[UPDATE 05/14/2008] 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 (Trasylol) 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. For more information visit the FDA website at: [Web], [Web] and [Web].
[Posted 11/05/2007] FDA announced that, at the agency's request, Bayer Pharmaceuticals Corp. has agreed to a marketing suspension of aprotinin injection (Trasylol), a drug used to control bleeding during heart surgery, pending detailed review of preliminary results from a Canadian study that suggested an increased risk for death. FDA requested the suspension in the interest of patient safety based on the serious nature of the outcomes suggested in the preliminary data. FDA has not yet received full study data but expects to act quickly with Bayer, the study's researchers at the Ottawa Health Research Institute, and other regulatory agencies to undertake a thorough analysis of data to better understand the risks and benefits of aprotinin injection.
Until FDA can review the data from the terminated study it is not possible to determine and identify a population of patients undergoing cardiac surgery for which the benefits of aprotinin injection outweigh the risks. However, understanding that individual doctors may identify specific cases where benefit outweighs risk, FDA is committed to exploring ways for those doctors to have continued, limited access to aprotinin injection. There are not many treatment options for patients at risk for excessive bleeding during cardiac surgery. Thus, FDA is working with Bayer to phase aprotinin injection out of the marketplace in a way that does not cause shortages of other drugs used for this purpose. For more information visit the FDA website at: [Web], [Web] and [Web].
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Prevention of Bleeding Associated with Cardiopulmonary Bypass during CABG
Used prophylactically to reduce both perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass during CABG who are at an increased risk for blood loss and blood transfusion, including that related to thrombolytic agents. (See Sensitivity and Dermatologic Reactions under Cautions and see Boxed Warning.)
Increased risk of serious cardiovascular, cerebrovascular, hypersensitivity, and renal complications with use of aprotinin; consider limiting use to situations in which benefits of the drug in reducing blood loss are thought to outweigh potential risks.
ACC and AHA state that routine use of aprotinin in patients undergoing cardiopulmonary bypass during CABGnot recommended but may be considered in selected high-risk patients (e.g., geriatric patients ≥65 years of age, females, patients with more than one diseased coronary artery, poor left ventricular function, history of heart surgery, patients requiring urgent CABG).
Dosage and Administration
General
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
For reduction of perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass during CABG, high-dose and low-dose prophylactic regimens of aprotinin have been used. No clinically important differences in efficacy between the high-dose and low-dose regimens in low-risk patients undergoing CABG; use either dosage at clinician’s discretion.
Administration
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Administered by IV injection, IV infusion through a central venous line, or by addition to the recirculating priming fluid of the cardiopulmonary bypass circuit.
Because of the risk for hypersensitivity reactions, all patients should receive a test dose. Administer test and loading doses when the patient is intubated and when conditions for rapid cannulation and initiation of cardiopulmonary bypass are present. Standard emergency treatments for hypersensitivity or anaphylactic reactions (e.g., epinephrine, corticosteroids) should be readily available in the operating room.
If no adverse reactions occur within 10 minutes following test dose, administer loading dose IV slowly over 20–30 minutes with patient supine. Avoid rapid IV administration of large (e.g., loading) doses of aprotinin because of the potential for hypotension and/or anaphylactoid reactions. Administer the loading dose after induction of anesthesia but prior to sternotomy. In patients with known previous exposure, administer the loading dose just prior to cannulation.
After the loading dose, administer by continuous IV infusion until the surgical procedure is completed and the patient is removed from the operating room.
Delay the addition of aprotinin into the recirculating fluid of the cardiopulmonary bypass circuit (pump-priming dose) until after the loading dose has been safely administered. Before initiating cardiopulmonary bypass, add the pump-prime dose to the recirculating priming fluid by replacing an aliquot of the priming fluid with the drug.
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Dosage and potency of aprotinin usually are expressed in terms of kallikrein inhibitor (KI) units, although expression in mg also has been used. Each mg of the drug has a potency of approximately 7143 units.
Adults
Prevention of Bleeding Associated with CABG
Prophylactic regimens include a test dose, a loading dose, a dose added to the recirculating priming fluid of the cardiopulmonary bypass circuit (pump-priming dose), and a dose administered by continuous IV infusion. Observe patients for manifestations of possible sensitivity reactions.
Test Dose
IV
Administer a test dose of 10,000 units (1.4 mg [1 mL]) by IV injection at least 10 minutes before the loading dose.
Loading Dose
IV
After successful administration of the test dose, administer an IV loading dose of 2 million units (280 mg [200 mL]) for the high-dose regimen or 1 million units (140 mg [100 mL]) for the low-dose regimen. Administer loading dose over 20–30 minutes.
After the loading dose, administer 500,000 units/hour (70 mg/hour [50 mL/hour]) by continuous IV infusion for the high-dose regimen or 250,000 units/hour (35 mg/hour [25 mL/hour]) by continuous IV infusion for the low-dose regimen.
Pump-priming Dose
IV
For the pump-priming dose with the high-dose regimen, replace an aliquot of priming fluid with 2 million units (280 mg [200 mL]). For the pump-priming with the low-dose regimen, replace an aliquot of priming fluid with 1 million units (140 mg [100 mL]).
Prescribing Limits
Adults
Total dosages exceeding 7 million units (980 mg) within a 24-hour period have not been studied in controlled trials. Dosages up to 17.5 million units (2.45 g) within a 24-hour period have been administered to patients without any apparent toxicity. However, maximum doses and/or dosages that can be administered safely have not been established.
Special Populations
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Hepatic Impairment
No dosage recommendations; no data are available.
Renal Impairment
The manufacturer states that dosage adjustment is not necessary in patients with renal impairment. Some clinicians recommend reduced dosages of the drug in patients with renal failure. (See Special Populations under Pharmacokinetics and see Renal Effects under Cautions.)
Geriatric Patients
Dosage adjustment not necessary.
Cautions
Contraindications
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Known or suspected exposure to aprotinin-containing products within the previous 12 months.
Known hypersensitivity to the drug. Patients with a history of allergic reactions to drugs or other agents may be at greater risk of developing an allergic reaction to aprotinin.
Warnings/Precautions
Sensitivity Reactions
Sensitivity and Dermatologic Reactions
Hypersensitivity reactions, including fatal anaphylactic or anaphylactoid reactions, reported during surgery. (See Boxed Warning.) Hypotension is most frequent sign of anaphylactic or anaphylactoid reactions and may progress to anaphylactic shock with circulatory failure. Other manifestations of hypersensitivity reactions include skin eruptions, pruritus, dyspnea, nausea, and tachycardia.
Because of the risk for hypersensitivity reactions, all patients should receive a test dose of aprotinin. Obtain history of any prior aprotinin exposure, including use of fibrin sealant products (e.g., Tissucol, Tisseel) that may contain aprotinin. However, hypersensitivity reactions to subsequent therapeutic doses of drug (e.g., loading dose, pump-prime regimen) may occur despite tolerance of the test dose. Discontinue aprotinin immediately if a hypersensitivity reaction occurs, and institute appropriate therapy (e.g., epinephrine, corticosteroids, antihistamines).
The incidence of hypersensitivity reactions and anaphylaxis is higher in patients reexposed to aprotinin. Particular caution is necessary when administering aprotinin (even in test doses) to such patients. Standard emergency treatments for hypersensitivity or anaphylactic reactions should be readily available in the operating room. Administer the test dose and loading dose of aprotinin when the patient is intubated and when the conditions for rapid cannulation (if necessary) and initiation of CABG are present. Delay pump priming dose of aprotinin until after the loading dose has been safely administered.
Renal Effects
Increased risk of renal dysfunction and need for dialysis in perioperative period. Generally, postoperative renal dysfunction observed was not severe and was reversible. However, renal dysfunction may progress to renal failure. Risk may be increased particularly in patients with preexisting renal impairment or in those receiving concomitant drugs that alter renal function (e.g., aminoglycosides). (See Interactions.) Limited data suggest an increased risk of renal failure and/or death in patients undergoing deep hypothermic circulatory arrest during aortic arch surgery†; such findings were not confirmed in a second case-control study.
Careful monitoring for occurrence of ischemic toxicity to kidneys recommended in patients undergoing CABG and receiving aprotinin. Manufacturer recommends monitoring Scr regularly. Weigh carefully the clinical benefit of reduced blood loss against the potential risks in patients with preexisting renal dysfunction (Clcr <60 mL/minute) or other risk factors for renal dysfunction. Promptly report serious and unexpected adverse effects to manufacturer or to FDA Medwatch program at 1-800-FDA-1088 or http://www.fda.gov/medwatch/index.html.
General Precautions
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Cardiovascular Effects
Increased risk of MI or heart failure during a postmarketing observational study in patients undergoing CABG and receiving aprotinin; such effects not observed in pooled analysis of premarketing clinical trials.
FDA recommends careful monitoring for the occurrence of ischemic toxicity to the heart in patients undergoing CABG and receiving aprotinin. Reserve use to situations when the clinical benefit of reduced blood loss outweighs the potential risks. Promptly report serious and unexpected adverse effects to the manufacturer or to the FDA Medwatch program at 1-800-FDA-1088 or http://www.fda.gov/medwatch/index.html.
Rapid IV administration can cause a transient fall in BP. Administer the IV loading dose over a period of 20–30 minutes while the patient is supine.
Nervous System Effects
Increased risk for cerebrovascular adverse events such as stroke, encephalopathy, or coma observed in patients receiving aprotinin compared with no treatment or treatment with other antifibrinolytic agents (i.e., aminocaproic acid, tranexamic acid).
FDA recommends careful monitoring for the occurrence of ischemic toxicity to the CNS in patients undergoing CABG and receiving aprotinin. Reserve use to situations when the clinical benefit of reduced blood loss outweighs the potential risks. Promptly report serious and unexpected adverse effects to the manufacturer or to the FDA Medwatch program at 1-800-FDA-1088 or http://www.fda.gov/medwatch/index.html.
Specific Populations
Pregnancy
Category B.
No adequate and controlled studies in pregnant women. Use during pregnancy only when clearly needed.
Pediatric Use
Safety and efficacy in children younger than 18 years of age not established.
Geriatric Use
No overall differences in efficacy or safety were observed between geriatric and younger patients.
Potential for increased risk of nephrotoxicity. Consider risks versus benefits of concurrent perioperative use of aprotinin and other nephrotoxic drugs.
Prolongs ACT and overestimates degree of anticoagulation with heparin
Minimum celite or kaolin ACTs of 750 or 480 seconds, respectively, suggested to ensure adequate anticoagulation
Alternatively, use additional heparin during extended extracorporeal circulation
Standard loading dose and dosage of heparin added to prime volume of cardiopulmonary bypass circuits should total ≥350 units/kg
Administer additional heparin based on patient weight and duration of cardiopulmonary bypass
Alternatively, use protamine titration (method not affected by aprotinin) to monitor heparin concentrations
Pharmacokinetics
Distribution
Extent
Distributes rapidly into the total extracellular space. In animals accumulates principally in the kidney and is stored in phagolysosomes.
Elimination
Metabolism
Slowly degraded by lysosomal enzymes in the kidneys.
Elimination Route
Excreted principally by the kidneys. Approximately 25–40% of a single, radiolabeled dose is excreted in urine over 48 hours.
Half-life
About 150 minutes (initial half-life). About 10 hours (terminal elimination half-life) when determined >5 hours after dosing.
Special Populations
Effect of hepatic impairment on pharmacokinetics not established.
Pharmacokinetics not altered substantially by age or renal impairment.
Stability
Storage
Parenteral
Injection
Store between 2–25°C. Protect from freezing.
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Do not administer other drugs concomitantly with aprotinin in the same central IV line.
To avoid incompatibility of heparin and aprotinin in the pump prime solution, add one agent during recirculation of the priming fluid to ensure adequate dilution prior to admixture with the other agent.
Actions
Inhibits contact activation of the intrinsic clotting system (i.e., contact phase of coagulation), a pathway that both initiates coagulation and promotes fibrinolysis.
Minimizes perioperative bleeding and need for blood transfusion associated with CABG through effects on platelet and granulocyte function, coagulation, and fibrinolysis. May improve hemostasis during and after cardiopulmonary bypass by preserving platelet membrane receptors that maintain the adhesive and aggregative capacity of platelets. Attenuates fibrinolysis, inflammatory responses, and thrombin generation through inhibition of plasmin and plasma and tissue kallikreins.
Because of its effects on kallikrein, aprotinin inhibits activation of the intrinsic clotting system. (See Specific Drugs and Laboratory Tests under Interactions.) The relative contribution of these effects to the drug’s therapeutic action remains to be fully elucidated.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Importance of informing clinician of prior exposure to aprotinin, including use of fibrin sealant products (e.g., Tissucol, Tisseel) that may contain aprotinin.(See Sensitivity and Dermatologic Reactions under Cautions.)
Importance of informing clinician of prior allergic drug reactions.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and any concomitant illnesses (e.g., kidney disease) or prior heart surgery.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
