FDA Issues Public Health Advisory for Trasylol
The Food and Drug Administration today issued a Public Health Advisory alerting doctors who perform heart bypass surgery, and their patients, that Trasyolol (aprotinin injection), a drug used to prevent blood loss during surgery, has been linked in two scientific publications to higher risks of serious side effects including kidney problems, heart attacks and strokes in patients who undergo artery bypass graft surgery.
"FDA is conducting a thorough evaluation of the safety profile for this drug in light of the recent publications," said Dr. Steven Galson, Director of FDA's Center for Drug Evaluation and Research. "We're working to evaluate the potential risks and determine whether there is a need for further action. In the meantime, we advise providers to carefully assess the benefits and risks of the drug for their patients."
FDA advises health care providers to be aware of the following:
- Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart or central nervous system and promptly report adverse event information to Bayer, the drug manufacturer, or through the FDA Medwatch program.
- Physicians should consider limiting Trasylol use to those situations in which the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks.
- FDA is working with the manufacturer to examine the safety and benefits of Trasylol in light of the recent data and the evolving practice of medicine.
- Patients should discuss all major risks for heart bypass surgery with their healthcare providers. These include the risks for bleeding and the available ways to lessen the risk for bleeding.
Trasylol (aprotinin injection) is the only product
approved by FDA for the prevention of peri-operative
blood loss and the need for blood transfusion among
patients undergoing coronary artery bypass graft surgery.
The drug aids the body's ability to stop bleeding and is
used to lessen the bleeding risk during this surgical
procedure. This surgery is done to bypass clogged
arteries.
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FDA is evaluating the studies more closely, along with
other scientific literature and reports submitted to the
FDA through the MedWatch program, to determine if
labeling changes or other actions are warranted. One
study, published in the New England Journal of Medicine,
reported that patients who received Trasylol had higher
rates of serious kidney problems, heart attacks, and
stroke compared to treatment with other drugs to prevent
bleeding or to no treatment; the second study, reported
in Transfusion, reported more cases of decreased kidney
function in patients treated with Trasylol compared to
another treatment to prevent bleeding. A limitation of
both studies was that doctors chose which patients were
to receive Trasylol or another treatment. It is possible
that patients treated with Trasylol may have been sicker
than other patients. The studies used complex statistical
methods to adjust for possible differences in patient
risk factors.
The agency also anticipates convening an advisory committee meeting in 2006 to discuss the existing data about the risks and benefits of Trasylol, and if additional safety measures need to be taken. The FDA will notify health care providers and patients in a timely manner following further scientific investigation of adverse event reports.
FDA also urges health care providers and patients to report adverse event information to FDA via the MedWatch program by phone (1800-FDA-1088), by fax (1-800-FDA-1078) or internet.
The Public Health Advisory is available on line at http://www.fda.gov/cder/drug/advisory/aprotinin.htm.
For more information please visit http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm,
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----------------FOR IMMEDIATE RELEASE
Statement
September 29, 2006
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FDA Statement Regarding New Trasylol Data
Since January, 2006, the Food and Drug Administration (FDA) has been conducting a safety review of Trasylol (aprotinin injection). The review was triggered by the results of two published research studies: one that reported an increase in the chance of kidney failure, heart attack and stroke in patients treated with Trasylol compared to those treated with other similar drugs, and the other that reported an increase in kidney dysfunction compared to another drug. On September 21, 2006, FDA held a public meeting of the Cardiovascular and Renal Drugs Advisory Committee to discuss the safety and overall risk-benefit profile for Trasylol. At that meeting, the committee discussed the findings from the two published observational studies, the Bayer worldwide safety review, and the FDA review of its own post-marketing database.
On September 27, 2006, Bayer Pharmaceuticals told FDA that it had conducted an additional safety study of Trasylol. The preliminary findings from this new observational study of patients from a hospital database reported that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes. FDA was not aware of these new data when it held the September 21, 2006, Advisory Committee meeting on Trasylol safety. FDA is actively evaluating these new data and their implications for appropriate use of the drug.
While FDA conducts its evaluation of this new safety study, we recommend the following to healthcare providers:
- Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, or brain, and promptly report observed adverse event information to Bayer Pharmaceuticals, the drug manufacturer, or to the FDA MedWatch program, by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet at http://www.fda.gov/medwatch/index.html.
- Physicians should consider limiting Trasylol use to those situations where the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks.
These recommendations are similar to those provided in a February 8, 2006, FDA Public Health Advisory and information sheets for health care professionals and patients which were based on the published studies mentioned above. See http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm.
Trasylol works to slow or prevent bleeding, and is used to reduce blood loss and the need for blood transfusion during some types of heart surgeries. Trasylol is made from the lung tissue of cattle.
In the published studies and the recently supplied Bayer study, patients were not assigned at random to receive various treatments, but rather had their treatment chosen by their physician as part of their standard medical care. Consequently, in these safety studies, patients receiving Trasylol may have had a higher chance for serious complications to begin with as compared to patients receiving no treatment or treatment with another drug intended to decrease bleeding. This possibility complicates the assessment of whether the available studies show that Trasylol treatment, rather than other factors, increased the chance for serious kidney or heart complications.
The new study was done for Bayer by a contract research organization. Existing hospital data from 67,000 records of patients undergoing coronary artery bypass graft surgery were examined. 30,000 of the patients were treated with Trayslol and 37,000 were treated with alternate products. Using complex epidemiological and statistical methods, the report suggested that patients receiving Trasylol were at increased risk for death, kidney failure, congestive heart failure and stroke.
Healthcare providers and patients are encouraged to report adverse event information to FDA via the MedWatch program by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet at http://www.fda.gov/medwatch/index.html.
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----------------FOR IMMEDIATE RELEASE
P06-203
December 15, 2006
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FDA Revises Labeling for Trasylol (Aprotinin Injection) to Strengthen Safety Warnings and Limit Usage of Drug to Specific Situations
The U.S. Food and Drug Administration (FDA) today approved revised labeling for Trasylol (aprotinin injection) to strengthen its safety warnings and to limit its approved usage to specific situations. Trasylol is given to patients before heart surgery to reduce bleeding and the need for blood transfusions. Trasylol is marketed by Bayer Pharmaceuticals Corporation, Leverkusen, Germany.
"The purpose of the label change is to inform physicians and patients about the risks associated with Trasylol and to ensure they understand the new warnings and use the product as directed by the label," said Steven Galson, M.D., MPH, Director of FDA's Center for Drug Evaluation and Research.
The new labeling specifies that Trasylol should only be given to patients who are at an increased risk for blood loss and blood transfusion in the setting of coronary bypass graft surgery (a procedure used to improve blood flow to the heart) when patients undergo cardiopulmonary bypass (a procedure that allows a machine to take over the heart's functions when it is stopped during surgery). The changes also include a warning that Trasylol increases the possible risk for kidney damage, and suggest ways to manage and reduce the patient's risk for hypersensitivity (exaggerated immune) reactions.
The labeling changes follow an FDA-conducted review of safety information that FDA became aware of after the product was introduced to the market. FDA began this safety review of Trasylol in January 2006. The review was triggered by the results of two published research studies. One study reported an increase in the possibility of kidney failure, heart attack and stroke in patients treated with Trasylol compared to those treated with other drugs. The other study reported an increase in the possibility of kidney damage compared to other drugs, but did not show an increased risk of heart attack or stroke. On February 8, 2006, FDA issued a Public Health Advisory regarding these new findings with Trasylol. On September 21, 2006, FDA held a public meeting of the Cardiovascular and Renal Drugs Advisory Committee to discuss the safety and overall risk-benefit profile for Trasylol. At that meeting, the committee discussed the findings from the two published observational studies, a Bayer worldwide safety review, and the FDA review of its own post-marketing database, and made recommendations for labeling changes. The labeling changes for Trasylol are based upon the recommendations of that advisory committee.
FDA announced on September 29, 2006, that Bayer informed the agency of an additional safety study on September 27, 2006. The preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes. The FDA review of this additional Trasylol safety information is continuing and it may result in other actions, including additional changes to the labeling. For additional information about Trasylol, see www.fda.gov/cder/drug/infopage/aprotinin/default.htm.
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----------------Early Communication about an Ongoing
Safety Review
Aprotinin Injection (marketed as Trasylol)
This information reflects FDA’s current analysis of available data concerning these drugs. Posting this information does not mean that FDA has concluded there is a causal relationship between the drug products and the emerging safety issue. Nor does it mean that FDA is advising health care professionals to discontinue prescribing these products. FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action. FDA intends to update this document when additional information or analyses become available.
On October 19, 2007, FDA was notified of the Data Safety Monitoring Board’s (DSMB) recommendation to stop patient enrollment in the aprotinin (marketed as Trasylol by Bayer, Inc.) treatment group arm of the: Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study. The preliminary findings suggest that, compared to the antifibrinolytic drugs, epsilon-aminocaproic acid and tranexamic acid, aprotinin increases the risk of death.
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 associated with cardiac surgery. The study had planned to enroll approximately 3,000 adult Canadian patients who were to undergo various types of cardiac surgery that placed them at high risk for bleeding.
Information from the interim analyses performed by the DSMB is limited, but FDA has been informed that:
- the 30- day mortality in the aprotinin group nearly had reached conventional statistical significance at the interim analysis, when compared to either epsilon-aminocaproic acid or tranexamic acid;
- a trend toward increased mortality in the aprotinin group had been observed throughout the study;
- the use of aprotinin was associated with less serious bleeding than either of the comparator drugs; however, more deaths due to hemorrhage had been observed among patients receiving aprotinin;
- the DSMB concluded that continued enrollment of patients into the aprotinin group was unlikely to significantly change the study findings.
Additional data collection and analyses must be performed to more thoroughly assess the findings from the BART study. However, these preliminary data support the findings from observational studies that also suggested increased risks for mortality when aprotinin was compared to other antifibrinolytic drugs. These observational studies were discussed at a September 12, 2007, joint meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committees.
In light of the preliminary BART study findings, FDA anticipates re-evaluation of the overall risks and benefits of Trasylol. This re-evaluation may result in the need to revise the labeling or other regulatory actions. Until this process has been completed, healthcare providers who are considering use of Trasylol should be aware of the risks and benefits described in the labeling for Trasylol and the accumulating data suggesting Trasylol administration increases the risk for death compared to other antifibrinolytic drugs.
Trasylol is currently approved 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 (CABG) surgery who are at an increased risk for blood loss and blood transfusion.
This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs. FDA will work with the sponsor of the BART study and the manufacturer of Trasylol to fully evaluate the risks and benefits associated with the use of Trasylol. As soon as this process is complete, FDA will communicate the conclusions and recommendations to the public.
The FDA urges healthcare professionals to promptly
report serious and unexpected adverse reactions
associated with Trasylol to Bayer or to the FDA MedWatch
reporting program. ----------------
FOR IMMEDIATE RELEASE
November 5, 2007
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FDA Requests Marketing Suspension of Trasylol
The U.S. Food and Drug Administration (FDA) today announced that, at the agency's request, Bayer Pharmaceuticals Corp. has agreed to a marketing suspension of 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 Trasylol.
There are not many treatment options for patients at risk for excessive bleeding during cardiac surgery. Thus, FDA is working with Bayer to phase Trasylol out of the marketplace in a way that does not cause shortages of other drugs used for this purpose.
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 Trasylol outweigh the risks. 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 Trasylol.
Two weeks ago, FDA was notified that researchers with the Ottawa Health Institute stopped a study on Trasylol because the drug appeared to increase the risk for death compared to two other antifibrinolytic drugs used in the study. Antifibrinolytic drugs help slow the breakdown of blood clots and subsequent excessive bleeding. The preliminary data from this terminated study also suggested that fewer patients receiving the drug experienced serious bleeding events.
On Oct. 26, FDA issued an Early Communication about an Ongoing Safety Review of Trasylol in response to the Canadian study's termination. In 2006, FDA revised the labeling for Trasylol to strengthen its safety warning and limit its approved usage to patients at an increased risk for blood loss and blood transfusion during coronary bypass graft surgery.
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