Gordox

Overdose

There is no specific antidote.

The maximum amount of Trasylol® (aprotinin) that can be safely administered in single or multiple doses has not been determined. Doses up to 17.5 million KIU have been administered within a 24 hour period without any apparent toxicity. There is one poorly documented case, however, of a patient who received a large, but not well determined, amount of Trasylol® (aprotinin) (in excess of 15 million KIU) in 24 hours. The patient, who had pre-existing liver dysfunction, developed hepatic and renal failure postoperatively and died. Autopsy showed hepatic necrosis and extensive renal tubular and glomerular necrosis. The relationship of these findings to Trasylol® (aprotinin) therapy is unclear.

Contraindications

Patients with a positive Gordox-specific IgG antibody test are at an increased risk of anaphylactic reaction when treated with Gordox. Therefore, administration of Gordox is contraindicated in these patients.

In case no Gordox specific IgG antibody test is possible prior to treatment, administration of Gordox to patients with a suspected previous exposure including in fibrin sealant products during the last 12 months is contraindicated.

Administration of Trasylol® (aprotinin) to patients with a known or suspected previous aprotinin exposure during the last 12 months is contraindicated. For patients with known or suspected history of exposure to aprotinin greater than 12 months previously, see WARNINGS. Aprotinin may also be a component of some fibrin sealant products and the use of these products should be included in the patient history.

Incompatibilities

Gordox is incompatible with antibiotics such as tetracyclines which react with proteins, corticosteroids, heparin and nutrient solutions containing amino acids or fat emulsions. The addition of Gordox to mixed infusions (particularly with beta-lactam antibiotics) should be avoided. Electrolyte and sugar solutions are compatible with Gordox.

Pharmaceutical form

Undesirable effects

Summary of the safety profile

The safety of Gordox has been evaluated in more than forty five phase II and phase III studies including more than 3800 patients exposed to Gordox. In total, about 11% of Gordox-treated patients experienced adverse reactions. The most serious adverse reaction was myocardial infarction. The adverse reactions should be interpreted within the surgical setting.

Tabulated summary of adverse reactions

Adverse drug reactions (ADRs) based on all placebo-controlled clinical studies with Gordox sorted by CIOMS III categories of frequency (Gordox n=3817 and placebo n=2682; status: April 2005) are listed in the table below:

Frequencies are defined as:

Common: >1/100 to <1/10

Uncommon: >1/1,000 to <1/100

Rare: >1/10,000 to <1/1,000

Very rare: <1/10,000

Not known: cannot be estimated from the available data

- ADRs derived from post-marketing reports are printed in bold italic

Description of selected adverse reactions

Allergic/anaphylactic reactions are rare in patients with no prior exposure to Gordox. In case of re-exposure the incidence of allergic/anaphylactic reactions may reach the five percent level. A retrospective review showed that the incidence of an allergic/anaphylactic reaction following re-exposure is increased when the re-exposure occurs within 6 months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for reexposures greater than 6 months). A retrospective review suggests that the incidence of severe anaphylactic reactions to Gordox may further increase when patients are re-exposed more than twice within 6 months. Even when a second exposure to Gordox has been tolerated without symptoms, a subsequent administration may result in severe allergic reactions or anaphylactic shock with, in very rare cases, fatal outcome.

The symptoms of allergic/anaphylactic reactions may include:

If allergic reactions occur during injection or infusion, administration should be stopped immediately. Standard emergency treatment may be required, i.e. adrenaline/epinephrine, volume substitution and corticosteroids.

Cardiovascular system

In the pooled analysis of all placebo-controlled clinical studies, the incidence of investigator-reported myocardial infarction (MI) in Gordox treated patients was 5.8% compared to 4.8% in placebo treated patients, with difference of 0.98% between the groups (Gordox n=3817 and placebo n=2682; status: April 2005).

A trend of increased incidence of MI in association with Gordox was observed in some studies, while other studies showed a lower incidence compared to placebo.

Mortality

Studies of patients undergoing CABG surgery, either primary or repeat, indicate that Trasylol® (aprotinin) is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to Trasylol® (aprotinin) therapy. Adverse events reported, up to the time of hospital discharge, from patients in US placebo-controlled trials are listed in the following table. The table lists only those events that were reported in 2% or more of the Trasylol® (aprotinin) treated patients without regard to causal relationship.

In comparison to the placebo group, no increase in mortality in patients treated with Trasylol® (aprotinin) was observed. Additional events of particular interest from controlled US trials with an incidence of less than 2%, are listed below:

Listed below are additional events, from controlled US trials with an incidence between 1 and 2%, and also from uncontrolled, compassionate use trials and spontaneous post-marketing reports. Estimates of frequency cannot be made for spontaneous post-marketing reports (italicized).

Body as a Whole: Sepsis, death, multi-system organ failure, immune system disorder, hemoperitoneum.

Cardiovascular: Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure, hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block, pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.

Digestive: Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.

Hematologic and Lymphatic: Although thrombosis was not reported more frequently in aprotinin 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 hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin.

Metabolic and Nutritional: Hyperglycemia, hypokalemia, hypervolemia, acidosis.

Musculoskeletal: Arthralgia.

Nervous: Agitation, dizziness, anxiety, convulsion.

Respiratory: Pneumonia, apnea, increased cough, lung edema.

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 Trasylol® (aprotinin) treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only Regimen A), in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI. Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below.

Graft Patency: In a recently completed multi-center, multi-national study to determine the effects of Trasylol® (aprotinin) Regimen A vs. placebo on saphenous vein graft patency in patients undergoing primary CABG surgery, patients were subjected to routine postoperative angiography. Of the 13 study sites, 10 were in the United States and three were non-U.S. centers (Denmark (1), Israel (2)). The results of this study are summarized below.

Although there was a statistically significantly increased risk of graft closure for Trasylol® (aprotinin) treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received Trasylol® (aprotinin) vs. placebo. These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% Trasylol® (aprotinin) vs. 3.8% placebo) or of death (1.4% Trasylol® (aprotinin) vs. 1.6% placebo) in this study.

Hypersensitivity and Anaphylaxis: See CONTRAINDICATIONS and WARNINGS. Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled clinical studies in patients with no prior exposure to Trasylol® (aprotinin) (1/1424 patients or <0.1% on Trasylol® (aprotinin) vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% level. A review of 387 European patient records involving re-exposure to Trasylol® (aprotinin) showed that the incidence of hypersensitivity or anaphylactic reactions was 5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months.

Serum Creatinine: Trasylol® (aprotinin) administration is associated with a risk for renal dysfunction (see WARNINGS: Renal Dysfunction).

Serum Transaminases: Data pooled from all patients undergoing CABG surgery in U.S. placebo-controlled trials showed no evidence of an increase in the incidence of postoperative hepatic dysfunction in patients treated with Trasylol® (aprotinin). The incidence of treatment-emergent increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the Trasylol® (aprotinin) and placebo-treated patients (p=0.687), while the incidence of increases > 3 times the upper limit of normal was 5% in both groups (p=0.847).

Other Laboratory Findings: The incidence of treatment-emergent elevations in plasma glucose, AST (formerly SGOT), LDH, alkaline phosphatase, and CPK-MB was not notably different between Trasylol® (aprotinin) and placebo treated patients undergoing CABG surgery. Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are expected in Trasylol® (aprotinin) treated patients in the hours after surgery due to circulating concentrations of Trasylol® (aprotinin) , 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 (see Laboratory Monitoring of Anticoagulation During Cardiopulmonary Bypass under PRECAUTIONS).

Preclinical safety data

Acute toxicity

In rats, guinea-pigs, rabbits and dogs, high doses (>150,000 KIU/kg) injected quickly caused a blood pressure reduction of varying magnitude, which rapidly subsided.

Reproduction toxicity

In rat intravenous studies, daily doses of up to 80,000 KIU/kg produced no maternal toxicity, embryotoxicity, or foetotoxicity. Daily doses of up to 100,000 KIU/kg did not interfere with the growth and development of the young and doses of 200,000 KIU/kg/day were not teratogenic. In rabbits, daily intravenous doses of 100,000 KIU/kg produced no evidence of maternal toxicity, embryotoxicity, foetotoxicity or teratogenicity.

Mutagenic potential

Gordox gave a negative mutagenic response in the salmonella/microsome and B. subtilis DNA damage system.

Therapeutic indications

Gordox is indicated for prophylactic use to reduce blood loss and blood transfusion in adult patients who are at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery (i.e. coronary artery bypass graft surgery that is not combined with other cardiovascular surgery).

Gordox should only be used after careful consideration of the benefits and risks, and the consideration that alternative treatments are available.

Trasylol® (aprotinin) is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antihemorrhagics, proteinase inhibitors, ATC code: B02AB01

Gordox is a broad spectrum protease inhibitor which has antifibrinolytic properties. By forming reversible stoichiometric enzyme-inhibitor complexes, Gordox 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.

Data from a global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the full-dose Gordox group compared with 6.6% (129/1957) in the placebo group, with an odds ratio of 1.41 (1.12-1.79). In the majority of instances, post-operative renal dysfunction was not severe and reversible. The incidence of serum creatinine elevations >2.0mg/dL above baseline was similar (1.1% vs 0.8%) in both the full-dose Gordox and placebo group, with an odds ratio of 1.16 (0.73-1.85).

The in-hospital mortality in a pool of randomized, clinical trials is summarised in the table below:

Pharmacokinetic properties

After intravenous injection, rapid distribution of Gordox occurs into the total extracellular space, leading to an initial decrease in plasma Gordox concentration with a half-life of 0.3 - 0.7 h. 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.

The placenta is probably not absolutely impermeable to Gordox, but permeation appears to take a very slow course.

Metabolism, elimination and excretion

The Gordox molecule is metabolised to shorter peptides or amino acids by lysosomal activity in the kidney. In man, urinary excretion of active Gordox accounts for less than 5% of the dose. After receiving injections of 131IGordox 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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Gordox should not be used when CABG surgery is combined with another cardiovascular surgery because the benefit risk balance of Gordox in other cardiovascular procedures has not been established.

Laboratory monitoring of anticoagulation during cardiopulmonary bypass

Gordox is not a heparin-sparing agent and it is important that adequate anticoagulation with heparin be maintained during Gordox-therapy. Elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (Celite ACT) are expected in Gordox-treated patients during surgery, and in the hours after surgery. Therefore, the partial thromboplastin time (PTT) should not be used to maintain adequate anticoagulation with heparin. In patients undergoing cardiopulmonary bypass with Gordox therapy, one of three methods is recommended to maintain adequate anticoagulation: Activated Clotting Time (ACT), Fixed Heparin Dosing, or Heparin Titration (see below). If activated clotting time (ACT) is used to maintain adequate anticoagulation, 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 Gordox.

Additional note on use with extracorporeal circulation

In patients undergoing cardiopulmonary bypass with Gordox therapy, one of the following methods is recommended to maintain adequate anticoagulation:

- Activated Clotting Time (ACT)

An ACT is not a standardized coagulation test, and different formulations of the assay are affected differently by the presence of Gordox. 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 Gordox as are diatomaceous earthbased (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 Gordox. Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Gordox.

- 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.

- Determination of Heparin Levels

Protamine titration, a method that is not affected by Gordox, can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of Gordox 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 (2.0mg/kg) or below the level indicated by heparin dose-response testing performed prior to administration of Gordox.

In Gordox 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: Gordox is not a heparin-sparing agent.

Graft Conservation

Blood drawn from the Gordox central infusion line should not be used for graft preservation.

Re-exposure to Gordox

Administration of Gordox, especially to patients who have received Gordox (including Gordox containing fibrin sealants) in the past requires a careful risk/benefit assessment because an allergic reaction may occur. Although the majority of cases of anaphylaxis occur upon reexposure within the first 12 months, there are also single case reports of anaphylaxis occurring upon re-exposure after more than 12 months.

Standard emergency treatment for allergic/anaphylactic reactions should be readily available during treatment with Gordox.

Assessment of potential for allergic reactions

All patients treated with Gordox should first receive a test dose to assess the potential for allergic reactions. The test dose of Gordox should only be administered when facilities and equipment for handling acute anaphylactic reactions are available on-site.

Renal impairment

Results from recent observational studies indicate that renal dysfunction could be triggered by Gordox, 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 >0.5mg/dL above baseline in patients with Gordox therapy. Careful consideration of the balance of risks and benefits is therefore advised before administration of Gordox to patients with pre-existing impaired renal function or those with risk factors (such as concomitant treatment with aminoglycosides).

An increase in renal failure and mortality compared to age-matched historical controls has been reported for Gordox-treated patients undergoing cardiopulmonary bypass with deep hypothermic circulatory arrest during operation of the thoracic aorta. Adequate anticoagulation with heparin must be assured (see also above).

Mortality

An association between Gordox use and increased mortality has been reported in some non randomised observational studies (e.g., Mangano 2007, Schneeweiss 2008, Olenchock 2008, Shaw 2008) while other non-randomised studies have not reported such an association (e.g., Karkouti 2006, Mangano 2006, Coleman 2007, Pagano 2008, Ngaage 2008, Karkouti, 2009). In these studies, Gordox was usually administered to patients who had more risk factors for increased mortality before surgery than patients in the other treatment groups.

Most of the studies did not adequately account for these baseline differences in risk factors and the influence of these risk factors on the results is not known. Therefore interpretation of these observational studies is limited and an association between Gordox use and increased mortality can neither be established nor refuted. Thus, Gordox should only be used as authorized in isolated CABG surgery, after careful consideration of the potential risks and benefits.

A publication by Fergusson et al. 2008 analysed data from a randomised controlled trial, Blood Conservation Using Antifibrinolytics in a Randomised Trial (BART), and reported a higher mortality rate in Gordox-treated patients compared to those treated with tranexamic acid or aminocaproic acid. However, due to several methodological deficiencies no firm conclusion on cardiovascular risks can be made on the BART study results.

Anaphylactic or anaphylactoid reactions have occurred with Trasylol® (aprotinin) administration, including fatal reactions in association with the initial (test) dose. The initial (test) dose does not fully predict a patient's risk for a hypersensitivity reaction, including a fatal reaction. Fatal hypersensitivity reactions have occurred among patients who tolerated an initial (test) dose.

Hypersensitivity reactions often manifest as anaphylactic/anaphylactoid reactions with hypotension the most frequently reported sign of the hypersensitivity reaction. The hypersensitivity reaction can progress to anaphylactic shock with circulatory failure. If a hypersensitivity reaction occurs during injection or infusion of Trasylol® (aprotinin) , administration should be stopped immediately and emergency treatment should be initiated. Even when a second exposure to aprotinin has been tolerated without symptoms, a subsequent administration may result in severe hypersensitivity/anaphylactic reactions.

Trasylol® (aprotinin) should be administered only in operative settings where cardiopulmonary bypass can be rapidly initiated. Before initiating treatment with Trasylol® (aprotinin) , the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction: 1) Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids). 2) Administration of the initial (test) dose and loading dose should be done only when the patient is intubated and when conditions for rapid cannulation and initiation of cardiopulmonary bypass are present. 3) Delay the addition of Trasylol® (aprotinin) into the pump prime solution until after the loading dose has been safely administered.

Re-exposure to aprotinin: Administration of aprotinin, especially to patients who have received aprotinin in the past, requires a careful risk/benefit assessment because an allergic reaction may occur (see CONTRAINDICATIONS). Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also case reports of anaphylaxis occurring upon re-exposure after more than 12 months.

In a retrospective review of 387 European patient records with documented re-exposure to Trasylol® (aprotinin) , the incidence of hypersensitivity/anaphylactic reactions was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and 5 days after surgery, respectively. The relationship of these 2 deaths to Trasylol® (aprotinin) is unclear. This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic reaction following re-exposure is increased when the re-exposure occurs within 6 months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months). Other smaller studies have shown that in case of re-exposure, the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level.

An analysis of all spontaneous reports from the Bayer Global database covering a period from 1985 to March 2006 revealed that of 291 possibly associated spontaneous cases of hypersensitivity (fatal: n=52 and non-fatal: n=239), 47% (138/291) of hypersensitivity cases had documented previous exposure to Trasylol® (aprotinin). Of the 138 cases with documented previous exposure, 110 had information on the time of the previous exposure. Ninety-nine of the 110 cases had previous exposure within the prior 12 months.

Renal Dysfunction: Trasylol® (aprotinin) administration increases the risk for renal dysfunction and may increase the need for dialysis in the perioperative period. This risk may be especially increased for patients with pre-existing renal impairment or those who receive aminogylcoside antibiotics or drugs that alter renal function. Data from Bayer's global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5 mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the high-dose aprotinin (Regimen A) group compared with 6.6% (129/1957) in the placebo group. In the majority of instances, post-operative renal dysfunction was not severe and was reversible. However, renal dysfunction may progress to renal failure and the incidence of serum creatinine elevations >2.0 mg/dL above baseline was slightly higher in the high-dose aprotinin group (1.1% vs. 0.8%). Careful consideration of the balance of benefits versus potential risks is advised before administering Trasylol® (aprotinin) to patients with impaired renal function (creatinine clearance < 60 mL/min) or those with other risk factors for renal dysfunction (such as perioperative administration of aminogylcoside or products that alter renal function). (See PRECAUTIONS and ADVERSE REACTIONS: Laboratory Findings: Serum Creatinine.)

Initial (Test) Dose: All patients treated with Trasylol® (aprotinin) should first receive an initial (test) dose to minimize the extent of Trasylol® (aprotinin) exposure and to help assess the potential for allergic reactions. Initiation of this initial (test) dose should occur only in operative settings where cardiopulmonary bypass can be rapidly initiated. The initial (test) dose of 1 mL Trasylol® (aprotinin) should be administered intravenously at least 10 minutes prior to the loading dose and the patient should be observed for manifestations of possible hypersensitivity reaction. However, even after the uneventful administration of the 1 mL initial (test) dose, any subsequent dose may cause an anaphylactic reaction. If this happens, the infusion of Trasylol® (aprotinin) should immediately be stopped and standard emergency treatment for anaphylaxis applied. It should be noted that serious, even fatal, hypersensitivity/anaphylactic reactions can also occur with administration of the initial (test) dose (see WARNINGS).

Allergic Reactions: Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing a hypersensitivity or anaphylactic reaction upon exposure to Trasylol® (see WARNINGS).

Loading Dose: The loading dose of Trasylol® (aprotinin) should be given intravenously to patients in the supine position over a 20-30 minute period. Rapid intravenous administration of Trasylol® (aprotinin) can cause a transient fall in blood pressure (see DOSAGE AND ADMINISTRATION).

Renal Dysfunction: Bayer's global pool of placebo-controlled studies in patients undergoing CABG showed aprotinin administration was associated with elevations of serum creatinine values > 0.5 mg/dL above baseline. Careful consideration of the balance of benefits and risks is advised before administering aprotinin to patients with pre-existing impaired renal function or those with other risk factors for renal dysfunction. Serum creatinine should be monitored regularly following Trasylol® administration (see WARNINGS: Renal Dysfunction).

Use of Trasylol® (aprotinin) in patients undergoing deep hypothermic circulatory arrest: Two U.S. case control studies have reported contradictory results in patients receiving Trasylol® (aprotinin) while undergoing deep hypothermic circulatory arrest in connection with surgery of the aortic arch. The first study showed an increase in both renal failure and mortality compared to age-matched historical controls. Similar results were not observed, however, in a second case control study. The strength of this association is uncertain because there are no data from randomized studies to confirm or refute these findings.

Long-term animal studies to evaluate the carcinogenic potential of Trasylol® (aprotinin) or studies to determine the effect of Trasylol® (aprotinin) on fertility have not been performed.

Results of microbial in vitro tests using Salmonella typhimurium and Bacillus subtilis indicate that Trasylol® (aprotinin) is not a mutagen.

Pregnancy Category B: Reproduction studies have been performed in rats at intravenous doses up to 200,000 KIU/kg/day for 11 days, and in rabbits at intravenous doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the human dose on a mg/kg basis and 0.37 and 0.36 times the human mg/m2 dose. They have revealed no evidence of impaired fertility or harm to the fetus due to Trasylol® (aprotinin). There are, however, 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.

Nursing Mother: Not applicable.

Pediatric Use: Safety and effectiveness in pediatric patient(s) have not been established.

Geriatric Use: Of the total of 3083 subjects in clinical studies of Trasylol® (aprotinin) , 1100 (35.7 percent) were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and older, 479 (43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either dose regimen, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Trasylol® (aprotinin) prolongs whole blood clotting times by a different mechanism than heparin. In the presence of aprotinin, prolongation is dependent on the type of whole blood clotting test employed. If an activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation, the prolongation of the ACT by aprotinin may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation. During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate.

In patients undergoing CPB with Trasylol® (aprotinin) therapy, one of the following methods may be employed to maintain adequate anticoagulation:

1) ACT - An ACT is not a standardized 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 hemodilution 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 Trasylol® (aprotinin).

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 CPB 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 CPB.

3) Heparin Titration - 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.

Protamine Administration- In patients treated with Trasylol® (aprotinin) , the amount of protamine administered to reverse heparin activity should be based on the actual amount of heparin administered, and not on the ACT values.

Effects on ability to drive and use machines

Not relevant.

Dosage (Posology) and method of administration

An appropriate Gordox-specific IgG antibody test may be considered before administration of Gordox.

Adult:

Owing to the risk of allergic/anaphylactic reactions, a 1ml (10,000 KIU) test dose should be administered to all patients at least 10 minutes prior to the remainder of the dose. After the uneventful administration of the 1ml test dose, the therapeutic dose may be given. A H1 antagonist and a H2 antagonist may be administered 15 minutes prior to the test dose of Gordox. In any case standard emergency treatments for anaphylactic and allergic reactions should be readily available.

A loading dose of 1 - 2 million KIU is administered as a slow intravenous injection or infusion over 20 - 30 minutes after induction of anaesthesia and prior to sternotomy. A further 1 - 2 million KIU should be added to the pump prime of the heart-lung machine. To avoid physical incompatibility of Gordox 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.

The initial bolus infusion is followed by the administration of a continuous infusion of 250,000 - 500,000 KIU per hour until the end of the operation.

In general, the total amount of Gordox administered per treatment course should not exceed 7 million KIU.

Paediatric population

The safety and efficacy in children below 18 years of age have not been established.

Renal impairment

Available clinical experience suggests that patients with decreased renal function do not require special dose adjustment.

Hepatic impairment

No data are available on dosage recommendations for patients with hepatic dysfunction.

Elderly

Reported clinical experience has not identified differences in responses in elderly patients.

Method of administration

Gordox should be infused using a central venous catheter. The same lumen should not be used for the administration of any other medicinal product.

When using a multi-lumen central catheter a separate catheter is not required.

Gordox must be given only to patients in the supine position and must be given slowly (maximum 5 - 10ml/min) as an intravenous injection or a short infusion.

Trasylol® (aprotinin) given prophylactically in both Regimen A and Regimen B (half Regimen A) to patients undergoing CABG surgery significantly reduced the donor blood transfusion requirement relative to placebo treatment. In low risk patients there is no difference in efficacy between regimen A and B. Therefore, the dosage used (A vs. B) is at the discretion of the practitioner.

Trasylol® (aprotinin) is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL. All intravenous doses of Trasylol® (aprotinin) should be administered through a central line. DO NOT ADMINISTER ANY OTHER DRUG USING THE SAME LINE. Both regimens include a 1 mL initial (test) dose, a loading dose, a dose to be added while recirculating the priming fluid of the cardiopulmonary bypass circuit ("pump prime" dose), and a constant infusion dose. To avoid physical incompatibility of Trasylol® (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. Regimens A and B, both incorporating a 1 mL initial (test) dose, are described in the table below:

The 1 mL initial (test) dose should be administered intravenously at least 10 minutes before the loading dose. With the patient in a supine position, the loading dose is given slowly over 20-30 minutes, after induction of anesthesia but prior to sternotomy. In patients with known previous exposure to Trasylol® (aprotinin) , the loading dose should be given just prior to cannulation. When the loading dose is complete, it is followed by the constant infusion dose, which is continued until surgery is complete and the patient leaves the operating room. The "pump prime" dose is added to the recirculating priming fluid of the cardiopulmonary bypass circuit, by replacement of an aliquot of the priming fluid, prior to the institution of cardiopulmonary bypass. Total doses of more than 7 million KIU have not been studied in controlled trials.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any unused portion.

Renal and Hepatic Impairment: Trasylol® (aprotinin) administration is associated with a risk for renal dysfunction (see WARNINGS: Renal Dysfunction). Changes in aprotinin pharmacokinetics with age or impaired renal function are not great enough to require any dose adjustment. Pharmacokinetic data from patients with pre-existing hepatic disease treated with Trasylol® (aprotinin) are not available.

Special precautions for disposal and other handling

Parenteral drug products should be inspected visually for particulate matter and colour change prior to administration. Any residual solution should not be kept for later use.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.