Transcript Document 7525474

Trasylol® (aprotinin injection)
Bayer Pharmaceuticals Corp.
NDA 20-304
Opening Remarks
___________
Dwaine Rieves, M.D.
Deputy Director
Division of Medical Imaging and Hematology
Products
Center for Drug Evaluation and Research
1
Trasylol®
(aprotinin injection)
Safety Update
FDA Cardiovascular and
Renal Drugs Advisory
Committee
September 21, 2006
2
Background
Publications:
– NEJM
– Transfusion
FDA Public Health Advisory
Sponsor’s review/FDA submissions
Advisory Committee
Completion of FDA review
Actions
3
Purpose
To obtain perspectives and advice for
FDA to consider in:
– completion of its review
Published data
Spontaneous post-marketing reports
Sponsor’s cumulative clinical data submissions
– possible regulatory actions
4
Considerations
Published data:
– Important source
– Limitations
– Data integrity/conclusions/opinions
Assumed by authors/publisher
Not FDA
“Off-label” use of marketed drugs:
– Practice of medicine
– Variable evidence of safety and efficacy
5
New England Journal of Medicine Publication
“The risk associated with aprotinin in cardiac
surgery”
NEJM 354(4): 353-365 (Jan 26, 2006)
– Multi-center, observational study of
patients undergoing CABG with CPB
– Compared aprotinin, aminocaproic acid,
tranexamic acid, no hemostatic drug
– Propensity adjustment methodology
6
New England Journal of Medicine Publication
– In certain patients, increased risk for:
Renal failure requiring dialysis
Myocardial infarction or heart failure
Stroke or encephalopathy
7
Transfusion Publication
"A propensity score case-control comparison of
aprotinin and tranexamic acid in high-transfusionrisk cardiac surgery”
Transfusion 46(3): 327-338 (January 20, 2006; March 2006)
– Single-center, observational study in high
transfusion risk patients undergoing
cardiac surgery with CPB
– Propensity adjustment methodology
– Renal dysfunction increased
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Topics
“Unlabeled” risks: e.g., renal, CV
– Safety concerns not described in product label
– New findings from:
Observational studies
Controlled clinical studies
“Labeled” risks: Hypersensitivity
– Safety concerns described in product label
– New summary from:
Sponsor’s database
FDA Adverse Event Reporting System
9
FDA Summary of “Labeled” Risks
– Office of New Drugs (OND)
Kathy Robie-Suh, MD, PhD
– Office of Surveillance and
Epidemiology (OSE)
Susan Lu, RPh
10
Trasylol® (aprotinin injection)
Bayer Pharmaceuticals Corp.
NDA 20-304
Regulatory Overview
___________
Kathy M. Robie-Suh, M.D., Ph.D.
Division of Medical Imaging and Hematology
Products
Center for Drug Evaluation and Research
11
Outline of Presentation
Current Trasylol label
Regulatory history highlights
New developments
12
Trasylol – Current Label
Trasylol is a bovine-sourced protease inhibitor approved
for the following indication:
Indication:
“For prophylactic use to reduce
perioperative blood loss and the need
for blood transfusion in patients
undergoing cardiopulmonary bypass
(CPB) in the course of coronary artery
bypass graft (CABG) surgery”
13
Trasylol – Current Label
Dose and Administration:
Regimen
Test
Dose
Loading
Dose
“Pump
Prime”
Constant
Infusion
A
“full dose”
10,000
KIU
2 million
KIU
2 million
KIU
500,000
KIU/hr
B
“half dose”
10,000
KIU
1 million
KIU
1 million
KIU
250,000
KIU/hr
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Trasylol – Current Label
Clinical Trials: Efficacy
Results from R, DB, PC, U.S. studies showed that Trasylol
Regimens A and B decreased percentage of patients
requiring donor blood in both repeat CABG patients (4
studies, total 412 patients) and primary CABG patients (4
studies, total 1440 patients):
Patients
Repeat CABG
% of Patients Receiving
Transfusions
PL
Reg A
Reg B
76%
47%
49%
Primary CABG
54%
37%
37%
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Trasylol – Current Label
“Black Box Warning”
______________________________________________
“Anaphylactic or anaphylactoid reactions are
possible when Trasylol is administered.
Hypersensitivity reactions are rare in patients with
no prior exposure to aprotinin. The risk of
anaphylaxis is increased in patients who are reexposed to aprotinin-containing products. The
benefit of Trasylol to patients undergoing primary
CABG surgery should be weighed against the risk of
anaphylaxis should a second exposure to aprotinin
be required. (See WARNINGS and PRECAUTIONS).”
16
Trasylol – Current Label
Warnings and Precautions
Anaphylactic or anaphylactoid reactions
• Hypersensitivity reactions rare in patients with
no prior exposure
• Risk greatest if re-exposure within six months
• Range from skin eruptions, itching, dyspnea,
nausea and tachycardia to fatal shock
• Severe (fatal) reactions can occur with test dose
17
Trasylol – Current Label
Adverse Reactions
Based on placebo controlled U.S. studies (2002 Trasyloltreated patients, 1084 placebo-treated patients)
Myocardial infarction
• No difference in rates (6% in both groups)
Renal: serum creatinine alterations
• No increase in renal dysfunction (3% in Trasylol
and 2% in placebo groups, respectively)
Graft Patency
• One study: higher graft closure rate
18
Regulatory History
1993 “for the prophylactic use to reduce
perioperative blood loss and the need for
transfusion in patients undergoing
cardiopulmonary bypass in the course of repeat
CABG surgery. Trasylol is also indicated in
selected cases of primary CABG surgery where
the risk of bleeding is especially high (impaired
hemostasis, e.g., presence of aspirin or other
coagulopathy) or where transfusion is
unavailable or unacceptable.”
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Regulatory History
1998 “For prophylactic use to reduce
perioperative blood loss and the need for
blood transfusion in patients undergoing
cardiopulmonary bypass (CPB) in the
course of coronary artery bypass graft
(CABG) surgery.”
Black box -- re: anaphylaxis risk
20
New Developments
Sponsor NDA submissions and proposals:
– Cumulative clinical study findings show
increased risk for renal dysfunction
– Proposed modifications to the label
– Other plans
21
Post-marketing review of
Hypersensitivity Reactions
associated with Trasylol®
(Aprotinin injection)
Susan Lu, R.Ph., Safety Evaluator Team
Leader
Division of Drug Risk Evaluation
Office of Surveillance and Epidemiology
CDER, FDA
22
Presentation
Overview of Adverse Event Reporting
System (AERS)
Hypersensitivity findings
– Sponsor
– FDA
Risk management of Trasylol-associated
hypersensitivity
23
FDA AERS Database
Computerized database containing > 3
million reports
Spontaneous reporting
– Not required of health care providers
– Sponsors required to report any adverse
events of which they become aware
Strengths
– Detection of rare but serious adverse
events (i.e., anaphylactic reactions)
– Descriptive case series
24
FDA AERS Database
Limitations
– Lower utility for expected events in an atrisk population (renal failure, MI, CHF)
– Underreporting
– Biases in reporting
– Quality of reports
Other considerations
– No pre-1993 reports for Trasylol
– Limited foreign reports
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U.S. Patient Exposure for Trasylol
300
246
250
200
169
131
150
189
145
101
41
56.8
68
19 99
27.9
19 96
50
46
78
19 98
100
19 95
Number of patients (thousands)
Domestic Patient Exposure by Year
0
20 05
20 04
20 03
20 02
20 01
20 00
19 97
19 94
Year
Source: Bayer Analysis of Aprotinin Spontaneous Data 7/26/06
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Reporting of Trasylolassociated Hypersensitivity
Bayer Global Drug Safety
Database
27
Overview of Hypersensitivity
Sponsor Analysis
41% of Bayer’s worldwide postmarketing
safety database consists of reports of
hypersensitivity reactions (306/745)
– 85% reports were coded as anaphylactic
reaction/anaphylactic shock
Sponsor’s review determined 291
hypersensitivity cases possibly associated
with Trasylol
52 of 291 cases were fatal
28
Re-exposure to Trasylol
Sponsor Analysis
47% (138/291) patients had documented
previous exposure to Trasylol
67% (93/138) cases with reported reexposure to Trasylol were re-exposed
within 6 months
29
Test Dose (N=139)
Sponsor Analysis
81 cases- reaction with test dose alone
– 19 fatal
– 62 non-fatal
38 cases -negative test dose but hypersensitivity
reaction with therapeutic dose
– 9 fatal
– 29 non-fatal
2 cases- positive test dose, infusion given
18 cases-test dose given but no result
documented
Sponsor Assessment Report 5/17/06
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Summary of Trasylol-associated
Hypersensitivity
Sponsor Analysis
Hypersensitivity reaction is the most frequently
reported spontaneous event associated with
Trasylol.
291 reports of hypersensitivity
– 52 fatal
– 47% patients had history of previous exposure
~2/3 patients with previous exposure had received
aprotinin in previous 6 months
– Test dose associated with 19 fatalities
– Despite a negative test dose result, 27% patients
experienced a hypersensitivity reaction
– The majority of cases occurred in the setting of
surgical procedures other than CABG surgery
31
Reporting of Trasylolassociated Anaphylaxis
FDA Adverse Event Reporting
System Database
32
Methods
AERS database searched for all reports of
anaphylactic/anaphylactoid and Type 1
hypersensitivity reactions
Individual review of reports identified from
AERS search
Analysis excluded reports in which:
– reaction was most likely due to another cause
– inadequate information was provided for
assessment
33
Initial Review of AERS Reporting
for Anaphylaxis
Total reports
70
Death outcome
23
Demographics
Gender (n=65)
Male (51%), Female (41%)
Age (n=55)
81% adult and 41% >60 yrs
Origin of report
U.S.
Foreign
58
12
34
Time to Onset (n=49)
Following test dose
<10 min
10-15 min
Unspecified
23
14
2
7
During Therapeutic dose
During loading dose
During infusion
Unspecified
26
15
9
2
35
Test Dose Administration (n=49)
Reaction after test dose alone
all
23
fatal
10
Test dose negative-reaction with
therapeutic dose
20
1
Test dose result not documentedreaction with therapeutic dose
6
1
36
Previous Exposure to Trasylol
Previous exposure documented
34 (48%)
– Timing of previous exposure (n=29)
<2 mo
2-4 mo
4-6 mo
>6 mo-1 yr
> 1yr
9
9
2
2
7
No previous exposure stated
Exposure history unknown
7 (10%)
29 *(41%)
*18/29 cases mentioned previous surgery
37
Indication for Use (n=64)
Where indication stated, 25% of patients
were receiving Trasylol for the approved
indication of CABG surgery
The most frequently reported use for valve
surgery (35%)
38
Clinical Features of Anaphylaxis
Reported signs of anaphylaxis (n=57)
Cardiovascular events (53)
– Hypotension (45)
– Cardiac arrest/CV collapse (13)
Respiratory events (11)
– Bronchospasm in 2 cases, changes in airway pressure/ventilator
readings in several cases
Dermatologic events (10)
– Erythema (5)
– Rash (5)
Most commonly reported treatment for anaphylaxis (n=46)
Vasopressors (32)
Steroids (10)
Antihistamines (7)
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Case #1
(2004)
Anaphylactic reaction with negative test dose and unknown previous
exposure to aprotinin
74 year-old female hx of MVR/CABG admitted for redo
mitral valve replacement. Preoperative records of prior
surgery (7 wks ago) from another hospital revealed no
prior aprotinin exposure. After induction of general
anesthesia, 2 cc test dose Trasylol (negative) given
followed by loading dose. Progressive hypotension
developed followed by bradycardia unresponsive to IV
phenylephrine, epi, norepi and atropine. CPR started
with return of BP/heart rate after 5 min. Surgery
cancelled and pt sent to ICU mechanically ventilated.
Other hospital again contacted due to high suspicion of
aprotinin reaction and anesthetic record confirmed
previous exposure to aprotinin.
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Case #2
Near fatal anaphylactic reaction to test dose in patient with
no previous exposure to aprotinin
3.5 year old male with no previous exposure to aprotinin
admitted for elective replacement of r. ventricular
pulmonary artery conduit. After induction of anesthesia/
intubation, received 1 ml test dose of aprotinin.
Immediately BP became undetectable with sudden
increase in airway pressures/difficulty maintaining
ventilation. CPR initiated with repeated boluses of
epinephrine, sodium bicarbonate and Ca Chloride and
also methylprednisolone, diphenhydramine and
cimetidine. After 50 min. of CPR, no recovery of cardiac
function. Cardio-pulmonary bypass instituted and patient
recovered after 1 hour. Subsequent immuno assays
showed highly elevated IgE levels in response to
aprotinin.
Ann Thorac Surg 1999;67:837-8
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Findings from AERS reports of
Trasylol associated anaphylaxis
Test dose
43% of fatal cases associated with test dose
40% of patients who were documented to have received
a test dose experienced an anaphylactic reaction despite
negative test dose result
Previous Exposure
48% of patients had previous exposure to aprotinin
– 67% of patients had been re-exposed within 6 months
10% patients had no previous exposure to aprotinin
Severity of presentation
Cardiovascular events (hypotension, cardiac arrest)
reported predominantly
Indication for Use
25% patients received Trasylol for approved indication
42
Sponsor Proposed Risk
Minimization Action Plan
(RiskMAP) for Hypersensitivity
Stated goal“The RiskMAP will identify those
patients most at risk of a
hypersensitivity reaction to Trasylol
and provide information to reduce
these patients from re-exposure to
the drug within the period of
highest risk of hypersensitivity”
43
RiskMAP Tools
Sponsor’s Proposal
Aprotinin IgG assay
Education targeted at physicians
Appropriate indication for use
Risk of hypersensitivity high with re-exposure
within 6 months
Complete medical history to uncover previous
exposure
Use of test dose
Readiness for handling hypersensitivity reactions
Information on cross-reacting products
44
Comments on RiskMAP
Clinical utility of Aprotinin IgG Assay
Educational message may not mitigate risk
– Value of test dose
Test dose frequently not predictive
Serious reactions occur with test dose
– Medical history may not uncover previous exposure
Patients not often aware of exposures to drugs during surgery
May not be part of a medical record
– Reactions may not be recognized in the surgical setting
Non-cardiovascular symptoms (e.g., nausea, dyspnea, and skin
reactions) may not be detected.
First recognizable sign may be circulatory failure
45
Acknowledgements
Mark Avigan, MD, Director, Div Drug Risk Evaluation (DDRE)
Allen Brinker MD, DDRE Epidemiology Team Leader
Tiffany Brown, DMIHP Project Manager
Yuan (Richard) Chen, PhD, Statistician, OB, OTS
Gerald Dal Pan, MD, Director, OSE
Mary Dempsey, Project Manager, OSE
Rosemary Johann-Liang, MD, DDRE Dep Division Director
Claudia Karwoski PharmD, OSE Scientific Coordinator
Cindy Kortepeter PharmD, DDRE SE Team Leader
Parivash Nourjah PhD, DDRE Epidemiologist
Dwaine Rieves, MD, DMIHP, Dep Director
Kathy Robie-Suh, MD, PhD, DMIHP Medical Team Leader
George Rochester, PhD, Statistical Team Leader, OB, OTS
George Shashaty, MD, DMIHP Medical Officer
Mary Ross Southworth PharmD, DDRE Safety Evaluator
Joyce Weaver PharmD, OSE Drug Risk Management Analyst
Mike Welch, PhD, Associate Director, OB, OTS
Jyoti Zalkikar, PhD, Statistical Team Leader, OB, OTS
46
Trasylol® (aprotinin injection)
Bayer Pharmaceuticals Corp.
NDA 20-304
FDA Topics of Discussion
___________
Dwaine Rieves, M.D.
Deputy Director
Division of Medical Imaging and Hematology
Products
Center for Drug Evaluation and Research
47
Outline
Guest Presentations
Dennis Mangano, MD, PhD
Keyvan Karkouti, MSc, MD
Sponsor Presentation
Public Hearing
Discussion
48
Questions
Discussions of:
– “Unlabeled” safety findings from:
Observational studies
Controlled studies
– “Labeled” hypersensitivity risks
– Efficacy, in light of current surgical,
anesthesia and blood transfusion
practices
– Overall safety and efficacy/Indication
49