Aprotinin

Registered South African indications: 

• Open heart surgery with extracorporeal circulation

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients 
• Patients with a positive aprotinin-specific IgG antibody test
• Suspected previous exposure to active ingredient, including in fibrin sealant products during the last 12 months (in the case where no aprotinin specific IgG antibody test is possible prior to treatment)

Cautions

• Breastfeeding
• Renal impairment 
• Hepatic impairment 
• Other cardiovascular surgery combined with coronary artery bypass graft surgery 

Forms avail. in SA and covered in this monograph: inj 

Prophylactic use to reduce blood loss and blood transfusion in patients at high risk of major blood loss during and following open heart surgery with extracorporeal circulation, including:
- Patients requiring re-operation through a previous median sternotomy
- Patients with infective endocarditis
- Coronary artery bypass graft surgery that is not combined with other cardiovascular surgery

• IV: Loading dose: 100-200ml, as an infusion over 15-30min following induction of anaesthesia; Maintenance: 25-50ml, as a continuous infusion, 1hrly, until completion of surgery; Max: 700ml/procedure

A 1ml test dose should be administered slowly over several minutes, 10 minutes prior to the remainder of the dose, to assess the risk of allergic or pseudo-allergic reactions

Should be infused using a central venous catheter

Should be given only in the supine position, slowly at a maximum rate of 5-10ml/min

In patients with infective endocarditis, the maintenance infusion may be continued into the early post-operative period

An additional 200ml pump prime dose should be added to the priming volume of the heart-lung machine

To avoid physical incompatibility of aprotinin and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to assure adequate dilution prior to admixture with the other component

Aprotinin is not a heparin-sparing agent and it is important that adequate anticoagulation with heparin be maintained during therapy (See additional prescribing points) 

Not established for use in children younger than 18 years

Pregnancy

• Caution; not recommended
• The safety of fibrin sealants/aprotinin for use in human pregnancy has not been established in controlled clinical trials
• Animal studies have also not been performed. Therefore, the product should be administered to pregnant women only if clearly needed

Breastfeeding

• Caution; not recommended
• The safety of fibrin sealants/aprotinin for use in human breastfeeding has not been established in controlled clinical trials
• Animal studies have also not been performed. Therefore, the product should be administered to breastfeeding women only if clearly needed

Fertility

• The effects of aprotinin on fertility have not been established

Renal Impairment 

• Caution; no dose adjustment recommended

Hepatic Impairment

• Caution; no information available

Elderly 

• No dose adjustment recommended

Porphyria Information

• Not porphyrinogenic (NP)

Cardiovascular Disorders

• Myocardial ischaemia
• Coronary occlusion/thrombosis
• Myocardial infarction
• Pericardial effusion
• Thrombosis
• Thrombophlebitis 
• Hypotension 

Respiratory Disorders

• Pulmonary embolism 
• Bronchospasm 

Gastrointestinal Disorders

• Nausea 

Genitourinary Disorders

• Oliguria
• Acute renal failure
• Renal tubular necrosis

Skin and Subcutaneous Tissue Disorders

• Injection site reactions 
• Pruritis 
• Rash
• Urticaria 

Immune, Blood and Lymphatic System Disorders

• Allergic reactions 
• Anaphylactoid reaction
• Anaphylactic shock 
• Disseminated intravascular coagulation
• Coagulopathy

• Streptokinase
• Urokinase
• Alteplase
• Agents causing impaired renal function

• Coagulation *see additional prescribing points
• Heparin levels
• Activated clotting time

Maintenance of anticoagulation:

Activated clotting time (ACT)

• An ACT is not a standardized coagulation test
• There are different formulations of the assay, namely kaolin-based and diatomaceous earthbased (celite) ACTs.
• A minimal celite ACT of 750 seconds or kaolin ACT of 480 seconds, independent of the effects of haemodilution and hypothermia experienced during cardiopulmonary bypass, is recommended in the presence of aprotinin

Fixed heparin dosing 

• A standard loading dose of heparin, administered prior to cannulation of the heart in addition to the quantity of heparin added to the prime volume of the cardiopulmonary bypass circuit, should total at least 350IU/kg
• Additional heparin should be administered in a fixed-dose regimen based on patient weight and duration of cardiopulmonary bypass

Heparin titration 

• A heparin dose response, assessed by protamine titration, should be performed prior to administration of aprotinin to determine the heparin loading dose.
• Additional heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7U/ml (2.0mg/kg) or below the level indicated by heparin dose-response testing performed prior to administration of aprotinin
• In aprotinin treated patients the neutralisation of heparin by protamine after discontinuation of cardiopulmonary bypass should either be based on a fixed ratio to the amount of heparin applied or be controlled by a protamine titration method

Pharmacokinetics

• Elimination half-life (t_1/2): 30-60mins for free aprotinin and its metabolites

Aprotinin inhibits several serine proteases including trypsin, chymotrypsin, plasmin, and kallikrein at higher doses. Its action on kallikrein leads to the inhibition of the formation of factor XIIa. This results in the inhibition of both the intrinsic pathway of coagulation and fibrinolysis. Its action on plasmin independently slows fibrinolysis.

Injection (per 100ml) 140mg

• Trasylol (Bayer) originator