_1/2 is 7-10 no. Aprotinin is excreted in the urine within 5-6 h as inactive metabolites.

When administered dose, reaching 1 000 000 KIE, aprotinin is not found in the urine in unchanged form.

If ligation of the renal vessels during pre-clinical trials slowing reducing the concentration of aprotinin in blood.

Testimony

- Therapy of primary giperfibrinoliticheskogo bleeding (posttraumatic, Postoperative / especially in surgical interventions on the prostate gland, Lung /);

- Surgical open heart surgery to reduce the intensity of bleeding and reduce the need for blood products;

- Acute pancreatitis, exacerbation of chronic pancreatitis, pancreatic necrosis;

- Surgery (in t. no. Diagnostic), performed on the pancreas and in the bordering abdominal (for preventing enzymatic autolysis pancreas);

- Shock (toxic, traumatic, ambustial, hemorrhagic);

- Extensive, affecting several layers of traumatic tissue damage;

- Massive bleeding (during thrombolytic therapy);

- Extracorporeal circulation;

- Prevention of postoperative pulmonary embolism and bleeding, fat embolism with multiple injuries, especially, fractures of the lower limbs and the skull bones.

Dosage regimen

The drug should be administered in / slow, the patient must be strictly in the supine position.

Test dose: no less, than 10 min before administration initial dose in / injected test dose, equal 1 ml (10 000 KIE aprotinin) for determining the presence of hypersensitivity to the drug.

For therapeutic purposes,: the initial dose is equal to 50 000 KIE (the maximum rate of introduction - 5 ml / min), then / drip, by 50 000 KIE / h.

At bleeding and hemorrhage, related hyperfibrinolysis, the drug is introduced into / in the drip in an amount 100 000-200 000 KIE, if necessary, the introduction to 500 000 KIE (depending on the intensity of bleeding).

At surgical intervention to, during and after surgery as a prophylactic measure: 200 000-400 000 KIE / O, bolus or slow infusion, then during the next 2 days 100 000 KIE.

At disorders of hemostasis children: 20 000 KIU / kg / day.

Perhaps the topical application of gauze, impregnated 100 000 KIE, which is applied to the site of bleeding.

At Acute pancreato: 500 000-1 000 000 KIE with a subsequent decrease to 50 000-300 000 KIE for 2-6 d, and the complete abolition of the enzyme after the disappearance toksinemii.

At exacerbation of chronic pancreatitis is administered singly at the rate of 25 000 KIE / day for 3-6 days; the daily dose is in the range 25 000-50 000 KIE.

In the postoperative period, and as a preventive (at danger of damaging the pancreas) the initial dose 200 000 KIE, then for 2 day after surgery for 100 000 KIE every 6 no.

Treatment of primary giperfibrinoliticheskogo bleeding:

To Adult starting dose is 500 000 KIE (50 ml), I /, slowly, the maximum rate of administration 5 ml / min, wherein the patient should be in a prone position. Babies the drug should be prescribed by 20 000 KIU / kg / day.

To reduce the amount of bleeding and reducing the need for blood products in cardiac surgery (pulsative cardiopulmonary bypass): 2 000 000 KIU be added to the liquid, filling the oxygenator. During the 2-hour operation the patient receives 5 000 000 KIE aprotinin. Correction mode for elderly patients not required.

Side effect

CNS: psychotic reactions, hallucinations, confusion.

Allergic reactions: hives, itch, rhinitis, conjunctivitis, bronchospasm, anaphylaxis, anaphylactoid reactions (skin rash, itch, breathlessness, nausea, acceleration of the heart rate – these symptoms may progress to anaphylactic shock with symptoms of circulatory failure, in some cases with fatal outcome). Repeated administration of the drug incidence of anaphylactic reactions - less 0.5%. Even with satisfactory tolerability second dose, further administration of aprotinin can cause severe anaphylaxis, the danger which continues to increase with repeated doses. In some cases, anaphylactoid reactions observed after the first dose. In case of hypersensitivity reactions during infusion of the drug administration should immediately stop, if necessary, conduct a standard event of emergency treatment (eg, administration of epinephrine, GCS, holding rehydration). During surgery on the heart and the introduction of aprotinin in high doses may (< 1%) a temporary increase in serum creatinine, In very rare cases, accompanied by clinically significant symptoms.

Co cardiovascular system: a higher incidence of myocardial infarction in repeated by-pass operations on the coronary vessels as compared with controls (while mortality rates are the same); decrease in blood pressure, tachycardia.

From the digestive system: nausea, vomiting (if enough slow administration of the drug).

Local reactions: thrombophlebitis after repeated puncture and prolonged administration.

Other: myalgia.

Contraindications

- I and III trimesters of pregnancy;

- Lactation (breast-feeding);

- Hypersensitivity to aprotinin.

FROM caution possible use of the drug during cardiopulmonary by-pass surgery, deep hypothermia, cardiac arrest (increased risk of developing renal failure and death), with a history indications of allergic reactions or by previous therapy aprotinin, ICE (except phase coagulopathy).

Pregnancy and lactation

The safety of the drug during pregnancy and lactation have not been established. The drug is contraindicated in I and III trimesters of pregnancy and lactation. Use of the drug during pregnancy is possible only in case, when the intended benefits to the mother outweighs the potential risk to the fetus.

Cautions

If you experience symptoms of side effects during administration of the drug should be discontinued immediately administration of the drug.

When hyperfibrinolysis syndrome and DIC appointment of aprotinin is possible only after the elimination of all forms of the syndrome on the background of prophylactic heparin.

Special care should be given to patients, which in the previous 2-3 day administered muscle relaxants.

The drug may be administered after careful risk-benefit ratio in the following states:

— during cardiopulmonary by-pass surgery, deep hypothermia, cardiac arrest due to an increased risk of kidney failure and death (desired anticoagulant effect of heparin is provided by appointment);

- With a history of treatment indications aprotinin, tk. Repeated dose increases the probability of allergic reactions due to the, that the active substance of protein nature can show the properties of an allergen and cause anaphylaxis and shock; while the group at particular risk include patients, receiving aprotinin in the preceding 15 days – 6-month period; these patients are not less than 10 minutes before the injection of a therapeutic dose must enter test dose of aprotinin (1 ml), and shortly before the administration of the therapeutic dose recommended the introduction of I / O blocker histamine H₁-and histamine receptor blocker H₂-receptors (eg, cimetidine);

- If the patient allergic diathesis aprotinin therapy is carried out under the strict supervision of the possibility of reactions pseudoallergic; these patients for at least 10 minutes before the injection of a therapeutic dose must enter a trial dose (1 ml) product, and shortly before the application of the therapeutic dose recommended I / O management blocker histamine H₁-and histamine receptor blocker H₂-receptors (eg, cimetidine).

The development of anaphylactic reactions possible in the absence of an allergic reaction to the test dose. If an anaphylactic reaction, administration of the drug should be discontinued immediately and proceed to the standard emergency treatment measures.

The test to detect hypersensitivity: at least 10 min before administration of the first therapeutic dose to enter in / 1 ml (10 000 KIE) aprotinin. When any allergic reaction to the test dose, It is forbidden to use aprotinin because of possible anaphylaxis.

Application of extracorporeal circulation

When adding aprotinin in blood, sodyerjashyei heparin, clotting time, measured Gemohronom or other comparative method “by activating the surface of an alien”, increases. Therefore, as a result of an elongated treatment with high doses of aprotinin activated clotting time (activating clotting time) It does not provide information about the current level of heparin.

When extracorporeal blood circulation during cardiac surgery patients, receive high therapeutic doses of aprotinin, activated clotting time is recommended to keep at the level of, exceeding 750 sec. Heparin levels and can be measured using a heparin-prothrombin test titrant.

One way to ensure sufficient amounts of heparin in the bloodstream is the heparin at a specified dosing regimen based on patient weight and the length of by-pass. Protamine dose, intended to neutralize heparin, It depends on the total dose of heparin, instead of activated clotting time, measured Gemohromom.

Use in Pediatrics

Available data on the use of the drug in pediatric cardiac surgery are few.

Effects on ability to drive vehicles and management mechanisms

No data on the effect of the drug on the ability to drive vehicles and to carry out activities, require high concentration and speed of psychomotor reactions.

Overdose

Treatment: symptomatic; No specific antidote.

Drug Interactions

Aprotinin dose-dependently blocks the action of thrombolytic agents (eg, streptokinase, alteplase and urokinase).

It enhances the effect of heparin (addition to heparinized blood increases the clotting time of whole blood).

Synergism observed with a joint appointment of aprotinin and dextran (sr.mol.massa 30000-40000). Do not use medication with dextran (sr.mol.massa 30000-40000) because of the increased risk of hypersensitivity reactions.

Pharmaceutical incompatibility

Pharmaceutically not compatible with other drugs (except for electrolyte solutions and dextrose).

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children, in a dark place at a temperature of 15 ° to 30 ° C. Shelf life – 5 years.