Applies to the following strengths: 10000 Kallikrein inhibitor units/mL
Usual Adult Dose for:
Additional dosage information:
Usual Adult Dose for Bleeding
In November 2007, Bayer agreed to suspend the marketing of aprotinin pending a comprehensive review of preliminary results from a Canadian study that suggested an increased risk for death. Following publication of the Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study in the May 14, 2008 online issue of The New England Journal of Medicine, Bayer Pharmaceuticals notified the FDA of their intent to remove all remaining supplies of aprotinin from hospital pharmacies and warehouses. Under a limited use agreement, access to aprotinin is limited to investigational use of the drug according to the procedures described in a special treatment protocol. The protocol allows treatment for certain patients who are at increased risk of blood loss and transfusions during coronary artery bypass graft surgery and who have no acceptable alternative therapy. Physicians using aprotinin in this situation must also verify that the benefits of the drug clearly outweigh the risks for their patients.
The following dosage information applies to when the drug was available in the U.S.
Test dose: 1 mL
Loading dose: 280 mg
Pump prime dose: 280 mg
Continuous infusion dose: 70 mg/hr
Test dose: 1 mL
Loading dose: 140 mg
Pump prime dose: 140 mg
Continuous infusion dose: 35 mg/hr
The manufacturer recommends both regimens. In low-risk patients there is no difference in efficacy. Thus the dosage is at the discretion of the practitioner.
Total doses of more than 7 million Kallikrein inhibitor units (KIU) have not been studied in controlled trials.
Renal Dose Adjustments
In the placebo-controlled clinical trials conducted in the U.S., patients with mildly elevated pretreatment serum creatinine levels did not have a notably higher incidence of clinically significant post-treatment elevations in serum creatinine following either aprotinin dosage regimen compared to administration of the placebo regimen. Changes in aprotinin pharmacokinetics with age or impaired renal function are not considered great enough to require any dose adjustment.
Liver Dose Adjustments
No pharmacokinetic data from patients with preexisting hepatic disease treated with aprotinin are available.
In November 2007, Bayer agreed to suspend the marketing of aprotinin pending a comprehensive review of preliminary results from a Canadian study that suggested an increased risk for death. In October 2007, the FDA informed healthcare professionals of the Data Safety Monitoring Board's recommendation to stop patient enrollment in the aprotinin treatment group arm of the BART study (Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population). The BART study was designed to test the hypothesis that aprotinin was superior to epsilon-aminocaproic acid and tranexamic acid in decreasing the occurrence of massive bleeding in association with cardiac surgery. The preliminary findings suggest that aprotinin increases the risk of death compared to antifibrinolytic drugs. The FDA anticipates a comprehensive re-evaluation of the overall risks and benefits of aprotinin. Following publication of the Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study in the May 14, 2008 online issue of The New England Journal of Medicine, Bayer Pharmaceuticals notified the FDA of their intent to remove all remaining supplies of aprotinin from hospital pharmacies and warehouses. Under a limited use agreement, access to aprotinin is limited to investigational use of the drug according to the procedures described in a special treatment protocol. The protocol allows treatment for certain patients who are at increased risk of blood loss and transfusions during coronary artery bypass graft surgery and who have no acceptable alternative therapy. Physicians using aprotinin in this situation must also verify that the benefits of the drug clearly outweigh the risks for their patients.
Previous advisories issued by either the FDA or the manufacturer include a February 2006 public health advisory issued by the FDA to notify healthcare professionals and consumers of recent publications reporting serious renal and cardiovascular toxicity associated with aprotinin administration in patients undergoing coronary artery bypass grafting surgery. Another advisory was issued in September 2006 by the manufacturer with the preliminary findings of an observational safety study which reported that the use of aprotinin may increase the chance for death, serious kidney damage, congestive heart failure, and strokes.
Aprotinin may cause fatal anaphylactic or anaphylactoid reactions. Fatal reactions have occurred with an initial (test) dose as well as with any of the components of the dosage regimen. Fatal reactions have also occurred in instances where the initial (test) dose was tolerated. A history of any prior aprotinin exposure must be sought prior to aprotinin administration since the risk for anaphylactic or anaphylactoid reactions is increased among patients with prior aprotinin exposure. The risk for a fatal reaction appears to be greater upon re-exposure within 12 months of the most recent prior aprotinin administration. Aprotinin should only be administered in operative settings where cardiopulmonary bypass can be rapidly initiated.
For patients undergoing primary coronary artery bypass graft surgery, the benefit of aprotinin should be weighed against the risk of anaphylaxis associated with any subsequent exposure to aprotinin.
Aprotinin is contraindicated in patients with a known or suspected previous aprotinin exposure during the last 12 months and in patients with a known or suspected history of exposure to aprotinin greater than 12 months previously.
Hypersensitivity reactions often manifest as anaphylactic/anaphylactoid reactions with hypotension being the most frequently reported sign of the hypersensitivity reaction. The hypersensitivity reaction can evolve to anaphylactic shock with circulatory failure. Administration should be stopped immediately and emergency treatment should be initiated if a hypersensitivity reaction occurs during injection or infusion of aprotinin. Even when a second administration of aprotinin has been tolerated without symptoms, a subsequent administration may result in severe hypersensitivity/anaphylactic reactions.
Before initiating treatment with aprotinin, the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction: 1) Have readily available standard emergency treatments for hypersensitivity or anaphylactic reactions 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 exist. 3) Delay the addition of aprotinin into the pump prime solution until after the loading dose has been administered safely.
Administration of aprotinin, especially to patients who have received aprotinin in the past, requires a careful risk/benefit assessment due to the risk of an allergic reaction. Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also case reports of anaphylaxis occurring after more than 12 months upon re-exposure.
In a retrospective study that included 387 European patient records with documented re-exposure to 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 causality of these 2 deaths to aprotinin is unclear.
This retrospective study 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 five percent.
An analysis of all spontaneous reports from the Bayer Global database encompassing a period from 1985 to March 2006 revealed that of 291 possibly associated spontaneous cases of hypersensitivity (fatal: n equal to 52 and non-fatal: n equal to 239), 47% (138/291) of hypersensitivity cases had documented previous exposure to aprotinin. Out of 138 cases with documented previous exposure, 110 had information on the time of the previous exposure. Ninety-nine out of 110 cases had previous exposure within the prior 12 months.
Aprotinin exposure increases the risk for renal dysfunction and may increase the need for dialysis in the perioperative period. This risk may be particularly increased for patients with pre-existing renal impairment or those who receive aminoglycoside antibiotics or drugs that alter renal function. Data from Bayer's global pool of placebo controlled trials in patients undergoing CABG surgery showed that the incidence of serum creatinine elevations greater than 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 cases, post-operative renal dysfunction was not severe and was reversible. Nevertheless, renal dysfunction may progress to renal failure and the incidence of serum creatinine elevations greater than 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 recommended before administering aprotinin to patients with impaired renal function (creatinine clearance less than 60 mL/min) or those with other risk factors for renal dysfunction (such as perioperative administration of aminoglycoside or products that alter renal function).
All patients treated with aprotinin should first receive an initial (test) dose to minimize the extent of aprotinin exposure and to help assess the risk for allergic reactions. Initiation of this initial (test) dose should only occur in operative settings where cardiopulmonary bypass can be rapidly initiated. The initial (test) dose of 1 mL aprotinin should be administered intravenously at least 10 minutes prior to the loading dose and the patient should be monitored for manifestations of possible hypersensitivity reaction. Nevertheless, even after the uneventful administration of the 1 mL initial (test) dose, any subsequent dose may cause an anaphylactic reaction. If this occurs, the infusion of aprotinin should immediately be stopped and standard emergency treatment for anaphylaxis applied. Serious, even fatal, hypersensitivity/anaphylactic reactions can also occur with administration of the initial (test) dose.
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 aprotinin.
The loading dose of aprotinin should be given intravenously to patients in the supine position over a 20 to 30 minute period. Rapid intravenous administration of aprotinin can cause a transient drop in blood pressure.
Two U.S. case control trials have reported contradictory results in patients receiving aprotinin while undergoing deep hypothermic circulatory arrest in connection with surgery of the aortic arch. The first trial 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 unclear because there are no data from randomized studies to confirm or refute these findings.
Aprotinin prolongs whole blood clotting times by a mechanism that is different than heparin. In the presence of aprotinin, prolongation is dependent on the type of whole blood clotting test utilized. 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 insufficient anticoagulation. During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear sufficient.
Data not available
All intravenous doses of aprotinin should be administered through a central line. Do not administer any other drug using the same line. Both regimens include a 1 mL 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 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.
The 1 mL test dose should be administered at least 10 minutes before the loading dose. With the patient in a supine position, the loading dose is given slowly over 20 to 30 minutes, after induction of anesthesia but prior to sternotomy. In patients with known previous exposure to aprotinin, the loading dose should be given just prior to cannulation.
Once loading dose is complete, the constant infusion dose should be administered 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.
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