APROSOL Aprotinin Injection

100,000 KIU/10 ml
500,000 KIU/50 ml


For the use of a Registered Medical Practitioner or a Hospital or a Institution only. 

Reduces Risk of Bleeding
Reduces Systemic Inflammatory Response
Reduces Risk of Stroke
Maintains Platelet Function
Decreases the Occurrence of Atrial Fibrillation

APROSOL (Aprotinin) is a highly purified natural proteinase inhibitor obtained from bovine lungs. It is made up of 58 amino acid residues that are arranged in a single polypeptide chain, cross-linked by three disulfide bridges. Chemically, Aprotinin is a polypeptide consisting of a chain of 58 amino acids. Its molecular formula is C284H432N84O79S7 and molecular weight is 6512 Daltons.

Its structural formula is :
          Aprotinin Injection

APROSOL is a clear, colourless, sterile isotonic solution for intravenous administration.

Each ml contains :
Aprotinin B.P.                10,000 KIU (1.4 mg/ml)
Sodium Chloride I.P.        9 mg
Water for Injections I.P.     q.s.

Aprotinin is a broad spectrum protease inhibitor which has antifibrinolytic properties. By forming reversible stoichiometric enzyme inhibitor-complexes, aprotinin acts as an inhibitor of human trypsin, plasmin, plasma kallikrein and tissue kallikrein, thus inhibiting fibrinolysis. It also inhibits the contact phase activation of coagulation which both initiates coagulation and promotes fibrinolysis. In the special situation of cardiopulmonary bypass and foreign-surface mediated contact activation, additional inhibition of plasma kallikrein appears to contribute to the desired effect, which in general can be described as minimising derangements in the coagulation and fibrinolysis system.
Aprotinin modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the inter-related activation of the haemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators (e.g., kallikrein, plasmin, trypsin) results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation.
Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b).
The effects of aprotinin use in cardiopulmonary bypass surgery (CPB) involves a reduction in inflammatory response which translates into a decreased need for allogenic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding.

Absorption, Distribution and Bioavailability :
After intravenous injection, rapid distribution of aprotinin occurs into the total extra-cellular space, leading to an initial decrease in plasma aprotinin concentration with a half-life of 0.3-0.7 hours. At later time points, (i.e. beyond 5 hours post dose) there is a terminal elimination phase with a half-life of about 5-10 hours. Average steady-state intra-operative plasma concentrations were 250 Kallikrein Inhibitor Units per ml (KIU/ml) in cardiac surgery patients receiving a dosage regimen of 2 million KIU as an intravenous loading dose, 2 million KIU added to the pump prime fluid, and 500,000 KIU per hour as a continuous intravenous infusion during the procedure. Average steady-state intra-operative plasma concentrations were 137 KIU/ml after administration of half of the above regimen.

The studies comparing the pharmacokinetics of aprotinin in healthy volunteers, cardiac patients undergoing cardiopulmonary bypass, and women undergoing hysterectomy, suggest linear pharmacokinetics over the dose range of 50,000 KIU to 2 million KIU.
The steady state volume of distribution is about 20 L and the total body clearance is approx. 40 ml/min in man.

Aprotinin accumulates in the kidneys and to a lesser degree in cartilaginous tissue. Accumulation in the kidneys is due to binding to the brush border of the epithelial cells of the proximal tubules and to accumulation in the phagolysosomes of these cells. Accumulation in the cartilaginous tissue results from the affinity of the basic aprotinin to the acid proteoglycans. Concentrations in other organs are similar to the concentrations in the serum. The lowest concentration occurs in the brain; practically no aprotinin passes into the cerebrospinal fluid. Only very limited amounts of aprotinin penetrate the placental barrier. The placenta is probably not absolutely impermeable to aprotinin, but permeation appears to be very slow.
No studies are available on the passage of aprotinin into the mothers milk. However, since aprotinin is not bio-available after oral administration, any drug contained in the milk would have no effect on the baby.
Metabolism, Elimination and Excretion :
The aprotinin molecule is metabolised to shorter peptides or amino acids by lysosomal activity in the kidney. In man, urinary excretion of active aprotinin accounts for less than 5 % of the dose. After receiving injections of 131l -aprotinin healthy volunteers excreted within 48 hours 25-40 % of the labelled substance as metabolites in the urine. These metabolites lacked enzyme-inhibitory activity. No pharmacokinetic studies are available in patients with terminal renal insufficiency. Studies in patients with renal impairment revealed no clinically significant pharmacokinetic alterations or obvious side effects. A special dose adjustment is not warranted.
APROSOL is indicated for prophylactic use to reduce peri-operative blood transfusion in those patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at increased risk of blood loss or blood transfusion.

Administration  :
All intravenous doses of APROSOL should be administered through a central venous line. Do not administer any other drug using the same line.

Dosage :
A 1 ml (10,000 KIU) test dose should always be administered to all patients at least 10 minutes prior to the remainder of the dose due to the risk of allergic/anaphylactic reactions. This is especially important in patients with documented previous exposure to aprotinin and in those patients for whom a previous exposure is uncertain. After the uneventful administration of the initial 1 ml dose, the therapeutic dose may be given. APROSOL must be given only to patients in the supine position and must be given slowly (maximum 5-10 ml/min) as an intravenous injection or a short infusion. 
Adults :
The recommended regimen involves a loading dose, maintenance dose and a pump prime dose, administered as follows : 
(i) Loading dose : A loading dose of 200 ml (2 million KIU) is administered as a slow intravenous injection or infusion over 20 - 30 minutes after induction of anaesthesia and prior to sternotomy.
(ii) Maintenance dose : The loading dose should be followed by the administration of a continuous infusion of 50 ml (500,000 KIU) per hour until the end of the operation except in patients with septic endocarditis where it may be continued into the early post-operative period.
(iii) Pump prime dose : An additional 200 ml (2 million KIU) should be added to the priming volume of the extracorporeal circuit. In patients with septic endocarditis 300 ml (3 million KIU) should be added to the pump prime. To avoid physical incompatibility of APROSOL 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. In general, the total amount of aprotinin administered per treatment course should not exceed 7 million KIU. 
Elderly :
No dosage adjustment in the elderly is necessary. 
Paediatric use : 
Infants, toddlers, children and adolescents Efficacy and safety have not been established in this patient population.
Hypersensitivity to aprotinin. Patients with a positive aprotinin-specific IgG antibody test are at an increased risk of anaphylactic reaction when treated with aprotinin. Therefore, administration of APROSOL is contraindicated in these patients. In case no aprotinin specific IgG antibody test is possible prior to treatment, administration of APROSOL to patients with a suspected previous exposure during the last 12 months is contraindicated.

Standard emergency treatments for anaphylactic and allergic reactions should be readily available whenever APROSOL is administered. An H1-antagonist and an H2-antagonist maybe administered 15 minutes prior to the test dose of APROSOL. Any administration of APROSOL to patients who have received aprotinin in the past requires a careful risk/benefit assessment because an allergic reaction may occur. A 1 ml (10,000 KIU) test dose of APROSOL should be administered to all patients with an observation time of at least 10 minutes before the main dose of APROSOL. 

Even after the uneventful administration of the initial 1 ml test dose, the therapeutic dose may cause an anaphylactic reaction. If an allergic/anaphylactic reaction occurs during the injection, administration should be stopped immediately and the appropriate therapeutic measures instituted, e.g. adrenaline, antihistamines and intravenous corticosteroids. Intravenous fluids, bronchodilators and respiratory support may also be needed. APROSOL should not be used throughout pregnancy unless clearly necessary and only after a careful risk/benefit evaluation. The addition of APROSOL to heparinised blood will prolong the activated clotting time (ACT). Thus, the ACT should not be taken as a reliable indicator of the need to administer additional heparin during a prolonged period of cardiopulmonary bypass. Furthermore, a prolonged ACT in the presence of APROSOL does not necessarily signify excess heparin requiring additional protamine. It is therefore not necessary to adjust the usual heparin/protamine regimen during treatment with APROSOL. An increase in renal failure and mortality compared to age-matched historical controls has been reported for aprotinin-treated patients undergoing cardiopulmonary bypass with deep hypothermic circulatory arrest during operation on the thoracic aorta. APROSOL should therefore be used with extreme caution under these circumstances. Results from recent observational studies indicate that renal dysfunction could be triggered by aprotinin, particularly in patients with pre-existing renal dysfunction. An analysis of all pooled placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) has found elevations of serum creatinine values >0.5 mg/dl above baseline in patients with aprotinin therapy. Careful consideration of the balance of risks and benefits is therefore advised before administering aprotinin to patients with pre-existing impaired renal function or those with risk factors (such as concomitant treatment with aminoglycosides). Adequate anti-coagulation with heparin must be assured (see also additional note below). Additional note on use with extracorporeal circulation In patients undergoing cardiopulmonary bypass with APROSOL therapy, one of the following methods is recommended to maintain adequate anticoagulation : 

 1. Activated Clotting Time (ACT) - An ACT is not a standardised coagulation test, and different formulations of the assay are affected differently by the presence of aprotinin. The test is further influenced by variable dilution effects and the temperature experienced during cardiopulmonary bypass. It has been observed that kaolin-based ACTs are not increased to the same degree by aprotinin as are diatomaceous earth-based (celite) ACTs. While protocols vary, a minimal celite-ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of haemodilution and hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of APROSOL.

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

3. Determination of Heparin Levels - Protamine titration, a method that is not affected by aprotinin, can be used to measure heparin levels. 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 2.7 U/ml (2.0 mg/kg) or below the level indicated by heparin dose-response testing performed prior to administration of aprotinin.

In APROSOL 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. Important - APROSOL is not a heparin-sparing agent. 

Pregnancy :

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.


Lactation :
It is not known whether aprotinin is excreted in human milk. However, since aprotinin is not bio-available after oral administration, any drug contained in the milk would have no effect on the baby.
Paediatric Use :
Safety and effectiveness in paediatric patient(s) have not been established.
Carcinogenesis, Mutagenesis, Impairment of Fertility : 
Long term animal studies to evaluate the carcinogenic potential of APROSOL on fertility have not been performed. Results of microbial in vitro tests using Salmonella typhimurium and Bacillus subtilis indicate that APROSOL is not a mutagen.
Laboratory Findings :
Serum Creatinine : In subjects undergoing CABG surgery, no statistically or clinically significant increase in the incidence of post-operative renal dysfunction was seen when treated with APROSOL. Patients with baseline elevations in serum creatinine were not at increased risk of developing post-operative renal dysfunction following APROSOL treatment. 
Serum transaminase : There is no evidence of an increase in the incidence of post-operative hepatic dysfunction in patients treated with APROSOL.
Other Laboratory findings :
There is no incidence of treatment-emergent elevations in plasma glucose, AST (formerly SGOT), IDH, alkaline phosphatase, and CPK-in patients undergoing CABG surgery. Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are expected in APROSOL treated patients in the hours after surgery due to circulating concentrations of APROSOL which are known to inhibit activation of the intrinsic clotting system by contact with a foreign material (e.g. celite), a method used in these tests.
APROSOL has a dose-dependent inhibitory effect on the action of thrombolytic agents, e.g. streptokinase, urokinase, alteplase (r-tPA). 
Studies of patients undergoing CABG surgery, either primary or repeat, indicate that APROSOL is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to APROSOL therapy. Body as a Whole : Sepsis, death, multi system organ failure, immune system disorder, haemoperitoneum. 
Cardiovascular :
Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure, haemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block, pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.
Digestive : 
Dyspepsia, gastrointestinal haemorrhage, jaundice, hepatic failure.
Haematologic and Lymphatic :
Although thrombosis was not reported more frequently in APROSOL versus placebo treated patients in controlled trials, it has been reported in uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting. These reports of thrombosis encompass the following terms : thrombosis, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other haematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation) decreased prothrombin. 
Metabolic and Nutritional : Hyperglycaemia, hypokalemia, hypervolemia, acidosis.
Musculoskeletal : Arthralgia.
Nervous : Agitation, dizziness, anxiety, convulsion.
Respiratory : Pneumonia, apnea, increased cough, lung oedema.
Skin : Skin discoloration.
Urogenital : Oliguria, kidney failure, acute kidney failure, kidney tubular necrosis.
Myocardial Infarction : In the pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator reported myocardial infarction (MI) in APROSOL treated patients as compared to placebo treated patients.

Symptoms of overdosage or intoxication are not known. There is no specific antidote. 

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Store between 2°C to 25°C (36°F to 77°F), protected from light. Do not freeze.
24 months from the date of manufacture.
APROSOL is supplied as below table :
Strength                Pack Size                         Packing
10,000 KIU/ml          10ml Vial                           Single vial pack
10,000 KIU/ml          50ml Vial                           Single vial pack
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.
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