Aprotinin Injection – Trasylol
Status – approved; marketed
Organizations involved:
Talecris Biotherapeutics Inc. – Manuf.; R&D; Tech.; USA mark.
Instituto Grifols, S.A. – Parent
NPS Pharmaceuticals Inc – Former
Bayer Schering Pharma AG – R&D; Intl. mark.; Parent
Bayer Corp. – Former
Description: Aprotinin is a protein derived from bovine lung tissue that acts as a serine-type proteinase (protease) enzyme inhibitor. Aprotinin inhibits proteolytic enzymes including chymotryp-sin, kallikrein, plasmin, and trypsin. Aprotinin is a 58 amino acid single-chain polypeptide cross-linked with three disulfide bridges, with a molecular formula of C284-H432-N84-O79-S7, and molecular weight of 6511.57 Dalton (6.51157 kDa). As a relatively simple peptide obtained from dead bovine tissue, this is considered a borderline biopharmaceutical product, more of a chemical substance and natural product, for purposes of this publication.
Biological.: Aprotinin inhibits multiple mediators of systemic inflammation, e.g., systemic inflammatory response syndrome (SIRS) associated with cardiopulmonary bypass (CAGB) surgery, by inhibiting proinflammatory cytokine release; decreasing complement activation; reducing thrombin- and plasmin-induced platelet defects; and stabilizing platelet membranes and preserving platelet function. This can result in reduced transfusions, reduced transfusion-related complications, and modulation bypass-induced SIRS.
Nomenclature: Aprotinin [BIO]; Trasylol [TR]; Aprotinin [USAN INN BAN]; Aprotinin Solution [JAN]; Trypsin inhibitor, pancreatic basic [CAS]; 12407-79-3 [CAS RN]; 11061-94-2 [CAS RN]; 9087-70-1 [CAS RN]; Basic pancreatic trypsin inhibitor [SY]; Bayer A-128 [SY]; EINECS 232-994-9 [EINECS]; 0026-8197-63 [NDC]
Companies.: Trasylol was developed and is manufactured by Bayer AG, now Bayer Schering Pharma AG (Leverkusen, Germany). In April 2005, Talecris Biotherapeutics Inc., a subsidiary of NPS Pharmaceuticals Inc., acquired the blood/plasma products business of Bayer, including manufacturing and U.S marketing, with Bayer Schering Pharma AG retaining international marketing.
In Feb. 2011, Grifols S.A./Instituto Grifols acquired Talecris Biotherapeutics.
FDA class: Drug NDA
Approvals: Date = 19931229, NDA 020-304; orphan designation (granted 11/17/1993; expired 12/29/2000)
Date = 19940821 (est. based on orphan drug designation expiration date of 8/21/2001 for this indication); Indication = 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
Date = 20061215; BLA supplement; Indication = safety revisions to the U.S. product insert/labeling
Indications: [full text of the "INDICATIONS AND USAGE” section of the product insert/labeling, 5/29/2007]:
Trasylol is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass surgery in the course of repeat coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.
Status: In the Jan. 26, 2006, issue of the New England Journal of Medicine, an article by the Ischemia Research and Education Foundation recommended against use of Trasylol in favor of use of alternatives that are safer and cheaper. However, many heart surgeons still consider Trasylol useful in some surgical patients with an unusually high risk of severe bleeding. The study conclusions were based on 4,374 patients having bypass surgery in Canada, Colombia, Europe, Israel, Mexico, Thailand and the U.S., with 1,295 given aprotinin and 1,705 one of two other drugs, both generics, aminocaproic acid or tranexamic acid, to reduce bleeding. A control group, 1,374 patients, had no therapy to prevent bleeding. Those treated with aprotinin had twice the rate of kidney failure, 5%, compared to those receiving other therapy or no therapy; a 50% increase in heart attacks; almost 200% increase in strokes; and also had increases in other serious problems, including heart failure and encephalopathy. The article stated that halting aprotinin use globally would prevent 10,000 to 11,000 cases of kidney failure a year and save more than $1 billion a year in dialysis costs, as well as nearly $250 million spent on the product itself. Bayer (now Bayer Schering) responded that it “believes that Trasylol is a safe and effective treatment.” A problem with the study was that physicians selected which treatment to give to the patients, i.e., the study was not randomized. But, on the other hand, the study was large, with much data collected for each patient in an effort to minimize biases. A spokesman for the American Heart Association said the article would have substantial effects on medical practice. In a related study published in Transfusion, Trasylol led to more cases of decreased kidney function compared with tranexamic acid.
On Feb. 8, 2006, FDA issued a public health advisory warning of risks of serious side effects associated with the use of Trasylol in patients undergoing coronary artery bypass graft (CABG) surgery. FDA stated it was considering whether label changes or other actions were needed.
In Sept. 2006, Talecris submitted new data to the FDA regarding risks of Trasylol, but did this several days after a meeting of FDA’s Cardiovascular and Renal Drugs Advisory Committee reviewed Trasylol, found it to be safe and effective when used to prevent blood loss in patients undergoing coronary artery bypass grafting, and issued a warning on the product. Preliminary findings from a new observational study of patients from a hospital database showed that Trasylol may increase the risk for death, serious kidney damage, congestive heart failure and strokes.
In Nov. 2006, Bayer Schering disclosed that two German employees had been suspended in connection with the company’s failure to disclose data about the risks of Trasylol. The company admitted that it failed to keep the FDA informed of data that could have had a bearing on the outcome of the Sept. 2006 advisory panel meeting looking at the safety of Trasylol, and whether its use increased the risk of kidney problems, heart attacks and strokes. Bayer noted the data had not been shared immediately because of its preliminary nature.
U.S. labeling changes in Dec. 2006 concerned anaphylactic reactions that may occur in patients with prior exposure to aprotinin within 12 months, with Trasylol con-traindicated in such patients. The labeling/insert now includes a black box warning regarding fatal anaphylactic or anaphylactoid reactions, and states that Trasylol should only be used in surgery in a setting where cardiopulmonary bypass (CPB) can be rapidly initiated. The European Union and many other regulatory authorities have made similar changes.
In Sept. 2007, a joint panel of FDA expert advisers voted 16-1, with one abstention, to recommend allowing sales of Trasylol to continue. The panel alsp voted that there was no need to add details from newer studies to Trasylol's label, but Trasylol merited further study. The FDA had been re-evaluating Trasylol's safety since the Jan. 2006 publication of two studies that linked its use to serious side effects, including kidney problems, heart attacks and strokes, with more studies indicating it also raises the risk of death. Further complicating the situation, one of those studies previously was withheld by Bayer from the FDA due to what a company investigation later characterized as a "regrettable human error."
Despite its safety issues, Trasylol (aprotinin) remains the only pharmaceutical approved by FDA (and other regulatory authorities) for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing CPB in the course of CABG surgery.
As of Feb. 2011, Bayer reported about 1,100 lawsuits pending in the United States against the company with plaintiffs claiming Trasylol caused injury and death and Bayer should have known and warned of the risks.
In Feb. 2012, EMA/EU recommended lifting its suspension on Trasylol, saying the results of a study that led to its being taken off the market were unreliable.
Bayer had pulled the product from the market globally in November 2007, after preliminary results of a Canadian study known as BART appeared to show an increased death rate in patients 30 days after taking the medicine. EMA/EU concluded the drug's benefits in preventing blood loss therefore outweighed its risks in patients undergoing isolated heart bypass surgery who were at high risk of heavy blood loss.
Trials: In April 2005, Talecris initiated a double-blind, placebo-controlled, North American Phase III trial in 360 patients of Trasylol for reduction of blood loss and the need for transfusion in patients undergoing elective primary total hip replacement surgery. Patients receive 200 mL I.V. Trasylol or placebo prior to operation, followed by 50 mL/hr of either until surgery is complete.
In Dec. 2005, Bayer initiated a Phase III trial to evaluate Trasylol for transfusion in adult patients undergoing elective spinal fusion surgery. Patients undergoing spinal fusion surgery are subject to a blood transfusion rate that can be six times greater than that of patients undergoing spinal surgery without fusion. About 300,000 spinal fusion surgeries take place each year in the U.S., a figure that has doubled in the last decade. The multi-center, randomized, double-blind, placebo-controlled trial will assess the ability of Trasylol to reduce bleeding and the need for blood transfusions in elective spinal fusion surgery involving three to seven vertebral levels. Over 450 adult patients will randomly receive 200 mL of intravenous Trasylol or placebo at the start of the operation, followed by 50 mL/hour of either agent until the surgery is complete.
In Jan. 2007, after the reports and controversy concerning Trasylol’s adverse effects (see the Status section) and its relabeling, Bayer halted three trials with Trasylol. These were studying the safety and efficacy of Trasylol on transfusion requirements and blood in adults undergoing elective spinal fusion surgery, pneumonectomy or esophagectomy for cancer, and radical or total cystectomy in bladder cancer. The studies were particularly halted in response to the change to U.S. labelling stating that Trasylol should be administered only in surgical settings where cardiopulmonary bypass (CPB ) can be rapidly initiated, with Bayer noting that “the use of CPB is not practical in non-cardiac surgical settings.” Bayer noted that its decision was not based on any safety findings in these non-coronary artery bypass graft surgery studies.
In Feb. 2007, Bayer Schering responded quickly to a study published in the Journal of American Medical Association that reported Trasylol may increase the risk of death during the five-year period after surgery when it has been used. Researchers assessed survival at six weeks, six months and on an annual basis for five years in 3,876 patients following CABG surger. The data showed that of the 1072 patients who received treatment with Trasylol following surgery, 20.8% or 223 patients died, compared to 12.7% in the control group. Bayer Schering cited methodological and analytical problems with the study, including physicians using Trasylol in more seriously ill patients who were already at greater risk for mortality.
In the Feb. 21, 2008 issue of the New England Journal of Medicine, it was reported that (Trasylol) used mitigate bleeding during coronary-artery bypass grafting (CABG) increases mortality. Electronic administrative records of the Premier Perspective Comparative Database were examined for hospitalized patients with operating-room charges for the use of aprotinin (33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone.
Market: Total 2006 worldwide sales of Trasylol were ~$195 million, down ~33% from sales ~$259 million in 2005 due to adverse publicity. In 2005, an estimated 150,000 American patients received Trasylol.
Bayer had projected peak annual sales for Trasylol of ~500 million euros (~$633 million), but with its subsequent safety concerns and warnings, this is unlikely. In recent years, Trasylol had been actively marketed to prevent inflammation, as well as bleeding, in bypass patients, including suggestions to use it in all patients put on heart-lung machines for bypass surgery. However, with its relatively high cost and adverse reports regarding the product’s safety and cost-benefits (e.g., see the Status section above), physician use of Trasylol is uneven, with some favoring it and others avoiding it because of concerns that it may cause clots. Some doctors have also resisted using Trasylol because of its cost.
The 2007 Average Wholesale Price (AWP) is $325.94/100 mL vial and $599.06/200 mL vial (Red Book, 2007). In contrast, drugs used for the same indications: cost only $10 to $50.
R&D: In Aug. 2004, ProdiGene Inc. (College Station, TX) launched, AproliZean, recombinant corn (Zea mays)-expressed bovine aprotinin for non-clinical uses, including cell culture and protein purification.
Medicago Inc. (Quebec City, Quebec, Canada), Acambis PLC and InterveXion Therapeutics LLC are jointly developing recombinant plant-expressed aprotinin as a biogeneric, biosimilar, follow-on biologic/protein, biocomparable, etc., product.
Companies involvement:
Full monograph
713 Aprotinin
Nomenclature:
Aprotinin [BIO TR]
EINECS 232-994-9 [EINECS]
Trasylol []
Aprotinin Solution [JAN]
Trypsin inhibitor, pancreatic basic [ CAS]
11061-94-2 [CAS RN]
12407-79-3 [CAS RN]
9087-70-1 [CAS RN]
Basic pancreatic trypsin inhibitor [SY]
Bayer A-128 [SY]
NDC 0026-8197-63 [NDC]
C284H432N84O79S7 [MF]
6.51157 kDa [MW]
FDA Class: Drug NDA
Year of approval (FDA) = 1993
Date of 1st FDA approval = 19931229
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
blood products
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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