The Agency received clearance from IMS Health
and the document can now carry the following disclaimer at the bottom of page
1.
“**This document contains proprietary data from IMS Health. The FDA
has received clearance from IMS Health to include this data in the background
package for the Cardiovascular and Renal Drugs Advisory Committee Meeting on
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MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN
SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER
FOR DRUG EVALUATION AND RESEARCH
______________________________________________________________________
DATE:
TO: Norman Stockbridge, M.D., Acting
Director
Division of Cardiorenal Drug Products (DCRDP), HFD-110
Office of Drug Evaluation I
Robert Justice, M.D., Director
Division of Gastrointestinal
and Coagulation Drug Products (DGCDP), HFD-180
Office of Drug
Evaluation III
THROUGH: Anne Trontell, M.D., M.P.H., Deputy Director
Office of Drug Safety (ODS), HFD-400
FROM: Mark Avigan, MD, C.M., Director
Division of Drug Risk Evaluation
(DDRE), HFD-430
Gerald
Dal Pan, MD, MHS, Director,
Division
of Surveillance, Research and Communication Support
(DSRCS),
HFD-410
DRUG: Exanta™ Tablets (ximelagatran); NDA 21-686
SPONSOR: AstraZeneca
SUBJECT: Review
of Risk Minimization Action Plan submitted
PID:
D040079
|
REVIEW CONTENTS |
page |
|
|
|
List of Abbreviations and
Definitions…………………………………….....………….. |
3 |
|
1. |
EXECUTIVE SUMMARY…….………………………………………………………. |
4 |
|
2. |
INTRODUCTION/BACKGROUND………………………………………………....... |
7 |
|
2.1 |
Product Information…………………...……………………………………………....... |
7 |
|
2.2 |
Risk
Assessment…………………………...…………………………………………… |
7 |
|
2.2.1 |
Risk Assessment with
Short-term Use………………………………………………….. |
7 |
|
2.2.2 |
Risk Assessment with
Long-term Use………………………………………………….. |
8 |
|
2.2.3 |
Risk Assessment Over
Time……………………………………………………………. |
10 |
|
2.2.4 |
Projection of Severe
Liver Injury in the Postmarketing Setting………………………... |
11 |
|
2.3 |
Compliance with ALT
Testing in the Ximelagatran Clinical Trials….……………........ |
11 |
|
3. |
PROPOSED RISK MINIMIZATION
ACTION PLAN………………………………... |
14 |
|
3.1 |
Goals and
Objectives………………………………………………………………… |
14 |
|
3.2 |
Tools……………………………………………………………………………………. |
14 |
|
3.2.1 |
Proposed Labeled
Recommendations to Monitor ALT…...…………………………. |
14 |
|
3.2.2 |
Targeted Education and
Outreach……………………………………………….…........ |
14 |
|
3.3 |
Evaluation Plan…………………………………………………………………………. |
15 |
|
4 |
RECOMMENDATIONS FOR
ADDITIONAL RISKMAP OPTIONS………………... |
16 |
|
4.1 |
Considerations in Risk
Management if Approved for Short-Term Use Only.....………. |
17 |
|
4.2 |
Considerations in Risk
Management if Approved for Long-Term Use………….......… |
19 |
|
5. |
DISCUSSION…………………………………………………………………...……… |
22 |
|
6. |
CONCLUSIONS/RECOMMENDATIONS……………………………………………. |
23 |
|
Appendix |
Managing the Risk of Drug
Induced Liver Injury …………........................................... |
25 |
|
A. |
Brief regulatory history:
withdrawals and risk management………………………........ |
25 |
|
B. |
Range of issues: timing,
tempo, and reversibility of hepatotoxicity……………………. |
26 |
|
C. |
Experience with clinical
trial data………………………………………………………. |
28 |
|
D. |
Specific Examples—long-term
indications…………………………………………….. |
29 |
|
E. |
Specific Examples—short-
or intermediate-term indications…………………….…….. |
33 |
|
F. |
Synopsis—RiskMAP tools
for drugs that induce liver injury-track record of efficacy... |
35 |
List of Abbreviations
ACS Acute coronary
syndrome
AF Atrial fibrillation
ALT Alanine aminotransferase
DCRDP Division of CardioRenal
Drug Products
DDRE Division of Drug Risk Evaluation
DGCDP Division of Gastrointestinal and Coagulation
Drug Products
DILI Drug-induced liver injury
DSRCS Division of Surveillance, Research, and
Communication Support
FDA Food and Drug Administration
LTE Long Term Exposure
MI Myocardial infarction
NDA New Drug Application
ODS Office of Drug Safety
RiskMAP Risk Minimization Action
Plan
TBL Total bilirubin
TKR Total knee replacement
ULN Upper limit of normal
VTE Venous thromboembolism
VTE-P VTE secondary prevention
VTE-T VTE treatment
List of Definitions
·
Severe Liver Injury— defined
as a concurrent increase in TBL >2 x ULN within 30 days of an increase in
ALT >3 x ULN
·
Fatal Liver Injury—Death associated with severe liver injury or liver failure
·
Surgical population—data from 11 Phase II and Phase III studies of patients undergoing
major orthopedic surgery (total knee replacement and total hip replacement)
undergoing ximelagatran or comparator treatment for up to 35 days but mainly
7-12 days (n=15,740)
·
Non-surgical population—Data from 10 Phase II and Phase III studies
(n=13,569) of patients with AF, VTE, or post ACS undergoing ximelagatran or
comparator treatment for > 35 days up to 3 years and includes the Long term
exposure (LTE) pool – 7 studies (N=13,147).
·
Long-term Use—refers
to use > 35 days
·
Short-term Use—refers
to use < 35 days
·
Short-term
indication—the short-term indication
currently being sought is for the prevention of VTE in patients undergoing knee replacement surgery at
36mg bid for 7-12 days.
·
Algorithm 1—the trigger for weekly
monitoring if ALT > 3 x ULN; for discontinuation if ALT > 7 x ULN
(implementation of first amendment was approximated to
·
Algorithm 2—the trigger for weekly
monitoring if ALT > 2 x ULN; for discontinuation if ALT > 5 x ULN (implementation
of second amendment was approximated to
1
EXECUTIVE
SUMMARY
The
Office of Drug Safety (ODS) has reviewed the Exanta (ximelagatran) Risk
Minimization Action Plan (RiskMAP) submitted by AstraZeneca as part
of its new drug application (NDA 21-686) to address the risk of hepatotoxicity
associated with long-term ximelagatran therapy. The RiskMAP does not address
the possible risks of delayed hepatotoxicity after short-term use with
ximelagatran, or the risk of myocardial infarction (MI) that was identified in
the FDA Clinical Safety Review. In
addition, reversal of excessive ximelagatran-induced bleeding was not addressed
by the sponsor.
Ximelagatran is an anticoagulant and if approved, will be the first available
oral direct thrombin inhibitor. The sponsor is seeking approval for three
indications: 1) for the short term prevention of venous thrombo-embolism
(VTE) in patients undergoing knee replacement surgery; 2) for the long-term
prevention of stroke and other thromboembolic complications
associated with atrial fibrillation; and 3) for the
long term secondary prevention of VTE after standard treatment for an episode
of acute VTE. In this document, we
occasionally refer to the combined safety experience with long term exposure
(LTE), which includes the treatment populations for indications (2) and
(3).
LONG-TERM
USE
During clinical
development, at least 37 cases of severe liver injury [defined as alanine aminotransferase (ALT)
> 3 x upper limit of normal (ULN) with concurrent increase in total bilirubin (TBL) >2 x ULN] were observed among patients
randomized to ximelagatran. The relative
risk of severe liver injury was 6.6 (95% CI 2.6 – 16.9) compared to warfarin/placebo, with one affected person in 200 treated
with ximelagatran. Preliminary analyses
suggest the risk of severe liver injury begins within the first month of
therapy.
Based on the
observation of Hy Zimmerman[1] that at least
10% of individuals with severe drug-induced liver injury (as defined above)
progress to liver failure, liver transplant, or death, ximelagatran-associated
fatal liver injury or liver failure could occur in as many as 1 in 2,000
patients treated long-term (i.e., 10% of 1 in 200.) Consistent with this prediction, three deaths
associated with severe liver injury occurred in the ximelagatran LTE clinical
development program, for a proportion of one fatal liver injury in 2,300
patients exposed to ximelagatran (n=6948 ximelagatran treated patients, mean
treatment duration of 357 days).
To address ximelagatran-induced
hepatotoxicity associated with long-term use, the sponsor proposes an
ALT-monitoring program similar to the program used during clinical
development. This program consisted of
baseline and monthly ALT assessments, with more frequent testing and
discontinuation linked to different thresholds of ALT elevation relative to the
upper limit of normal. The initial algorithm specified an ALT >7 times the
ULN as a threshold for drug discontinuation, but this was revised to 5 times
the ULN after the occurrence of a death associated with severe liver
injury. Cases of severe liver injury and
a case of fatal liver injury continued to be observed after the implementation
of the revised algorithm. More conservative algorithms were not tested, so it
remains unknown whether timely discontinuation with any ALT elevation can
prevent irreversible life-threatening liver injury with ximelagatran.
The sponsor’s
proposed RiskMAP targets [ ]
compliance with ALT monitoring and algorithm-triggered discontinuation. In the clinical development program, severe
liver injury, including fatal liver injury occurred even though compliance with
ALT testing and discontinuation met or exceeded 83%. The sponsor has not provided sufficient
evidence about whether timely transaminase monitoring
and early discontinuation of the drug at the first signs of liver toxicity
could prevent severe liver injury and associated fatalities with ximelagatran.
Even if evidence were sufficient to support the claim that monitoring can reduce
the risk of severe liver injury and associated fatalities, the sponsor’s
projected lower adherence with recommended ALT monitoring in clinical use has
the potential to result in a higher
rate of severe liver injury and liver failure/fatal liver injury than was
observed in clinical development.
The demonstrated severity and rate of hepatotoxicity is substantial
with long term treatment with ximelagatran. Since no adequate mechanism to
prevent or limit this toxicity has been demonstrated, there is no basis for
proposing RiskMAP tools to reliably limit hepatotoxicity risk in individual
patients.
Should it be determined that ximelagatran offers selected populations
of patients sufficient benefits to counter the hepatotoxicity risk,
consideration should be given to a restrictive RiskMAP that would limit risk on
a population basis. One example might be a performance-linked access system
with a registry for patients entering long-term ximelagatran therapy. Such a system should focus on appropriate
education of patients and providers about risk, and appropriate patient
selection. We would also advocate
further quantification of the risk of hepatotoxicity over time, and
clarification of the ability of ALT monitoring and early discontinuation of the
drug to mitigate the risk of severe liver injury and liver failure/fatal liver
injury.
SHORT-TERM
USE
In comparison to warfarin controls, there does not appear to be an elevated
risk of severe liver injury during the short-term use (<12 days) of
ximelagatran. However, in the two
pivotal studies of total knee replacement (TKR) patients, an imbalance in ALT
> 3 x ULN was observed at the follow-up visit approximately 6 weeks after
surgery in ximelagatran-treated patients (8 ximelagatran- vs. 1 warfarin-treated subject). Whether delayed onset of severe
liver injury after short-term ximelagatran treatment could occur is unknown,
since no additional routine study visits were conducted.
Analysis of data
from the LTE population shows that initial signs of liver injury (ALT > 3 x
ULN) were observed during the first month of ximelagatran therapy in 6 of 37
patients who went on to develop severe liver injury (ALT > 3 x ULN and TBL
> 2 x ULN). This suggests that severe liver injury can potentially begin
during the first month of treatment with ximelagatran. Since practice
guidelines recommend anticoagulation of certain high risk patients with TKR for
more than 12 days, we anticipate physicians will want to treat some TKR
patients for a longer period with ximelagatran.
Since the risk of severe liver injury could increase with longer
duration of ximelagatran therapy, even during the first month, “short-term”
duration of use after TKR would need to be strictly limited to prevent
potential severe liver injury.
The sponsor did
not submit a RiskMAP to constrain ximelagatran use to a defined period (i.e.,
7-12 days). Again, ODS
remains concerned about the intrinsic risk and poorly characterized pace of
hepatotoxicity with ximelagatran. Should
the benefit of ximelagatran therapy be sufficient to warrant approval for
short-term prevention of VTE in patients undergoing TKR, we recommend close
discussion with FDA to design and implement a RiskMAP to assure that total
duration of therapy in individual patients does not exceed 12 days or whatever
interval is found to be appropriate.
We note
other safety risks of ximelagatran may merit consideration of a RiskMAP. These include (1) the risk of MI identified
in the FDA Clinical Safety Review, and
(2) the absence of clear methods to control excessive bleeding with
ximelagatran should it occur. Neither of these risks was addressed by the
sponsor, and one or both may warrant exploration of various risk management
tools.
2
INTRODUCTION/BACKGROUND
This consult follows a request by the
Division of Gastrointestinal and Coagulation Drug Products (DGCDP) to review a Risk
Minimization Action Plan (RiskMAP) submitted for ximelagatran. The primary goal
of the ximelagatran RiskMAP as stated by the sponsor is to optimize the
benefit-risk of ximelagatran by minimizing the potential risk of severe liver
injury in patients who present with an elevation in hepatic transaminases.
This memorandum will include a review of the sponsor’s RiskMAP in light of FDA
experience with other drug products that also cause serious hepatic injury.
The RiskMAP does not address
the risk for myocardial infarction (MI), as identified in the FDA Clinical
Safety Review. ODS comments toward
safety are restricted only to ximelagatran-induced hepatotoxicity. In addition,
measures to be taken in the management of ximelagatran-induced bleeding have
not been fully addressed by the sponsor.
2.1
PRODUCT
INFORMATION
Ximelagatran is
an anticoagulant and if approved, will be the first available oral direct thrombin
inhibitor. It is a prodrug that is bioconverted to melagatran which
is a potent, reversible, competitive and direct inhibitor of thrombin. Melagatran specifically inhibits thrombin versus other
coagulation factors. Ximelagatran is approved in
The sponsor is seeking approval for the following 3 indications:
·
For the prevention of VTE in
patients undergoing knee replacement surgery at 36mg bid for 7-12 days.
·
For the prevention of stroke and
other thromboembolic complications associated with atrial fibrillation at 36mg bid.
·
For the long-term secondary
prevention of VTE after standard treatment for an episode of acute VTE at 24mg
bid.
2.2
RISK
ASSESSMENT
2.2.1
Risk
Assessment with Short-term Use
The risk of liver injury with the short-term use of ximelagatran is
largely uncharacterized.
In the two pivotal Phase III studies of total knee replacement (TKR)
patients (SH-TPO-0010 and SH-TPO-0012), there was no signal of an elevated risk
of severe liver injury during the short-term use (<12 days) of ximelagatran
in comparison to warfarin. It is not known whether
delayed onset of clinically severe liver injury could occur after short-term
(<12 days) ximelagatran therapy. Follow-up visits were conducted at 6 ± 2
weeks after TKR surgery. More ximelagatran-treated subjects were found to have
ALT > 3 x ULN at the time of the follow-up visit, especially at the higher
dose [8 patients (0.5%) receiving ximelagatran vs. 1 patient (0.06%) in the warfarin group].[2] Routine study
visits beyond 4 to 6 weeks post TKR were not conducted.
Analysis of data
from the LTE population shows that severe liver injury can potentially begin
during the first month of treatment with ximelagatran. Of 37
ximelagatran-treated patients identified as having severe liver injury
(concomitant ALT >3x ULN and TBL >2x ULN), the initial onset of increased
ALT was noted within the first 30 days of study treatment in six patients, and
sponsor causality assessment was stated as “related” to ximelagatran for four
of these six cases[3]. (The
investigator considered the liver injury to be possibly related to study drug
in one additional case which was disputed by the sponsor). In the comparator
group (N=6230), only two such patients, who then went on to develop increased
ALT and TBL, were found to have an increased ALT during the first 30 days of
study treatment. Of these, one patient was considered by the sponsor to have
drug-related liver injury.
Since the risk of severe liver injury with ximelagatran might begin as
soon as the first month of therapy, “short-term” duration of use after TKR
would need to be strictly defined in terms of minimal hepatotoxicity risk and
limited accordingly.
2.2.2
Risk Assessment with Long-term Use
A significant risk for ximelagatran-associated liver injury has been
identified in the long-term exposure (LTE) population. There were 37 (0.5%;
n=6948) ximelagatran-treated patients[4] in the LTE
population who developed severe liver injury defined as a concurrent increase
in TBL >2 x ULN within 30 days of an increase in ALT >3 x ULN, compared
to 5 (0.08%; n=6230) in comparator groups, relative risk=6.6 (95% confidence
interval 2.6 – 16.9).
In addition to an
imbalance in cases of severe liver injury in ximelagatran-treated patients, two
other observations also support a causal association of liver injury with
ximelagatran. First, in the LTE population, an increase in ALT > 3 X ULN was
observed in 6 to 13% of ximelagatran-treated patients, compared to 0 to 2% in
comparator groups. Second, an assessment
of likelihood of causality by the sponsor also shows increased risk of severe
liver injury with ximelagatran.[5] Based on clinical and diagnostic information
obtained at the time of liver injury, such assessments of causality of individual
cases may complement the measurement of relative rates among the treatment
groups of the randomized clinical studies. In 19/6948 ximelagatran-treated
patients who developed severe liver injury, the sponsor indicated that liver
toxicity was causally related to study drug.
In contrast, in only 2/6230 patients assigned to comparator, severe
liver injury was considered related to study drug. Based
on the sponsor’s causality assessment the relative risk of severe liver injury
ximelagatran in study treatment related
cases is high and statistically significant; relative risk 8.52 (95% CI 1.98 -
36.56).
Additional
analyses of drug-related liver injury cases (based on sponsor’s causality
assessment) which also include cases that did not meet the cut-off for severe
liver injury as defined in this consult (i.e., concurrent ALT > 3 X ULN and
TBL > 2 X ULN), also showed a highly significant relative risk for
ximelagatran-treated patients vs. comparator. As indicated in Sponsor’s Table
2-8, there were a total of 66 ximelagatran-treated patients in the LTE pool who
developed concurrent increases in TBL > 1.5 X ULN and ALT > 3 X ULN. Of
these, 45 cases (0.65%) were considered related to ximelagatran treatment.[6] In contrast, as
noted in Sponsor’s Table 2-14, there were a total of 11 cases which met this
lab value cut-off in the comparator group,[7] of which only 5
cases (0.08%) were considered drug-related by the sponsor (relative risk 8.1,
95% CI 3.2 – 20.3).
In two additional
cases of severe liver injury (SH-TPA-0003-309-2522 and SH-TPV-0002-265-5442),
the investigator considered the liver injury to be possibly related to
ximelagatran therapy, although the sponsor considered it to be unrelated. Also,
one additional case of fatal liver injury (SH-TPA-0005-3030-7859) which was
considered by the investigator to be possibly related to study drug was not
included in the sponsor’s analysis.
Alternative
explanations for severe liver injury in ximelagatran cases judged by the
sponsor to be unrelated to study drug included active cancer, hepatic
congestion associated with heart failure, cholelithiasis,
concomitant therapy with flucloxacillin,
sepsis, hepatitis B, and mechanical biliary
obstruction. Alternative explanations for comparator cases included active
cancer. Taken together with the previously mentioned findings, the striking
imbalance in the number of unrelated cases in the ximelagatran treatment group
vs. comparator suggests that ximelagatran therapy may have caused or
contributed to severe liver injury in some of the unrelated cases, as well.
It is notable that there were three deaths associated with ximelagatran
associated hepatocellular necrosis leading to liver
failure or reduced clotting factors synthesis. These are briefly summarized
below.
·
SH-TPA-0005-0620-7259:
80-year-old male developed increased ALT after 56 days of ximelagatran 36 mg
bid; drug stopped on day 88; ALT 1502 U/L, TBL 2.4 mg/dL
on day 100; liver biopsy showed acute submassive
necrosis on day 108; death due to GI bleed from duodenal ulcer on day 143;
investigator considered liver failure related to ximelagatran.
·
SH-TPA-0005-3030-7859:
77-year-old male developed increased ALT after 57 days of ximelagatran 36 mg
bid; drug stopped on day 74; hospital admission with GI bleed (ALT 569 U/L, TBL
6.2 mg/dL) on day 75; respiratory failure and death
due to coagulopathy on day 76; investigator
considered events possibly related to ximelagatran.[8]
·
SH-TPV-0002-265-5442:
73-year-old male with fulminant hepatitis B died from
hepatic failure after 24 days of ximelagatran 36 mg bid; investigator
considered events possibly related to ximelagatran.
The sponsor’s analysis of potential risk factors predisposing to liver
injury (ALT > 3 x ULN) in the ximelagatran treatment group versus comparator
showed increased risk in the post acute coronary syndrome population, patients
treated for venous thromboembolism, female patients,
patients with low body mass index, and patients receiving concomitant therapy
with statins. However, the sponsor concluded these
relationships were not strong enough
to recommend that any patients with these attributes should not be given
ximelagatran.[9]
2.2.3
Risk
Assessment Over Time
Thus far, the sponsor’s evaluation of the risk of hepatic injury with
ximelagatran has been primarily focused on the occurrence of isolated elevation
of serum ALT (>3xULN). The sponsor’s analysis of cumulative risk of hepatic
injury is presented in Figure NP31 (reproduced below). However, ODS believes
that cases of severe liver injury (defined as concurrent elevation of ALT and
TBL) are of greater prognostic significance in evaluating the potential impact
of ximelagatran-associated hepatotoxicity. This belief is based on a guiding
principle, articulated by Hy Zimmerman and referred
to as “Hy’s Law”, that seeks
to correlate clinical trial experience with projected risk of severe liver
injury.[10] ODS has
requested additional analyses from the sponsor which will look at cumulative
risk of concurrent ALT and TBL elevations observed during the ximelagatran
clinical program (pending at the time of writing).
The observation that “instances (even very few of them) of transaminase elevation accompanied by elevated bilirubin (even if obvious jaundice was not present) have
been associated with, and have often predicted, post-marketing serious liver
injuries (fatal or requiring transplant)” was first made by Dr. Hyman Zimmerman
in his textbook,[11] and has since
been proven true for drugs including bromfenac, dilevalol, troglitazone, and trovafloxacin.[12]
Zimmerman noted that drug-induced hepatocellular
jaundice is a serious lesion, with mortality ranging from 10 to 50 percent.[13] More recent mortality estimates continue to
regard the combination of pure hepatocellular injury
and jaundice as ominous, with about 10-15% of patients who show such findings
as a result of drug-induced injury having death as an outcome [14]. The explanation
for this outcome is that hepatocellular injury great
enough to interfere with bilirubin excretion must
involve a large fraction of the liver cell mass.[15]
2.2.4
Projection
of Severe Liver Injury and Liver Failure in the Postmarketing Setting
As noted above, the clinical development program for ximelagatran shows
that long-term use of ximelagatran can cause severe liver injury and liver
failure/fatal liver injury in some patients.
Furthermore, cases of severe and fatal liver injury occurred under the
ALT monitoring algorithm proposed within the RiskMAP, the more stringent of two
algorithms used in the clinical development program. In the clinical
development program, compliance rates were higher than those projected by the
sponsor for the postmarketing setting.
Thus, we project that the frequency of severe liver injury observed in
the general population will be equal to or greater than that observed in the
clinical trials. As noted previously in
this review, the frequency of severe liver injury observed in the LTE
population was 0.53% for ximelagatran-treated patients versus 0.08% for
patients randomized to warfarin or placebo; relative
risk=6.6 (95% confidence interval 2.6 – 16.9). Based on a hypothetical scenario
of 100,000 patients in the general population exposed to ximelagatran for a
similar treatment duration, and managed by health care providers as seen in the
long-term clinical trials, we could then expect some 500 individuals to develop
severe ximelagatran-associated liver injury, including 50 patients (10%) who
would progress to fulminant liver failure, liver
transplant, or death.
2.3
COMPLIANCE
WITH THE ALT TESTING IN THE XIMELAGATRAN CLINICAL TRIALS
The sponsor’s review of
compliance in the clinical trials was evaluated in terms of adherence to serum
ALT testing as described in the study protocols and compliance with
discontinuing ximelagatran. Data regarding compliance with recommended testing
is limited to patients who were identified to undergo weekly testing, and did not
examine compliance with routine testing (monthly) among all patients.
Compliance with ALT testing was determined by comparing the date of when the
test occurred versus when it should have occurred. This review of compliance
with hepatic monitoring during the clinical trial revealed the following:
Compliance with Weekly Monitoring
Patients were considered
compliant with weekly monitoring if the serum ALT was performed within 1 to 10
days of previous test. For patients monitored under algorithm 1, about 70% of
patients identified to undergo weekly serum testing (those with ALT >3 x
ULN), were monitored within 10 days of the increased ALT. For patients
monitored under algorithm 2, the compliance decreased to about 63%. Nonetheless at least 30% of patients that were
identified to undergo weekly monitoring under either algorithm were considered
non-compliant.
Percent reaching Discontinuation Level
Of patients who met the
threshold for ximelagatran discontinuation[16], those initially
identified with elevated ALT levels[17] before
they reached the level of discontinuation increased from 39% to 49%, following
the implementation of algorithm 2. Nevertheless,
under either algorithm, at least 50% of the patients who were discontinued did
so without a preceding ALT value above the algorithm threshold for triggering
weekly monitoring.
For those that were not identified before they reached
the ALT levels of discontinuation, it is
not clear if the reason was noncompliance with monitoring or that the rate of
ALT increase was too rapid for timely
detection of rising levels by the monitoring scheme outlined in either of the
two algorithms.
Impact of
Monitoring on Discontinuation
Approximately 83% of patients monitored according to
algorithm 1 who developed an ALT > 7 x ULN discontinued ximelagatran. This
rate of discontinuation increased to 93% in the patients who developed an ALT
> 5 x ULN when monitored under algorithm 2 which requires weekly monitoring
of those patients with ALT > 2 x ULN.
It is unclear why 7 and 17% of ximelagatran treated patients who met
the threshold ALT levels for discontinuation under algorithms 2 and 1,
respectively, failed to do so and what impact this had on patient outcomes.
Compliance in Patients with Severe Liver Injury
DDRE examined the impact of monitoring on discontinuation among
the subset of 36 patients who were identified by the sponsor with concurrent
elevations in serum ALT >3x ULN and TBL >2x ULN (defined in this review
as severe liver injury). In this group of patients, 23 of these 36 patients
were monitored under algorithm 1, and 13 under algorithm 2. Fourteen (39%) of these 36 patients failed to
discontinue study drug at the correct time, and of these, nine patients did not
recover to TBL ≤1x ULN and ALT ≤2x ULN.[18]
We note that among the three cases of fatal liver injury; two
patients were monitored under algorithm 1 and one was monitored under algorithm
2.
§
SH-TPA-0005-0620-7259
was monitored under algorithm 1. At month 2, his serum ALT was mildly elevated
but less than the 3 x ULN threshold that required
weekly monitoring. The following month his ALT >20 x ULN. He discontinued
ximelagatran; however, he progressed to fatal liver injury.
Compliance with algorithm 1 in this case did not
prevent liver failure. Based upon this case, the sponsor modified the algorithm
so that the threshold for weekly monitoring was lowered to an ALT of > 2 x
ULN.
§
SH-TPV-0002-265-5442
was monitored under algorithm 2. Nine days after starting ximelagatran, his serum
ALT was mildly elevated (60 U/L). He was diagnosed with Hepatitis B and was
hospitalized on day 18. On day 24 ximelagatran was discontinued. Two days later
his ALT > 10 x ULN and TBL was 4 mg/dL. He
progressed to liver failure and died.
This patient developed rapid liver injury that may not
have been preventable by any transaminase monitoring.
§
SH-TPA-0005-3030-7859
was presumably monitored under algorithm 1 based on therapy and event dates. At
month two, his serum ALT was elevated to 4.5 x ULN (216 U/L) a value which did
not meet the threshold of discontinuation, using algorithm 1. He was scheduled
to undergo weekly testing but he was non-compliant with weekly testing. Two weeks later, he was admitted with severe coagulopathy, ALT 569 U/L, TBL 6.2 mg/dL,
and a fatal upper gastrointestinal bleed.
This patient was identified as requiring weekly
testing but was not compliant. Use of algorithm 2 would not have changed the
outcome in this case because the patient did not reach ALT values at the time
of his month two visit which would have signaled discontinuation utilizing
either algorithm.
Median
Compliance to Algorithm 2
For the ximelagatran SPORTIF V trial, in which
clinicians were educated and reinforced on the importance of applying the
LFT-testing algorithm, median compliance with the algorithm was 83%.[19]
3
PROPOSED
RISK MINIMIZATION ACTION PLAN
3.1
GOALS
AND OBJECTIVES
The primary goal of the
ximelagatran RiskMAP as stated by the sponsor is to optimize the benefit-risk
of ximelagatran by minimizing the potential risk of severe hepatic injury in
patients who present with an elevation in hepatic transaminases.
The RiskMAP objectives are
to:
·
Facilitate
compliance of the monitoring recommendations by healthcare workers and patients
·
Minimize the risk
of severe hepatic injury
3.2
TOOLS
The sponsor has proposed recommending voluntary ALT
monitoring via professional labeling and associated educational support
initiatives to address the risks associated with the long-term or chronic use
of ximelagatran. The sponsor has not proposed reminder system tools, which are
systems that help reinforce desired behaviors by involving additional processes
or paperwork to usual prescribing or the use of performance linked access
system (PLAS) or restricted distribution systems which link drug product access
to compliance with RiskMAP elements.[20]
3.2.1
Proposed
Labeled Recommendations to Monitor ALT
The ALT monitoring recommended
in the labeling would consist of the following:
- Obtaining baseline ALT; if < 2 x ULN, patient
may initiate ximelagatran
- Screen ALT monthly
- If < 2 x ULN, continue to screen monthly for
6 months and periodically thereafter
- If > 2 x ULN, monitor ALT weekly; stop drug
if:
i.
ALT > 3 x ULN
after 4 weeks
ii.
ALT > 5 x ULN
at anytime
iii.
Symptoms of
hepatic injury (e.g. jaundice w/o obvious cause)
This algorithm is the more
stringent of two algorithms utilized during the clinical trials.
3.2.2
Targeted
Education and Outreach Communication
The sponsor has submitted a comprehensive educational
plan to address the risk of severe liver injury associated with the long-term
use of ximelagatran by promoting compliance with ALT monitoring. As stated in
the October 2003 ODS review[21], a wide
array of educational tools are planned for physicians, pharmacists and patients
to achieve the steps outlined in the Medication Administration and Use Process.[22]
Qualitative and quantitative field testing have been conducted with physicians,
pharmacists, and patients. Pharmacists’
and physicians’ reactions to each tool were evaluated for the tool being easy
to understand and useful as well as having the ability to help manage the ALT
testing requirements. Patient
comprehension and acceptance of materials were examined.
Positive aspects include an analysis of the medication
administration and use process, development of redundant interventions based on
analysis, use of adult learning principles, involvement of stakeholders in the
process and field testing of tools and materials. An additional positive aspect
is that the RiskMAP is planned to be integrated at launch into the marketing
messages for Exanta®.
However, education as the sole mechanism to modify
physician behavior with regard to appropriate laboratory monitoring is
concerning. The sponsor acknowledges,
and we agree, that labeling and other modalities to communicate laboratory
monitoring recommendations have been largely unsuccessful. [23], [24]
Additionally, the educational tools are quite extensive and we have concerns
about the ability of stakeholders to incorporate the elements (curriculum,
algorithm, worksheets, flowsheets, patient reminders,
etc.) into daily practice. The educational program also does not focus on
messages that would limit the duration of use of the ximelagatran should only
the short-term indication be approved. Moreover, there is no evidence that
education alone will successfully drive the Medication Administration and Use
Process and lead to compliance with monitoring recommendations.
3.3
EVALUATION
PLAN
The evaluation component of the RiskMAP is designed to
assess:
·
Actual compliance
by healthcare providers and patients with ALT testing recommendations
·
Occurrence of
hepatic outcomes measured through both pharmacovigilance and pharmacoepidemiologic methods.
3.3.1
Proposed
Compliance with ALT Testing
The sponsor proposes monitoring ALT algorithm
compliance following the launch of ximelagatran through various databases and
offers the following metrics to determine RiskMAP success or if additional
actions are indicated. These metrics are based upon three sources of data which
the sponsor considers to be “benchmarks” for “an appropriate ALT-testing
compliance target for ximelagatran”.[25]
·
The sponsor
proposes a target mean compliance level of [ ] for with ALT-testing postmarketing. They
assert that this level of compliance roughly corresponds to the levels observed
with warfarin INR monitoring in a similar patient
population.
·
If ALT monitoring falls between [ ], then relevant aspects (not defined
by sponsor) of the RiskMAP will be evaluated.
·
They consider a
compliance level of less than [ ]
to be unacceptable and if ALT testing falls below this value, then additional
action(s) or substantive changes in the program will be implemented. Details concerning the additional actions or
changes were not provided.
3.3.2
Measuring
Hepatic Outcomes
The sponsor has proposed monitoring for serious hepatotoxic adverse events through spontaneous
post-marketing surveillance, special agreements with registries of acute liver
failure (e.g., the Acute Liver Failure Group), and by analyzing the [ ] database
12 months post launch and every six months thereafter to assess rates of events
in the population of interest.
To our knowledge the sponsor has not assessed the
power of [ ] to detect an effect
within 12-18 months given the projected level of use within the [ ] population. The sponsor has not
offered targets for rates of serious hepatotoxicity or liver failure that are
acceptable/ unacceptable and would trigger additional actions or modification
of the RiskMAP.
3.3.3
Comments
on Proposed Evaluation Plan for Risk Management
Specific
comments on the metrics of the proposed evaluation plan and the methods
proposed to measure compliance and hepatic outcomes will be deferred until the
Advisory Committee has commented on the potential benefits of ximelagatran in
short-term and long-term treatment, and the appropriateness of the tools
proposed as well the possible need for additional tools to address the risk of
hepatotoxicity.
4
RECOMMENDATIONS
FOR ADDITIONAL RISKMAP OPTIONS
The development and/or strategies around a RiskMAP for
ximelagatran depend largely upon the risk assessment and the benefit-risk
profile of ximelagatran for each of the proposed indications. Two of the
proposed indications (prevention of stroke in patients with AF and secondary
prevention of VTE) are for the long term use (> 35 days) of ximelagatran and
the third indication (prevention of VTE following knee replacement surgery)
involves short term therapy of 7-12 days of ximelagatran.
The risk management considerations outlined below take
into account the different risk profiles that are related to the proposed
short-term and long-tem indications. Two risk management scenarios will be
considered. These include:
·
Use of
Ximelagatran for short-term indications only
·
Use of
Ximelagatran for both short-term and long-term therapy.
4.1
CONSIDERATIONS
IN RISK MANAGEMENT OF XIMELAGATRAN IF APPROVED FOR SHORT-TERM USE ONLY
There does not appear to be a high risk of severe
liver injury during the short-term use (<12 days) of ximelagatran relative to
warfarin. However, the risk of severe liver injury for
the short-term use has not been fully characterized. The time at which the risk
of severe liver injury begins to rise is largely unknown but appears to be
within the first month of therapy.[26] This
finding suggests the importance of limiting the duration of ximelagatran
therapy to 12 days of therapy to avoid risk of severe drug-induced liver injury
(although it does not provide assurance that a delayed-onset of injury after
cessation of exposure cannot occur with this drug).
A brief overview of published medical literature
regarding state-of-the-art treatment in managing thromboembolic
risk in knee replacement surgery has revealed that recommendations for extended
prophylaxis beyond the 12 post-surgical days are supported by clinical data.[27] A meta-analysis of studies evaluating
outcomes in 13,169 total hip replacement (THR) and total knee replacement (TKR)
patients who received 7 to 10 days of anticoagulant prophylaxis after surgery
determined that a significant risk for thromboembolism
was present.[28] The authors concluded that, without extended
prophylaxis beyond 10 days, nonfatal venous thromboembolism
will occur in approximately 1 of 32 patients and fatal pulmonary embolism will
occur in approximately 1 of 1000 patients within three months of surgery. Risk
stratification, including a checklist which can be used to aid surgeons in
deciding which patients have post-operative risk factors that warrant extended
prophylaxis after hospital discharge, has been recommended by some authors.[29] If the
risk of long-term use of ximelagatran is determined to outweigh the benefit,
and practice guidelines encourage extended therapy for some patients in the
post-surgical setting (e.g. TKR), voluntary compliance with limited duration of
therapy may be difficult to achieve.
Experience with other drugs
suggests that attempting to limit the duration of therapy to minimize the risk
of hepatotoxicity via labeling has had mixed results. Bromfenac
was a drug labeled for short-term use but marketed to a patient population with
a high percentage of individuals suffering from chronic pain and seeking
long-term analgesic treatment.[30] Analysis
of drug utilization[31] during
the two years prior to bromfenac’s withdrawal from
the market (1997-1998), shows that approximately 10-20% of bromfenac
mentions in outpatient office visits were for more than 10 days of intended
treatment and 25-30% had “unspecified” intended duration, suggesting that an
even higher percentage of mentions could have been for more than 10 days of
intended treatment.[32] More
recent experience with ketorolac has been more
encouraging. Ketorolac is a nonsteroidal
anti-inflammatory drug, indicated for use up to 5 days in adults.[33] An analysis of the average length of
a prescription[34]
for oral ketorolac during the five year period from
June 1999 to May 2004 showed a fairly consistent pattern, ranging from
If the benefit of ximelagatran for the prevention of
VTE in patients undergoing TKR outweighs the risk, and it is approved for the
short-term use of 7-12 days, we recommend the goal of the risk management be to
strictly limit the duration of use to 12 days or less, thereby minimizing the
risk of hepatotoxicity associated with longer use. We offer the following risk management
options for consideration for the short-term use of ximelagatran but
acknowledge that there is a paucity of data on the effectiveness of these
methods to limit duration of therapy.
a)
Labeling
·
boxed warning to
limit therapy to <12 days to avoid risk of severe drug-induced liver
disease, including acute liver failure
b)
Education
·
of prescribers
and patients (and possibly PBMs) about need to limit
duration of therapy to avoid severe drug-induced liver disease, including acute
liver failure
·
should contain
the appropriate safety messages for indication
·
should reach the
appropriate target audience of prescribers, pharmacists, and associated allied
health professionals
·
if patient
comprehension studies are to be conducted that the Sponsor assess comprehension
with open-ended questions rather than alternate-response items since the
open-ended format allows respondents to demonstrate comprehension through
translation and interpretration of information
·
Sponsor should
submit draft or mock print copies of educational materials to DDMAC for their
review prior to launch
·
Patient Starter
kit should be available not only in physician offices but other areas of
distribution such as pharmacies, managed health care organizations, and
hospitals
·
All prescribing
physicians, those that are visited by a sales representative and those that are
not visited, should receive the same materials.
·
Since the results
of field testing[35]
indicated that physicians want programs that are “simple, practical,
patient-oriented, and do not increase cost and/or workload” and pharmacists
want programs that “do not disrupt the normal work flow” the Sponsor should
consider evaluating the actual use of the program to determine the ability of
stakeholders to incorporate the elements (curriculum, algorithm, worksheets, flowsheets, patient reminders, etc.) into daily practice.
c)
Special conditions of dispensing
·
special packaging
– such as a dosepak with no more than a 12-day supply
·
dispensing
limited to inpatient pharmacy following post-operative procedure – feasibility
of this approach requires discussion with clinical and payor
community
d)
Provision of a physician /patient agreement (for
charting)
·
Patient signs to
indicate awareness of risks and that therapy should be limited to no more than
12 days.
·
MD signs to
attest that product use is warranted and appropriate and the prescription will
be limited to duration of 12 days.
e) Voluntary
limitation of advertising/promotion options- examples include:
·
Limited
professional promotion to specific, defined specialties and journals
·
No DTC
advertising to reduce pressure to prescribe this particular product.
·
FDA approval of
launch and all marketing materials for a limited and well-defined period of
time
·
Very limited or
no product sampling
·
If sampling is
done, consider attestation by the physician to provide no greater than a 12 day
supply to patients.
f) Performance-linked
Access System (PLAS)
·
Limit
distribution to inpatient hospital pharmacies that would agree to dispense:
o
No greater than a
12-day supply with no refills or new prescriptions for a patient that has
received the product in a specified period of time.
o
Dispense to only
patients that have an ALT of < 2 x ULN
o
No distribution
of product to retail pharmacies
The utility and feasibility of serum ALT testing for
short-term use does not appear relevant for two reasons: 1) a signal of
hepatotoxicity has not been demonstrated in the clinical trials for the
short-term use of ximelagatran although full risk assessment was incomplete and
2) monthly monitoring has been recommended by the sponsor, and therefore
patients would not be treated with ximelagatran long enough for monitoring to
occur. Baseline serum ALT testing, as
was done as a basis for exclusion from study, could be considered. However it
is unknown whether patients with an elevated ALT at baseline are at increased risk
of serious hepatotoxicity relative to patients with normal baseline ALT values.
Whatever
tools are selected for appropriate risk management for this product for
short-term therapy, it is essential that the sponsor develop a comprehensive
evaluation plan to determine the effectiveness of the program, accompanied by timely
plans of action if stated goals are not met.
4.2
CONSIDERATIONS
IN RISK MANAGEMENT OF XIMELAGATRAN IF APPROVED FOR LONG-TERM USE
Utilization of ximelagatran
for long-term therapy is complicated by the appearance of a strong signal for
serious, ximelagatran-associated hepatotoxicity observed in the long-term
clinical trials. The sponsor has submitted a RiskMAP based on monthly ALT
screening [“ALT algorithm”]. As outlined
by the sponsor, the stated goal for this RiskMAP would be to maximize
compliance with the ALT algorithm, including assessment of baseline LFT status,
monthly monitoring, and application of the weekly testing and possible drug
discontinuation based on ALT elevations. This
scenario assumes that progression of liver injury can be mitigated through
monitoring liver function tests at a proven interval. ODS
notes the absence of data to support this assumption.
The sponsor proposes a
commitment to monitor compliance with the ALT algorithm for patients on therapy
with ximelagatran through observational databases. However, experience with a
number of agents including troglitazone, pemoline, and isoniazid suggest
that such programs utilizing transaminase monitoring have
been generally ineffective.[36],
[37]
In the case of troglitazone, reports of fatal liver injury received by FDA
shortly after marketing prompted a black box warning and a series of Dear
Healthcare Professional letters recommending monthly transaminase
monitoring. Despite these measures, transaminase
monitoring was not regularly performed.[38] Moreover, in some patients, liver injury
still progressed to fatal liver failure despite stopping the drug in response
to monthly transaminase monitoring due to rapid
progression (within a one month interval) of liver injury to a state of
irreversibility. Pemoline was approved by FDA in 1975
for ADHD with recommendations in the Precautions
section to monitor transaminase levels periodically
due to a 1% to 2% incidence of drug-induced liver injury. Reports of ALF led to
a boxed warning and Dear Healthcare Professional letters in 1996 and 1999,
shifting the drug to second line therapy and recommending baseline and
bi-weekly transaminase monitoring. Although
compliance with these recommendations was assessed to be poor,[39] the use
of pemoline dropped off substantially over the next
five years,[40]
and no additional drug-related cases of liver failure were subsequently
reported to FDA.[41]
Extensive clinical experience with isoniazid, a drug
which can cause a more chronic liver injury pattern, has shown that risk of
severe hepatotoxic reactions can be effectively
minimized by instructing patients to stop drug and immediately report symptoms
of liver injury as soon as they occur.[42] Increased levels of aminotransferase
are observed in 15 to 30 percent of patients who take the medication and one in
1000 patients will have severe hepatic necrosis.[43],
[44] Conclusions
based on recent studies were that due to the course of liver injury in most isoniazid users who develop hepatocellular
necrosis, clinical evaluation as the primary monitoring method is often effective.
Moreover, the high rates of asymptomatic transaminase
elevations in isoniazid-treated patients limit the
utility of routine periodic monitoring in detecting clinically meaningful liver
injury that will progress to irreversibility.[45]
Notwithstanding serious
reservations that have been described and in light of the projected risk of
severe liver injury, the following risk management tools might be considered if
the product is approved for the long-term use.
a)
Labeling
·
strengthen the label to a boxed warning, and strengthen patient
education materials, a medication guide which clearly describes the risk
associated with treatment.
b)
Education
·
should reach the
appropriate target audience of prescribers, pharmacists, and associated allied
health professionals such as nurse practitioners, physician assistants, and
anticoagulation clinic managers identified in field testing
·
if patient
comprehension studies are to be conducted that the Sponsor assess comprehension
with open-ended questions rather than alternate-response items since the
open-ended format allows responsdents to demonstrate
comprehension through translation and interpretration
of information
·
Sponsor should
submit draft or mock print copies of tools to DDMAC for their review prior to
launch
·
Patient Starter
kit should be available not only in physician offices but other areas of
distribution such as pharmacies, managed health care organizations, and
hospitals
·
All prescribing
physicians, those that are visited by a sales representative and those that are
not visited, should receive the same materials.
·
Since the results
of field testing (see pg.12 of RMP) indicated that physicians want programs
that are “simple, practical, patient-oriented, and do not increase cost and/or
workload” and pharmacists want programs that “do not disrupt the normal work
flow” the Sponsor should consider evaluating the actual use of the program to
determine the ability of stakeholders to incorporate the elements (curriculum,
algorithm, worksheets, flowsheets, patient reminders,
etc.) into daily practice.
c)
Provision of a physician /patient agreement (for
charting)
·
The patient signs to indicate awareness of risks and that safe use includes
baseline and monthly liver function monitoring.
·
MD signs to
attest that product use is warranted and appropriate and that he/she will
conduct the required laboratory monitoring.
d) Voluntary
limitation of advertising/promotion options
·
Limited professional
promotion to specific, defined specialties and journals
·
No DTC
advertising to reduce pressure to prescribe this particular product.
·
FDA approval of
launch and all marketing materials for a limited and well-defined period of
time
·
No product sampling
e) Performance-linked
Access System (PLAS)
·
Mandatory
registration of all patients
·
Requirement for
all patients to have baseline and monthly monitoring
·
Limit
distribution to pharmacies that would agree to dispense:
·
To only patients
that present with ALT <2x ULN
·
No refills
·
Dispense no more
than a 30 day supply
If ximelagatran long-term therapy is found to offer a
substantial and important benefit that offsets the risk of severe drug-induced
liver injury, and is approved on this basis, we recommend that consideration be
given to the use of a PLAS. The goals for PLAS could be several fold: 1) To
improve compliance with ALT-monitoring, although we acknowledge that in the
case of ximelagatran treatment, serum ALT monitoring has not been proven to
prevent progression to liver failure; 2) To identify and limit product use to subpopulations
of patients for whom the benefits exceed the risks; and 3) to accurately
quantify the frequency or incidence and range of severity of most/all ximelagatran-associated
hepatotoxicity cases post-marketing. Data from this cohort could then quantify
if the frequency of serious, ximelagatran-associated hepatotoxicity
approximates 0.5% (1 in 200) as seen in the clinical trials, or, based on
application of the 95% CI, closer to 1 in 460 (2.6x control) or 1 in 70 (16.9x
control). By prospective recruitment and
collection of data, this cohort would also further define qualitative data,
such as potential risk factors for serious, ximelagatran-associated
hepatotoxicity.
Whatever tools are selected for appropriate risk
management for this product for short-term and long-term therapy, it is
essential that the sponsor develop a comprehensive evaluation plan to determine
the effectiveness of the program, accompanied by timely plans of action if
stated goals are not met.
5
DISCUSSION
The sponsor has submitted a RiskMAP
based on voluntary monthly ALT screening [“ALT algorithm”] via product
labeling. As outlined by the sponsor,
the stated objectives for this RiskMAP are to facilitate compliance of the
monitoring recommendations by healthcare workers and patients through education
and to minimize the risk of severe liver injury. The ALT-testing is designed to
address the risk of hepatotoxicity associated with long-term treatment (>35
days) with ximelagatran.
Success in minimizing the
risk of severe liver injury associated with long-term use of ximelagatran with
serum ALT monitoring is contingent on two assumptions: 1) monitoring ALT with
discontinuation of ximelagatran at pre-specified levels of ALT elevation would
be effective in reversing the severe liver injury and so preventing serious sequelae and death and 2) patients and healthcare workers
will be compliant with monitoring. There are no data to support the first
assumption. In fact, at least one and possibly three cases of liver failure
occurred in the ximelagatran clinical trials despite protocol requirements for transaminase monitoring and patient follow-up. Regarding
the second assumption, the sponsor acknowledges that compliance with
ALT-testing observed in the clinical trials as well as postmarketing laboratory
monitoring of other hepatotoxins and warfarin show imperfect compliance and as such have set a
target rate of compliance of ALT monitoring for ximelagatran post-marketing at [ ]. This target is less than what was achieved
in the clinical trials. Based on the rates of severe liver injury observed in
the long-term clinical trials, if the drug is approved and this program
implemented, we anticipate at least 500/100,000 individuals treated with
ximelagatran for long-term indications might develop severe
ximelagatran-associated liver injury, including 50 (10%) with severe
manifestations who could progress to liver failure, liver transplant, or death.[46]
The sponsor has not submitted risk management material
directed towards restriction of ximelagatran to a defined period (i.e., 7-12
days) relevant for a short-term indication, nor suggested further assessment other
than observational studies after marketing to examine the frequency or risk
factors for ximelagatran-associated severe liver injury. It is of concern that
some patients after TKR may require anticoagulation for substantially long than
12 days. In addition, prior experience with certain products labeled for
short-term use only and associated with hepatotoxicity after a longer period of
use (e.g., bromfenac) has demonstrated the difficulty
in preventing risk for serious outcomes. Additional risk management measures,
based in part on a thorough assessment of the benefit-risk profile that
characterizes ximelagatran for each of the proposed short-term and long-term
indications, should be discussed pending approval for marketing.
6
CONCLUSION/RECOMMENDATIONS
SHORT-TERM USE ONLY
If the benefit of ximelagatran therapy is determined
to warrant approval for short-term prophylaxis for prevention of VTE in
patients undergoing TKR, we recommend implementation of a risk minimization action
plan designed to assure that total duration of therapy in individual patients
will not exceed 12 days. This should include at a minimum labeling (boxed
warning), education, special packaging and conditions of dispensing, a
physician/patient agreement, limits on promotion, and consideration of
restricted distribution. If approved with a RiskMAP, it is also essential that
the sponsor develop a comprehensive evaluation plan to determine the
effectiveness of the program, accompanied by plans of action if stated goals
are not met.
LONG-TERM USE
If the benefit of long-term
ximelagatran therapy is determined to exceed its risk of hepatotoxicity, we
recommend restricted distribution measures to limit population risk. For
example, approval could be conditioned upon establishment of a performance
linked access system including a mandatory patient registry for patients
entering long-term ximelagatran therapy. Other risk management tools, such as
restricted distribution, labeling (boxed warning), physician /patient
agreement, limitation in promotion, and education would require additional
consideration. If a RiskMAP is employed, it is also essential that the sponsor
develop a comprehensive evaluation plan to determine the effectiveness of the
program, accompanied by plans of action if stated goals are not met.
As noted above, we do not
agree that the sponsor’s proposed RiskMAP for minimization of
ximelagatran-associated severe liver injury is adequate. To date, serum transaminase
monitoring in ximelagatran treated patients has not been demonstrated to be
effective in preventing idiosyncratic severe drug-induced liver injury.
Currently, the proposed monitoring plan provides no guarantee of safeguarding
the patient from developing a rapid onset and life-threatening reaction.
APPENDIX—DRUG-INDUCED LIVER INJURY
A. Brief
regulatory history: withdrawals and risk management
During the past ten years,
two drugs, DURACT (bromfenac) and REZULIN (troglitazone), have been withdrawn from marketing in the
Also during the past ten
years, there have been instances where regulatory action prompted by concern
about severe DILI included risk management actions which stopped short of
market withdrawal. Examples include CYLERT (pemoline)
and TROVAN (trovafloxacin).
Pemoline was approved by FDA in 1975 for ADHD with
recommendations in the Precautions section to monitor transaminase
levels periodically due to a 1% to 2% incidence of drug-induced liver injury.
Reports of acute liver failure (ALF) led to a series of black box warnings and
Dear Healthcare Professional letters in 1996 and 1999, shifting the drug to
second line therapy and recommending baseline and bi-weekly transaminase
monitoring. Although compliance with these recommendations was assessed to be
poor,[50] the use
of pemoline dropped off substantially over the next
five years,[51]
and no additional drug-related cases of liver failure were subsequently
reported to FDA.[52]
Trovafloxacin (a fluoroquinolone
antibiotic) received FDA approval in 1997. During the first two years of
marketing in the
Examples of drugs never
marketed in the
B. Range
of issues: timing, tempo and reversibility of hepatotoxicity
Drug-induced liver injury is
an important cause of fulminant liver failure. The
Acute Liver Failure Study Group found that, between 1998 and 2000, 52% of all
cases of ALF in the
Drug-induced liver disease
can be predictable (dose-related, occurring at doses exceeding recommendations)
or unpredictable (idiosyncratic, and occurring in susceptible individuals at
usual therapeutic doses).[61] Idiosyncratic liver injuries occur with a
pattern that is consistent for each drug and for each drug class.[62]
As Lee has proposed in a
recent review of drug-induced liver injury,[63] most
idiosyncratic drug reactions result from a succession of unlikely events, a “multihit” process. This implies that a “series of events
that first involve intracellular disruption, cell necrosis, or apoptosis,
followed by activation of the immune sequence, might explain the features of
idiosyncratic drugs reactions: their rarity, their severity, and their
resolution despite continued use of the drugs by patients with phenotypes that
appear to be adaptive.”[64]
Timing: Risk vs. duration of treatment
(hazard rate over time)
Idiosyncratic reactions are
characterized by a variable delay or latency period, typically ranging from
Tempo and reversibility of injury
The range of tempos of injury
is a characteristic both of individual drugs and patients. Rapid acceleration
of liver injury in some individuals may preclude an absolute protective value
of standardized periodic transaminase monitoring.[70]
A key issue in effective
intervention to prevent fatal liver injury is “recoverability” at time of sign
or symptom onset. This refers to a “point of irreversibility”, after which
there is an inexorable progression to liver failure and often death. The
contrast between isoniazid liver injury (chronic parenchymal injury)[71] and
that characteristic of troglitazone[72]
demonstrates the contrast between a situation where stopping the drug at the
time of symptom onset most often prevents progression to irreversible injury,
and one where it does not in many cases. Drugs that can cause severe DILI generally
demonstrate a range of responses, with varying proportions of patients who
recover whether or not the drug is stopped, versus the proportion of patients
who go on to develop irreversible injury.
Dose-related hepatotoxicity
Acetaminophen is an example
of a drug with predictable dose-related toxic effects. At higher doses,
acetaminophen can rapidly cause hepatocyte injury.
Acetaminophen toxicity produces the most common form or cause of ALF in the US,
accounting for 39% of cases in a recent survey of tertiary care centers,[73] both
after attempted suicide by acetaminophen overdose and after unintentional
overdose, in which use of the drug for pain relief in excess of the recommended
dose has occurred over a period of days.[74]
C. Experience
with clinical trial data
Possible “signals” for severe
DILI are abnormalities (signs or symptoms) that reflect ongoing liver injury 1)
in the same individual if drug is continued, and 2) in other drug-treated
individuals due to a common mechanism of toxicity.[75] Signals can be generated in clinical trials
by subjects with clinically mild reversible drug-induced liver injury.
The observation that
“instances (even very few of them) of transaminase
elevation accompanied by elevated bilirubin (even if
obvious jaundice was not present) have been associated with, and have often
predicted, post-marketing serious liver injuries (fatal or requiring
transplant)” was first made by Dr. Hyman Zimmerman,[76] and has
been dubbed “Hy’s Law”.[77] The ominous implications of Hy’s Law proved to be true for bromfenac,
dilevalol, troglitazone,
and trovafloxacin, even though no cases of
life-threatening serious injury were seen for any of these drugs pre-marketing.[78]
Zimmerman noted that
drug-induced hepatocellular jaundice is a serious
lesion, with mortality ranging from 10 to 50 percent.[79] More recent mortality estimates continue to
regard the combination of pure hepatocellular injury
and jaundice as ominous, with about 10-15% of patients who show such findings
as a result of drug-induced injury going on to die[80]. The
explanation for this outcome is that hepatocellular
injury great enough to interfere with bilirubin
excretion must involve a large fraction of the liver cell mass.[81]
Increased transaminases
alone – examples
Clinical trials with statins have generally shown an imbalance in transaminase elevations (ALT >3x ULN) between active
drug and placebo. However, extensive marketed experience with the older statins (e.g., simvastatin), as
well as several large morbidity and mortality trials[82], have shown
that serious liver injury occurs rarely, not exceeding background, with several
of these drugs. For instance, during clinical trials with lovastatin,
ALT > 3x ULN occurred in 2.6% and 5.0% of patients on doses of 20 mg and 80
mg/day, respectively. The elevations are reversible with continuing therapy and
are dose related. Postmarketing, lovastatin exposure
is estimated worldwide to be 24 million patient-years. Rare cases of liver
failure have been reported at a rate of approximately 1/1.14 million patient
years, which is approximately equal to the background rate of idiopathic ALF.[83]
Increased Hy’s
cases – examples
Troglitazone is an example where “Hy’s
cases” observed during clinical trials portended a significant postmarketing
issue with severe DILI and fatal liver failure. Troglitazone
is discussed below in Section D.
D. Specific
Examples – long-term indications (chronic therapy)
Troglitazone
In the clinical trials which
led to troglitazone’s approval by the FDA in 1997,[84] there
were no cases of liver failure in 2510 patients. In the NDA database (N=2510),
1.9% of troglitazone-treated patients had ALT >3x
ULN, 1.7% had ALT >5x ULN, and 0.2% (5 patients) had ALT >30x ULN (two of
whom also experienced jaundice). The median duration of troglitazone
therapy before peak ALT elevation was 121 days. In 1997, NIH sponsored a large
Diabetes Prevention Program[85]
designed to determine whether non-insulin-dependent diabetes mellitus can be
prevented or delayed in persons with impaired glucose tolerance. Study groups
included intensive lifestyle intervention with diet and exercise, metformin or troglitazone with
standard diet and exercise, and a control group. The troglitazone
arm was discontinued in 1998 due to reports of severe hepatotoxicity.[86] In the
NIH Diabetes Prevention Trial (N=585), 3.0% of troglitazone-treated
subjects had ALT >3x ULN, 1.5% had ALT >8x ULN, and two patients had ALT
>30x ULN. One of these patients developed liver failure and died, despite
receiving a liver transplant. The second patient recovered. The median duration
of troglitazone therapy before initial ALT elevation
was 126 days, and to peak elevation was 143 days.[87]
In response to worrisome and
continuing reports of ALF associated with troglitazone
use, a series of “Dear Healthcare Professional” letters were sent to practicing
physicians between 1997 and 1999, warning about severe liver injury and
recommending monthly transaminase monitoring.
Unfortunately, transaminase monitoring was not
regularly performed.[88]
Moreover, an analysis of 94 cases of liver failure which were reported
spontaneously to the FDA showed that the progression from normal hepatic
functioning to irreversible liver injury occurred within one month in 19
patients who were indistinguishable clinically from the 70 patients who had an
unknown time course to irreversibility. Of the 89 cases of ALF, only 11 (13%)
recovered without liver transplantation. The onset of injury began from three
days to after more than two years of troglitazone
use. Progression from jaundice to hepatic encephalopathy, liver
transplantation, or death was rapid, averaging 24 days. The authors concluded
that “progression to irreversible liver injury probably occurred within a
one-month interval in most patients, casting doubt on the value of monthly monitoring”
of serum transaminase levels as a means of preventing
severe DILI.[89]
A marked increase in risk
with each month of troglitazone use was demonstrated
by Graham[90]
in an analysis of interval-specific hazard rates (per million person-years) for
each month of continued troglitazone use, based on
ALF cases reported to the FDA (numerator) and the estimated person-years of troglitazone exposure for that corresponding month of use
(denominator). A table in that report is
reproduced below,[91] and
shows the cumulative risk of ALF calculated as “1-survival probability” for
each month of continued use, derived from the life-table analysis, and
expressed in the form of “1 case per x persons treated” for each month of
continued use (slide 29 in the original document).
This analysis of troglitazone data through the close of 1999 showed that the
interval-specific hazard rate was substantially elevated above the expected
background rate of one per million person-years beginning with the first month
of troglitazone use. The cumulative risk of ALF
increased from one case per 131,000 users at one month of use to one case per
7,000 users with 18 months of continued troglitazone
use.[92]
Table reproduced from Graham DJ, Green L. Final
Report: Liver Failure Risk with Troglitazone (Rezulin). FDA/CDER/ODS/DDRE consult, dated December 19,
2000.
More recently, the incidence
of hospitalized idiopathic acute liver injury and ALF in troglitazone-treated
patients was estimated in an observational retrospective cohort study using
claims data from a large multistate health care
organization.[93] The inception cohort included 7568 patients
who began troglitazone during the study period. A
total of 4020 person-years of exposure were observed. The incidence rates per
million person-years of acute idiopathic liver injury (95% CI) were as follows:
hospitalization with jaundice (n=4), 995 per million person-years (271, 2546);
ALF (n=1), 240 per million person-years (6.3, 1385). This represents a marked
increase in risk compared to estimated background rates of hospitalization for
idiopathic acute liver injury (22 per million person-years) and ALF (1 per
million person-years).[94]
Although the pathogenesis of troglitazone toxicity is not understood,[95]
experience with troglitazone provides a clear example
of a situation where “Hy’s Law” cases observed during
clinical trials prior to approval were predictive of a high risk of severe DILI
and ALF post marketing. Troglitazone was withdrawn
from the
Isoniazid
Isoniazid remains a first-line agent against tuberculosis, even
though increased levels of aminotransferase are
observed in 15 to 30 percent of patients who take the medication and one in
1000 patients will have severe hepatic necrosis.[97] [98] Recent
experience in public health clinics has shown that risk of severe hepatotoxic reactions to isoniazid
can be effectively minimized by instructing patients to stop drug and
immediately report symptoms of liver injury as soon as they occur.[99] In a recent 7-year survey from a public
health tuberculosis clinic in
Similar experience was
reported from a tuberculosis clinic in
Pemoline
Pemoline (Cylert®), a drug for the
treatment of ADHD, was approved by the FDA in 1975 as a Schedule IV stimulant.
At the time of approval, hepatic enzyme abnormalities were noted in 1% to 2% of
patients, leading to recommendations in the precautions section to monitor transaminase levels periodically. Postmarketing, cases of
liver injury, including ALF, were reported. An analysis of 13 cases of fulminant liver failure in children treated with pemoline which had been reported to the FDA prior to 1996
found that the median duration of pemoline use prior
to symptomatic liver disease was about 13 months, with the shortest duration
among the 13 cases being six months.[102]
These reports of serious DILI
and ALF prompted a labeling change in 1996 (black box warning) and a Dear
Healthcare Professional letter, shifting the drug from first-line to
second-line therapy for ADHD. In June 1999 another labeling change and Dear HCP
letter was issued, with new recommendations for baseline and bi-weekly transaminase monitoring. Compliance with labeling
recommendations was subsequently assessed, and was found to be poor in a
retrospective cohort study using administrative claims data.[103] Recently,
use of this drug has dropped sharply since there are several therapeutic alternatives.
A search of the AERS safety database (covering the period from June 1999
through January 2004) indicates that no unconfounded
cases of liver failure associated with pemoline
therapy administered after June 1999 have been received by the FDA.[104] An analysis
of drug utilization[105],[106]
shows that the use of the drug (brand and generic) has decreased substantially
over the last six years such that domestic use in 2003 (171,000 prescriptions)
was about 22% of its use in 1998 (773,000 prescriptions).
E. Specific
Examples – short- or intermediate-term indications
Bromfenac
Bromfenac (Duract®) was approved by
FDA in 1997 for use as a short-term analgesic for periods of 10 days or less.
Although no cases of serious liver injury were seen in clinical trials, the
product was approved only for short term use because a higher incidence of transaminase elevations were observed in patients treated
long-term in clinical trials. Bromfenac was never
approved as a treatment for chronic conditions such as osteoarthritis or
rheumatoid arthritis.[107] However, when used off label in such
patients, need for chronic pain relief increased the risk of longer term use,
despite precautions in the label.
During clinical trials, bromfenac use was associated with transaminase
elevations in approximately 15% of patients, and elevations >3x ULN were
seen in 2.7% of patients at some time during treatment. In contrast, the
incidence of such elevations was <0.4% during short-term therapy. In longer
term trials, marked elevations more than 8x ULN occurred in 0.4% of patients.[108]
Post-approval, reports of
hepatic failure, including four deaths and eight cases requiring liver
transplant, were received. All but one of these cases involved the use of bromfenac for more than ten days, the maximum recommended
duration of treatment. In response to the reports, FDA and the company
strengthened the warnings in the
Four patients with severe bromfenac hepatotoxicity were identified at three tertiary
care centers participating in the US Acute Liver Failure Study Group. Bromfenac had been administered for a minimum of 90 days at
usual dosages to four women who presented with severe, symptomatic hepatocellular injury with associated hypoprothrombinemia.
Despite supportive measures, all the subjects developed progressive liver
failure over 5 to 37 days, leading to liver transplantation in three patients
and death in one patient while awaiting transplantation. The authors concluded
that the “poor outcomes in this series, coupled with the inability to identify
individuals at risk for severe, idiosyncratic bromfenac
hepatotoxicity preclude further use of bromfenac in
the medical community.”[110]
Given the availability of
other therapies, in 1998 FDA and the company concluded that it would not be
practical to implement the restrictions necessary to ensure the safe use (less
than ten days) of bromfenac, and that the drug should
be withdrawn from the market.[111]
Analysis of drug utilization
during the two years prior to bromfenac’s withdrawal
from the market (1997-1998), shows that 55-60% of bromfenac
mentions in outpatient office visits were for intended therapy of 10 days or
less, based on information from an IMS Health, National Disease and Therapeutic
Index (NDTI™)[112],
which reflects the intention of the physician at the time of prescribing. Approximately
10-20% of mentions were for more than 10 days of intended treatment and 25-30%
had “unspecified” intended duration, suggesting that an even higher percentage
of mentions could have been for more than 10 days of intended treatment. Among
those physicians mentioning bromfenac during an
office-based visit, the intended duration of therapy ranged from one to 90
days, with the most mentions occurring for 10 days of therapy (approximately
21%).[113]
Trovafloxacin
Following the marketing of trovafloxacin (a fluoroquinolone
antibiotic) in 1998, FDA began receiving reports of patients with serious liver
reactions.[114] During pre-marketing clinical trials with trovafloxacin (N = 7000), there were no reports of liver
failure. Post-marketing, FDA received reports of over 100 cases of clinically
symptomatic liver toxicity, including 14 cases of ALF, many of which were fatal
and/or required liver transplant. Trovafloxacin-associated
liver failure appeared to be unpredictable, occurring after as few as two days exposure, but with a substantially increased risk noted
in patients receiving the drug for longer than two weeks.[115]
Time-to event analysis
(life-table estimation) showed an association between risk of developing ALF
and duration of therapy with trovafloxacin. A background
incidence rate for ALF due to idiopathic causes was estimated at one case per
million per year. Based on the 14 reports of ALF received by the FDA over a two
year period, the relative risk of ALF with trovafloxacin
was shown to be above background from the start of therapy, and to increase
rapidly with increasing duration of exposure.[116]
A Public Health Advisory was
issued by the FDA in 1999 which effectively restricted use of this drug to
hospitalized patients with certain serious life or limb-threatening infections.
The efficacy of liver function monitoring in acceptably monitoring the risk of
severe liver injury associated with trovafloxacin was
considered uncertain. The manufacturer of trovafloxacin
agreed to direct distribution of trovafloxacin only
to pharmacies in inpatient health care facilities (i.e., hospitals and
long-term nursing care facilities).[117]
F. Synopsis
- RiskMAP tools for drugs that induce liver injury - track record of efficacy
Transaminase Monitoring
A rationale of regular serum transaminase monitoring is predicated on full
characterization of the timing and tempo of liver injury as well as a high
level of compliance by patients and physicians. In fact, the utility of transaminase monitoring in preventing severe DILI has never
been convincingly demonstrated. Moreover, transaminase
monitoring has been shown to be ineffective as a risk minimization tool in the
case of troglitazone, isoniazid,
and lovastatin (as described in previous sections of
this review). Transaminase monitoring is ineffective
when the tempo of liver injury is such that inexorable progression occurs even
after the drug has been stopped in response to a signal of transaminase
elevation. The foremost requirement that determines the usefulness of transaminase monitoring in preventing frank liver injury is
that “the time interval between onset of liver chemistry abnormality and
subsequent liver injury must exceed the screening interval.”[118]
This was not the case with troglitazone. An analysis of spontaneously reported cases
of ALF associated with troglitazone showed that
“progression to irreversible liver injury probably occurred within a one-month
interval in most patients, casting doubt on the value of monthly monitoring” of
serum transaminase levels as a means of preventing
severe DILI.”[119] In addition, despite a series of “Dear
Healthcare Professional” letters recommending monthly monitoring, transaminase monitoring was not regularly performed.[120]
With regard to the utility of
transaminase monitoring as a method of minimizing
risk of liver injury, Lee concluded in a recent review article[121] that
“monitoring is unlikely to be effective in the case of a rare adverse reaction.
Monitoring is seldom performed consistently, and even if it were, it provides
no guarantee of safeguarding the patient, since many drug reactions develop
abruptly.” Rapid acceleration of liver injury in some individuals may preclude
an absolute protective value of standardized periodic transaminase
monitoring.[122]
Limited Duration of Therapy
Hepatotoxicity was generally
only observed with bromfenac in patients who took the
drug for more than 30 days; however, despite attempts to regulate the duration
of therapy by clear statements in product labeling, prescribers often did not
heed this information and fatal liver injuries still occurred (as described
previously in this review).[123]
Although not primarily for
reasons of hepatotoxicity, the USPI for Toradol (ketorolac tromethamine tablets)
includes a boxed warning which states that the duration of use is “not to
exceed 5 days because of the increased risk of serious adverse events.” An
analysis (using data from IMS NPAPlus™)[124] of the
average length of a prescription for oral ketorolac
during the five year period from June 1999 to May 2004 showed a fairly
consistent pattern, ranging from
Restricted Access and/or Restricted
Distribution
A Public Health Advisory was
issued by the FDA in 1999 which effectively restricted use of trovafloxacin to hospitalized patients with certain serious
life or limb-threatening infections. The efficacy of liver function monitoring
in acceptably monitoring the risk of severe liver injury
associated with trovafloxacin was
considered uncertain. The manufacturer of trovafloxacin
agreed to distribute trovafloxacin only to pharmacies
in inpatient health care facilities (i.e.,
hospitals and long-term nursing care facilities).[127] These
actions have resulted in a substantial decrease in trovafloxacin
utilization, and a corresponding decrease in spontaneous reports of liver
failure caused by this drug (there have been none reported to FDA since 1999).
Because of potential serious
liver injury, as well as potential fetal damage if taken during pregnancy, Tracleer (bosentan), a drug recently
approved for the treatment of pulmonary arterial hypertension in patients with
Class III or IV heart failure, is only available through the Tracleer Access Program. FDA approval of this drug was
contingent on several actions by the sponsor including 1) developing an
enhanced prescriber educational program; 2)
developing a program which ensures complete registration of all patients
receiving Tracleer; 3) developing a program to
provide complete registration and certification of practitioners who prescribe Tracleer; 4) developing a comprehensive program to track
and report to CDER all severe liver injuries; and, 5) developing a monitoring
program to facilitate on an annual basis an assessment of risk management
goals.
The Tracleer™
Access Program (TAP) provides a toll free line to physicians with initial
information about Tracleer, a site to report adverse
events, and customer service. Following the toll-free call, a completed patient
enrollment form is faxed to TAP to initiate the prescription, allowing a one
month supply (with refills), providing patient information and including
physician certifications. Each specialty distributor must agree to a defined
set of rules to sell Tracleer, including insertion of
patient reminders in the monthly prescription, generating a letter to the
prescribing physician stating the prescription has been filled, calling the
patient prior to shipment of the next month’s medication supply and asking
whether they’ve had a blood draw for liver tests, calling the physician if the
patient has not had a test within the last month, and determining the reason if
a planned refill does not occur. The patient enrollment form contains a
statement: “I certify that I am prescribing Tracleer
for this patient for a medically appropriate use in the treatment of pulmonary
arterial hypertension, as described in the Tracleer
full prescribing information. I have reviewed the liver and pregnancy warnings
with the patient and commit to undertaking appropriate blood testing for
monitoring liver function in this patient and testing for pregnancy (if the
patient is a female of child-bearing potential)”. This statement is followed by
a place for the physician’s signature.[128]
Labeling
A recent study of
FDA-approved product labeling for identified hepatotoxic
drugs indicated that the Physicians Desk Reference for the year 2000 included
black box warnings for severe liver toxicity for eleven non-generic drugs.
The labels for an additional
52 drugs were found to include Warnings or Precautions about liver failure
and/or necrosis.[129] The utility of Warnings or Precautions in
communicating risk information in an effort to prevent liver injury has not
been systematically evaluated. However, several studies of particular drugs
have found that product labeling may not meaningfully affect physician behavior.[130] [131] [132]
EXANTA RiskMAP
Review Team
Jeanine Best, MSN, RN, PNP,
Patient Product Information Specialist, DSRCS /s/7-23-04
Allen Brinker, M.D., M.P.H., Epidemiologist Team Leader, DDRE/s/
Mary Dempsey, Project Management Officer, ODS /s/8-02-04
Kate Gelperin, M.D., M.P.H., Medical
Epidemiologist, DDRE /s/8-3-04
Claudia
Karwoski, PharmD, Scientific Coordinator of RMP
(Detail), ODS IO /s/8-4-04
Quynh Nguyen, Pharm.D., Project Manager, DDRE /s/7-23-04
David Moeny, R.Ph., Drug Use Specialist,
DSRCS /s/
Toni Piazza-Hepp, Pharm.D., Deputy Director,
DSRCS /s/7-27-04
Giana Rigoni, Pharm.D., M.S.,
Epidemiologist, DSRCS /s/7-16/04
John Senior, M.D., Hepatology Expert, OPaSS
/s/7-23-04
Judy Staffa, Ph.D, R.Ph., Epidemiology Team
Leader /s/7-26-04
Leslie Wheelock,
M.S., R.N., Associate Director, DSRCS /s/7-28-04
______________________________
Anne
Trontell, M.D., M.P.H., Deputy Director
Office
of Drug Safety (ODS), HFD-400