800-845-6913

Tuteur & Associates, LLC | Knowledge is Power.

Headlines

FDA Patient Safety News: Trasylol

Marketing of Trasylol Suspended

Manufacturer [Bayer] Removes Remaining Stocks of Trasylol

FOR IMMEDIATE RELEASE
May 14, 2008

Manufacturer [Bayer] Removes Remaining Stocks of Trasylol
Access Limited to Investigational Use

Background: On Nov. 5, 2007, the U.S. Food and Drug Administration announced that Bayer Pharmaceuticals Corp. agreed to an FDA-requested marketing suspension of Trasylol, a drug used to control bleeding during heart surgery. At that time, preliminary results from a Canadian study suggested an increased risk for death compared to two other drugs used to control bleeding.

Bayer HealthCare Pharmaceuticals Inc. has notified the FDA that the company will begin removing the remaining Trasylol stock from the U.S. market, most of which is in warehouses and hospital or physician’s stock. The FDA will work with Bayer to ensure a smooth and complete process.

Under a limited use agreement, access to Trasylol 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 Trasylol in this situation must also verify that the benefits of the drug clearly outweigh the risks for their patients.

FDA limits access to certain drugs to patients with serious or immediately life-threatening disease or conditions who lack other therapeutic options and may benefit from such therapies. This type of access requires the submission of a protocol, which is reviewed and approved by the agency. Bayer has agreed to provide Trasylol through this mechanism for the limited use described above.

Trasylol is an antifibrinolytic drug approved to reduce blood loss during surgery and the need for blood transfusion in certain patient undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery. Antifibrinolyitc drugs help slow the breakdown of blood clots and subsequent excessive bleeding.

Results from a randomized Canadian study that prompted last November’s marketing suspension of Trasylol are expected to be published this week. The data contained in this article suggest that Trasylol appears to increase the risk for death compared to two other antifibrinolytic drugs used in the study.

The findings from this randomized study are similar to those from an observational study that was discussed at a September 2007 FDA advisory committee meeting. Based upon the data available at the time, the advisory committee recommended continued marketing of Trasylol. However, FDA requested the marketing suspension in the interest of patient safety based on the serious nature of the outcomes suggested in the preliminary data. The committee also advised that a large, randomized clinical study was needed to further assess Trasylol’s safety compared to other drugs. This recently published Canadian study helps address this need for additional information.

The FDA has not yet received full study data from the study’s researchers at the Ottawa Health Research Institute but supports Bayer’s decision to completely remove Trasylol from regular use in the U.S. market. FDA is also reviewing the available Canadian study data to reassess the currently active special treatment protocol that provides access to Trasylol.

FDA oversight requires comprehensive and thorough studies of a drug not only during the pre-market review phase but throughout the drug’s life cycle. As studies and data on Trasylol emerged over the years, FDA actions included labeling changes, safety communications to physicians and other health care professionals, public discussion and review of study data at two Advisory Committee meetings, as well as close scrutiny of the ongoing studies.

The agency will consider a variety of study designs to support the review process for future antifibrinolytics, and will incorporate into these considerations information from the recently published Canadian study. FDA will continue to publicly disseminate safety information.

Full text of the Early Communication about an Ongoing Safety Review can be found at “http://www.fda.gov/bbs/topics/NEWS/2008/NEW01834.html.

FDA MedWatch Alert - Trasylol (aprotinin injection) (10-25-07)

Aprotinin Injection (marketed as Trasylol)

Audience: Cardiac surgeons, other healthcare professionals

[Posted 10/25/2007] FDA informed healthcare professionals of the Data Safety Monitoring Board’s recommendation to stop patient enrollment in the aprotinin treatment group arm of the Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study. 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, compared to the antifibrinolytic drugs, epsilon-aminocaproic acid and tranexamic acid, aprotinin increases the risk of death.

FDA anticipates re-evaluation of the overall risks and benefits of Trasylol which may result in the need to revise the prescribing information or other regulatory actions. Healthcare professionals who are considering use of Trasylol should be aware of the risks and benefits described in the prescribing information for Trasylol and the accumulating data suggesting Trasylol administration increases the risk of death compared to other antifibrinolytic drugs.

[October 25, 2007 – Early Communication – FDA]

FDA MedWatch Alert - Trasylol (aprotinin injection) (11-5-07)

Trasylol (aprotinin injection)

Audience: Cardiac surgeons and other healthcare professionals

[Posted 11/05/2007] FDA announced that, at the agency’s request, Bayer Pharmaceuticals Corp. has agreed to a marketing suspension of Trasylol (aprotinin injection), 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.

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. 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 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.

[November 5, 2007 – FDA News – FDA]
[November 5, 2007 – Drug Information Page – FDA]

Previous MedWatch Alert:

October 25, 2007

Detailed View: Trasylol Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) -- December 2006

Detailed View: Trasylol Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) — December 2006

Trasylol (aprotinin injection)

Prescribing Information

See MedWatch Safety Alert posted 12/15/2006.

BOXED WARNING (new)

CONTRAINDICATIONS

WARNINGS

• Anaphylactic or Anaphylactoid Reactions
• Re-exposure to Aprotinin
• Renal Dysfunction

PRECAUTIONS

• General
  

  * Initial (Test) Dose

  * Renal Dysfunction

ADVERSE REACTIONS

• Myocardial Infarction
  

  * Table: Incidence of Myocardial Infarctions
  by Treatment Group Population

• Laboratory Findings
  

  * Serum Creatinine

  * Serum Transaminases

BOXED WARNING

Trasylol administration 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 dose regimen. Fatal reactions have also occurred in situations where the initial (test) dose was tolerated. The risk for anaphylactic or anaphylactoid reactions is increased among patients with prior aprotinin exposure and a history of any prior aprotinin exposure must be sought prior to Trasylol administration. The risk for a fatal reaction appears to be greater upon re-exposure within 12 months of the most recent prior aprotinin exposure…..

CONTRAINDICATIONS

Administration of Trasylol 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.

WARNINGS

See highlighted WARNINGS section of prescribing information for revisions.

Transcript of Second FDA Press Conference on Trasylol (11/5/07)

Transcript of FDA Second Press Conference on Trasylol

FTS HHS FDA US
Moderator: Peper Long
November 5, 2007
11:45 am CT

Coordinator: I would like to thank all participants for holding all lines will be on listen only until the question and answer portion of today’s conference.
I also did want to inform participants today’s call is being recorded, if
you have objections you may disconnect at this time.

I’d now like to turn the call over to Peper Long, thank you, you may begin.

Peper Long: Thank you, good morning and welcome my name is Peper Long with the Food and Drugs Administrations Office of Public Affairs.

This is a FDA Teleconference for credentialed media only to announce
that FDA’s request for market suspension of Trasylol a drug used to
control bleeding in certain patients undergoing cardiac surgery.
With me today are Dr. John Jenkins, Director of the Office of New
Drugs at FDA Center for Drug Evaluation and Research, Dr. Gerald
Dal Pan, Director of the Office of Surveillance and Epidemiology at
FDA Center for Drug Evaluation and Research, and Dr. Dwaine
Reeves, Director of the Office of Medical Imaging and Hematology also
at FDA Center for Drug Evaluation and Research.

Page 2

Dr. Jenkins and Dr. Dal Pan will make brief remarks, and then Dr.
Reeves will join them for the question and answer segment which will
move into immediately following the remarks.

Reporters will be in a listen only mode until we open up the call for
questions. And the news release accompanying this announcement
has been sent out to our media list, but it’s posted as well on our
Website at www.FDA.gov.

I will now turn the call over to Dr. Jenkins thank you.

John Jenkins: Thank you Peper and good morning everyone, as you know we are announcing that Bayer Pharmaceuticals has agreed to suspend marketing of Trasylol in the United States at FDA’s request.

Trasylol is a drug that is approved to treat, or to reduce bleeding in
patients ongoing a particular type of cardiac surgery known as
coronary artery bypass surgery. And in specific surgery where patients
are also on cardio pulmonary bypass.

FDA made this request for our marketing suspension to Bayer late last
week, and Bayer agreed to that request and is working cooperatively
with FDA at this time to implement that suspension.

We planned for a phase out of the product from the marketplace in an
orderly way so that there will not be undue harm to patients because
there could be drug shortages for the alternatives that are used to treat
the same condition.

Page 3

FDA made this decision after considering further the information from
the recently halted Canadian study commonly referred to as BART – B-
A-R-T, which was stopped two weeks ago by the Data Safety Monitoring Committee due to an apparent increase in (depth) in patients treated with Trasylol compared to the other two agents that were being studied in that trial.

Over the past couple of weeks FDA has had interactions with the
Monitoring Committee and the investigators to attempt to obtain more
information about the results from that study.

It became clear to us that it was going to be six weeks or longer before
we will receive any additional information, therefore we decided that it
was appropriate to suspend marketing in the interim until we can learn
more about the specifics of those data.

FDA decided that we could not identify at this time a specific patient
population for the benefit of using Trasylol would outweigh the serious
risk identified in the BART study.

That said however we understand and recognize that there maybe
situations where individual doctors determine that for a particular
patient the benefit of Trasylol may outweigh its risk, and therefore FDA
is committed to exploring with Bayer options that would allow those
doctors to obtain Trasylol under a IND program.

The details of that program have not yet been sorted out, but we are
continuing to work with Bayer on that process.

Page 4

I’ll stop there and let Dr. Dal Pan make a few comments about the
safety findings before we open it up for questions.

Gerald Dal Pan: Good morning this is Gerald Dal Pan from the Office of Surveillance
and Epidemiology.

Trasylol also known as aprotinin injections was approved in 1993 and
is currently indicated for prophylactic use to reduce blood loss and
blood transfusions in patients who are increased risk for bleeding while
undergoing cardiac surgery.

One observational study published in early 2006 suggested that
Trasylol use may increase the risk for kidney damage compared to
other drugs are used to prevent bleeding. A second observational
study published around the same time confirmed the risk of kidney
damage.

These two studies led FDA to convene an advisory committee in
September of 2006 which focused on kidney damage and certain
serious allergic reactions known as hypersensitivity reactions that can
occur with Trasylol use.

After that meeting FDA narrowed the indicated use in patients at high
risk for bleeding from cardiac surgery or from a cardiac artery bypass
grafting surgery, and strengthen the warnings in the label regarding
hypersensitivity and kidney damage.

Shortly after the September 2006 Advisory Committee Meeting, FDA
learned of another study which Bayer had commissioned that

Page 5

suggested Trasylol increase the risk for in-house (unintelligible) in
cardiac surgery patients.

Another publication February 2007 suggested that Trasylol increased
the long term mortality in patients undergoing cardiac surgery who
received Trasylol.

This led FDA to convene another advisory committee in September
2007 which focused on the mortality findings.

The committee didn’t find the results compelling enough to warrant a
withdraw, so the committee recommended more studies where
needed, and specifically the committee recommended a randomized
controlled trial was needed.

The Canadian study that Dr. Jenkins just referred to the BART Study,
was a randomized control trial designed to test the ability of Trasylol to
reduce serious bleeding compared to other agents during cardiac surgery.

And the study was halted because Trasylol appeared to increase the
risk of death compared to the other two drugs used in that study. And based on the preliminary findings of this most recent study – the Canadian BART Study, combined with the fact that FDA does not expect to receive study data for at least six weeks and perhaps longer, FDA requested that Bayer suspend Trasylol pending further review of the data. That’s it.

Page 6

Peper Long: All right thank you very much for your remarks, now we’ll move into a
question and answer session.

I’d like to remind everyone to please limit yourself to one question and one follow-up.

So if we’re ready for the first question.

Coordinator: Sure at this time if anyone would like to ask a question you can press
star 1, that’s star 1 to ask a question.

And our first question comes from Andrew Bridges your line is open.

Andrew Bridges: Hi thank you for taking my question and doing this I guess twice in the day.

In light of the passage of (Padofo) and the obviously strong emphasis there on drug safety, was this withdraw done any differently than you would have done previously and you were able to move more quickly or was anything done differently and if so how?

John Jenkins: Yes this is John Jenkins, I’ll start the answer and see if Dr. Dal Pan
wants to add.

My brief answer would be no I don’t think this was handled any differently that we would handled it previously. And I would point out that I think you’re referring to FD Triple AAA or FDAAA the new legislation…

Andrew Bridges: The new amendment that’s exactly…

Page 7

John Jenkins: …that (unintelligible) about a month ago. The safety provisions, the
new regulatory authority included in that law do not go into effect until
March of 2008.

Andrew Bridges: Oh.

John Jenkins: So really the ability of the FDA to manage safety issues has not been
changed yet with the passage of that law.

So I think we – we handled this the way we’d would normally handle drug safety issues as Dr. Dal Pan mentioned we have been to two advisory committee meetings to review the observational data.

And at the most recent advisory committee meeting there was a very
strong view expressed that we knew that controlled clinical trials that
answer this question.

And at that meeting the BART study was pointed to as just the type of
studies that would answer this question.

So the fact that it was stopped early for an adverse finding laid very
heavily in our decision to go forward with the request for marketing
suspension. Gerald anything you want to add?

Gerald Dal Pan: I think that summarizes it.

Andrew Bridges: Thank you very much.

Coordinator: Our next question comes from John Wilkerson your line is open.

Page 8

John Wilkerson: Yes thank you, what – why can’t you get the data for the next 6
weeks from the BART Study?

Man: Well the study is being run by a group of investigators in Canada, and
we have had contact with them they are in the process of obtaining all
the data and looking at it themselves.

We do not have any regulatory authority to require them to provide us
any additional data at this point.

We are working with our colleagues that help Canada the Canadian
equivalent of FDA to try to obtain the additional data as quickly as
possible.

John Wilkerson: Okay and the second question actually I was going to ask the same question as the AP did.

But, is, can you envision any of the new authorities that you don’t yet
have that come into effect in March ’08. Could you have used any of
those new powers in this case had you had them?

Man: Well I think the three main new authorities that are in the FD Triple AAA legislation are the ability to require risk evaluation and mitigation strategies which we formally called risk maps – or risk management plans, the ability to require a specific cross marketing studies, and the ability to require labeling changes.

I don’t know that I want to speculate how we might have used any of those authorities differently. We think we proceeded in any orderly way

Page 9

as we learned about the safety signal as Dr. Dal Pan said in 2006 from the observational studies.

We reviewed those data, presented them to an advisory committee in September of last year once we became aware of additional observational studies that suggested a mortality risk, we reviewed those data in great detail and presented them again to advisory committee this past September.

So I don’t think we would have handled things differently under the new authorities, but we don’t have those authorities yet so it’s hard to speculate and apply them retroactively.

John Wilkerson: Okay, thanks.

Coordinator:

My next question comes from Susan Edelman you line is open.

Susan Edelman: Yes thank you, I wanted to find out how many deaths linked to
Trasylol has the FDA been made aware of either through these outside studies or your own adverse incident report.

John Jenkins: Well as far as – this is Dr. Jenkins again…

Susan Edelman: Mmm-hmm.

John Jenkins: …as far as the study itself – the BART study we do not have those
details at this point.

Page 10

The only information we were provided were the relative rates of death comparing the three arms of the study which I believe were approximately 1.5 and 1.6 for the rate of reported death.

The other study drugs versus Trasylol I don’t know if Dr. Dal Pan wants to address any other parts of that question in regarding adverse event reports.

Gerald Dal Pan: Right so to examine the issue of mortality associated with Trasylol or any kind of agent given during cardiac surgery. Adverse event reports that are in our air system are generally not helpful.

And the reason for that is that mortality did something that does accompany cardiac surgery, there is a mortality rate associated with it and trying to tease apart all the different factors that lead to that aren’t possible in individual case reports.

In fact when we – the data from the 66,000 person observational study were presented at the advisory committee in September, data collected in a reasonably systematic way.

Even (unintelligible) advisors had trouble assigned (closality) to Trasylol. So it was really…

Susan Edelman: I just…

Gerald Dal Pan: …the randomized clinical trial that they were looking for.

Page 11

Susan Edelman: Well I need to just find out what – how many deaths are linked to Trasylol as possibly then cause that you have to further investigate. How many deaths have been reported to the FDA?

Gerald Dal Pan: Well we don’t have that number right now.

Susan Edelman: Can you get that for me?

Gerald Dal Pan: Well see what we can do.

Susan Edelman: Thank you.

John Jenkins: This is Dr. Jenkins, I would also refer you to the transcript and the
briefing documents for the Advisory Committee that are available on our Website from the September 2007 meeting.

A lot of the information was presented there and slides both from the
FDA the sponsor.

Susan Edelman: Okay.

Peper Long: Next question.

Coordinator: Once again if anyone would like to ask a question you can press star 1 that is star 1 to ask a question.

Peper Long: May I please ask those reporters asking questions to identify their
publication or media outlet.

Page 12

Coordinator: Okay our next question comes from Anna Matthews, and once again
please state your affiliation.

Anna Matthews: I’m with the Wall Street Journal, forgive me if this has already been stated or I missed it. But I think Dr. Jenkins you mentioned that the rate of reported deaths for the other two drugs in the BART study was 1.5 and 1.6 I assume I that was – those were percents? I was wondering what was the rate for Trasylol.

John Jenkins: No, no what I said was that the relative rate of reporting.

Anna Matthews: Ah.

John Jenkins: …that we received from the BART investigators was that the rate for
the other drugs versus the rate for Trasylol – the ratio was 1.5 for one drug, and 1.6 for the other drug, and those approached statistically significant fee values, but we don’t even know which of the other two drugs was Drug A, and which of the other two drugs was Drug B they have not provided us with that information. So that was not a incidence rate that was relative rate of 1.5 and 1.6.

Gerald Dal Pan: This is Gerald Dal Pan, we don’t know the total number of deaths in
the BART Study. So we don’t know what proportion of patients with Trasylol died, we don’t know what proportion of patients with the other agents died. We know that the ratio of those is approximately 1.5 for each of the two agents.

Page 13

But we don’t have the level of detail to note the absolute risk.

John Jenkins: And one other follow up I would offer is that Trasylol in the United
States is specifically indicated for use in coronary artery bypass surgery in patients who are also receiving cardio pulmonary bypass. It’s our understanding that the BART Study also included patients undergoing valvular cardiac surgery which would not be part of the improved indication for the US labeling.

We don’t know how many of the patients and the risk ratios for patients undergoing bypass surgery versus valve surgery. So there is a lot of information from the BART Study we would really like to be able to review in greater detail. But it’s clear that we’re not going to have those data for some time.

Anna Matthews: Can I ask a brief follow up just clarifying?

John Jenkins: Yes.

Anna Matthews: So, the risk – those relative ratios – just to make sure I’m going to understand them correctly, essentially patients were dying at a 50% higher rate with Trasylol than with Drug A whatever it might have been.

And, a 60% higher rate with Trasylol than for Drug B whatever it might have been, that difference did not achieve the physical significance but came close and we don’t know the absolute risk for any of the three drugs.

Page 14

John Jenkins: I think that’s all correct – Gerald any other comments?

Gerald Dal Pan: I actually thought it was 1.5 for both drugs, but we could check that.

Anna Matthews: Dr. Jenkins has 1.5 and 1.6.

Gerald Dal Pan: I have 1.5 and…

John Jenkins: Dr. Reeves do you recall?

Dwaine Reeves: 1.5 – right, 1.5 it’s 1.5 for both drugs.

Anna Matthews: Okay.

John Jenkins: Okay my mistake, so 50% increase for the other two drugs versus
Trasylol. A perched conventional statistical significance meaning a .05 P Value but they had not achieved that level by the time the study was stopped.

But as you may know the stopping rules for safety in a (unintelligible) analysis of a controlled clinical trial are more conservative than they are for stopping for efficacy. So approaching traditional .05 is still considered to be a worrisome signal.

Anna Matthews: And valvular cardiac surgery means valve replacement essentially? Is that – could I describe it as that?

Page 15

John Jenkins: That would one type of valve surgery there could be others. Again we don’t know the you know, the background of what all the surgical procedures were that were included in the BART Study, but one type of valvular surgery would be valve replacement.

Anna Matthews: Okay, and I’ll shut up this is one more question, do you how many of the – I think it was 3,000 patients had been enrolled when they
halted the study?

John Jenkins: We do not.

Anna Matthews: Thank you.

Coordinator: Once again to ask a question press star 1 and our next question
comes from Andrew Bridges and please state your affiliation sir.

Andrew Bridges: I’m with the Associated Press, thanks for allowing me a follow up. What degree of coordination was there among the various agencies. I guess the Germans ask that it’d be withdrawn or demanded I guess. You asked to help Canada I guess also wade in as well as others. Were you able to coordinate with your colleagues abroad or how did this all come about at once.

John Jenkins: Yes this is Dr. Jenkins, we have information sharing agreements with
many of the regulatory agencies around the world. And as we were reviewing the results of the BART study in the past couple of weeks we’ve had frequent communications with them and they’ve shared information and they’re communications with us.

Page 16

*We were aware that the German Regulatory Agency was considering a withdraw – a suspension action toward the middle of last week. I would say though that the FDA decisions to request the marketing suspension was one that we reached independently of the German authorities or any other regulatory agency.

Peper Long: I think we have time for one more question.

Coordinator: Okay once again to ask a question press star 1.

Peper Long: Okay if anybody else has any additional questions you can call me my
name is Peper Long I’m with the FDA Office of Public Affairs. I can be reached at 301-827-0599, or 240-429-9205 thank you very much.

END

Transcript of FDA Press Conference on Trasylol (11/5/07)

Transcript of First FDA Press Conference on Trasylol
FTS HHS FDA
Moderator: Peper Long
November 5, 2007
7:30 am CT

Coordinator: Welcome and thank you all for standing by. At this time all parties will be in a listen-only mode until the question and answer portion of
today’s call. The call is being recorded. If anyone has an objection, you
may disconnect your line at this time.

I would now like to turn the call over to Ms. Peper Long. Ma’am, you
may begin.

Peper Long: Good morning everyone and welcome. My name is Peper Long with the Food and Drug Administration’s Office of Public Affairs. This is an
FDA teleconference for credentialed media only to announce FDA’s
request for market suspension of Trasylol, a drug used to control
bleeding in certain patients undergoing cardiac surgery.

With me today are: Dr. Gerald Dal Pan, Director of the Office of
Surveillance and Epidemiology at FDA’s Center for Drug Evaluation
and Research; Dr. John Jenkins, Director of the Office of New Drugs at
FDA’s Center for Drug Evaluation and Research; and Dr. Rafel Rieves,
Director of the Office of Medical Imaging and Hematology at FDA’s
Center for Drug Evaluation and Research.

Page 2

Dr. Jenkins and Dr. Dal Pan will make brief remarks and Dr. Rieves will
join them for the question and answer segment, which we’ll move into
immediately following the remarks.

Reporters will be in a listen-only mode until we open up the call for
questions and the News Release accompanying this announcement
has been sent to reporters on our media list, and is also posted on our
Web site at www.fda.gov.

I will now turn the call over to Dr. Jenkins. Thank you.

John Jenkins: Thank you, Peper. Good morning. This is John Jenkins. I’m the
Director of the Office of New Drugs at Cedar. This morning we are
announcing that Bayer Pharmaceuticals Corporation has agreed to
suspend marketing of Trasylol, also known as a Aprotinin – a drug that
is marketed to treat bleeding or to reduce bleeding in patients
undergoing cardiac surgery.

FDA requested this suspension on – last week and Bayer has agreed
to implement the marketing suspension. FDA will be working with
Bayer over the next several days to implement the details of the
suspension which will include a slow phase-out of Trasylol from the
marketplace in order to decrease the possibility of shortages of the
alternative drugs.

At this time, FDA cannot identify a specific patient population where we
believe the benefit of using Trasylol outweighs the risk. But it’s possible
that individual doctors may be able to identify unique patients in which
they judge the benefits of Trasylol will outweigh its risks.

Page 3

Therefore, FDA is committed to exploring with Bayer options on
allowing access in a limited manner for those patients if the antics of
such access can be established.

I’ll stop there and let Dr. Dal Pan briefly review the reason for the
suspension, including the safety (station).

Gerald Dal Pan: Okay, good morning. This is Gerald Dal Pan. I’m the Director of the
Office of Surveillance and Epidemiology at FDA’s Center for Drug
Evaluation and Research.

Trasylol, also known as Aprotinin injection, was approved in 1993 and
is currently indicated for prophylactic use to reduce blood loss and
blood transfusion in patients who are at increased risk for bleeding
while undergoing cardiac surgery.

Two observational studies were published in early 2006, which – and
both of them suggested that Trasylol use may increase the risk for
kidney damage compared to other drugs.

So we held an Advisory Committee in September 2006, which focused
on kidney damage as well as serious allergic reactions — known as
paper sensitivity reactions — to Trasylol.

And after that meeting, FDA narrowed the indicated use in patients at
high risk for bleeding from cardiac surgery and we also strengthened
the warnings on the label regarding hypersensitivity and kidney
damage.

Page 4

Now shortly after that September 2006 Advisory Committee Meeting,
FDA learned of another study which Bayer had commissioned that
suggested Trasylol increased the risk for in-hospital death in cardiac
surgery patients.

Another publication in February of 2007 suggested that Trasylol
increased the long term mortality in patients undergoing cardiac
surgery.

So we held another Advisory Committee in September 2007, this one
focusing on the mortality risks that those two studies identified. The
Committee didn’t find the results compelling enough to warrant a
withdrawal so the Committee recommended more study.

Specifically, the Committee recommended a randomized control
clinical trial with (unintelligible). Now the Canadian study that was
(unintelligible) two weeks ago, was a randomized controlled trial
designed to test the hypothesis that Trasylol was superior to other
drugs increasing – in decreasing the occurrence of massive bleeding
during cardiac surgery.

And that study was halted because Trasylol appeared to increase the
risk for death compared with two other drugs. And based on the
preliminary findings of this most recent study, combined with the fact
that FDA doesn’t expect to receive any (unintelligible) study data for
nearly six or eight weeks, FDA requested that Bayer suspend Trasylol
pending further review.

Peper Long: Okay. I think we’re ready for question and answer.

Page 5

Coordinator: Thank you. At this time if there’s any questions on the phone line,
please press star 1 on your touchtone phone – star 2 to withdraw.
Please record your name.

We’ll stand by for the first question. (Jeanie Whalen), your line is open.

: Hi, it’s (Jean Whalen) from the Wall Street Journal. I wondered
whether the FDA had any discussions with the German regulators or
Health Canada before making this decision?

I understand – I believe the German regulator told Bayer to take the
drug off of the market rather than requesting. Did FDA act after the
German request or the German Demand?

John Jenkins: Yeah. This is Dr. Jenkins. I can answer that question. We’ve been in
communication with a number of our regulatory partners around the
world since we learned about the preliminary results of the (bart) study
two weeks ago.

We have had conversations with our colleagues from Health Canada.
We also have had conversations with our colleagues from the German
regulatory agency as well as other agencies.

We were aware that the Germans were considering a marketing
suspension for Trasylol, which they did announce this morning.
However, FDA’s decision was made independently based on our own
assessment of the potential benefits and risk of Trasylol.
Germans do have the authority to require marketing suspension. FDA
does not have that specific regulatory authority. However, when we

Page 6

requested that Bayer suspend marketing they agreed and they are
working cooperatively with us to effect that marketing suspension.

: May I ask another question or are there others waiting?

Peper Long: You can have on follow-up question, (Jean). Thank you.

: I just wondered whether FDA feels it was a mistake to not request this drug’s suspension or withdrawal earlier given its kind of checkered
past over the last few years?

John Jenkins: Again, this is John Jenkins. I’ll start and if Dr. Dal Pan or Dr. Rieves
wants to weigh in. I think it’s important to recall what this drug is
approved for. It’s approved to reduce serious bleeding in patients
undergoing cardiac surgery where bleeding can often be very serious
and even life-threatening.

So that was the basis for the original approval. As we’ve learned about
the safety concerns from the observational studies, we’ve taken those
data very seriously. And as Dr. Dal Pan said, we’ve gone the two FDA
Advisory Committee meetings for public discussion of these data, most
recently in September.

I think it’s best to characterize the meeting in September, that the
Committee members were concerned about the findings from the
observational data, but the thing that was lacking from the
observational data that they were most interested in was a randomized
controlled clinical trial.

Page 7

And at that meeting, the (bart) study was actually pointed to as a study
of that type that might give us more answers. So finding out that the
study has been stopped because of mortality, certainly is supportive of
what we’ve seen from the observational data.

But even as recently as September, the Advisory Committee noted
overwhelmingly that they thought the drug should continue to be
available on the market.

Dr. Dal Pan or Dr. Rieves – any comments?

Gerald Dal Pan: No. I don’t have any additional comments.

Rafel Rieves: This is Dr. Rieves. I think it’s also notable to consider that we have the
preliminary findings from the (bart) study. The indication for Trasylol
use is very specific to coronary artery bypass grafting.

The (bart) study enrolled patients not only undergoing coronary artery
bypass grafting, but also valvular surgery. So dissecting out the (bart)
study results will be important to – again, considering the overall risk
and benefits for Trasylol.

Peper Long: Okay, next question?

Coordinator: Our next question comes from (Ed Silverman). Your line is open.

: Hi, good morning. This is (Ed Silverman) with (Farm A lot). I just
wanted to clarify my understanding of the surgery for which the drug is
approved. You said for valve surgery – is it approved for CABG (and
valve)? Is it approved for CABG?

Page 8

John Jenkins: Dr. Rieves, do you want to take that question?

Rafel Rieves: Yes. It is approved specifically for use in patients at high risk for
bleeding, who are undergoing — and this is important — coronary artery
bypass grafting with cardiopulmonary bypass. As you know, certain
coronary artery bypass graft procedures are sometimes performed
without cardiopulmonary bypass.

Trasylol is indicated specifically for use in high risk patients – patients
who are at a high risk for bleeding who are undergoing coronary artery
bypass grafting with cardiopulmonary bypass.

It is not approved for use in (unintelligible).

: So is it CABG and valve procedure?

Rafel Rieves: No, sir. It’s solely coronary artery bypass grafting with cardiopulmonary
bypass.

: Okay. So it’s – so of the three options that I mentioned, it’s only CABG?

Rafel Rieves: It’s only CABG, right.

John Jenkins: Okay, just to clarify – I think I heard Mr. (Sullivan), was part of your
question about what happens if a patient was undergoing both bypass
and valve surgery at the same time?

: No, but that was my follow-up.

Page 9

John Jenkins: Okay. (Wayne), do you want to address that?
: This – it’s specifically for coronary artery bypass grafting. The data
have – did not support the – of it simultaneous. The procedure – it’s
indicated specifically for the CABG situation. The valvular use is not
included in the product label.

: Okay, thank you.

Peper Long: Next question, please?

Coordinator: If anyone else would like to ask a question, please press star 1. I’m
showing no further questions.

Peper Long: Okay, thank you all very much. If you have any questions, you can
reach me at (301) 827-0599 or (240) 429-9205. Thank you very much.

Coordinator: Ma’am, I apologize. We do have one additional question. Would you
like to take that at this time?

Peper Long: We can take one more.

Coordinator: All right. (Rob Stein) with the Washington Post, your line is open.

: Yeah, hi. Thanks very much. I was wondering if you had any estimates
on the number of – how commonly this drug is used? And any
estimates on how many deaths it might have caused?

John Jenkins: Dr. Dal Pan, do you have estimates on the use of the drug?

Page 10

Gerald Dal Pan: I don’t have any estimates with me now on the use of the drug – no.

: might it be possible to have somebody get that to me later?

Gerald Dal Pan I’ll see if we can – if we have those kinds of estimates.

Peper Long: We’ll see what we have and see what we can get to you, (Rob). I’ll get

back to you on that.

John Jenkins: I know that those data were presented at the September Advisory
Committee meeting in the transcripts of that and the background
package should be available online.

As far as your second part of your question, it’s not going to be
possible for us to answer that question. We still only have very
preliminary results from the (bart) study plus, in addition to that, cardiac
surgery is a complex procedure.

Effecting out which patients who had serious adverse events in clinical
practice that may have been related to Trasylol versus other factors
will be very difficult.

That’s why we needed the randomized controlled clinical trial. We’re
working as well as we can with the Canadian authorities and the
Canadian investigators to get additional data.

But it looks like it’s going to be six or eight weeks — or longer — before
we will be able to get any additional information to better tease out the
findings from that study.

Page 11

Peper Long: Any follow-up?

: No, that’s okay. Thank you.

Peper Long: Okay, thank you. All right, that’ll end our call now. Again, if you need
more information you can contact me at (301) 827-0599 or (240) 429-
9205. Thank you.

Coordinator: That does conclude today’s call. Thank you all for joining. You may
disconnect your lines at this time.
END

FDA Statement Regarding New Trasylol Data (9-29-06)

September 29, 2006

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.

FDA Revises Labeling for Trasylol (Aprotinin Injection) to Strengthen Safety Warnings and Limit Usage of Drug to Specific Situations (12-15-06)

December 15, 2006

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.

Questions and Answers on Trasylol/Aprotinin (2-7-06)

February 7, 2006

1. What is Trasylol and what is it used to treat?

Trasylol, or aprotinin, a product derived from bovine lung tissue, inhibits certain enzymes that increase the risk for bleeding. Trasylol administration aids the body’s ability to prevent bleeding.

Patients undergoing coronary artery bypass grafting (CABG) using cardiopulmonary bypass may be at risk for bleeding complications due to prior use of anticoagulants or clinical conditions that predispose to bleeding. Trasylol is used to decrease this bleeding risk.

2. What is the concern regarding Trasylol?

A January 26, 2006 report in The New England Journal of Medicine suggests that Trasylol administration may increase the risk for serious side-effects among some patients undergoing CABG. This report describes the occurrence of serious kidney damage, heart attack (myocardial infarction) and stroke among CABG patients receiving Trasylol. More patients receiving Trasylol experienced these events than patients receiving either no medications intended to decrease blood loss or other medications intended to decrease blood loss.

Another recently published study has suggested that patients receiving Trasylol may be at higher risk for kidney damage. This report (published January 20, 2006 in the on-line edition of Transfusion) used methods similar to those used in The New England Journal of Medicine study but included a smaller number of patients.

3. Did the patients who developed these serious side-effects have other possible reasons to develop these reactions?

It is not known if the patients receiving Trasylol in The New England Journal of Medicine report were sicker and thus at higher risk prior to receiving Trasylol than the patients in the other study groups. The study report authors used statistical procedures to try to adjust for this consideration. In the Transfusion report, the patients seemed to be similar in both study groups.

4. Have other studies indicated problems with Trasylol?

In addition to the previously described studies, one additional study suggested that Trasylol administration may increase the risk for clot formation within coronary artery bypass grafts. In this study, patients receiving Trasylol were compared to those receiving a placebo. The study reported an increased rate of bypass graft closure for patients receiving Trasylol.

5. What are the strengths and limitations of The New England Journal of Medicine Report when compared to other reports?

The major strength of The New England Journal of Medicine study is the collection of information from a large number of patients who were managed according to common medical practice.

The major limitation of The New England Journal of Medicine study is that patients were not randomly assigned to any of the treatments (or to no treatment) for preventing bleeding. The treating physicians determined, based on their experience and judgment, whether to administer Trasylol, another drug to prevent bleeding, or no treatment. It is possible that the treating physicians may have chosen to administer Trasylol only to the sicker patients while the less sick patients received other products or no therapy to prevent bleeding. Consequently, the study outcomes may not truly indicate Trasylol side-effects. Instead, the study outcomes may indicate the seriousness of the underlying condition of the patients chosen to receive Trasylol. It is important to note that the study investigators used statistical analyses to try to correct for this limitation.

In clinical studies where the choice to use Trasylol or not was decided by chance alone, Trasylol administration was not associated with the detection of any increase in the risks for the serious side-effects described in The New England Journal of Medicine report. These types of studies were performed in order to rigorously detect the Trasylol effects. However, these studies also have limitations; for example, the patients enrolled in the study may not truly reflect all types of patients undergoing CABG and the other cardiovascular therapies used in the studies may differ from those routinely used in medical practice. These considerations are especially important when clinical advances may rapidly change the practice of medicine.

6. Was Trasylol responsible for the serious side-effects detected in The New England Journal of Medicine report?

The report suggests that Trasylol administration was associated with the serious side-effects. However, the limitations of the reported study require that the study findings be examined more closely.

7. Based on this report, why isn’t FDA immediately removing this product from the market?

The findings from The New England Journal of Medicine report differ from the data submitted to the FDA in support of a marketing application. These other reports indicate that Trasylol has benefits that outweigh the risks associated with the product. The FDA is re-examining all these study findings in light of The New England Journal of Medicine report and other information.

8. Are other drugs available to decrease the risk for bleeding during CABG?

No other products are approved by FDA for use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing CABG with cardiopulmonary bypass. However, other products have been used by physicians in order to try to prevent bleeding during CABG. As described in The New England Journal of Medicine report, these other products include aminocaproic acid and tranexamic acid.

9. What actions will FDA take regarding these reports?

FDA is continuing to evaluate these reports, assessing other reports and working with the Trasylol manufacturer in order to determine if product labeling changes or other actions are necessary.

10. What information was known about serious side-effects prior to Trasylol approval?

In pre-marketing clinical studies, Trasylol was administered to approximately 2,000 patients undergoing CABG with cardiopulmonary bypass. In these studies, approximately 1,000 patients received a placebo instead of Trasylol. These studies found that Trasylol decreased the need for blood cell transfusion. The studies did not detect an increased risk for serious kidney or heart side-effects. Certain pre-marketing clinical studies showed that some patients may experience allergic-type reactions to Trasylol, especially patients who receive more than one Trasylol administration. These reactions, including hypersensitivity reactions and anaphylaxis, were rare among patients who received a single Trasylol administration (< 0.1%) but were more common among patients receiving repeat Trasylol administrations (approximately 5% in patients treated within 6 months of prior Trasylol exposure).

11. What should patients do regarding this new information?

Patients should be aware that the FDA is examining 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 CABG with their healthcare providers, including the risks for bleeding and the options to lessen the risk for bleeding.

12. What should healthcare providers do in response to this new information?

Healthcare providers should be aware that The New England Journal of Medicine report and another published report raise important questions regarding the on-going safety and benefits of Trasylol administration. FDA will provide healthcare workers and patients with the results of the on-going review of Trasylol effects as soon as possible.

13. What additional actions are likely to follow?

Once FDA completes its preliminary findings, multiple options are available to address the findings. These options include potential modifications of the product label, the performance of additional non-clinical and/or clinical studies and options related to marketing risk management plans. Additionally, FDA anticipates the public presentation of the recently reported study and other information at an advisory committee in the near future.

14. When was Trasylol approved?

Trasylol was approved in 1993.

15. Why was Trasylol approved?

Clinical studies showed that patients receiving Trasylol had less of a need for blood transfusions and less bleeding than patients receiving a placebo. These clinical studies did not detect an increase in the risk for serious side effects.

16. I’ve received Trasylol. Am I going to have some of these serious reactions?

In general, the serious side effects described in The New England Journal of Medicine report are the type of reactions that occur within days following CABG. Patients are unlikely to experience these side-effects from Trasylol after this time period.

17. Where can I find more information about Trasylol?

The package insert provides more information about Trasylol.