Aprotinin

(BAN, USAN, rINN)
Synonyms: Aprotiniini; Aprotinina; Aprotininas; Aprotinine; Aprotininum; Aprotynina; Bayer A-128; Riker 52G; RP-9921.
Cyrillic synonym: Апротинин.

💊 Chemical information

CAS — 9087-70-1.
ATC — B02AB01.
ATC Vet — QB02AB01.

Pharmacopoeias.

In Chin., Eur., and US.

Ph. Eur. 6.2 (Aprotinin). A polypeptide consisting of 58 amino acids that inhibits the activity of several proteolytic enzymes such as chymotrypsin, kallikrein (kallidinogenase), plasmin (fibrinolysin), and trypsin. It contains not less than 3 Ph. Eur. units/mg calculated with reference to the dried substance. An almost white, hygroscopic powder. Soluble in water and in isotonic solutions; practically insoluble in organic solvents. Store in airtight containers. Protect from light.

Ph. Eur. 6.2 (Aprotinin Concentrated Solution). A solution of aprotinin containing not less than 15 Ph. Eur. units/mL. A clear colourless solution. Store in airtight containers. Protect from light.

USP 31

(Aprotinin). A polypeptide consisting of a chain of 58 amino acid residues, which inhibits stoichiometrically the activity of several proteolytic enzymes such as chymotrypsin, kallikrein (kallidinogenase), plasmin (fibrinolysin), and trypsin. It is obtained from bovine tissues and purified by a suitable process, and is stored as a bulk solution or lyophilised powder. Its potency is not less than 3 USP units/mg calculated with reference to the dried substance. The lyophilised powder should be stored in airtight containers at a temperature between 8° and 15°. Protect from light. The bulk solution should be stored in airtight containers at a temperature not exceeding 25°. Do not allow to freeze.

Incompatibility.

Aprotinin is reported to be incompatible with corticosteroids, heparin, tetracyclines, and nutrient solutions containing amino acids or fat emulsions.

💊 Units

The potency of aprotinin is expressed in terms of kallikrein (kallidinogenase) inactivator units (KIU) or of trypsin inactivation (Ph. Eur. units). One KIU is contained in 140 nanograms of aprotinin. One Ph. Eur. and one USP unit is equivalent to about 1800 KIU. Potency has also been expressed in terms of plasmin inactivation (antiplasmin units).

💊 Adverse Effects and Precautions

Aprotinin is usually well tolerated. Local thrombophlebitis can occur. Adverse effects including bronchospasm, hypotension, cardiac arrhythmias, gastrointestinal disturbances, and skin rashes are considered to be hypersensitivity reactions; anaphylaxis, including fatalities, has occurred. Licensed UK product information warns that the risk of anaphylactic reaction increases when re-exposure occurs within 6 months, but product information in the US extends this warning to contra-indicate the use of aprotinin for 12 months after a previous exposure. A test dose is recommended for all patients and the use of prophylactic histamine antagonists may be considered; a hypersensitivity reaction to the therapeutic dose of aprotinin can still occur even after an uneventful test dose. There have been reports of renal dysfunction and reversible renal failure in patients given aprotinin during open-heart surgery with extracorporeal circulation; the risk may be increased in patients with pre-existing renal impairment or risk factors for altered renal function. For further details of an increased risk of cardiovascular and cerebrovascular events, renal failure, and death in patients undergoing surgery, see Haemorrhagic Disorders under Uses and Administration, below.

Disseminated intravascular coagulation.

Fatal disseminated intravascular coagulation has been reported in a patient after the use of intraoperative autotransfusion and aprotinin during surgery.1 Activation of the clotting system occurs during autotransfusion although this usually causes no systemic adverse effects. While there were other possible causes, it was suggested that aprotinin could have contributed to deposition of fibrin microthrombi in the microvasculature and prevented subsequent fibrinolysis.
1. Milne AA, et al. Disseminated intravascular coagulation after aortic aneurysm repair, intraoperative salvage autotransfusion, and aprotinin. Lancet 1994; 344: 470–1.

Effects on coagulation tests.

In patients receiving heparin, aprotinin may prolong the activated clotting time when measured by some methods, but this may not represent increased anticoagulation. It has been recommended that an alternative to the activated clotting time should be used to monitor heparin therapy when aprotinin is used concurrently. It should also be noted that aprotinin injection and heparin injection are pharmaceutically incompatible.

Effects on the respiratory system.

Acute respiratory distress syndrome developed in a 24-year-old male 2 hours after the start of an intravenous infusion of aprotinin for bleeding after tonsillectomy.1 Mechanical ventilation was required for 4 days.
1. Vucicevic Z, Suskovic T. Acute respiratory distress syndrome after aprotinin infusion. Ann Pharmacother 1997; 31: 429–32.

Hypersensitivity.

Hypersensitivity reactions, including anaphylaxis, can occur with the use of aprotinin both on primary and secondary exposure. In a study1 of 248 re-exposures to aprotinin in 240 patients undergoing cardiac surgery, there were 7 cases of anaphylactic reactions ranging from mild to severe with a higher incidence of reactions occurring in those patients re-exposed within 6 months of the previous dose. A review2 of 124 reported reactions in 122 patients also found that reactions ranged from mild to severe, and that about half were life-threatening and 11 were fatal. The risk of reaction was greatest with re-exposure to aprotinin as this had been the situation in 80% of the cases, although there were 19 cases associated with the first use of aprotinin. The average risk of anaphylaxis was estimated to be 2.8% in re-exposed patients. Most reactions occurred within 6 months of previous exposure, and the risk was greatest in the first 3 months. Various diagnostic tests have been tried in an attempt to predict hypersensitivity risk. Aprotinin-specific serum-IgG was reported to be detectable in about 50% of patients who had received only one aprotinin treatment, but other tests such as preoperative skin testing were not found to be reliable. A number of measures have been suggested in order to reduce the risk of hypersensitivity reactions to aprotinin, including the use of an intravenous test dose in all patients, but it must be noted that these also have the potential to trigger a reaction.1 For patients who have previously received aprotinin it has been recommended that re-exposure should be avoided for at least 6 months,1,2 that aprotinin-specific antibody screening should be done,2 and that prophylactic histamine H1- and H2-antagonists should be given to ameliorate severe anaphylactic reactions1 although there are reports of reactions occurring despite antihistamine and corticosteroid prophylaxis.2 It has also been suggested that in cardiac surgery, aprotinin should only be given when cardiopulmonary bypass is available to assist resuscitation.1,2 There have also been rare reports of hypersensitivity reactions on re-exposure to aprotinin used locally as a component of fibrin sealant.3,4 In one fatal case4 the previous exposure to fibrin sealant had been 5 years before.
1. Dietrich W, et al. Prevalence of anaphylactic reactions to aprotinin: analysis of two hundred forty-eight reexposures to aprotinin in heart operations. J Thorac Cardiovasc Surg 1997: 113: 194–201
2. Beierlein W, et al. Forty years of clinical aprotinin use: a review of 124 hypersensitivity reactions. Ann Thorac Surg 2005; 79: 741–8
3. Beierlein W, et al. An immediate, allergic skin reaction to aprotinin after reexposure to fibrin sealant. Transfusion 2000; 40: 302–5
4. Oswald A-M, et al. Fatal intraoperative anaphylaxis related to aprotinin after local application of fibrin glue. Anesthesiology 2003; 99: 762–3.

💊 Interactions

Heparin.

For comment on the use of aprotinin with heparin, see Effects on Coagulation Tests, above.

Neuromuscular blockers.

For reports of apnoea when aprotinin was used with neuromuscular blockers.

Retinoids.

Aprotinin should be used with caution in patients receiving oral tretinoin.

💊 Pharmacokinetics

Aprotinin, being a polypeptide, is inactivated in the gastrointestinal tract. After intravenous use, it is excreted in the urine as inactive degradation products. The terminal elimination half-life is about 5 to 10 hours.

Renal impairment.

The terminal elimination half-life of aprotinin was reported as 13.3 and 14.9 hours, respectively, in two patients with chronic renal impairment given aprotinin by intravenous infusion over 30 minutes.1 A study2 of cardiac surgical patients undergoing cardiopulmonary bypass also found that aprotinin clearance was reduced in those with renal impairment. The elimination half-life was about 20 hours in patients with end stage renal disease compared with about 8 hours in those with creatinine clearance greater than 50 mL/min.
1. Müller FO, et al. Pharmacokinetics of aprotinin in two patients with chronic renal impairment. Br J Clin Pharmacol 1996; 41: 619–20
2. O’Connor CJ, et al. The impact of renal dysfunction on aprotinin pharmacokinetics during cardiopulmonary bypass. Anesth Analg 1999; 89: 1101–7.

💊 Uses and Administration

Aprotinin is a haemostatic. It is an inhibitor of proteolytic enzymes including chymotrypsin, kallikrein (kallidinogenase), plasmin, and trypsin. Aprotinin has been used to reduce blood loss and transfusion requirements in patients at increased risk of major blood loss during coronary artery bypass graft surgery with cardiopulmonary bypass. However, the marketing of aprotinin injection has been suspended worldwide because of a possible increased risk of death associated with its use in cardiac surgery (see Haemorrhagic Disorders, below). Nevertheless, it may be available in some countries, such as the USA, using a special access protocol. It has also been used in the treatment of hyperfibrinolytic haemorrhage associated with raised plasma concentrations of plasmin. Aprotinin is applied topically as a component of fibrin glues. It is recommended that because of the risk of hypersensitivity reactions an intravenous test dose of 10 000 KIU should be given to all patients at least 10 minutes before the therapeutic dose. All intravenous doses of aprotinin should be given through a central venous line. In coronary artery bypass graft surgery, the test dose is followed by a loading dose given with the patient in a supine position, after induction of anaesthesia but before incision; 2 000 000 KIU is given intravenously over 20 to 30 minutes. The loading dose is followed by a continuous infusion of 500 000 KIU/hour until the end of the operation. An additional dose of 2 000 000 KIU is added to the prime volume of the extracorporeal circuit. In patients with septic endocarditis, a dose of 3 000 000 KIU is added to the prime volume of the circuit and the continuous infusion may be continued into the early postoperative period. The total amount of aprotinin used is usually no more than 7 000 000 KIU. A regimen using half the dose for loading, maintenance, and to prime the circuit, may be used in low-risk patients.

Haemorrhagic disorders.

Aprotinin has been used in the treatment of life-threatening haemorrhage caused by raised plasma concentrations of plasmin. It has also been used in the treatment of severe bleeding arising from overdosage with thrombolytics. Aprotinin has been used to reduce blood loss in patients undergoing surgery, particularly cardiac surgery involving cardiopulmonary bypass. This bypass procedure is complicated by a postperfusion syndrome that includes impairment of haemostasis and pulmonary dysfunction. Contributing factors include ischaemia reperfusion, surgical trauma, endotoxaemia, and blood contact with the artificial surfaces of the bypass apparatus. This syndrome has been interpreted as a ‘whole body inflammatory response’, and the beneficial effect of aprotinin has been attributed to an attenuation of this response. As well as its inhibitory effect on fibrinolysis, aprotinin is thought to have effects on the complement system, cytokines, neutrophil activation, and platelet function.1,2 Aprotinin has reduced blood loss and transfusion requirements in patients undergoing both primary and repeat cardiac surgery.1,3-6 The usual dosage regimen (as given in Uses and Administration, above) and low-dosage regimens (50% of the usual dose) appear to be equally effective, but regimens that use aprotinin only as a pump prime dose appear to be less effective.1,5 The safety of aprotinin in cardiac surgery has been questioned, however, because of the results of two observational studies. One analysis7 of patient outcome after the use of aminocaproic acid, aprotinin, tranexamic acid, or no treatment, found that although the three drugs had reduced blood loss to a similar extent, aprotinin was associated with an increased risk of cardiovascular and cerebrovascular events (myocardial infarction, heart failure, stroke, or encephalopathy) and renal failure. Observational follow-up also found that aprotinin, but not aminocaproic acid or tranexamic acid, was associated with an increased risk of death in the 5 years after surgery.8 In another study9 that compared data from patients who had received either aprotinin or tranexamic acid, there was an increased risk of renal dysfunction associated with aprotinin, particularly in patients with abnormal pre-operative renal function. In response to these studies, the FDA recommended10 that patients receiving aprotinin should be carefully monitored, and that physicians should consider limiting its use to situations where the clinical benefit of reduced blood loss is essential and outweighs the potential risks. The concerns raised by these studies and the FDA’s recommendation prompted further analysis of data relating to the effects of aprotinin. A meta-analysis5 that included studies in different types of surgery, although the majority were in cardiac surgery, found no increased risk of death, cardiovascular events, or renal failure. However, because the reporting of renal function was lacking for many studies, and therefore a potential for bias, the authors were not confident that a modest increase in risk could be ruled out. Another meta-analysis11 that was limited to studies in cardiac surgery also found no increased risk of death or cardiovascular events with aprotinin. There was also no increase in the risk of dialysis-dependent renal failure, but high-dose aprotinin did increase the risk of renal dysfunction, compared with placebo. Two large retrospective studies, which attempted to account for confounding variables, were also undertaken in cohorts of patients who had undergone coronary artery bypass graft surgery. One study found that, compared with aminocaproic acid, aprotinin increased the risk of in-hospital death.12 The other found increased in-patient renal dysfunction, and death at 30 days and 1 year, in patients given aprotinin compared with aminocaproic acid or no antifibrinolytic therapy. Survival estimates also found an association between aprotinin use and reduced survival for up to 10 years after surgery.13 Preliminary data analysis from a randomised study (BART) also found an increased risk of death with aprotinin, compared with aminocaproic acid or tranexamic acid, and in November 2007, authorities such as the FDA14 and EMEA15 recommended that marketing of aprotinin injection be suspended. Aprotinin has been used to reduce transfusion requirements during liver transplantation, by its effect on intra-operative hyperfibrinolysis.16,17 However, concerns about an increased risk of thromboembolism in these patients has been raised.18 A systematic review19 of 23 studies using antifibrinolytic drugs, 18 of which used aprotinin, found no evidence of an increased risk of thromboembolic complications in liver transplant patients, but noted that the studies were underpowered and that identification of subgroups of patients at risk may have been missed. Aprotinin has also been used to reduce transfusion requirements during orthopaedic surgery.20
1. Peters DC, Noble S. Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery. Drugs 1999; 57 233–60
2. Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg 2001; 71: 745–54
3. Bidstrup BP, et al. Aprotinin cardiac centers in the United Kingdom. Ann Thorac Surg 1993; 55: 971–6
4. Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. Anesth Analg 1997; 85: 1258–67
5. Henry DA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Available in The Cochrane Database of Systematic Reviews; Issu
4. Chichester: John Wiley; 2007 (accessed 25/06/08)
6. Sedrakyan A, et al. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004; 128: 442–8
7. Mangano DT, et al. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353–65
8. Mangano DT, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007; 297: 471–9
9. Karkouti K, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006; 46: 327–38
10. FDA. Aprotinin injection (marketed as Trasylol) (issued 8th February, 2006). Available at: http://www.fda.gov/cder/drug/ advisory/aprotinin.htm (accessed 26/11/07
11. Brown JR, et al. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007; 115: 2801–13
12. Schneeweiss S, et al. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008; 358: 771–83
13. Shaw AD, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008; 358: 784–93
14. FDA. FDA requests marketing suspension of Trasylol (issued 5th November, 2007). Available at: http://www.fda.gov/bbs/ topics/NEWS/2007/NEW01738.html (accessed 26/11/07
15. EMEA. European Medicines Agency recommends suspension of marketing authorisation of aprotinin-containing medicines for systemic use (issued 21st November, 2007). Available at: http://www.emea.europa.eu/pdfs/human/press/pr/ 53467807en.pdf (accessed 26/11/07
16. Porte RJ, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised doubleblind study. Lancet 2000; 355: 1303–9
17. Rentoul TM, et al. The effect of aprotinin on transfusion requirements in pediatric orthotopic liver transplantation. Pediatr Transplant 2003; 7: 142–8
18. Lentschener C, et al. A review of aprotinin in orthotopic liver transplantation: can its harmful effects offset its beneficial effects? Anesth Analg 2005; 100: 1248–55
19. Molenaar IQ, et al. Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2007; 7: 185–94
20. Kokoszka A, et al. Evidence-based review of the role of aprotinin in blood conservation during orthopaedic surgery. J Bone Joint Surg Am 2005; 87-A: 1129–36.

Pancreatitis.

Aprotinin has been tried in the management of pancreatitis because of the postulated role of proteolytic enzymes in this condition. However, results have been largely disappointing.

💊 Preparations

BP 2008: Aprotinin Injection; USP 31: Aprotinin Injection.

Proprietary Preparations

Arg.: Quagu-Test; Rivilina; Austral.: Trasylol†; Austria: Pantinol†; Trasylol†; Belg.: Trasylol†; Braz.: Trasylol†; Canad.: Trasylol†; Chile: Trasylol†; Cz.: Antilysin†; Gordox†; Trasylol†; Denm.: Trasylol†; Fin.: Trasylol†; Fr.: Trasylol†; Ger.: Trasylol†; Gr.: Trasylol†; Hong Kong: Trasylol†; Hung.: Gordox†; Trasylol†; Indon.: Trasylol; Israel: Protosol; Malaysia: Trasylol†; Mex.: Protinin†; Trasylol†; Neth.: Trasylol†; NZ: Trasylol†; Pol.: Tr as ko lan†; Trasylol†; Rus.: Aprotex (Апротекс); Contrykal (Контрикал); Gordox (Гордокс); Trasylol (Трасилол)†; S.Afr.: Trasylol†; Singapore: Trasylol†; Spain: Trasylol†; Swed.: Trasylol†; Switz.: Trasylol†; Thai.: Trasylol†; Turk.: Trasylol†; UK: Trasylol†; USA: Trasylol†; Venez.: Trasylol†. Multi-ingredient: Arg.: Beriplast P; Lacrimax; Maxus; Optilac; Tissucol; Tissucol Duo Quick†; Austral.: Tisseel Duo; Austria: Beriplast; TachoComb; Tissucol; Tissucol Duo Quick; Belg.: Tissucol Duo; Braz.: Beriplast P; Tissucol†; Canad.: Tisseel; Chile: Beriplast P; Cz.: TachoComb†; Tissucol; Denm.: Tisseel Duo Quick; Fin.: Tisseel Duo Quick; Fr.: Beriplast; Tissucol; Ger.: Beriplast; TachoComb†; Tissucol Duo S; Tissucol-Kit; Gr.: Beriplast P; Hong Kong: Beriplast P; TachoComb; Tisseel; Hung.: Beriplast P; TachoComb†; Tissucol-Kit; Indon.: Beriplast; Israel: Beriplast; Tisseel; Ital.: Beriplast; Tissucol; Mex.: Beriplast P; Tissucol†; Neth.: Beriplast P; Tissucol; Tissucol Duo; Pol.: Beriplast; Port.: Tissucol Duo; Rus.: TachoComb (ТахоКомб); Spain: Beriplast P Combi; Tissucol Duo; Swed.: Tisseel Duo Quick; Switz.: Beriplast P; Tissucol; Tissucol Duo S; Thai.: TachoComb†; Turk.: Beriplast P; Tisseel VH; UK: Tisseel.
Published October 20, 2018.