# *FOOD AND DRUG ADMINISTRATION*

DIVISION OF ANTI-INFLAMMATORY, ANALGESIC AND OPHTHALMIC DRUG PRODUCTS
\-- HFD-550

### Medical Officer Review

NDA 21-042 and NDA 21-052

(Rofecoxib tablets and rofecoxib oral solution)

Re: [Complete response to Approvable letter for 21-042/S 007 and
21-052/S 004]{.underline}

Submission date (letter): July 12, 2001

End of Review date: November 28, 2001

Reviewer: Maria Lourdes Villalba, M.D.

Applicant: Merck Research Laboratories

Pharmacologic category: NSAID (COX-2 inhibitor)

Proposed indications: Management of acute pain, dysmenorrhea and signs
and symptoms of osteoarthritis.

Dosage form and route: Oral capsule, 12.5, 25 mg and 50 mg

Oral solution 12.5 mg/5ml and 25 mg/5ml

Project Manager:

Related reviews: NDA 21-042/S007 (VIGOR study)

Consults: Douglas Throckmorton, M.D. (HFD-110)

Eric Bastings, M.D. (HFD- 120)

Orig NDA \# 21042s007

HFD-550/Div File

HFD-550/PM/Gould
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

HFD-550/Statistics/SLin/QLi Maria Lourdes Villalba, M.D. (M.O).

HFD-550/MO/Villalba

HFD-550/TL/Goldkind

HFD-110/DDD/Thorckmorton

HFD-120/MO/EBastings

> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Lawrence Goldkind, M.D.,
>
> Deputy Division Director, DAIAODP

***Table of Contents***

**Table of Contents
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2**

**Executive Summary
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....
3**

**I. Recommendations
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....4**

> A. Recommendation on Approvability
> \...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...
> 4
>
> B. Recommendation on Phase 4 Studies and/or Risk Management
> Steps...........4

**II. Summary of Clinical Findings
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...
4**

> A. Brief Overview
> \...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....4
>
> B
> Safety\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....4
>
> C. Dosing
> \...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....6
>
> D. Special Populations
> \...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....6

**Clinical
Review\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....
8**

**I. Introduction and Background
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....
8**

**II. Description of Clinical Data and Sources
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....
8**

**III. Clinical Review Methods
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....
9**

**IV. Integrated Review of Efficacy (Not
applicable)\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....
9**

**V. Integrated Review of Safety
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\....
9**

> A. Brief Statement of Conclusions
> \...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\.....
> 9
>
> 1\.
> Advantage..............................................................\...............9
>
> 2\. Safety Update
> Report................................................\................12
>
> 3\. Rheumatoid Arthritis efficacy Safety
> database..................................13
>
> B. Description of Patient
> Exposure.......................................................13
>
> C. Summary of Critical Safety Findings and Limitations of
> Data.................\...14

**VI . Dosing, Regimen, and Administration Issues
\...\...\...\...\...\....,,,,,,,,,,,,\...\...\...\...\...\.... 14**

**VII. Use in Special
Populations..............................................................15**

**VIII. Appendices
\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...\...16**

> A. Review of Individual
> Studies.....................................\...............16
>
> 1\.
> ADVANTAGE..............................................................\...16
>
> 2\. Safety Update
> Report...............................................\............35
>
> 2.1 Overall
> Safety.....................................................\....35
>
> 2.2 Alzheimer\'s
> studies................................................. .37
>
> 3\. RA Safety
> database............................................................45
>
> B. Other relevant
> materials...........................\...\...\...\...\......................48
>
> Appendix 1.Narratives of deaths in ADVANTAGE
> study...................48
>
> Appendix 2.Serious AE's that resulted in hospitalization
> ............\.......50
>
> Appendix 3.List of preferred terms referred for
> adjudication...............53
>
> Appendix 4. Narratives of cases re-adjudicated by FDA
> reviewers........54
>
> Appendix 5. Cardiovascular data in
> VIGOR..................................56
>
> Appendix 6.Listing of deaths in Alzheimer\'s
> studies.........................59

##### **Clinical Review**

**NDA 21-042/s007**

**Complete Response to Approvable Letter (4/7/01)**

# *Executive Summary*

## **I. Recommendations**

### A. Recommendation of Approvability

NDA 21-042/s007 should be Approved including labeling language that
reflects available overall safety, gastrointestinal safety and
cardiovascular safety in the VIOXX databases. Until prospective,
randomized, adequately powered studies are performed, rofecoxib should
be used with caution in patients with known cardiovascular risk,
congestive heart failure and hypertension. FDA proposed labeling was
sent to the applicant in October 15, 2001.

### Recommendation on Phase 4 studies and/or Risk Management Steps

## 

## **If the sponsor proposes a new indication such as a preventive claim, studies should not exclude patients at high cardiovascular risk, should be adequately powered to detect statistical significant differences in cardiovascular safety and should incorporate overall safety, including total cause mortality, as part of the safety endpoints.**

The sponsor should consider long term safety studies of rofecoxib in
patients taking low dose aspirin to assess cardiovascular,
gastrointestinal and overall safety in this population.

## 

## **II. Summary of Clinical Findings**

### A. Brief Overview of the Submission 

The Complete Response to the Approvable letter issued to NDA 21-042/s007
in April 7, 2001 includes the report of the **ADVANTAGE** study (a
3-month study of rofecoxib 25 mg/day and naproxen 500 mg twice daily in
approximately 5600 patients with osteoarthritis -OA-) and a **Safety
Update Report** **(SUR)** (long-term follow up of patients in the
original OA program and safety data from studies not previously
submitted to the FDA). For completeness, a summary of the preliminary
**safety review of the rheumatoid arthritis (RA) efficacy application**
(NDA 21-042/s012) is included in this document. The RA efficacy
supplement evaluated rofecoxib 25 and 50 mg doses. The active comparator
was naproxen 500 mg twice daily. The current review focuses on overall
safety and cardiovascular safety from all these databases.

### 

### B. Efficacy -- Not applicable 

### Safety

1.  The following findings apply to the ADVANTAGE and RA safety
    databases:

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a.  Rofecoxib (25 or 50 mg) showed no overall safety advantage over
    naproxen 500 mg twice daily as measured by total number of deaths,
    serious AE's, hospitalizations, discontinuations due to AE's, and
    common AE's.

b.  Rofecoxib (25 or 50 mg) was associated with a nominally higher
    incidence of discontinuations due to HTN, edema and CHF-related
    events compared to naproxen 500 mg twice daily.

c.  Rofecoxib (25 mg or 50 mg) was associated with a nominally higher
    cardiovascular thrombotic risk (particularly an increased risk
    of MI) as compared to naproxen 500 mg twice daily.

> These trends (a, b and c) were observed in all studies that compared
> rofecoxib to naproxen: in OA and RA patients; users and non-users of
> low dose ASA for cardiovascular prophylaxis; short term studies (3
> months) and long-term follow up datasets (up to 3 years). These
> findings are highly consistent with those in VIGOR, a large
> prospective outcome study that compared rofecoxib 50 mg daily to
> naproxen 500 mg twice daily over a median treatment period of 9
> months. In VIGOR rofecoxib was associated with two fold risk of
> developing cardiovascular thrombotic events (p=0.001) and higher
> incidence of dropouts due to hypertension, edema and CHF related
> events compared with naproxen.
>
> The reason for the increased cardiovascular risk with rofecoxib 25mg
> and 50 mg compared to naproxen is still unknown.

2.  Cardiovascular safety of rofecoxib compared to NSAIDs other than
    naproxen.

> There is a spectrum of COX-1/COX-2 selectivity among NSAIDs. There are
> no adequate long-term data comparing the cardiovascular risk of
> rofecoxib to traditional NSAIDs other than naproxen. Studies in the
> original NDA 21-042 and the SUR, were inadequate in size and duration
> to assess safety differences (particularly GI and CV) between either
> dose of rofecoxib and individual NSAIDs. Meta-analyses of small
> studies of different design and duration using different NSAIDs and
> different doses of rofecoxib are not adequate to assess whether
> rofecoxib has a cardiovascular safety profile similar to other NSAIDs.

3.  Cardiovascular safety of rofecoxib compared to placebo.

> Data from the original NDA 21-042 and the SUR (including one-year
> placebo-controlled data from three studies of rofecoxib 25 mg in the
> prevention of Alzheimer's disease) do not provide adequate evidence
> that rofecoxib has a cardiovascular safety profile similar to placebo.
> Total cause mortality in the Alzheimer's studies was higher in
> rofecoxib (n=33) compared to placebo (n=20) (p=0.07, crude rate
> comparison). Of those, 9 and 4 were confirmed cardiovascular
> thrombotic deaths in the rofecoxib and placebo group respectively. Of
> note, although this was an elderly population (mean age 75 years),
> patients at high cardiovascular risk were not enrolled.

### D. Dosing

Large studies included in this application used the 25 mg dose.
Cardiovascular thrombotic events, hypertension, edema and congestive
heart failure-related findings at the 25 mg dose were consistent in
trend with the rofecoxib 50 mg dose.

### E. Special Populations

1\. Gender, age, race.

Effects of gender, age and race have not been addressed in this
supplement. For the purpose of addressing CV or GI safety, the number of
cases is small.

2\. Population using low dose aspirin for cardiovascular prophylaxis.

There are no adequate long term data on concomitant use of rofecoxib in
patients taking low dose aspirin (ASA) for cardiovascular prophylaxis.
Limited available data from ADVANTAGE suggest that:

-   the use of low dose ASA for cardiovascular prophylaxis may not
    eliminate the excess of cardiovascular events on rofecoxib 25 mg
    compared to naproxen among those patients at known cardiovascular
    risk.

-   the use of prophylactic low dose ASA may eliminate the GI advantage
    of rofecoxib compared to naproxen.

# *Clinical Review*

## I. Introduction and Background

Rofecoxib (VIOXX) is a non-steroidal anti-inflammatory drug (NSAID) with
selective COX-2 inhibitory properties. VIOXX was approved in May 1999
for the signs and symptoms of osteoarthritis (OA) at the doses of 12.5
and 25 mg once a day, and for the management of acute pain in adults and
dysmenorrhea (50 mg once a day). The use of VIOXX in children younger
than 16 years of age has not been studied.

There are currently multiple NSAID products approved for the above
indications. Celecoxib (CELEBREX), another COX-2 selective NSAID, is
approved for OA, rheumatoid arthritis (RA) pain and for the prevention
of polyps in patients with familial polyposis.

NDA 21-042/s007 was submitted in June 29, 2000. The submission included
the "VIGOR" study (VIOXX Gastrointestinal Outcome Research study),
studies 085 and 090 and preliminary safety data from a large study
referred to as the "ADVANTAGE" study (For a detailed review of this
submission the reader is referred to the 3/30/01 medical officer
review). NDA 21-042/s007 proposed the removal of the NSAID template GI
WARNING section of the VIOXX label. Review of the data supported some
modification but not removal of the GI WARNING section of the VIOXX
label. Additionally, rofecoxib 50 mg showed no advantage in overall
safety compared to naproxen 500 mg twice daily (deaths, serious adverse
events, discontinuations due to adverse events) and raised new concerns
regarding the cardiovascular safety of VIOXX: increased risk of serious
cardiovascular thrombotic events with rofecoxib compared to naproxen (RR
2.37, p =0.0016).

In April 6, 2001, FDA issued an Approvable letter to supplement 007
noting that changes from VIGOR should be incorporated into the label.
However, to optimally characterize the safety profile of VIOXX -
particularly overall safety and cardiovascular safety -- at doses
indicated for chronic use in a patient population that did not
specifically exclude low dose aspirin use, the division requested that
the complete report of the ADVANTAGE study be submitted for review.

## II. Description of Clinical Datasources 

The current document includes the review of:

-   The complete report of the **ADVANTAGE** study (submitted in pieces
    3/30/01, 4/13/01 and 4/16/01).

-   The **Safety Update report** **(SUR)**(submitted 7/12/01) which
    includes serious adverse events from the extension studies submitted
    in the original OA program (studies 029, 058, 034 and 035) and from
    studies that had not been previously submitted to the FDA: studies
    083 (bone mineral density); 120 and 121 (low back pain); 118
    (prostatitis pain); 903 (OA); five small studies of  6weeks
    duration comparing rofecoxib to other NSAIDs and studies 078, 126
    and 091 (prevention of Alzheimer's).

-   Safety data from the **RA efficacy application** database (NDA
    21-042/s012, submitted 2/28/01). (A summary of the Safety review is
    included in this document. A more detailed safety review and the
    Efficacy of the RA supplement are presented in a separate review).

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-   Additional data submitted in response to specific FDA requests for
    information (7/26, 7/30, 8/04, 8/17, 9/20, 20/01, 10/03, 10/05,
    10/08, 11/05, 11/26/01).

## 

## III. Clinical Review Methods

### 

### **The review was conducted by corroboration of sponsor's tables against full listings of adverse events as well as reviewing case report tabulations, selected case report forms and adjudication packages for cardiovascular events. Consults were obtained from the Division of Cardio-Renal (HFD-110) and Neuropharm (HFD-120) products for evaluation of specific cases where HFD-550 reviewer had concerns over accuracy of case adjudication. Published literature related to preclinical and clinical studies of COX-2 inhibitors was reviewed.**

The trials appeared to be conducted in accordance with accepted ethical
standards.

Evaluation of Financial Disclosure is not applicable. The main study in
this application -- the ADVANTAGE study -- was not a covered study.

## Integrated Review of Efficacy -- Not applicable

ADVANTAGE was a safety study. The SUR contained no efficacy data. The
efficacy of the RA supplement (s012) is reviewed separately.

## Integrated Review of Safety

A.  **Brief Statement of Conclusions:**

**1. ADVANTAGE**

ADVANTAGE was a double blind, randomized, 12-week controlled study (mean
duration of exposure 69  30 days), comparing rofecoxib 25 mg/day to
naproxen 1000 mg/day in patients with osteoarthritis. Approximately 2700
patients were randomized into each treatment arm. Approximately 13% of
patients were taking low dose aspirin for cardiovascular prophylaxis in
each treatment group.

a.  Rofecoxib 25 mg -- the dose approved for chronic use - showed no
    overall safety advantage over naproxen 500 mg twice daily, as
    measured by the total number of deaths, serious adverse events
    (AE's), discontinuations due to clinical/ laboratory AE's compared
    to naproxen. This is somewhat striking, given the theoretical
    assumptions of the COX-2 hypothesis and literature publications
    suggesting that COX-2 selectivity would provide superior safety than
    non-selective NSAIDs.

Table 1. ADVANTAGE Overall Safety parameters. Percentage of patients
with events.

+----------------------+----------------------+------------------------+
|                      | Rofecoxib 25 mg      | Naproxen 500mg bid     |
|                      |                      |                        |
|                      | (N= 2785)            | (N=2772 )              |
+----------------------+----------------------+------------------------+
| Deaths               | 0.2                  | 0.1                    |
|                      |                      |                        |
| Serious AE           | 2.4                  | 2.6                    |
|                      |                      |                        |
| Dropouts AE          | 13.4                 | 13.9                   |
|                      |                      |                        |
| Hospitalizations     | 1.9                  | 1.7                    |
|                      |                      |                        |
| Dropouts Lab AE      | 0.4                  | 0.2                    |
+----------------------+----------------------+------------------------+

b.  Consistent with VIGOR, there was a trend of excess in serious
    cardiac thrombotic events in the rofecoxib 25 mg group, compared to
    the naproxen group (ten and three events, respectively, as per FDA
    review). There were five myocardial infarction (MI), two anginal
    events and three sudden deaths in the rofecoxib 25 mg group and one
    MI and two angina (no sudden deaths) in the naproxen group. There
    were also two and five ischemic cerebrovascular events in the
    rofecoxib and naproxen groups, respectively. Two of the four CVA's
    on naproxen were on concomitant estrogen replacement therapy. There
    were no hemorrhagic strokes in the naproxen group.

c.  Consistent with VIGOR twice the number of patients discontinued due
    to cardiovascular related adverse events (40 and 21 from the
    rofecoxib and naproxen groups, respectively). More patients
    discontinued due to HTN related events (15 and 7); edema related
    events (19 and 12) and laboratory adverse events (11 and 6) in the
    rofecoxib 25 mg group as compared to the naproxen group. There were
    more CHF related events (11 and 6) in the rofecoxib group as
    compared to the naproxen group.

d.  More patients discontinued due to serious GI events in the naproxen
    group (142) as compared to the rofecoxib 25 mg group (113). There
    were 1 and 4 confirmed complicated PUBs in the rofecoxib and
    naproxen arm, respectively. The number of clinically relevant GI
    events is small but the trend was consistent with the VIGOR study.

e.  Special populations: co-use of low dose ASA for cardiovascular
    prophylaxis

-   Data suggest that the use of prophylactic ASA may not eliminate the
    excess of cardiovascular events on rofecoxib compared to naproxen.

> The number of investigator reported serious cardiovascular adverse
> events for all patients (ASA users and non-users) was 23 (0.8 %) and
> 17 (0.6%) in the rofecoxib and naproxen groups, respectively. The
> number of these events in the subgroup of patients at known
> cardiovascular risk -- as defined by concomitant use of low dose ASA
> -- was 7/ 352 (2.0 %) and 2/ 367 (0.5 %) in the rofecoxib and naproxen
> group, respectively. These findings are not inconsistent with VIGOR,
> in which a post-hoc analysis conducted by the sponsor showed that the
> relative risk of developing serious cardiovascular thrombotic events
> for rofecoxib compared to naproxen increased from two fold in the
> whole population (RR:2.37, p= 0.001 for rofecoxib vs. naproxen) to
> five fold among those patients who might have benefited from
> prophylactic ASA (RR: 4.89, p= 0.01 for rofecoxib vs. naproxen).
>
> If the cardiovascular findings in VIGOR were all explained by naproxen
> anti-platelet effect, a difference would not be expected between
> naproxen and rofecoxib in ADVANTAGE, when patients at risk in both
> treatment groups were already maximally protected by ASA.

-   Data suggest that the use low dose aspirin -- such as the dose used
    for cardiovascular prophylaxis - may eliminate the GI advantage of
    rofecoxib over naproxen.

> The number of serious gastrointestinal adverse events for all patients
> in the trial showed a trend in favor of rofecoxib (n=7, 0.3%) as
> compared to naproxen (n= 21, 0.8%). In this short trial, co-use of low
> dose ASA increased the risk of serious GI events for rofecoxib (n=2
> out of 352, 0.6%) but did not appear to increase the risk for naproxen
> (2 out of 367, 0.8%, unchanged). The ADVANTAGE study was too short and
> the number of events too small to adequately assess clinically
> significant GI events, particularly in the subgroup of patients using
> ASA, but the limited data suggest that the effects of low dose aspirin
> may counterbalance the COX-1 spearing effect of rofecoxib in the GI
> tract.

f.  The findings of the ADVANTAGE study are consistent with those of the
    VIGOR and the RA efficacy databases. The CV findings are of concern
    because this is only a 12-week study, the dose of rofecoxib used in
    this study is 25 mg/day (half of the dose used in VIGOR), this was a
    different population of patients (OA instead of RA) and patients
    were allowed to use aspirin if indicated for cardiovascular
    prophylaxis. However, ADVANTAGE was not designed to address serious
    gastrointestinal or cardiovascular adverse events. It was too short
    and the number of clinically relevant adverse events was relatively
    small.

2\. **Safety Update Report.**

There is no adequate evidence that rofecoxib has a cardiovascular safety
profile similar to placebo or other NSAIDs.

a.  Studies that compared rofecoxib to non-naproxen NSAIDs in the
    original NDA database and subsequently, involved too few patients to
    adequately assess differences in cardiovascular safety between
    rofecoxib and each NSAID. Studies with nabumetone were of 6 weeks
    duration; studies with ibuprofen were of 6 weeks to 6 months
    duration.; studies with diclofenac were of one year duration. Some
    of these studies had blinded extensions, but the actual number of
    patients exposed for a year or longer is very limited.

> Meta-analyses of small studies of different duration, different size
> and different design, involving different patient populations and
> different doses of rofecoxib can not adequately assess the
> cardiovascular safety of rofecoxib compared to individual NSAIDs.

b.  Analyses of data from the Alzheimer's studies provide valuable one-
    year placebo-controlled data in patients age 50 years or older.
    However, the studies were not powered to detect differences in
    cardiovascular safety between rofecoxib and placebo (approximately
    1500 patients randomized per treatment arm, considering the three
    studies together). Additionally, the studies excluded patients who
    had an indication for aspirin prophylaxis and those taking estrogen
    replacement therapy. After enrollment was complete, a protocol
    amendment allowed the use of low dose aspirin in those patients who
    might benefit from it for cardiovascular prophylaxis. A small
    percentage of patients were put on low dose ASA (approximately 7%).

> Although not a pre-specified endpoint, total cause mortality in the
> Alzheimer's studies was higher in the rofecoxib group (n=33) compared
> to the placebo group (n=20) (p= 0.07 for crude rate comparison). The
> trend of more deaths in the rofecoxib group as compared to placebo was
> consistent in study 091 and 078. Study 126 was terminated early due to
> lack of efficacy in study 091.
>
> Of all deaths, eight and four were confirmed cardiovascular thrombotic
> deaths by the CV adjudication committee in the rofecoxib 25 mg and
> placebo groups, respectively. This finding suggests a drug effect,
> rather than a lack of anti-platelet effect of rofecoxib. There were no
> differences in the number of serious cardiovascular potentially
> thrombotic events referred for adjudication in each treatment group
> (approximately 60 in each). A detailed review of these cases is being
> conducted by the Division of Cardio-renal products (HFD-110).

3\. RA efficacy supplement safety database

a.  Consistent with VIGOR and ADVANTAGE, rofecoxib 25 and 50 mg showed
    no overall safety advantage over naproxen, as measured by the total
    number of deaths, serious adverse events (AE's), discontinuations
    due to clinical and laboratory AE's and common AE's compared to
    naproxen.

b.  Consistent with VIGOR and ADVANTAGE, rofecoxib 25 and 50 mg was
    associated with higher incidence of HTN, edema and CHF-related
    events compared to naproxen 500 mg twice daily. Incidence of HTN was
    consistently two to three fold higher for rofecoxib 25 and 50 mg as
    compared to naproxen.

c.  Consistent with VIGOR and ADVANTAGE, the RA databases suggest an
    increased cardiovascular thrombotic risk (particularly an increased
    risk of MI) for rofecoxib 25 and 50 mg as compared to naproxen 500
    mg twice daily. There were 4 MI in the rofecoxib 25 mg group (501
    patient/years at risk), 5 MI and one sudden death in the rofecoxib
    50 mg group (430 patient years at risk) and one MI in the naproxen
    group (406 patient years at risk).

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B.  **Description of Patient Exposure**

The ADVANTAGE study included approximately 5600 patients exposed to
either rofecoxib 25 mg or naproxen 500 mg bid, with a median duration of
exposure of 84 days.

The Safety Update Report includes approximately 4000 patients who
received rofecoxib 25 or 50 mg of whom 1000 participated in extension
studies to the original NDA OA program and 3000 participated in new
studies not previously submitted to the Agency. The duration of these
studies were from 4 weeks to 15 months. The size of the studies varied
from a 50-patient per arm study to a 700-patient per arm study. The
comparators were naproxen (approximately 500 patients), diclofenac/
misoprostol (approximately 500 patients) and ibuprofen ( approximately
150 patients). The Alzheimer's studies randomized approximately 3000
patients to rofecoxib 25 mg (1500) or placebo (1500) and provide safety
information for approximately 1500 patient years at risk. At the time of
the submission (cut-off date for the SUR was April 2001) one of the
three studies was completed (#091) one was ongoing (#078) and one had
been terminated earlier (#126).

Approximately 1500 patients were randomized to rofecoxib 25 mg (n= 797)
and 50 mg (n= 677) in 3-month placebo controlled studies. Approximately
180, 140 and 80 patients were exposed to rofecoxib 25mg, rofecoxib 50mg
and naproxen 1000 mg respectively, for one year or more.

**C. Summary of Critical Safety Findings and Limitations of Data**

Consistent with the VIGOR study, a 8000-patient study of rofecoxib 50 mg
and naproxen 1000 mg in patients with RA, the data reviewed in this
submission (ADVANTAGE, SUR, RA efficacy) suggest an increased
cardiovascular risk (cardiovascular thrombotic events, hypertension,
edema, congestive heart failure) in patients treated with rofecoxib 25
and 50 mg as compared with naproxen 1000 mg daily. The major limitations
of these databases are

1.  Patients at high cardiovascular risk regardless of the use of
    aspirin were excluded from most of the studies.

2.  The majority of studies of rofecoxib did not allow inclusion of
    patients using prophylactic low dose ASA. The only large study that
    allowed prophylactic ASA was ADVANTAGE, a study too short to assess
    long term effects of co-use of rofecoxib and low dose ASA. (13% of
    patients were on low dose ASA in each group). A few other studies
    that allowed inclusion of patients on low dose ASA were small and
    shorter than 6 weeks.

3.  Naproxen was the NSAID comparator for most trials (ADVANTAGE, VIGOR,
    RA efficacy studies). Comparative safety data to NSAIDs other than
    naproxen are limited to small numbers in relatively short trials.

4.  The complete comparative safety information between rofecoxib and
    placebo in the Alzheimer's studies has not been provided. Listings
    of serious adverse events and deaths and adjudication packages for
    cases that were referred to the CV adjudication committee have been
    provided for all three studies. Discontinuations due to AE were
    provided only study 091. Full safety reports are to be submitted.

**VI. Dosing, Regimen and Administration issues**

VIOXX (rofecoxib) is approved for the treatment of the signs and
symptoms of OA at the doses of 12.5 and 25 mg daily and for the
management of acute pain in adults and dysmenorrhea, at the dose of 50
mg once a day.

Large studies included in this application used the 25 mg dose.
Hypertension, edema and congestive heart failure related findings with
rofecoxib 25 mg dose were consistent in trend with the 50 mg dose.

The current label states that the use of the 50 mg dose in acute pain
for more than 5 days has not been studied. However, in view of the
safety issues associated with the chronic use of 50 mg (i.e.
hypertension, edema, congestive heart failure and cardiovascular
thrombotic events) in the VIGOR study, the label should state that the
chronic use of VIOXX 50 mg dose is not recommended.

## VII. Use in Special Populations

A. Effects of gender, age and race have not been addressed in this
supplement. Number of events are small to adequately assess CV or GI
safety in these subgroups.

B. Comments on Data Available or Needed in Other Populations: Population
using low dose aspirin for cardiovascular prophylaxis.

Available data from VIGOR and the RA efficacy database suggest an
increased risk of serious cardiac thrombotic events in patients with
prior cardiovascular risk taking rofecoxib 25 and 50 mg as compared to
naproxen 500 mg twice daily. The sponsor has speculated that the excess
risk in the rofecoxib group may be due to the lack of anti-platelet
effect of rofecoxib compared to naproxen and that addition of low dose
ASA in high risk patients may bring down that excess cardiovascular
risk.

The limited data from the ADVANTAGE study suggest that the use of low
dose ASA in patients with prior cardiovascular history, might not
eliminate the excess risk of serious cardiovascular events of rofecoxib
compared to naproxen. Patients on low dose aspirin prophylaxis showed a
trend towards more cardiovascular events than those not requiring
aspirin in the rofecoxib arm (2.0% and 0.5%). This was not the case in
the naproxen treated subjects (0.6% and 0.5%, respectively). This
information suggests that the excess risk of CV thrombotic events on
rofecoxib as compared to naproxen may be due to some mechanism other
than the antiplatelet effect of naproxen. (See IV, 1, d.).

The long term effects of rofecoxib on the cardiovascular and
gastrointestinal system in patients taking low dose aspirin has not been
adequately assessed.

**VIII. Appendices**

**A. Review of Individual Studies**

**1.0 ADVANTAGE study**

1.1 Protocol design

The ADVANTAGE study (**A**ssessment of **D**ifferences between
**V**IOXX™ **A**nd **N**aproxen **to** **A**scertain
**G**astrointestinal Tolerability and **E**ffectiveness) was a
randomized, double-blind, multicenter, active-controlled, 12-week study
to evaluate rofecoxib 25 mg q.d. and naproxen 500 mg b.i.d. in patients
with osteoarthritis (Protocols 102 and 903-0A). The use of low dose
aspirin for cardiovascular prophylaxis was allowed in the study.
Acetaminophen was allowed as a rescue medication in a PRN basis.

The study enrolled approximately 5,500 patients with OA of the knee,
hip, hands, or spine, involving 581 investigators in the United States
(protocol 102) and 19 investigators in Sweden (protocol 903-0A), from
March 1999 to April 2000. Both protocols were identical as written and
as implemented, except that the Swedish protocol did not enroll patients
with OA of the hands. The data from both protocols were combined into
one dataset, and the methods and results sections of this study report
describe both protocols as a single study.

> *Reviewer's note: Although the title suggests that the protocol
> evaluated the effectiveness of rofecoxib, this was a safety study. The
> heterogeneity of the population regarding OA signal joint and the
> endpoints used in this trial do not allow adequate efficacy
> assessments. The trial was intended as a GI tolerability study. The
> primary hypothesis was GI tolerability but given size of the study,
> overall safety is as important as GI safety from the Public Health and
> consumer awareness point of view.*

2.  Eligibility criteria

In general, the inclusion/exclusion criteria were similar to those used
for other rofecoxib trials. The main differences between VIGOR and
ADVANTAGE were:

1.  ADVANTAGE included a population of patients with OA instead of RA.

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2.  Patients taking low dose aspirin (ASA) for cardiovascular
    prophylaxis were allowed in the ADVANTAGE study. Patients with
    recent history of MI, TIA or stroke were not explicitly excluded
    from the study. However, similar to VIGOR, patients on warfarin,
    heparin, ticlopidine and high dose aspirin were not to be included
    in the study.

> Low dose ASA was defined for this study as doses of 81 mg/day or less.
> Some patients took up to 325 mg/day during the trial and they were
> included under the low-ASA user group.

1.3 Endpoints

The primary variable was GI tolerability, defined by the sponsor for
this particular protocol as the cumulative incidence of discontinuation
due to a GI AE (digestive events and abdominal pain). Other safety
measures were AE incidence profiles, vital signs, and laboratory
evaluations. Clinical data were collected during clinic visits (at
baseline, at 6 and 12 weeks and early discontinuation) and via telephone
contact (at 3 and 9 weeks of therapy). Laboratory parameters were
measured at entry, week 12 and at early discontinuation visits.

> *Reviewer's comment: This review will focus on the overall safety,
> cardiovascular safety and NSAID-related AE's.*

All subgroup safety analyses, including ASA user subgroups, were
performed post hoc. All post hoc analyses were specified in the Data
Analysis Plan (DAP), and most parameters were established prior to study
unblinding, except the analysis of cardiovascular thrombotic events and
the analysis of the number of perforations, ulcerations, and GI bleeds
(PUBs) confirmed by adjudication and per 100 patient years.

1.4 Results.

1.4.1 Patient disposition and accounting is presented in Table 2.

Table 2. Patient disposition and accounting (Source: Sponsor's Table 20)

+------------------------+----------------------+----------------------+
|                        | Rofecoxib 25 mg qd   | Naproxen 500mg bid   |
+------------------------+----------------------+----------------------+
| Patients randomized    | 2799                 | 2787                 |
|                        |                      |                      |
| Patients treated       | 2785                 | 2772                 |
|                        |                      |                      |
| Discontinued           | 757 (27.2)           | 788 (28.4)           |
|                        |                      |                      |
| Clinical AE            | 374 (13.4)           | 386 (13.9)           |
|                        |                      |                      |
| Laboratory AE          | 11 (0.4)             | 5 (0.2)              |
|                        |                      |                      |
| Protocol deviation     | 29 (1.0)             | 24 (0.9)             |
|                        |                      |                      |
| Lost to follow up      | 52 (1.9)             | 64 (2.3)             |
|                        |                      |                      |
| Withdrew consent       | 89 (3.2)             | 112 (4.0)            |
|                        |                      |                      |
| Lack of efficacy       | 177 (6.4)            | 176 (6.3)            |
|                        |                      |                      |
| Other                  | 25 (0.9)             | 21 (0.8)             |
+------------------------+----------------------+----------------------+

Similar number of patients discontinued from each treatment group
(27-28%). The cause of discontinuation was also similar in both
treatment groups. Of note, a relatively high number of patients (89 (3%)
and 112 (4%) in the rofecoxib and naproxen arm, respectively) withdrew
consent.

> *Reviewer's comment: Sponsor states that due to questionable validity,
> data from the 12 patients enrolled from site No. 378 were excluded
> from all analyses. These patients are not included in the total
> patient count noted above.*

2.  Demographic characteristics

The two treatment groups had similar demographic characteristics,
arthritis treatment history at baseline and history of GI symptoms
associated with NSAID use. The majority of patients were female (71.0%),
and most were white (86.8%). The mean and median duration of disease
were similar for both groups (approximately 69 and 84 months,
respectively).

The majority of patients had used only NSAIDs prior to study entry
(approximately 62% in each group). Approximately 15% had stopped NSAID
treatment due to GI symptoms in the past in each arm. Patient age ranged
from 36 to 97 years, with a mean age of 63 years. The most common signal
joint was the knee followed by hand, spine and hip.

> *Reviewer's comment: The rofecoxib group included somewhat more
> patients with knee OA and less patients with hip OA as compared to the
> naproxen group. Since this is not an efficacy study, this difference
> is irrelevant.*

1.4.3 Secondary diagnoses

The incidence of secondary diagnoses at entry were similar in both
groups. Of note, 58.6% and 60.6% of patients had a diagnosis related to
the cardiovascular system in the rofecoxib and naproxen groups,
respectively. Approximately 45% of patients in each group had a history
of hypertension.

> *Reviewer's comment: The percentage of patients with diagnoses related
> to the CV system is similar, but a 2 % difference represents 50 more
> patients with history of cardiovascular disease in the naproxen group
> and may meaningfully impact cardiovascular event rates..*

1.4.4 Prior medications

The most common medications received within 30 days prior to visit 1
were acetaminophen (38%), celecoxib (19%), ibuprofen (19%) conjugated
estrogenic hormones (17%) and aspirin (17%). Prior medications related
to the cardiovascular system, coagulation system and hormonal
replacement are presented in Tables 3, 4 & 5.

Table 3. ADVANTAGE: Prior medication related to the cardiovascular
system

+---------------------------+--------------------+--------------------+
|                           | Rofecoxib 25 mg/d  | Naproxen 1000 mg/d |
|                           |                    |                    |
|                           | N= 2785            | N= 2772            |
|                           |                    |                    |
|                           | n %                | n %                |
+---------------------------+--------------------+--------------------+
| Renin-angiotensin system  | 593. (21.3)        | 614. (22.2)        |
|                           |                    |                    |
| Antihypertensives         | > 132 (4.7)        | ```{=html}         |
|                           |                    | <!-- -->           |
| Beta blocking             | 390. (14.0)        | ```                |
|                           |                    | 149. (5.4)         |
| Calcium channel blockers  | ```{=html}         |                    |
|                           | <!-- -->           | ```{=html}         |
| Cardiac therapy           | ```                | <!-- -->           |
|                           | 408. (14.6)        | ```                |
| Diuretics                 |                    | 418. (15.1)        |
|                           | > 114 (4.1)        |                    |
| Peripheral vasodilators   |                    | ```{=html}         |
|                           | 536. (19.2)        | <!-- -->           |
| Serum lipid reducing      |                    | ```                |
| agents                    | ```{=html}         | 440. (15.9)        |
|                           | <!-- -->           |                    |
|                           | ```                | ```{=html}         |
|                           | 13. (0.5)          | <!-- -->           |
|                           |                    | ```                |
|                           | 564 (20.3)         | 127. (4.6)         |
|                           |                    |                    |
|                           |                    | ```{=html}         |
|                           |                    | <!-- -->           |
|                           |                    | ```                |
|                           |                    | 560. (20.0)        |
|                           |                    |                    |
|                           |                    | ```{=html}         |
|                           |                    | <!-- -->           |
|                           |                    | ```                |
|                           |                    | 16. (0.6)          |
|                           |                    |                    |
|                           |                    | 523 (18.9)         |
+---------------------------+--------------------+--------------------+

(source Sponsor's Table 14, appendix 1.4)

Table 4. Prior use of antithrombotic agents

+---------------------------+--------------------+--------------------+
|                           | ROFECOXIB 25 MG    | NAPROXEN 1000 MG   |
|                           |                    |                    |
|                           | N= 2785            | N= 2772            |
|                           |                    |                    |
|                           | n %                | n %                |
+---------------------------+--------------------+--------------------+
| Clopidogrel bisulfate     | 4 (0.1)            | > 7 (0.3)          |
|                           |                    | >                  |
| Dipyridamole              | 4 (0.1)            | > 10 (0.4)         |
|                           |                    | >                  |
| Ticlopidine               | 1 (0.1)            | > 0                |
|                           |                    | >                  |
| Warfarin sodium           | 6 (0.3)            | > 1 (0.0)          |
+---------------------------+--------------------+--------------------+

(source Sponsor's Table 14, appendix 1.4)

> *Reviewer's comment: Similar percentage of patients had received
> cardiovascular medication and discontinued antithrombotic therapy
> within 30 days of entering the study. At the reviewer's request the
> sponsor provided information that none of these patients developed a
> serious cardiovascular thrombotic event during the trial.*

Table 5. Advantage: Prior use of hormonal therapy

+---------------------------+--------------------+--------------------+
|                           | Rofecoxib 25 mg/d  | Naproxen 1000 mg/d |
|                           |                    |                    |
|                           | N= 2785            | N= 2772            |
|                           |                    |                    |
|                           | n %                | n %                |
+---------------------------+--------------------+--------------------+
| Endocrine therapy^1^      | 86. (3.1)          | > 64 (2.3)         |
|                           |                    | >                  |
| Sex hormones and          | 875 (31.4)         | > 859 (31.0)       |
| modulators of the genital |                    |                    |
| system^2^                 |                    |                    |
+---------------------------+--------------------+--------------------+

Soruce: Sponsor's Table 14. Appendix 4.1) ^1^: Endocrine therapy
includes mainly raloxifene and tamoxifen. ^2^: Sex hormones includes
mainly estrogenic and progesterone-related hormones.

There were no significant differences in the number of patients who took
hormone replacement therapy (HRT) prior to the trial. Approximately 31 %
of patients took "hormones and modulators of the genital system" during
the trial, including different estrogenic preparations with or without
progesterone (n=741 and 720) progestins alone (n=145 and 151) or
testosterone (n=12 and 10) in the rofecoxib and naproxen group
respectively.

ASA was a prior medication in 470 (16.9%) and 474 (17.1%) patients in
the rofecoxib and naproxen groups, respectively*.* Aspirin is listed
among the analgesic, regardless of the dose that was taken.

> *Reviewer's comment. The sponsor did not specify the dose of ASA taken
> prior to entry. Of note, 360 and 372 patients used concomitant ASA
> during the study, in the rofecoxib and naproxen group, respectively.
> Therefore, approximately 100 patients in each arm discontinued the use
> of ASA before entering the study. At the reviewer's request the
> sponsor provided information that only one of the patients who
> discontinued ASA prior to study entry developed a serious CV
> thrombotic event (AN 2401) who was taking ASA 1300 mg/day for the
> treatment of OA, not for cardioprotection. This patient (on rofecoxib
> 25 mg) developed superficial venous thrombophlebitis. The event was
> not confirmed as serious cardiovascular thrombotic by the adjudication
> committee.*

1.4.5 Exposure

Although designed as a 3-month study, actual exposure was significantly
shorter. Median exposure to both rofecoxib and naproxen was 84 days
(mean was approximately 69  30 days). Overall, most of the patients
were compliant with dosing (88.8%). The percentage of patients with 80%
compliance was similar in both treatment groups.

4.  Safety Results

    1.  Overall safety

There was no overall advantage for rofecoxib 25 mg/d over naproxen 1000
mg/d. The numbers of patients with one or more adverse events (AE's),
serious AE's, who died or discontinued due to an AE were similar in both
treatment groups.

Table 6. NDA 21-042. ADVANTAGE study. Clinical Adverse Event Summary.

+------------------------------+--------------------+------------------+
|                              | Rofecoxib 25 mg/d  | Naproxen 500 mg  |
|                              |                    | b. (N= 2772)     |
|                              | (N= 2785)          |                  |
+------------------------------+--------------------+------------------+
| With one or more AEs         | 1814 (65.1)        | 1825 (65.8)      |
|                              |                    |                  |
| With serious AEs             | 68 (2.4)           | 72 (2. 6)        |
|                              |                    |                  |
| Who died                     | 5 (0.2)            | 4 (0.1)          |
|                              |                    |                  |
| Who discontinued due to an   | 374 (13.4)         | 386 (13.9)       |
| AE                           |                    |                  |
+------------------------------+--------------------+------------------+

Source sponsor's table 21.

1.5.1.1 Deaths

There were 5 deaths in the rofecoxib group (0.2%) and 4 in the naproxen
group (0.1%) (Table 7). Except for one 56-year-old patient who died of
complications of gallbladder carcinoma, all patients were older than 70
years.

Four of the five deaths in the rofecoxib group were due to
cardiovascular causes (three sudden death, one ruptured aortic
aneurism). There were no cardiovascular deaths in the naproxen group. Of
note, one patient with prior borderline renal function taking furosemide
died of complications of acute renal failure in the naproxen group. None
of the deaths were considered by the investigator to be drug-related.
Narratives of deaths are presented in Appendix 1.

Table 7. Listing of Deaths in the ADVANTAGE study

+-------+----+----------------+-------------------+--------------+---+
| AN    | Ag | Prior Medical  | Concomitant       | Cause of     | D |
| /site | e/ | History        |                   | death        | a |
|       | s  |                | medications       |              | y |
|       | ex |                |                   |              |   |
|       |    |                |                   |              | \ |
|       |    |                |                   |              | # |
+-------+----+----------------+-------------------+--------------+---+
| Rofe  |    |                |                   |              |   |
| coxib |    |                |                   |              |   |
+-------+----+----------------+-------------------+--------------+---+
| 500   | 73 | HTN, lip, K  | none              | Sudden death | 4 |
| 5/065 | F  |                |                   |              | 0 |
|       |    | DM, CAD, CABG, | **ASA, ACE(-),    | Sudden death |   |
| 370   | 74 | lip           | statin, glybur**  |              | 4 |
| 0/200 | M  |                |                   | Astrocytoma  | 2 |
|       |    | \-             | none              |              |   |
| 485   | 71 |                |                   | Sudden death | 1 |
| 6/210 | F  | A fib, HTN,    | digoxin,          |              | 2 |
|       |    | CAD,           | diltiazem         | Rupture      | 0 |
| 404   | 71 |                |                   | aortic aneur |   |
| 9/658 | M  | Hematuria      | none              |              | 6 |
|       |    |                |                   |              | 0 |
| 342   | 75 |                |                   |              |   |
| 3/679 | F  |                |                   |              | 4 |
|       |    |                |                   |              | 2 |
+-------+----+----------------+-------------------+--------------+---+
| Nap   |    |                |                   |              |   |
| roxen |    |                |                   |              |   |
+-------+----+----------------+-------------------+--------------+---+
| 184   | 56 | \-             | none              | Gallbladder  | 1 |
| 1/059 | F  |                |                   | Ca.          | 2 |
|       |    | DM, HTN,       | aleandronate,     |              | 0 |
| 715   | 79 | anasarca       | glypzide          | Pancreatic   |   |
| 4/702 | F  |                |                   | Ca.          | 9 |
|       |    | HTN,C          | verapamil,        |              | 0 |
| 310   | 74 | HF,depression, | ACE(-), lasix,    | Acute renal  |   |
| 5/777 | F  | hyperuricemia, | fluoxetine        | failure      | 4 |
|       |    | Cr. 1.5        |                   |              | 0 |
| 711   | 78 |                | ASA               | Lung Ca      |   |
| 4/831 | M  | COPD, PVD,     |                   |              | 6 |
|       |    | smoker         |                   |              | 0 |
+-------+----+----------------+-------------------+--------------+---+

Source: Advantage CSR.

> *Reviewer's comment:*
>
> *Of note, the cause of death for patient \# 065 5005 (on rofecoxib),
> had been listed by the investigator as hypertensive heart disease and
> **[not]{.underline} [referred]{.underline} for adjudication** as a
> potential cardiovascular thrombotic event to the cardiovascular
> adjudication committee. The patient called her son complaining of
> chest pain and by the time the son arrived she was dead. In the
> opinion of this medical reviewer, the cause of death for this patient
> was sudden death, which would in fact meet criteria for cardiovascular
> thrombotic event.*

1.5.1.2 Serious AEs

A total of 140 patients - 68 (2.4%) in the rofecoxib group and 72 (2.6%)
in the naproxen group - had at least one serious clinical AE during the
study.

The findings of this large but relatively short study (3 months) with
the rofecoxib 25 mg dose are consistent with those in the longer term
(9-month) VIGOR study at the 50 mg dose. Again there is a lower number
of digestive system related AE's in the rofecoxib group, but there is no
overall advantage of rofecoxib over naproxen.

Table 8. Serious AE's occurring in two or more patients in ADVANTAGE.

+-------------------------------+------------------+------------------+
|                               | Rofecoxib 25 mg  | Naproxen 1000 mg |
|                               |                  |                  |
|                               | N= 2785          | N= 2772          |
|                               |                  |                  |
|                               | n %              | n %              |
+-------------------------------+------------------+------------------+
| Patients with at least one    | 68 (2.4)         | 72 (2.6)         |
| serious AE                    |                  |                  |
|                               | 7 (0.3)          | 10 (0.4)         |
| Body as a whole               |                  |                  |
|                               | 23 (0.8)         | 17 (0.6)         |
| Cardiovascular system         |                  |                  |
|                               | 7 (0.3)          | 21 (0.8)         |
| Digestive system              |                  |                  |
|                               | 1 (0.0)          | 1 (0.0)          |
| Endocrine                     |                  |                  |
|                               | 1 (\<0.1)        | 2 (0.1)          |
| Hemic and lymphatic           |                  |                  |
|                               | 3 (0.1 )         | > 1 (\<0.1)      |
| Hepatobiliary system          |                  | >                |
|                               | 7 (0.3)          | > 7 (0.3)        |
| Musculoskeletal system        |                  |                  |
|                               | 4 (0.1)          | 2 (0.1)          |
| Nervous system                |                  |                  |
|                               | 4 (0.1)          | 1 (0.0)          |
| Psychiatric disorder          |                  |                  |
|                               | 6 (0.2)          | 5 (0.2)          |
| Respiratory system            |                  |                  |
+-------------------------------+------------------+------------------+

(Source sponsor's table 24).

> *Reviewer's comment: Of note, the dose of rofecoxib used in this trial
> is half of the dose used in VIGOR but the dose of naproxen is the same
> (500 mg bid) in both trials. The incidence of serious adverse events
> in ADVANTAGE (2.4 and 2.6% in rofecoxib and naproxen respectively) is
> much lower than in VIGOR (9.3 and 7.8% in rofecoxib and naproxen
> respectively). This observation may be in part explained by the
> shorter duration of the study and the different population (OA in
> ADVANTAGE, RA in VIGOR).*

A table of serious events that required hospitalizations is presented in
Appendix 2. Again, there was no overall advantage of rofecoxib over
naproxen. Twice the number of patients required hospitalization for GI
related serious AE's in the naproxen group (5 and 12 for rofecoxib and
naproxen respectively) and a numerically higher number of patients
required hospitalization for CV related events in the rofecoxib group
(18 and 13 on rofecoxib and naproxen respectively).

1.5.1.3 Serious AE's by ASA use

Table 9. ADVANTAGE study. Concomitant ASA use during study by dose\*

+-------------------------+---------------------+---------------------+
|                         | ROFECOXIB 25 MG     | NAPROXEN 1000 MG    |
|                         |                     |                     |
|                         | N= 2785             | N= 2772             |
|                         |                     |                     |
|                         | n %                 | n %                 |
+-------------------------+---------------------+---------------------+
| Low dose (20-325        | 352 (12.7)          | 367 (13.3)          |
| mg/day)                 |                     |                     |
|                         | 2425 (87.0)         | 2400 (86.5)         |
| Non-ASA user (\<20      |                     |                     |
| mg/day)                 | 8 (0.3)             | 5 (0.2)             |
|                         |                     |                     |
| Other ASA user (\>325   |                     |                     |
| mg/day)                 |                     |                     |
+-------------------------+---------------------+---------------------+

\* Categories defined by the sponsor for this study as follows: "Low
dose": 20 to 325 mg/day; "Non user": Average of \<20 mg/day or following
a CV event; "Other": \>325 mg/day or started therapy during study.
Source: Table 10 Advantage CSR and response to request for information
submitted by sponsor 6/29/01.

Distribution of ASA use in the ADVANTAGE study is presented in Table 8.
Analysis of serious AE's by ASA use demonstrated a similar incidence of
events in the low aspirin users and non-users, except for the
cardiovascular and the digestive system.

Table 10. Serious AE's by ASA use (events with incidence 0.5%), as
reported by investigators.

+---------------------+-----------+-----------+-----------+-----------+
|                     | Rofecoxib |           | Naproxen  |           |
|                     |           |           |           |           |
|                     | N= 2785   |           | N= 2772   |           |
+---------------------+-----------+-----------+-----------+-----------+
|                     | Non ASA   | Low dose  | Non ASA   | Low dose  |
|                     | users     | ASA       | users     | ASA       |
+---------------------+-----------+-----------+-----------+-----------+
|                     | N= 2422   | N= 352    | N= 2398   | N= 367    |
+---------------------+-----------+-----------+-----------+-----------+
|                     | n (%)     | n (%)     | n (%)     | n (%)     |
+---------------------+-----------+-----------+-----------+-----------+
| Patients with at    | 54 (2.2)  | 14 (4.0)  | 59 (2.5)  | 12 (3.3)  |
| least one event in  |           |           |           |           |
| any body system     | 16. (0.7) | 7.  (2.0) | 14. (0.6) | 1.  (0. 5 |
|                     |           |           |           |     )     |
| # *Cardiovascular*  | 3         | 2         | > 1       |           |
|                     |           |           | >         | \-        |
| MI                  | 2         | 1         | > \-      |           |
|                     |           |           |           | \-        |
| #  *Sudden death*   | 5 (0.2)   | 2 (0.6 )  | 18 (0.8)  |           |
|                     |           |           |           | 3 (0. 8 ) |
| #                   |           |           |           |           |
|  *Digestive system* |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+

Source: Corrected Table 68 of Advantage CSR submitted 8/801).

> *Reviewer's comment:*
>
> *In this short trial, the data suggest that co-use of low dose ASA
> increased the risk of serious GI events for rofecoxib (0.6%) but not
> for naproxen (0.8%, unchanged). The trial, however, was not designed
> to adequately assess the long-term effect of co-administration of ASA
> in the gastrointestinal system.*
>
> *Most importantly, patients with known cardiovascular risk --as
> defined by patients using low dose prophylactic ASA - receiving
> rofecoxib had four fold more serious cardiovascular adverse events
> than those receiving naproxen (2.0% vs 0.5%).*
>
> *In this three-month study with a dose of rofecoxib approved for
> chronic use in patients with OA, those on cardiovascular prophylaxis
> showed a trend towards more cardiovascular events (2.0 %) than those
> not on aspirin in the rofecoxib group (0.7%). Presumably, these
> patients are at higher cardiovascular risk than those not taking
> aspirin, therefore the finding is not unexpected. However, this was
> not the case in the naproxen treatment group (0.5 % and 0.6 %, for
> those who were and were not on ASA, respectively ).*
>
> *The sponsor has speculated that the excess risk of cardiovascular
> thrombotic events in the rofecoxib group as compared to naproxen in
> the VIGOR study may be due to the lack of anti-platelet effect of
> rofecoxib and has proposed that addition of low dose ASA in high risk
> patients may prevent the problem. The limited data on rofecoxib and
> ASA use from the ADVANTAGE study suggest that low dose ASA in patients
> with prior cardiovascular history, might not eliminate the excess risk
> of serious cardiovascular events of rofecoxib compared to naproxen.*

3.  Dropouts due to adverse events

Table 11. ADVANTAGE. Dropouts due to adverse events

+-------------------------------+------------------+------------------+
|                               | Rofecoxib        | Naproxen         |
|                               |                  |                  |
|                               | N= 2785          | N= 2772          |
|                               |                  |                  |
|                               | n %              | n %              |
+-------------------------------+------------------+------------------+
| Number of AE dropouts         | **374 (13.4)**   | **386 (13.9)**   |
|                               |                  |                  |
| Body as a whole               | 87 (3.1)         | 102. (3.7)       |
|                               |                  |                  |
| Cardiovascular                | 40 (1.4)         | ```{=html}       |
|                               |                  | <!-- -->         |
| Digestive system              | > 113 (4.1)      | ```              |
|                               |                  | 21. (0.8)        |
| Endocrine                     | 1 (0.0)          |                  |
|                               |                  | ```{=html}       |
| Eyes, ears, nose and throat   | 7 (0.3)          | <!-- -->         |
|                               |                  | ```              |
| Hemic and lymphatic           | 1 (0.0)          | 142. (5.1)       |
|                               |                  |                  |
| Hepatobiliar system           | 2 (0.1)          | > (0.0)          |
|                               |                  | >                |
| Musculoskeletal system        | 45. (1.6)        | > 8 (0.3)        |
|                               |                  |                  |
| Nervous system                | ```{=html}       | 2 (0.1)          |
|                               | <!-- -->         |                  |
| Psychiatric disorder          | ```              | 1 (0.0)          |
|                               | 30. (1.1)        |                  |
| Respiratory system            |                  | 49. (1.8)        |
|                               | ```{=html}       |                  |
| Skin and skin appendages      | <!-- -->         | ```{=html}       |
|                               | ```              | <!-- -->         |
|                               | 14. (0.5)        | ```              |
|                               |                  | 24. (0.9)        |
|                               | ```{=html}       |                  |
|                               | <!-- -->         | ```{=html}       |
|                               | ```              | <!-- -->         |
|                               | 8.  (0.3)        | ```              |
|                               |                  | 7.  (0.3)        |
|                               | > 21 (0.8)       |                  |
|                               |                  | 10 (0.4)         |
|                               |                  |                  |
|                               |                  | 23 (0.8)         |
+-------------------------------+------------------+------------------+

> *Reviewer's comment:*
>
> *Consistent with the VIGOR study, there was no overall advantage of
> rofecoxib 25 mg/day over naproxen 1000 mg/day, based on the number of
> dropouts due to AE's. The percentages of dropouts due to AE's in the
> ADVANTAGE study are similar to those in VIGOR (15.9 and 15.8% for
> rofecoxib and naproxen, respectively). Of note, the number of dropouts
> due to cardiovascular related events was almost twice in the rofecoxib
> arm (n=40, 1.4%) when compared to the naproxen arm (n=21, 0.8%).*

3.  Most common adverse events

The total number of adverse experiences was approximately 65% in each
treatment group. Adverse experiences by body system were generally also
similar between treatment groups, including the digestive system (24%
and 26 % in the rofecoxib and naproxen arms, respectively). Again there
was no overall advantage of rofecoxib 25 mg/day over naproxen 1000 mg
/day.

1.5.1.5 Laboratory adverse events

Mean changes

Laboratory measurements were taken at baseline and at Week 12. Mean
changes from baseline in each laboratory parameter were small and
comparable between treatment groups, including hemoglobin, hematocrit,
BUN, creatinine and liver function tests.

Serious Laboratory Adverse Experiences

Only one patient had a serious laboratory AE during the study. The event
was moderately decreased hemoglobin. No action was taken with regard to
study drug.

Discontinuations Due to Laboratory Adverse Experiences

Eleven patients (0.4%) in the rofecoxib group and 6 (0.2%) in the
naproxen group, were withdrawn from the study due to a laboratory AE.
None of them were serious.

# *1.5.1.6 Vital signs*

Vital signs (diastolic and systolic blood pressure, heart rate, and
respiration rate) were measured at each study visit. Mean changes and
exceeding limits of change from baseline at week 6 and 12 were analyzed.

Maximum increases in systolic blood pressure at Week 12 were 94 mmHg and
60 mmHg for the rofecoxib and naproxen groups, respectively; **mean
increases** were **1.04** mmHg and **0** mmHg in the rofecoxib and
naproxen groups respectively. Maximum increases in diastolic blood
pressure at Week 12 were 40 mmHg and 30 mmHg in the rofecoxib and
naproxen treatment groups respectively; **mean increases** were **0.32**
mmHg and **-0.66** mmHg in the rofecoxib and naproxen groups,
respectively.

Defined limits of change for blood pressure were as follows: systolic
blood pressure \>140 mmHg with an increase from baseline \>20 mmHg at
either week 6 or 12; and diastolic blood pressure \>90 mmHg with an
increase from baseline \>15 mmHg at either week 6 or 12.

Percentage of patients who exceeded the limit change for SBP at either
week 6 or 12 were 10.7% and 9.1% for rofecoxib and naproxen,
respectively. The percentage of patients who exceeded limits in SBP at
both week6 and 12 were 2.3% and 1.6% in the rofecoxib and naproxen
groups, respectively. Few patients in either treatment group (0.5%) had
a change in diastolic blood pressure exceeding the defined limit at both
visits.

> *Reviewer's comment: Patients in the rofecoxib group tended to have a
> larger increase in blood pressure compared to the naproxen group,
> although, in this three-month study, the differences in blood pressure
> changes were small.*

1.  Analyses of Cardiovascular Safety

1.5.2.1 Cardiovascular thrombotic events. Serious cardiovascular (CV)
AEs occurring in a patient while on study treatment or within 14 days of
discontinuation of study treatment were reviewed by the sponsor for
inclusion in the adjudication process.

Of the 23 and 17 investigator reported serious CV AEs in the rofecoxib
and naproxen arm respectively, 14 and 13 were considered by the sponsor
to be thrombotic-related (as per Merck's Vascular SAE Terms Eligible for
Case Adjudication, Appendix 3) and referred for blinded adjudication to
the Cardiovascular Adjudication Committee. Two additional cases obtained
through the WAES (Worldwide Adverse Event System) database were also
referred for adjudication by the sponsor, making a total of **14 and
15** cases **referred** for adjudication from the rofecoxib and naproxen
arms, respectively.

> *Reviewer's comment: The two cases referred for adjudication from the
> WAES database were not technically investigator reported events. It is
> unclear whether these cases represent unblinded data (both cases were
> on naproxen).*

Investigator reported serious CV AEs are presented in the following
table.

Table 12. Investigator reported Serious AE's related to the CV system by
ASA use

+---------------------+-------+-------+-------+-------+-------+-------+
|                     | Rofe  |       |       | Nap   |       |       |
|                     | coxib |       |       | roxen |       |       |
+---------------------+-------+-------+-------+-------+-------+-------+
|                     | All   | No    | ASA   | All   | No    | ASA   |
|                     |       | ASA   |       |       | ASA   |       |
|                     | N=    |       | N=352 | N=    |       | N=    |
|                     | 2785  | N=    |       | 2772  | N=    | 367   |
|                     |       | 2425  |       |       | 2400  |       |
+---------------------+-------+-------+-------+-------+-------+-------+
|                     | n %   | e     | e     | n %   | e     | e     |
|                     |       | vents | vents |       | vents | vents |
+---------------------+-------+-------+-------+-------+-------+-------+
| **Any CV related    | **23  | **16  | **7   | **17  | **15  | **2   |
| event**             | (0    | (0    | (2    | (0    | (0    | (0    |
|                     | .8)** | .7)** | .0)** | .6)** | .6)** | .5)** |
| Acute Myocardial    |       |       |       |       |       |       |
| Infarction          | 1     | \-    | 1     | \-    | \-    | \-    |
|                     |       |       |       |       |       |       |
| Arterial Oclusion   | 1     | 1     | \-    | \-    | \-    | \-    |
|                     |       |       |       |       |       |       |
| Arterial rupture    | 1     | 1     | \-    | \-    | \-    | \-    |
|                     |       |       |       |       |       |       |
| Atherosclerosis     | 1     | 1     | \-    | 1     | 1     | \-    |
|                     |       |       |       |       |       |       |
| Atrial fibrillation | 2     | 2     | \-    | 1     | \-    | 1     |
|                     |       |       |       |       |       |       |
| Cardiac arrest      | \-    | \-    | \-    | 1     | 1     | \-    |
|                     |       |       |       |       |       |       |
| Cardiovascular      | 1     | \-    | 1     | \-    | \-    | \-    |
| disorder            |       |       |       |       |       |       |
|                     | 1     | \-    | 1     | \-    | \-    | \-    |
| Carotid artery      |       |       |       |       |       |       |
| obstruction         | \-    | \-    | \-    | 1     | 1     | \-    |
|                     |       |       |       |       |       |       |
| Cerebellar          | 1     | 1     | \-    | \-    | \-    | \-    |
| hemorrhage          |       |       |       |       |       |       |
|                     | \-    | \-    | \-    | 1     | 1     | \-    |
| Cerebral aneurysm   |       |       |       |       |       |       |
|                     | \-    | \-    | \-    | 3     | 3     | 0     |
| Cerebral infarction |       |       |       |       |       |       |
|                     | 4     | 3     | 1     | 2     | 2     | \-    |
| Cerebrovascular     |       |       |       |       |       |       |
| accident            | 2     | 1     | 1     | 2     | 1     | 1     |
|                     |       |       |       |       |       |       |
| Congestive heart    | \-    | \-    | \-    | 3     | 3     | \-    |
| failure             |       |       |       |       |       |       |
|                     | 1     | 1     | \-    | \-    | \-    | \-    |
| Coronary artery     |       |       |       |       |       |       |
| disease             | 1     | 1     | \-    | \-    | \-    | \-    |
|                     |       |       |       |       |       |       |
| Deep venous         | 3     | 2     | 1     | 1     | 1     | \-    |
| thrombosis          |       |       |       |       |       |       |
|                     | 1     | \-    | 1     | \-    | \-    | \-    |
| Hypertension        |       |       |       |       |       |       |
|                     | 1     | 1     | \-    | \-    | \-    | \-    |
| HTN heart disease   |       |       |       |       |       |       |
|                     | 1     | 1     | \-    | \-    | \-    | \-    |
| Myocardial          |       |       |       |       |       |       |
| infarction          | 1     | 1     | \-    | 1     | 1     | \-    |
|                     |       |       |       |       |       |       |
| MI- age             | 1     | 1     | \-    | \-    | \-    | \-    |
| indetermined        |       |       |       |       |       |       |
|                     | 1     | 1     | \-    | 1     | 1     | \-    |
| Non-Q wave MI       |       |       |       |       |       |       |
|                     | 1     | \-    | 1     | \-    | \-    | \-    |
| Pulmonary edema     |       |       |       |       |       |       |
|                     | 1     | \-    | 1     | \-    | \-    | \-    |
| Sick sinus syndrome |       |       |       |       |       |       |
|                     | 2     | 2     | \-    | 2     | 2     | \-    |
| Subarachnoid        |       |       |       |       |       |       |
| hemorrhage          | 1     | 1     | \-    | \-    | \-    | \-    |
|                     |       |       |       |       |       |       |
| Supraventricular    | 1     | 1     | \-    | \-    | \-    | \-    |
| tachycardia         |       |       |       |       |       |       |
|                     | \-    | \-    | \-    | 1     | 1     | \-    |
| Third degree AV     |       |       |       |       |       |       |
| block               | 1     | \-    | 1     | \-    | \-    | \-    |
|                     |       |       |       |       |       |       |
| Thrombophlebitis    |       |       |       |       |       |       |
|                     |       |       |       |       |       |       |
| Transient ischemic  |       |       |       |       |       |       |
| attach              |       |       |       |       |       |       |
|                     |       |       |       |       |       |       |
| Unstable angina     |       |       |       |       |       |       |
|                     |       |       |       |       |       |       |
| Vasospasm           |       |       |       |       |       |       |
|                     |       |       |       |       |       |       |
| Ventricular         |       |       |       |       |       |       |
| fibrillation        |       |       |       |       |       |       |
|                     |       |       |       |       |       |       |
| Ventricular         |       |       |       |       |       |       |
| tachycardia         |       |       |       |       |       |       |
+---------------------+-------+-------+-------+-------+-------+-------+

(Source: sponsor's tables 60, 68 & 69, corrected tables submitted
8/8/01). (N= patients randomized; n= patients with events). This list
does not include two additional cases obtained though WAES.

> *Reviewer's comment: The incidence of investigator related serious CV
> AEs was higher among those patients taking concomitant aspirin in the
> rofecoxib group. The subgroup of patients taking aspirin presented
> four fold more serious CV adverse events in the rofecoxib group than
> the naproxen group.*

2.  Adjudicated serious CV/thrombotic events.

Each clinical event referred for adjudication was reviewed blindly by
three cardiologists (CV adjudication committee). The criteria for
adjudication of cardiovascular serious thrombotic events were the same
as the ones used in the VIGOR study.

Table 13. Criteria for Adjudication of Cardiovascular Serious Thrombotic
events

+-----------------------------------------------------------------------+
| a\. Coronary *-- Cardiology*                                          |
|                                                                       |
| 1\. Acute MI (fatal or non-fatal)                                     |
|                                                                       |
| > a\. Spontaneous                                                     |
| >                                                                     |
| > b\. Secondary to an antecedent stressor (major surgery, GI bleed)   |
| >                                                                     |
| > c\. Complication of PTCA or coronary revascularization procedure    |
|                                                                       |
| 2\. Unstable angina pectoris                                          |
|                                                                       |
| 3\. Cardiac (atrial or ventricular thrombus)                          |
|                                                                       |
| 4\. Resuscitated cardiac arrest (without identified cause listed      |
| elsewhere)                                                            |
|                                                                       |
| 5\. Sudden or unexplained death                                       |
|                                                                       |
| b\. Peripheral (other than cardiac or cerebrovascula*r)* vascular *-- |
| Peripheral Vascular*                                                  |
|                                                                       |
| 1\. Pulmonary embolism (fatal or non-fatal)                           |
|                                                                       |
| > a\. Spontaneous                                                     |
| >                                                                     |
| > b\. Secondary to an antecedent stressor                             |
|                                                                       |
| 2\. Peripheral venous thrombosis                                      |
|                                                                       |
| > a\. Spontaneous                                                     |
|                                                                       |
| b.  b\. Secondary to an antecedent stressor                           |
|                                                                       |
| 3\. Peripheral arterial thrombosis/thromboembolism (fatal or          |
| non-fatal)                                                            |
|                                                                       |
| c\. Cerebrovascular *-- Neurology*                                    |
|                                                                       |
| 1\. Ischemic cerebrovascular stroke (fatal or non-fatal) with         |
| adequate documentation                                                |
|                                                                       |
| to subclassify as follows:                                            |
|                                                                       |
| > a\. Large-artery atherosclerosis                                    |
| >                                                                     |
| > b\. Cardioembolism                                                  |
| >                                                                     |
| > c\. Small-artery occlusion (lacune)                                 |
|                                                                       |
| d.  d\. Other determined etiology                                     |
|                                                                       |
| 2\. Ischemic cerebrovascular stroke (fatal or non-fatal) without      |
| adequate                                                              |
|                                                                       |
| documentation to subclassify etiology                                 |
|                                                                       |
| 3\. Hemorrhagic cerebrovascular stroke or hemorrhagic change (fatal   |
| or non-fatal)                                                         |
|                                                                       |
| 4\. Transient ischemic attack                                         |
|                                                                       |
| 5\. Cerebrovascular venous thrombosis (fatal or non-fatal)            |
|                                                                       |
| d\. Non-Thromboembolic event                                          |
+-----------------------------------------------------------------------+

> *The SOP for this adjudication of cardiovascular events seem
> appropriate to FDA reviewers. The SOP includes a summary of the
> available data used by the committee and guidelines on the
> interpretation of cardiac data (e.g., how to interpret an elevated
> CPK-MB or an abnormal ECG).*

Table 14. Listing of events referred for adjudication and adjudication
results

+------------+---+----------------+------+---+------------------------+
| Site/      |   | Prior Hx/ CV   | Low  | # |                        |
| Allocation |   | risk factors   | dose |   |                        |
|            |   |                |      | * |                        |
| Age/sex/   |   |                | ASA  | A |                        |
| Treatment  |   |                |      | d |                        |
|            |   |                |      | j |                        |
|            |   |                |      | u |                        |
|            |   |                |      | d |                        |
|            |   |                |      | i |                        |
|            |   |                |      | c |                        |
|            |   |                |      | a |                        |
|            |   |                |      | t |                        |
|            |   |                |      | i |                        |
|            |   |                |      | o |                        |
|            |   |                |      | n |                        |
|            |   |                |      | * |                        |
+------------+---+----------------+------+---+------------------------+
| 0064 4746  | * | HTN            | Yes  | # | Non fatal MI           |
| 54M        | R |                |      | # |                        |
|            | * | COPD, varicose | No   | # | Superficial            |
| 0126 2401  |   | ve             |      | # | thromboflebitis        |
| 70F        | * |                | No   | # |                        |
|            | R | DM, CAD        |      |   | Unstable angina        |
| 0193 5751  | * |                | Yes  | Y |                        |
| 78F        |   | CAD, CABG      |      |   | Sudden death           |
|            | * |                | No   | N |                        |
| 0200 3700  | R | Atrial fib     |      | o | Aneurism. Subarachnoid |
| 74M        | * |                | Yes  |   | hemorr                 |
|            |   | Lipid, CVA,   |      | * |                        |
| 0212 1955  | * | ERT            | No   | * | Non thromboembolic\*   |
| 70F        | R |                |      | Y |                        |
|            | * | IBS,           | Yes  | * | Non fatal MI           |
| 0215 4378  |   | Peyronie's     |      | * |                        |
| 72F        | * |                | No   |   | Non fatal MI           |
|            | R | Lipid, HTN,   |      | * |                        |
| 0357 0047  | * | PVD            | Yes  | * | Sudden death           |
| 69M        |   |                |      | Y |                        |
|            | * | HTN, CAD, Afib | No   | * | Non thromboembolic     |
| 0644 2176  | R |                |      | * | event                  |
| 79M        | * | HTN,           | No   |   |                        |
|            |   | hypothyroidism |      | N | TIA. (w/Ventricular    |
| 0658 4049  | * |                | No   | o | thrombus)              |
| 71M        | R | HTN, CAD       |      |   |                        |
|            | * |                | Yes  | N | Non fatal (Non Q wave) |
| 0760 3253  |   | Lipid, HTN,DM |      | o | MI                     |
| 72F        | * |                | No   |   |                        |
|            | R | HTN, angina    |      | * | Non fatal MI           |
| 0810 6272  | * |                | No   | * |                        |
| 76M        |   | Lipid, HTN,   |      | Y | Non thromboembolic\*   |
|            | * | SyndrmX        | Yes  | * |                        |
| 0821 5108  | R |                |      | * | TIA                    |
| 72M        | * | DM             | No   |   |                        |
|            |   |                |      | * | Non fatal MI           |
| 0831 5382  | * | \-             | No   | * |                        |
| 70M        | R |                |      | Y | Ischemic CVA (no       |
|            | * | ? Hx of CVA ,  | No   | * | subclassif)\*          |
| 0002 9009  |   | ERT            |      | * |                        |
| 60M        | * |                | Yes  |   | Non thromboembolic     |
|            | R | CAD, HTN       |      | * |                        |
| 0016 9145  | * |                | No   | * | Worsening CHF          |
| 71F        |   | CAD,HTN, DM    |      | Y |                        |
|            | * |                | No   | * | Ischemic CVA, small    |
| 0187 0665  | R | Lipid, HTN,DM |      | * | artery occlus\*        |
| 60M        | * |                | No   |   |                        |
|            |   | **CAD,CABG,    |      | N | Unstable angina        |
| 0283 2182  | * | HTN**          | No   | o |                        |
| 58F        | R |                |      |   | Unstable angina        |
|            | * | Lipid, DM     | No   | * |                        |
| 0314 1477  |   |                |      | * | Deep venous thrombosis |
| 70M        | * | HTN,           | No   | Y |                        |
|            | R | depression,    |      | * | Deep venous            |
| 0340 6823  | * | ERT            | No   | * | thrombosis\*\*         |
| 67M        |   |                |      |   |                        |
|            | N | DM, postop     | No   | * | Cerebral infarction    |
| 0386 3155  |   | per, ERT       |      | * |                        |
| 77F        | N |                |      | Y | Ischemic CVA           |
|            |   | HTN, ERT       |      | * |                        |
| 0408 4129  | N |                |      | * | Deep venous thrombosis |
| 54M        |   | Lipid, HTN    |      |   |                        |
|            | N |                |      | * | Ischemic CVA           |
| 0443 1418  |   | HTN, prostatic |      | * |                        |
| 45F        | N | ca.            |      | Y | Ischemic CVA           |
|            |   |                |      | * |                        |
| 0449 4783  | N | Cerebral       |      | * |                        |
| 70F        |   | hemorr, ERT    |      |   |                        |
|            | N |                |      | N |                        |
| 0462 1867  |   | HTN, CAD, MI,  |      | o |                        |
| 84F        | N | ERT            |      |   |                        |
|            |   |                |      | * |                        |
| 0521 5761  | N |                |      | * |                        |
| 58F        |   |                |      | Y |                        |
|            | N |                |      | * |                        |
| 0580 6099  |   |                |      | * |                        |
| 80M        | N |                |      |   |                        |
|            |   |                |      | * |                        |
| 0614 2792  | N |                |      | * |                        |
| 74M        |   |                |      | Y |                        |
|            | N |                |      | * |                        |
| 0702 6480  |   |                |      | * |                        |
| 59F        | N |                |      |   |                        |
|            |   |                |      | # |                        |
| 0774 3189  | N |                |      | # |                        |
| 66F        |   |                |      | # |                        |
|            |   |                |      | # |                        |
|            |   |                |      | # |                        |
|            |   |                |      |   |                        |
|            |   |                |      | Y |                        |
|            |   |                |      |   |                        |
|            |   |                |      | N |                        |
|            |   |                |      | o |                        |
|            |   |                |      |   |                        |
|            |   |                |      | N |                        |
|            |   |                |      | o |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      |   |                        |
|            |   |                |      | Y |                        |
|            |   |                |      |   |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
|            |   |                |      | Y |                        |
|            |   |                |      | * |                        |
|            |   |                |      | * |                        |
+------------+---+----------------+------+---+------------------------+
| 0065 5005  | * | Lipid, syst   | No   | \ | Sudden death\*\*\*     |
| 73F        | R | mumur          |      | - |                        |
|            | * |                |      |   |                        |
+------------+---+----------------+------+---+------------------------+

Source: Advantage CSR, CV adjudication package. R: rofecoxib. N:
naproxen. CAD: coronary artery disease. HTN: hypertension, DM: diabetes
mellitus. ERT**:** Estrogen replacement therapy. \* FDA reviewers do not
agree with adjudication. \*\* Occurred outside window determined by SOP
and should have not been referred for adjudication. \*\*\* Not referred
for adjudication.

Results of the adjudication:

Of the 29 cases evaluated by the CV adjudication committee (14 and 15 in
the rofecoxib and naproxen groups respectively), seven were considered
non-thrombo-embolic events, resulting in 9 and 12 adjudicated serious
CV/thrombotic events.

1.5.2.3 Review of serious CV events by FDA reviewers.

> *Reviewer's comment:*

-   *The referral for adjudication of two additional cases obtained from
    WAES - not reported by the investigators as cardiovascular
    thrombotic events - is of concern. One of these cases was
    adjudicated by the CV adjudication committee (102 462 1867, DVT on
    naproxen). However, a hand written note in the CRF for this case
    states that it is not known whether the patient ever took the
    assigned medication because she did not return the diary. As per the
    sponsor's June 22, 2001 correspondence, the event occurred more than
    14 days after discontinuation of study drug. The SOP establishes a
    14-day window period. Therefore, this case should have never been
    referred for adjudication.*

```{=html}
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-   *One cardiovascular death that should have been referred for
    adjudication was not referred because the term used by the
    investigator was not in the list of potential cardiovascular
    thrombotic events (hypertensive heart disease). This case was
    actually a case of sudden death (102 065- 5005, on rofecoxib). See
    Appendix 3a ("Terms eligible for adjudication").*

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-   *Post-hoc determination of the 'thrombotic' nature of some of these
    events may be difficult. Final interpretation of some data -- often
    limited data - is by necessity, somewhat subjective. The Medical
    Officer assigned to this NDA reviewed all adjudication packages. For
    those cases in which the MO did not agree with the committee,
    adjudication packages were provided to the Divisions of Cardio-Renal
    and Neuropharm products. Two different FDA reviewers disagreed with
    the adjudication of four cases (0215 4378 211 and 0002 9009 308,*
    *on rofecoxib; and 0386 3155 209 and 0283 2182 222 on naproxen).*

Table 15. Cases for which FDA reviewers disagree with the results of CV
adjudication committee\*.

+--------+--------+-----------------+----+----------------------+----+
| P      | Tre    | Adjudication    | C  | FDA reviewers        | C  |
| atient | atment | Committee       | VT |                      | VT |
+--------+--------+-----------------+----+----------------------+----+
| 0215   | Rof    | Non             | N  | Ischemic CVA         | Y  |
| 4378   | ecoxib | -thromboembolic |    |                      |    |
|        |        |                 | Y  | Unable to            | N  |
| 0386   | Na     | Ischemic CVA,   |    | adjudicate, Chorea   |    |
| 3155   | proxen |                 | Y  | of unknown etiology  | N  |
|        |        | small artery    |    |                      |    |
| 0283   | Na     | occlusion       | N  | Unable to adjudicate | Y  |
| 2182   | proxen |                 |    |                      |    |
|        |        | Ischemic CVA    |    | Unstable angina      |    |
| 0002   | Rof    |                 |    |                      |    |
| 9009   | ecoxib | Non             |    |                      |    |
|        |        | -thromboembolic |    |                      |    |
+--------+--------+-----------------+----+----------------------+----+
| 0462   | Na     | DVT             | Y  | Out of adjudication  | N  |
| 1867   | proxen |                 | \* | period               |    |
|        |        | Death due to    | \* |                      | Y  |
| 0065   | Rof    | HTN             |    | Sudden death         |    |
| 5005   | ecoxib |                 | \* |                      |    |
|        |        |                 | \* |                      |    |
|        |        |                 | \* |                      |    |
+--------+--------+-----------------+----+----------------------+----+

*Re-adjudication based on review of cases by reviewers from HFD-550,
HFD-110 and HFD-120). CVT: serious cardiovascular thrombotic event. \*
Narratives are presented in Appendix 4. \*\* It should not have been
referred for adjudication. \*\*\* It was not referred for adjudication.*

Table 16. ADVANTAGE: Summary CV Thrombotic events as presented by the
sponsor (adjudicated by CV Adjudication Committee) and FDA
re-adjudicated events.

+-----------------+------------+------------+------------+------------+
|                 | Number of  |            | Number of  |            |
|                 | patients   |            | patients   |            |
|                 | with       |            | with       |            |
|                 |            |            |            |            |
|                 | CV         |            | FDA        |            |
|                 | Committee  |            | re-a       |            |
|                 | a          |            | djudicated |            |
|                 | djudicated |            | serious    |            |
|                 | serious    |            |            |            |
|                 | CV-        |            | CV-        |            |
|                 | thrombotic |            | thrombotic |            |
|                 | events     |            | events     |            |
+-----------------+------------+------------+------------+------------+
|                 | Rofecoxib  | Naproxen   | Rofecoxib  | Naproxen   |
|                 |            |            |            |            |
|                 | (N= 2785)  | (N= 2772)  | (N= 2785)  | (N= 2772)  |
+-----------------+------------+------------+------------+------------+
|                 | 9          | 12         | 12         | 10         |
+-----------------+------------+------------+------------+------------+
| Cardiac         | **8**      | **3**      | **10**     | **3**      |
|                 |            |            |            |            |
| Sudden death    | 2          | 0          | 3          | 0          |
|                 |            |            |            |            |
| MI              | 5          | 1          | 5          | 1          |
|                 |            |            |            |            |
| Angina          | 1          | 2          | 2          | 2          |
|                 |            |            |            |            |
| Cerebrovascular | **1**      | **7**      | **2**      | **5**      |
|                 |            |            |            |            |
| CVA             | 0          | 6          | 1          | 4          |
|                 |            |            |            |            |
| TIA             | 1          | 1          | 1          | 1          |
|                 |            |            |            |            |
| Peripheral      | **0**      | **2**      | **0**      | **1**      |
|                 |            |            |            |            |
| DV              | 0          | 2          | 0          | 1          |
| T/thromboflebit |            |            |            |            |
+-----------------+------------+------------+------------+------------+

There were **10 cardiac** events in the **rofecoxib** arm compared to
**3** in the **naproxen** arm**.** Eight of the 10 cardiac events in the
rofecoxib arm (5 MI, 2 sudden deaths, one angina) were in males; two
additional cardiac events were in women. The cardiac cases in the
naproxen arm were 2 unstable angina (1 man, 1 woman) and one MI (in a
man with no prior CV history). Most of the cardiac events were in
patients older than age 60, with known risks factors for CAD such as
hypertension, diabetes, hyperlipidemia or prior history of CAD. Five of
the ten cardiac events were in patients taking ASA. The number of events
is small to allow interpretation regarding distribution of events in ASA
users and non users.

> *Reviewer's comment: A trend towards an excess of **cardiac events**
> in the rofecoxib 25 mg group in this 12 week study is noted. This
> observation is consistent with the pattern seen in VIGOR.*
>
> *Of note, there were 2 and 5 cerebrovascular thrombotic events in the
> rofecoxib and naproxen arm, respectively, as adjudicated by the FDA
> Neuropharm reviewer. Two of the four CVA's were in patients taking
> hormonal replacement therapy. The reason for a lack of consistency
> between VIGOR and ADVANTAGE in regards to the risk of CVA's is
> unclear. It may be that cardiac and cerebrovascular events are
> different entities. However, the lack of power in the ADVANTAGE study
> may be an explanation.*
>
> *A summary of the sponsor analyses of serious investigator reported CV
> events, adjudicated serious cardiovascular thrombotic and APTC (Anti
> Platelet Trialist's Collaboration) endpoints is presented in Appendix
> 3b. While the 95% CI's cross, the trend is consistent with FDA review
> for cardiac events.*
>
> *The number of events is small, however, the finding is concerning
> because:*

1.  *This is only a three month study.*

2.  *The dose of rofecoxib is 25 mg a day, the approved dose in OA (not
    twice the dose, as in VIGOR),*

3.  *The OA population is known to have lower cardiovascular risk than
    the RA population.*

> *The study is of extremely short duration to evaluate the
> cardiovascular effect of a drug in the prevention or increased risk of
> MI and stroke. Studies designed to evaluate cardiovascular outcomes
> are usually of 3-4 years duration.*

1.5.3 NSAID-related events. The sponsor provided analyses of
pre-specified NSAID-related adverse events similar to the ones that had
been done in the VIGOR study.

1.  NSAID-related adverse events related to edema, HTN and CHF

In this short-term, 12-week study, more patients had CHF related events
and discontinued due to edema-related and HTN-related events in the
rofecoxib 25 mg/day group than in the naproxen 1000 mg/day group.

Table 17. ADVANTAGE study. NSAID-related adverse events related to
edema^1^, hypertension^2^ and congestive heart failure^3^.

+---------------------------------------+--------------+---------------+
|                                       | Rofecoxib    | Naproxen      |
|                                       |              |               |
|                                       | N= 2785      | N= 2772       |
|                                       |              |               |
|                                       | n %          | n %           |
+---------------------------------------+--------------+---------------+
| Patients with Edema-related events    | 151 (5.42)   | 135 (4.87)    |
|                                       |              |               |
| discontinued due to Edema related     | 19 (0.68)    | 12 (0.43 )    |
| event                                 |              |               |
|                                       | 90 (3.23)    | 72 (2.59)     |
| Patients with HTN related event       |              |               |
|                                       | 15 (0.54)    | 7 (0.25)      |
| discontinued due to HTN related event |              |               |
|                                       | 11 (0.39)    | 6 (0.22)      |
| Patients with at least one            |              |               |
| CHF-related event                     |              |               |
+---------------------------------------+--------------+---------------+

(Source Table 73, 74, 75 and appendix 4.1.57, Advantage CSR). Note:
patients with two or more adverse events within a body system is counted
only once within a body system. ^1^ Includes terms such as edema,
peripheral edema and lower extremity edema. ^2^ Includes terms such as
blood pressure increased, diastolic hypertension, systolic hypertension,
labil hypertension, hypertension, uncontrolled hypertension.

Of the discontinuations due to edema-related events, only one patient
(AN 1757, rofecoxib) was considered to have a serious event. The
patient, a 72 year old male with history of HTN, DM, CAD, hyperlipidemia
and CABG developed anasarca and was hospitalized approximately on
treatment day #40. The physician indicated that the *patient lost about
30 pounds of fluid* with diuretic therapy during hospitalization.

CHF related events were defined as either congestive heart failure or
left ventricular failure. Of the CHF related events, six were considered
to be serious by the investigator: four in rofecoxib (AN 0085, 1082,
7389, 5108) and two in naproxen (6823 and 6398). Patient 5108 (a 72
year-old male) had a non-Q wave MI.

> *Reviewer's comment: The number of events is relatively small but
> despite the short duration of treatment and the fact that this is the
> 25 mg dose, the trend is consistent with findings in the VIGOR study.*

1.5.3.2 Renal safety

There was one case of acute real failure (AN 3105/777) in the naproxen
arm, and one case of acute tubular necrosis (AN 1332/537 in the
rofecoxib arm).

Twice the number of patients presented increased serum creatinine and
BUN in the rofecoxib compared to the naproxen arm, respectively. Only
one patient (in the naproxen arm) required discontinuation due to
increased creatinine.

Table 18 Renal related Laboratory AE experiences

+---------------------------+--------------------+---------------------+
|                           | Rofecoxib N=2785   | Naproxen N=2772     |
|                           |                    |                     |
|                           | n (%)              | n (%)               |
+---------------------------+--------------------+---------------------+
| Blood urea nitrogen       | 15. (0.5)          | 7 (0.3)             |
| increased                 |                    |                     |
|                           | > 21 (0.8)         | 10 (0.4)            |
| Serum creatinine          |                    |                     |
| increased                 |                    |                     |
+---------------------------+--------------------+---------------------+

1.5.3.3 Liver safety

There were two discontinuations due to liver-related clinical or
laboratory adverse events, one in each treatment arm.

1.5.3.4 GI safety

The sponsor defined primary endpoint for this study was the cumulative
incidence of discontinuations due to GI AE and abdominal pain at end of
study endpoint.

The sponsor conducted a post-hoc analysis of PUBs (perforation,
symptomatic ulcers and bleedings) similar to the analysis conducted for
the VIGOR study. Of all the serious AE related to the digestive system,
6 and 12 events were referred to the GI adjudication committee from the
rofecoxib and naproxen arms, respectively. Of those, 2 and 9 were
confirmed PUBs by the adjudication committee. Of the confirmed PUBs, one
was complicated in the rofecoxib group (the patient was taking ASA) and
four were complicated in the naproxen group (one patient was taking
ASA). The number of cases is small but the trend is consistent with the
findings in VIGOR.

> *Reviewer's comment: The study succeeded in the sponsor's defined
> primary endpoint. However, this endpoint is not of clinical
> significance unless it is consistent with the overall safety profile,
> including cardiovascular events which are highly morbid. Only 7 of the
> 113 and 21 of the 142 discontinuations due to digestive symptoms were
> considered serious adverse events in the rofecoxib and naproxen arm
> respectively. Five of the 7 and 12 of the 21 serious digestive AE's
> required hospitalization in the rofecoxib and naproxen arm,
> respectively. Two of the seven and 3 of the 21 serious digestive AE's
> were on patients using concomitant aspirin in the rofecoxib and
> naproxen arm, respectively.*

2.  Safety Update Report (SUR)

2.1 Overall Safety.

The Complete SUR was submitted to the Agency in July 12, 2001. This
report includes the safety update of the extension studies in the
original OA program (029, 058, 034 and 035), studies 083 (bone mineral
density), 120 and 121 (low back pain), 118 (prostatitits pain), 903 (OA)
and 078, 126 and 091 (prevention of Alzheimer's). The SUR, however, does
not contain the complete study reports for these studies.

Table 19. Studies included in Safety Update Report

+------------------+---------+--------+--------+--------+------------+
| Study/protocol   | D       | Dose   | Pa     |        |            |
| \#               | uration | of     | tients |        |            |
|                  |         |        | random |        |            |
|                  |         | rof    | ized\* |        |            |
|                  |         | ecoxib |        |        |            |
+------------------+---------+--------+--------+--------+------------+
|                  |         |        | Rof    | P      | Active     |
|                  |         |        | ecoxib | lacebo | control    |
+------------------+---------+--------+--------+--------+------------+
| # *Exten         | some    | 12.5   | 415    | \-     | 409        |
| sion to Original | p       | mg     | *      |        | Diclofenac |
|  NDA OA studies* | atients |        | *(1)** | \-     | **(1)**    |
|                  | up to   | 25 mg  |        |        |            |
| 034, 035         | \>2     |        | 475    |        | 36         |
|                  | years   | 50 mg  |        |        | Nabumetone |
| Elderly--- 058   |         |        | 78     |        |            |
|                  | Some    | 12.5   |        |        |            |
|                  | p       | mg     | 46     |        |            |
|                  | atients |        |        |        |            |
|                  | up to 2 | 25 mg  | 25     |        |            |
|                  | years   |        |        |        |            |
+------------------+---------+--------+--------+--------+------------+
| # *New c         | Up to   | 25 mg  | 136    | 100    | 148        |
| ompleted trials* | 65      |        |        |        | Ibuprofen  |
|                  | weeks   | 25 mg  | 346    | 346    | **(1)**    |
| Bone Density---  |         |        | **     | *      |            |
| 083              | Up to   | 25 mg  | (14)** | *(8)** | \-         |
|                  | 479     |        |        |        |            |
| Alzheimer's      | days    | 50 mg  | 53     | 59     | \-         |
| Disease--- 091   |         |        |        |        |            |
|                  | 6 weeks | 25 mg  | 49     | 228    | \-         |
| Chronic          |         |        |        |        |            |
| Prostatitis---   | 4 weeks | 50 mg  | 232    | \-     | 473        |
| 118              |         |        |        |        | Naproxen   |
|                  | 6 weeks | 12.5   | 233    | \-     |            |
| Chronic Low Back |         | mg     |        |        | 456        |
| Pain--- 120/121  | 6 weeks |        | 471    | 729    | (D         |
|                  |         | 12.5   | *      | *      | iclofenac/ |
| OA Versus        | Up to   | mg     | *(1)** | *(9)** |            |
| Naproxen --- 901 | 1052    |        |        |        | mi         |
|                  | days    | 25 mg  | 453    | 376    | soprostol) |
| OA Versus        |         |        | *      | *      |            |
| ARTHROTEC ---    | Up to   | 25 mg  | *(1)** | *(3)** | \-         |
| 902              | 430     |        |        |        |            |
|                  | days    |        | 721    |        | \-         |
| New ongoing      |         |        | **     |        |            |
| trials           |         |        | (15)** |        |            |
|                  |         |        |        |        |            |
| Alzheimer's      |         |        | 381    |        |            |
| Disease--- 078   |         |        | *      |        |            |
|                  |         |        | *(4)** |        |            |
| Alzheimer's      |         |        |        |        |            |
| Disease--- 126   |         |        |        |        |            |
+------------------+---------+--------+--------+--------+------------+

\* Patients randomized (Few patients were actually exposed to 2 years in
the extension to the original NDA). The number of patients who died for
any cause are in parenthesis. Source: modified from sponsor's table 1 of
the SUR submitted 7/12/01 and data on deaths from individual studies.

2.1.1 Deaths in the SUR.

There were a total of 58 deaths in the SUR. The number of deaths appears
in parenthesis in Table 17.

Two deaths occurred during the extension period of the original NDA OA
studies (029,034,035, 058):

-   AN 8353, 64 M on rofecoxib 12.5 mg (post-op complication after CABG,
    day 607 of therapy)

-   AN 5568, study 034: 75 F on diclofenac 150 mg, day 719 (post-op
    complication of hip replacement).

> *The total number of deaths in the entire original NDA and extensions
> was: 4 on rofecoxib 12.5 mg, one on rofecoxib 50 mg (in a patient with
> RA), one on naproxen, one on nabumetone and 9 deaths in the diclofenac
> group. For more detailed review the reader is referred to the MO
> review of NDA 21-042.*

One death occurred in each of the remaining protocols submitted in this
SUR:

-   AN 0063, (protocol 083) a 60-year-old white woman with a history of
    hypertension and obesity was found dead in bed approximately 5
    months into receiving ibuprofen 800 mg TID.

```{=html}
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-   AN 2301, (protocol 901) a 55 year old woman with history of chest
    pain and palpitations was found dead in bed 4 days after taking
    rofecoxib 12.5 mg a day. Autopsy showed coronary artery disease.

```{=html}
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```
-   AN 1659 (protocol 902), a 94-year-old man (AN 1659) on rofecoxib
    12.5 mg for 15 days committed suicide by putting a plastic bag over
    his head.

Fifty-three of the 58 deaths were in the Alzheimer's studies: 33 on
rofecoxib 25 mg and 20 on placebo (see below). Excluding the Alzheimer's
studies, the number of deaths were small and do not raise additional
safety concerns.

2.  Serious AE's and Discontinuations due to AE's in the SUR

The pattern of SAE's and discontinuations due to AE's in the SUR was
consistent with that observed in the original NDA. Of note, except the
Alzheimer's studies most of these studies were of small size and short
duration.

2.2 Alzheimer's studies

Of all the data submitted in the SUR, the three studies for prevention
of Alzheimer's disease potentially provide the most valuable information
about long term exposure to rofecoxib 25 mg in comparison to placebo.
However, limited safety data has been supplied from these studies. At
the time of the submission of the SUR, study 091 had been completed;
study 078 was ongoing and the data were not frozen by the cutoff date
for the SUR (April 2001); study 126 had been terminated early (March
2001) and full report was not available. The SUR included listing of
serious fatal and nonfatal AE's from the three studies as well as
adjudication packages of all serious potentially cardiovascular
thrombotic events referred for adjudication to the CV adjudication
committee. In subsequent submissions, at request of FDA reviewers,
listing of discontinuations due to AE's and analyses of HTN, edema and
CHF related events were provided.

Protocol 091 was a placebo-controlled, parallel-group, multicenter,
15-month double-blind study to evaluate the efficacy and safety of
rofecoxib 25 mg to slow the progression of symptoms of Alzheimer's
Disease. Patients of either gender who were 50 years of age with
possible or probable Alzheimer's Disease were eligible to participate.
Patients using NSAIDs for 7 days/month for the 2 months immediately
prior to entry were not eligible. Patients were excluded if they were
living in a nursing home or skilled nursing facility. Eligible patients
were randomized to rofecoxib 25 mg or placebo for 12 months. This was
followed by an additional 3-month treatment phase in which 90% of the
patients initially assigned to rofecoxib were treated with placebo while
the other patients remained on their initial treatment. Safety and
tolerability were assessed at each visit (screening, Months 1, 3, 6, 9,
12, 13.5, and 15).

Protocol 078 This is a placebo-controlled, parallel-group, double-blind,
multicenter study to evaluate the effects of rofecoxib 25 mg on the
prevention of Alzheimer's Disease and cognitive decline in patients 65
years of age with mild cognitive impairment. Eligible patients were
randomized to receive rofecoxib 25 mg or placebo for 2 years or until
220 cases of clinically diagnosed probable or possible Alzheimer's
Disease are observed, whichever comes later. Safety and tolerability
were to be assessed at all visits.

Study 126 was similar in size and design to study 091.

As per the sponsor's listings the demographic characteristics, co-morbid
conditions and concomitant medications were similar in both treatment
groups in each study. The mean age of these patients was 75 years and
the number of patients included in each study per treatment arm was
approximately 370 for study 091 and 126, and approximately 700 for study
078.

The Alzheimer's studies specifically excluded patients at high
cardiovascular risk. The following are some of the exclusion criteria
used in the Alzheimer's studies (protocol 078):

1.  Patient with a history (within 2 years) or current evidence of major
    stroke,

multiple lacunar infarcts or transient ischemic events.

2.  Patient with a history of angina or congestive heart failure with
    symptoms at rest.

3.  Patients with a history of myocardial infarction or coronary artery
    bypass grafting, angioplasty, or stent placement within 1 year prior
    to study start.

4.  Patients taking the following medications:

-   Warfarin, heparin, ticlopidine.

-   NSAIDs (including salicylates or other aspirin-containing compounds)
    on a

> chronic basis (defined as =7 total days out of the last 30 days for 2
> consecutive months prior to potential study entry).

-   Estrogen replacement therapies (excluding topical cream
    preparations)

At some point, patients on warfarin were made eligible for the study,
provided that there was an increased frequency of monitoring of
prothrombin time after initiation of blinded study therapy (amendment
78-02). In a later amendment, done after enrollment was complete,
patients *who developed a need for cardio-protective doses of aspirin
while in the trial* were permitted to use aspirin up to 100
mg/day(78-06).

Exposure

The following tables were presented by the sponsor in the SUR (July 12,
2001):

Table 20 (a, b and c). Patient exposure in Alzheimer's studies.

![](media/image1.png){width="5.145833333333333in" height="1.46875in"}

> *Reviewer's comment: As noted in the above tables, mean exposure to
> rofecoxib 25 mg in 346 patients in study 091 was 348.25 days (standard
> deviation not provided), with a range of one to 480 days. Mean
> exposure to rofecoxib 25 mg in 721 patients in study 078 was 500 days
> ( 276 days) with a range of 0 to 1052 days of treatment. Mean
> exposure to rofecoxib 25 mg in 381 patients in study 126 was 156 days
> (95 days) with a range of one to 350 days of treatment. The sponsor
> has not provided median time of exposure in each of the trials but has
> provided patient years at risk (see table below).*

Table 21. Alzheimer's studies. Exposure to rofecoxib and placebo.

+----------+-------------+--------------+--------------+--------------+
|          | Rofecoxib   |              | Placebo      |              |
|          | 25 mg       |              |              |              |
+----------+-------------+--------------+--------------+--------------+
| *091*    | Randomized  | Pt. Years at | Randomized   | Pt. Years at |
|          |             | risk         |              | risk         |
| *078*    |             |              |              |              |
|          |             |              |              |              |
| *126*    |             |              |              |              |
+----------+-------------+--------------+--------------+--------------+
|          | 346         | 301          | 346          | 366          |
|          |             |              |              |              |
|          | 721         | 996          | 729          | 1098         |
|          |             |              |              |              |
|          | 381         | 165          | 376          | 169          |
+----------+-------------+--------------+--------------+--------------+
| *Total*  | 1448        | 1461         | 1451         | 1634         |
+----------+-------------+--------------+--------------+--------------+

*Source: sponsor's table. SUR.*

1.  Overall Safety in the in Alzheimer's studies

    1.  Deaths

Pooled data from the three Alzheimer's studies showed that all cause
mortality was higher in the rofecoxib 25 mg group, as compared to
placebo (33 and 20 respectively). The p-value for the crude rate
comparison between rofecoxib and placebo was 0.07. Of all deaths, 9 and
4 were confirmed as cardiovascular thrombotic by the CV adjudication
committee.

Table 22. Deaths in Alzheimer's studies

+----------------+-------------------------+--------------------------+
| *Study \#*     | Rofecoxib 25 mg         | Placebo                  |
|                |                         |                          |
|                | N= 1448                 | N= 1451                  |
+----------------+-------------------------+--------------------------+
|                | n/Pt Years of exposure  | n/Pt Years of exposure   |
+----------------+-------------------------+--------------------------+
| > 091          | 15/301                  | 8/366                    |
|                |                         |                          |
| 078            | 14/996                  | 8/1098                   |
|                |                         |                          |
| 126            | 4/165                   | 3/169                    |
+----------------+-------------------------+--------------------------+
|                | n (%)                   | n (%)                    |
+----------------+-------------------------+--------------------------+
| Total\*        | 33 (2.3)                | 20 (1.4)                 |
|                |                         |                          |
| CVT^1^         | 8 (0.6)                 | 4 (0.3)                  |
|                |                         |                          |
| Other^2^       | 24 (1.7)                | 16 (1.1)                 |
+----------------+-------------------------+--------------------------+

N= patients randomized. n= number of deaths. (%) crude rate. \* P=0.007.
^1^CVT: cardiovascular thrombotic death. Includes sudden death,
myocardial infarction and ischemic cerebrovascular events confirmed as
cardiovascular thrombotic by the CV adjudication Committee. ^2^ Other:
Includes death associated with malignancy, sepsis, trauma,
CHF/pneumonia, pulmonary embolism, hemorrhagic stroke, unclassified
cause of death.

![](media/image4.png){width="5.833333333333333in"
height="4.125in"}Figure 1. Kaplan Meier estimates. All Cause Mortality
in the Alzheimer's studies.

The p-value for the logrank comparison between rofecoxib 25 mg and
placebo = 0.026. (Source of Kaplan Meier curve: provided by Sponsor on
11/12/01)

> *Reviewer's comment: Listing of the cause of death in all patients in
> Alzheimer's studies is presented in Appendix 6. Of note, the trend is
> consistent in study 091 and 078. Study 078 is still ongoing. The
> sponsor has reported that study 126 was terminated early because of
> lack of efficacy in study 091 (Information submitted 11/26/01).*

2.2.1.2 Serious Adverse events in Alzheimer's studies.

Review of Serious Adverse events from the pooled Alzheimer's studies did
not show major differences in all serious AE's, serious cardiovascular
thrombotic events or serious digestive system events between rofecoxib
and placebo.

Table 23. SUR. Summary of Serious AE's in Alzheimer's studies.

+-----------------------------+---------------------+-----------------+
|                             | Rofecoxib 25 mg     | Placebo         |
|                             |                     |                 |
|                             | N=1448              | N=1451          |
|                             |                     |                 |
|                             | n (%)               | N (%)           |
+-----------------------------+---------------------+-----------------+
| Patients with at least one  | **261 (18.0)**      | **260 (17.9)**  |
| event                       |                     |                 |
+-----------------------------+---------------------+-----------------+
| Body as a whole             | 70 (4.8)            | 55 (3.8)        |
|                             |                     |                 |
| CV AE's                     | 77 (5.3)            | 82 (5.7)        |
|                             |                     |                 |
| Digestive AE's              | 40 (2.8)            | 32 (2.2)        |
|                             |                     |                 |
| Musculoskeletal             | 37 (2.6)            | 29 (2.0)        |
|                             |                     |                 |
| Skin and Appendices         | 20 (1.4)            | 42 (2.9)        |
+-----------------------------+---------------------+-----------------+

> *Reviewer's comment:*
>
> *There was a slightly higher number of serious digestive events in the
> rofecoxib group (2.8%) as compared to the placebo group (2.2%). These
> events included 2 gastric ulcers, 5 GI bleeding, 1 GI perforation, 2
> hemorrhagic duodenal ulcer, 4 hemorrhagic gastric ulcer in the
> rofecoxib arm (N=12) and 1 GI bleeding, 2 GI perforation, 2
> hemorrhagic gastric ulcer in the placebo arm (N=5) in the placebo arm.
> Of note, these are investigator reported terms, not confirmed events*.
>
> *There was a slightly lower number of reported serious CV events in
> the rofecoxib group (5.3%) as compared to the placebo group (5.7%).*

Discontinuations due to AE's were provided by the sponsor only for study
091. In this study of approximately 300 patients per treatment arm,
there were differences in the digestive system (4.2 and 1.4% for
rofecoxib and placebo respectively); respiratory system (2.3 and 0.3%)
and urogenital system (1.9 and 0% had renal insufficiency) in the
rofecoxib and placebo group, respectively.

2.  Cardiovascular Safety in Alzheimer's studies

2.2.2.1 Cardiovascular thrombotic events referred for adjudication.

There was no substantial difference in the number of investigator
reported serious cardiovascular potentially thrombotic events referred
for adjudication between rofecoxib (n= 81) and placebo (n= 76). (Source:
listing of serious CV thrombotic events referred for adjudication ,
submitted 9/6/01).

> *Reviewer's comment: By looking at the list of events referred for
> adjudication in the Alzheimer's studies it appears that the sponsor
> took a very conservative approach by referring all deaths, including
> terms such as "hepatic carcinoma" or "pulmonary fibrosis". However,
> even if only terms included in the original "Vascular SAE Terms
> Eligible for Case Adjudication" (Appendix 3a.) were included, the
> number of patients with events was not substantially different: 62 and
> 60, in the rofecoxib 25 and placebo groups, respectively. Of those,
> the sponsor reports that 22 and 30 were considered adjudicated APTC
> events in the rofecoxib and placebo groups, respectively.*
>
> *The size of the database is relatively small to detect differences in
> cardiovascular safety. The three Alzheimer's studies all together had
> approximately 1500 patients on rofecoxib 25 mg and 1500 on placebo. As
> per calculations made by FDA statisticians and presented at the
> February 8, 2001 AAC meeting, based on the cumulative data of serious
> CV thrombotic events observed in VIGOR, at least 2500 patients would
> be needed in each treatment group to detect statistically significant
> differences between treatments, if they existed at the same rate as
> presented in VIGOR.*
>
> *Of note, although the studies included an elderly population (mean
> age 75 years), patients with high cardiovascular risk such as those
> with a recent history of myocardial infarction and stroke, and
> patients taking estrogen replacement therapy were excluded from the
> Alzheimer's studies. Studies specifically designed to evaluate
> cardiovascular effects (e.g. protective effect of a drug in the risk
> of myocardial infarction or stroke) usually involve thousands of
> patients for several years.*
>
> *The Alzheimer's studies showed a trend towards an excess of
> cardiovascular deaths in the rofecoxib 25 mg group: 8 and 4 confirmed
> cardiovascular thrombotic deaths, in the rofecoxib 25mg and placebo
> groups, respectively. The Division of Cardio-Renal drug products has
> been consulted for detailed evaluation of potential cardiovascular
> thrombotic events in the Alzheimer's database. Results are pending at
> the time of this review.*

Data provided with the Alzheimer's studies do not cancel out the
findings in the VIGOR and ADVANTAGE studies.

2.  Hypertension-related, edema related and CHF related events

At the reviewer's request, the sponsor provided data on hypertension,
edema and CHF related events in studies 091 and 126 (submitted 10/1/01).
Data from study 078 were not available because this study is still
ongoing and blinded.

Table 24. SUR. Summary of HTN, edema and CHF-related events in
Alzheimer's studies 091 and 126.\*

+-----------------------------+---------------------+-----------------+
|                             | Rofecoxib 25 mg     | Placebo         |
|                             |                     |                 |
|                             | N= 726              | N= 722          |
|                             |                     |                 |
|                             | n (%)               | N (%)           |
+-----------------------------+---------------------+-----------------+
| HTN-related                 | 63 (8.7)            | 19 (2.6)        |
|                             |                     |                 |
| Edema-related               | 21 (2.9)            | 6 (0.8)         |
|                             |                     |                 |
| CHF-related                 | 16 (2.2)            | 6 (0.8)         |
+-----------------------------+---------------------+-----------------+

*\** Nine patients discontinued rofecoxib therapy due to the above AE's
(3 in each

category). One patient discontinued placebo due to a HTN- related event.

> *Reviewer's comment: consistent with prior databases, rofecoxib 25 mg
> is associated with higher incidence of hypertension, edema and CHF
> related events than placebo.*

2.  Short term placebo controlled studies in the SUR.

As part of the SUR, at the Agency's request, the sponsor provided data
from five recently completed short term (4-6 weeks) studies that
compared rofecoxib to placebo or other NSAIDs not included in the
initial ADVANTAGE SUR. Three of these studies were placebo controlled
(112, 116 and 905). In these studies, involving 456, 947 and 317
patients in the rofecoxib 12.5, rofecoxib 25 mg and placebo treatment
arms respectively, four patients presented serious cardiovascular
thrombotic events (one myocardial infarction and three coronary artery
disease events), all in the rofecoxib 25 mg group.

The size and duration of these studies is too small to assess
cardiovascular safety differences, however, the data suggest an
increased risk in the rofecoxib 25 mg group as compared to placebo.

**3.0 Safety from the RA efficacy studies (21-042/s012).**

This is the summary of a preliminary safety review of the RA efficacy
application. A more detailed review is presented in a separate review
(NDA 21-042/s012).

The protocols included in the RA efficacy application had a complicated
design, with some patients switching treatments between parts. The RA
safety database contains approximately 2000 patients exposed to
rofecoxib (12.5, 25 and 50 mg); 550 patients exposed to naproxen and
1000 patients exposed to placebo. The bulk of the exposure was to 3 and
6 months of treatment. Approximately 1500 patients were randomized to
rofecoxib 25 mg (n= 797) and 50 mg (n= 677) in 3-month placebo
controlled studies. Approximately 180, 140 and 80 patients were exposed
to rofecoxib 25mg, rofecoxib 50mg and naproxen 1000 mg respectively, for
one year or more.

1.  Overall safety in the RA application database

There were a total of six deaths: four on rofecoxib, one on naproxen and
one on placebo. None of the deaths were considered by the investigator
to be treatment related. None of them were cardiovascular deaths.

The pattern of adverse events, discontinuations due to adverse events,
laboratory AE's and vital signs was consistent with data submitted in
the original NDA submission.

3.2 Cardiovascular safety in the RA application database.

3.2.1 Investigator reported serious cardiovascular thrombotic events

The risk of developing serious cardiovascular thrombotic events with
rofecoxib 50 mg in the RA application safety database is higher than
with naproxen (2.6 vs. 1.5 per 100 patient years). The findings are
consistent with the VIGOR study. The cardiovascular risk for the 25 mg
dose (2.2 per 100 patient years) is also higher risk than naproxen. Risk
comparisons to the rofecoxib 12.5 mg and placebo groups is inadequate
because of the difference in exposure.

Table 25. RA database. Summary of Investigator Reported Serious CV
thrombotic events and Adjudicated events.(mostly 3-6 mo. studies, some
patients exposed up to 3 years; placebo-controlled studies were only 3
months duration).

+--------------+------------+---------+-----------+---+--------+----------+
| Treatment    | In         | Patien  | Risk per  | A |        | Risk per |
|              | vestigator | t-years | 100 pt    | d |        | 100 pt   |
|              | reported   | at risk | years     | j |        | years    |
|              | serious CV | \*      |           | u |        |          |
|              | thrombotic |         |           | d |        |          |
|              |            |         |           | i |        |          |
|              |            |         |           | c |        |          |
|              |            |         |           | a |        |          |
|              |            |         |           | t |        |          |
|              |            |         |           | e |        |          |
|              |            |         |           | d |        |          |
|              |            |         |           | e |        |          |
|              |            |         |           | v |        |          |
|              |            |         |           | e |        |          |
|              |            |         |           | n |        |          |
|              |            |         |           | t |        |          |
|              |            |         |           | s |        |          |
+--------------+------------+---------+-----------+---+--------+----------+
| Studies 096, |            |         |           |   |        |          |
| 097, 098 and |            |         |           |   |        |          |
| 103 (pivotal |            |         |           |   |        |          |
| and          |            |         |           |   |        |          |
| endoscopic)  |            |         |           |   |        |          |
+--------------+------------+---------+-----------+---+--------+----------+
| Placebo      | 2          | 160     | 1.3       |   | 1      | 0.5      |
|              |            |         |           |   |        |          |
| Vioxx 12.5   | 3          | 29      | 10.3      |   | 3      | 10.3     |
|              |            |         |           |   |        |          |
| Vioxx 25     | 11         | 501     | 2.2       |   | 6      | 1.2      |
|              |            |         |           |   |        |          |
| Vioxx 50     | 11         | 430     | 2.6       |   | 7      | 1.6      |
|              |            |         |           |   |        |          |
| Naproxen     | 6          | 406     | 1.5       |   | 1      | 0.3      |
+--------------+------------+---------+-----------+---+--------+----------+

\* patient-years at risk, provided by sponsor. Additionally, study 068
had 4, 7 and 5 investigator reported serious cv thrombotic events in the
VIOXX 25, 50 and naproxen respectively, but only deaths were referred
for adjudication, therefore, events from study 068 are not included in
this analysis.

> *Reviewer's comment: Number of events is small. Finding is consistent
> with VIGOR. There are more CV thrombotic events in rofecoxib groups
> (12.5, 25 or 50 mg) as compared to naproxen. Interpretation of placebo
> data is difficult given the small number of patients and short
> exposure.*

3.2.2 Edema-related AE's in RA application database.

The number of patients with edema-related events was higher in the
rofecoxib 25 and 50 mg groups as compared to naproxen.

Table 26. Edema related events\* (Source: sponsor's table 13 and 22 RA
SUR).

+--------------------+-----------+-----------+-----------+-----------+
|                    | Placebo   | Rofecox   | Rofecox   | Naproxen  |
|                    |           | 25        | 50        |           |
|                    | n/N %     |           |           | n/N %     |
|                    |           | n/N %     | n/N %     |           |
+--------------------+-----------+-----------+-----------+-----------+
| Placebo controlled | 15/989    | 39/797    | 23/677    | 9/516     |
| phase (12 weeks)   | **1.5**   | **4.9**   | **3.4**   | **1.7**   |
+--------------------+-----------+-----------+-----------+-----------+
| Long-term          | \-        | 36/491    | 30/458    | 15/296    |
| continuous         |           | **7.3**   | **6.6**   | **5.1**   |
| (one-year data)    |           |           |           |           |
+--------------------+-----------+-----------+-----------+-----------+

\* Includes terms such as edema, fluid retention, lower extremity edema,
peripheral edema. n= patients with events. N= patients randomized.

3.  Hypertension-related AE's in the RA application database.

Hypertension related events were observed two to three times more often
in each of the rofecoxib arms, as compared to the naproxen arm or
placebo. A higher percentage of patients presented important increase of
blood pressure and required concomitant medication in the rofecoxib arms
compared to the naproxen arm. More patients discontinued due to HTN
related events from each of the rofecoxib arms as compared to the
naproxen arm. Of note, more patients had a prior history of hypertension
in the rofecoxib 12.5 mg group.

Table 27. Summary of Hypertension related events in RA application\* .
(Source Table 13 and 22 RA SUR).

+--------------------+----------+------------+------------+-----------+
|                    | Placebo  | Rofecox 25 | Rofecox 50 | Naproxen  |
|                    |          |            |            |           |
|                    | n/N %    | n/N %      | n/N %      | n/N %     |
+--------------------+----------+------------+------------+-----------+
| Placebo controlled | 22/989   | 49/797     | 43/677     | 10/516    |
| phase (12 weeks)   | **2.2**  | **6.1**    | **6.4**    | **1.9**   |
+--------------------+----------+------------+------------+-----------+
| Long-term          | \-       | 59/491     | 71/458     | 16/296    |
| continuous         |          | **12.0**   | **15.5**   | **5.4**   |
| (one-year data)    |          |            |            |           |
+--------------------+----------+------------+------------+-----------+

\* Includes terms such as blood pressure increased, diastolic
hypertension, hypertension, uncontrolled hypertension. n= patients with
events. N= patients randomized.

Of note, hypertension related events were two to three times more common
in the rofecoxib groups as compared to the naproxen group.

3.2.4 CHF related events in RA application database

Three CHF related events occurred during the placebo controlled and long
term therapy periods. All in the rofecoxib 50 mg group. Two additional
cases occurred in the extension period, one in rofecoxib 25 mg and one
in rofecoxib 50 mg. The number of CHF events is small to draw definitive
conclusions but is consistent with VIGOR in which rofecoxib 50 mg was
associated with higher risk of developing CHF related events than
naproxen.

Table 28. Summary of CHF-related events (Source: Tables 13, 22 and 31,
RA SUR)

+---------------------+-----------+-----------+-----------+-----------+
|                     | Placebo   | Rofe 25   | Rofe 50   | Naproxen  |
|                     |           |           |           |           |
|                     | n/N %     | n/N %     | n/N %     | n/N %     |
+---------------------+-----------+-----------+-----------+-----------+
| Placebo controlled  | 0/898     | 0/797     | 1/677     | 0/516     |
| phase (12 weeks)    | **0**     | **0**     | **0.1**   | **0**     |
+---------------------+-----------+-----------+-----------+-----------+
| Long-term           | \-        | 0/491     | 2/458     | 0/296     |
| continuous          |           | **0**     | **0.4**   | **0**     |
| (one-year)          |           |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+

\* Includes pulmonary edema, congestive heart failure and cardiac
failure. n= patients with events. N= patients randomized.

> *Reviewer's comment: In this database, rofecoxib 25 mg and 50 mg had
> higher incidence of cardiovascular thrombotic events, HTN-, edema- and
> CHF-related events compared to naproxen 1000 mg/day or placebo.*

**B. Additional relevant data**

**Appendix 1.** Narratives of Deaths

Patients allocated to Rofecoxib

**065- 5005.** Cause of death listed as "Hypertensive heart disease"

73 F, Hx HTN, hyperlipidemia, soft systolic murmur and hyokalemia. Not
on ASA. Sept 11, 99 allocated to rofecoxib.

patient called son with c/o SOB When son arrived the patient was dead.
Last contact with patient was on Oct 6, 99 when she indicated lack of
efficacy. An autopsy was performed. Cause of death as per the coroner
was "hypertensive heart disease and that the manner of death was
"natural".

In the opinion of FDA reviewers' this is a case of sudden death. **THIS
CASE HAD NOT BEEN REFERRED FOR ADJUDICATION TO THE CV ADJUDICATION
COMMITTEE**.

**200- 3700.** Cause of death listed as MI. This case was [adjudicated
as Sudden Death.]{.underline}

74 M, hx angina, CAD, hyperchol, hypothyr, DM, CABG (1964), GI bleeding.
Concom therapy symvastatin, lisinopril, cyclobenzaprine, **ASA**,
furosemide, levothyroxine, glyburide. In August 18, 99 allocated to
rofecoxib. In

patient was thought to have suffered a massive MI. He expired at home.
Autopsy not performed.

**210- 4856.** Cause of death: Glioblastoma multiforme

71 F, allocated to rofecoxib on Sept 29, 99. On Oct 8,99 patient had
change in mental status. Oct 21 left side weakness and seizures. CT scan
of head, large glioma in the frontal lobe. Patient expired .

**658 -- 4049.** Cause of death listed as MI. [Adjudicated as Sudden
Death.]{.underline}

71 M, hx Afib, HTN, CAD. Conc; digoxin, diltiazem. No ASA.

Oct 15, 99 allocated to rofecoxib.

Patient attended visti 2 on Nov 22, 99 witout compaints. On family
informed the investigator that patient had been found dead in his home.

**679- 3423.** Cause of death listed as arterial rupture. Autopsy:
Ruptured Aortic Aneurism.

75 F, no cv risk factors. Aug 24, 99 allocated to rofecoxib. August 25
reported pruritus and metallic taste. Reported she was under process of
diagnostic testing for hematuria. On morning patient was found dead in
her kitchen. Autopsy showed ruptured aortic aneurism.

Patients allocated to Naproxen

**059-1841** Cause of death malignant neoplasm: gallbladder carcinoma

56F allocated to naproxen Jul 2, 99. Patient reported she has been
hospitalized in cholecystectomy and was diagnosed with gallbladder
carcinoma. In the patient expired.

**702-7154** Cause of death: malignang neoplasm: pancreatic carcinoma.

79F, hx of DM, HTN , anasarca, abdominal pain with constipation. In Oct
27, 99 allocated to naproxen.

increasing abdominal pain and distention. CT scan of abdomen showed
large pancreatic mass 5.7 cm in the tail of the pancreas w/metastatic
disease to the liver. Patient expired .

**777-3105** Cause of death: acute renal failure; respiratory failure;
acidosis

74 F, hx of HTN, CHF, depression, cellulitis. Baseline labs K 5.4 mEq/L,
BUN 49 mg/dl, Creatinine 1.5 g/dL, uric acid 11.4 mg/dL.

Augst 26, 99 patietn allocated to naproxen. Conc Verapamil, lisinopril,
furosemide, fluoxetine.

admited to ER with respiratory distress, Cxray c/w CHF pneumonia or
both. EKG IV conduction delay, sinus rhythm and first degree AV block.
Creatinine of 4.8. UA WBC 5-7; RBC 10-12, bacteria 3+, mucus 3+. Patient
diagnosied with acute renal failure. Echocardiogram showed enlarged
right sided chambers with severe tricuspid regurgitation and pulmonary
HTN and calcified mitral valve anulus. Patient deteriorated with
elevated WBC count of 19l1 K/L, HB 8.5 mg/dL, severe mixed metabolic and
respiratory acidosis. Patient expired in .

Last contact between patient and study coordinator was Oct 21, 99, at
the 6 week visit. At that time the patient had a cold and had no
complaints. Additional follow up stated that study therapy was dc on Oct
20,99 due to bronchitis.

In summary, this is a patient with history of HTN, CHF, tricuspid
regurgitation and pulmonary hypertension and borderline renal function
who started naproxen 500 mg bid on August 99. In she presented to the ER
with acute renal failure, respiratory failure and acidosis, and died two
days later. The investigator considered the episode not related to study
medication. The cause of death in this patient is not clear. We might
hypothesize that an NSAID worsened her borderline renal function and
exacerbated her CHF. However, she may also have been septic. She did
have an elevated WBC of 19 K but there are no available
blood/urine/sputum cultures.

**0831- 7114** Cause of death: Non-small cell carcinoma

78 M, hx glaucoma, doe, COPD peripheral vascular disoerder and smooker.
Conc included ASA. Allocated Nov 19 99. Nov 23 99 rx disc due to
nabdominal bloating. patient hospitalized and diagnosed with metastatic
adenocarcinoma of the lung and died on .

**Appendix 2.** Serious AE's that resulted in hospitalization

Fifty-three out of 68 (78%) patients with serious AE's in the rofecoxib
group and 48 out of 72 (67%) patients with serious AE's in the naproxen
group, required hospitalization.

Appendix 2. Hospitalizations (Source: Sponsor's Table 60, appendix
4.1.62)

+-------------------------------+------------------+------------------+
|                               | Rofecoxib 25 mg  | Naproxen 1000 mg |
|                               |                  |                  |
|                               | N= 2785          | N= 2772          |
|                               |                  |                  |
|                               | n %              | n %              |
+-------------------------------+------------------+------------------+
| Patients with at least one    | 53 (1.9%)        | 48 (1.7%)        |
| serious AE requiring          |                  |                  |
| hospitalization               | 7 (0.3)          | 8 (0.3)          |
|                               |                  |                  |
| Body as a whole               | 18 (0.6)         | 13 (0.5)         |
|                               |                  |                  |
| Cardiovascular system         | 5 (0.2)          | 12 (0.4)         |
|                               |                  |                  |
| Digestive system              | 1 (0.0)          | 1 (0.0)          |
|                               |                  |                  |
| Endocrine                     | \-               | 1 (0.0)          |
|                               |                  |                  |
| Eyes, ears, nose and throat   | \-               | 1 (0.0)          |
|                               |                  |                  |
| Hemic and lymphatic           | 2 (0.1 )         | > --             |
|                               |                  |                  |
| Hepatobiliary system          | \-               | 1.  (0.0)        |
|                               |                  |                  |
| Immune system                 | 7 (0.3)          | > 5 (0.2)        |
|                               |                  |                  |
| Musculoskeletal system        | 4 (0.1)          | 1 (0.0)          |
|                               |                  |                  |
| Nervous system                | 3 (0.1)          | 1 (0.0)          |
|                               |                  |                  |
| Psychiatric disorder          | 6 (0.2)          | 3 (0.1)          |
|                               |                  |                  |
| Respiratory system            |                  |                  |
+-------------------------------+------------------+------------------+

**Appendix 3a.**

![](media/image5.png){width="6.09375in" height="8.947916666666666in"}

![](media/image6.png){width="6.0in" height="5.885416666666667in"}

**(**Source: NDA 21-042/s007, Appendix 3.2.1).

**Appendix 3.b** Sponsor's cardiovascular analyses.

Table Summary analysis of investigator reported serious cardiovascular
thrombotic SAE's in ADVANTAGE.

![](media/image8.png){width="5.8493055555555555in"
height="1.5625in"}Source: sponsor's table 80. Appendix 4.1.80

Table. Summary of analysis of adjudicated thrombotic CV SAE in ADVANTAGE

![](media/image9.png){width="5.844444444444444in"
height="1.5833333333333333in"}Source: sponsor's table 78 Appendix 4.1.78

![](media/image10.png){width="5.989583333333333in"
height="1.61875in"}Table Summary of analysis of APTC endpoints in
ADVANTAGE

Source: sponsor's table 79 Appendix 4.1.79

APTC: Anti Platelet Trialist Collaboration endpoints: CV death,
non-fatal MI, non-fatal stroke. (Difference with "Adjudication
thrombotic endpoints": Includes hemorrhagic stroke. Excludes angina, TIA
and peripheral arterial and venous events).

**Appendix 4.** Narratives of patients for which FDA reviewers did not
agree with sponsor's adjudication.

102 462 1867 - 84 year old woman with history of DM, osteoporosis,
hypothyroidism and partial gastrectomy allocated to receive naproxen in
July 29 1999. Concomitant therapy included estrogens, insulin and
synthroid. On she was hospitalized for severe back pain with a vertebral
compression fracture. She was transferred to a rehab center in . In

she developed leg edema, was diagnosed with DVT and started
anticoagulation. Subsequently developed colon hemorrhage (9/15/99)
secondary to anticoagulation. The case report form originally had
8/16/99 as the stop date for taking the study medication. The date was
later corrected to 7/9/99. There is a hand written note stating that it
is not known whether the patient ever took the assigned medication
because she did not return the diary. [As per the sponsor's June 22,
2001 correspondence, the event occurred more than 14 days after
discontinuation of study drug.]{.underline}

102 065- 5005. 73 year old woman with history of HTN, hyperlipidemia,
soft systolic murmur and hyokalemia. Allocated to rofecoxib in Sept 11,
1999. In patient called son with c/o SOB. When son arrived the patient
was dead. Last contact with patient at the study site had been in Oct 6,
1999 when she indicated lack of efficacy. An autopsy was performed.
Cause of death as per the coroner was "hypertensive heart disease" and
that the manner of death was "natural". This is actually a sudden death.

102 0215 4378 211: 72 year old female with history of hyperlipidemia,
CVA and carotid endarterectomy. Concomitant meds: ASA, clopidogrel,
prevastatin, estradiol. Patient was randomized in Oct 6, 1999. In
patient developed numbness and tingling similar to her prior CVA. She
went to surgery. A thrombus of the right carotid artery with severe
stenosis was found intraoperatively. This case was considered
"non-thromboembolic" by the CV adjudication committee. The Division of
Neuropharm products considered this case as an "ischemic cerebrovascular
accident". This patient was on rofecoxib 25 mg.

102 0386 3155 209: 77 year old female with history of HTN,
hyperlipidemia, hypothyroidism, DM and dyspepsia. Concomitant therapy
included omeprazole, atenolol, nifedipine, atrovastatin, levothiroxine,
clopidogrel temazepam, rosiglitazone, potassium and furosemide. Patient
was randomized in June 18, 1999. In Aug 5,1999, a physician reported
that the patient developed abnormal head and arm movements diagnosed as
dyskinesia of unknown cause. Study therapy was discontinued. Follow up
information from a physician indicated that the diagnosis was changed to
possible small CVA. In an MRI showed lacunar type infarctions
bilaterally in the caudate region; an old hemorrhagic infarct in the
right putamen and bilateral thalamic lacuna with no definitive evidence
of acute infarct. Patient recovered within 5 days with "adjustment" of
medications and haloperidol. This event was adjudicated as "ischemic
with small artery occlusion". Acute choreic symptoms can rarely be
caused by a lacunar infarct. Acute symptoms are most likely related to
metabolic imbalances, e.g. hyperglycemia, which the patient had,
exceeding 450 mg/dL during her hospital stay. The Division of Neuropharm
products considered this case as "Unable to adjudicate. Acute chorea of
unknown etiology". This patient was on naproxen.

102 0283 2182 222 58 year old female with history of cardiac murmur,
allergic cough and intermittent anemia. Patient family history includes
development of TIA's with symptoms including dysphagia. Patient was
randomized in July 21, 1999. Concomitant medications included conjugated
estrogenic hormone w/medroxyprogesterone and famciclovir. Documentation
for this case is poor and confusing. In August 5, 1999 for no particular
reason, she was started on baby ASA "for general health". Apparently,
starting August 16, 1999 the patient had one or two neurologic episodes
characterized by speech difficulty and left side weakness in the context
of severe headache. In September 11, 1999 ASA was increased from baby
ASA to 235 mg/day. Between September 23, 1999 and October 12, 1999 she
had another transient episode of dysphagia for 24 hours. The
adjudication package and narrative provided by the sponsor is unclear as
to when exactly those TIA's occurred. The patient did not look for
medical attention at the time of the events. Additionally, recurrent
episodes of weakness appeared to precede study entry. Neurologic
examination did not confirm left side weakness. Head CT, carotid
ultrasound and echocaridogram (September 24-27) were all normal. The
patient completed the trial in October 12, 1999. The CV adjudication
committee adjudicated these events as "ischemic CV stroke". The Division
of Neuropharm products considered this case to be "Unable to
adjudicate". The patient was on naproxen.

903 0002 9009 308. 60 year old male with a history of osteoarthritis,
obesity, HTN, and hypercholesterolemia. His PMH is significant for a
history of a subendocardial MI in 1990. A coronary angiogram in 1991
revealed 'normal coronary arteries with a bit slow flow'. He had several
normal stress tests in the past. He was diagnosed with Syndrome X. The
patient was randomized and took study drug for approximately 80 days
before the onset of chest pain leading to hospitalization. Chest pain
lasted 2.5 hours (6 pm to 8:30 pm), was associated with nausea and not
affected by 6 nitroglycerin tablets. ECGs on admissions showed no
ischemic changes. Per the hospital discharge summary, MI was excluded
*despite an elevated CPK-MB (5 mcg/ml on admission, normals 0 to 3
mcg/ml) and troponin (0.8, normals 0-0.4).* After an echocardiogram and
a stress test that was reported as negative ('without steadily ground
for ischemia') the patient's pain was attributed to Syndrome X and
discharged. The event was adjudicated as not an APTC endpoint per the CV
adjudication committee. Because of the persistently elevated CPK-MB and
troponin, in the presence of chest pain accompanied by nausea and chest
pressure, in patient with prior history of CAD (subendocardial MI) the
division of Cardio-Renal products considered this event likely to be due
to a cardiac thrombotic event. The patient was on rofecoxib.

**Appendix 5. a. Cardiovascular safety in VIGOR study**

![](media/image11.png){width="5.979166666666667in"
height="4.302083333333333in"}Confirmed (Adjudicated) Thrombotic CV
serious adverse experiences in the VIGOR study. Time to event plot (all
patients randomized). RR=2.37 for rofecoxib relative to naproxen
(p=0.001).

**Appendix 5.b.** VIGOR study. Confirmed or "adjudicated" thrombotic
cardiovascular serious adverse experiences in all patients randomized
and in subgroups of patients identified retrospectively by the sponsor
as patients who may have or may have not benefited from low dose ASA.

+-----------------+----+---------+-----+-----+------+---------+-----+
|                 | N  | P       | PYR | Ra  | Rela |         |     |
|                 |    | atients | ^1^ | tes | tive |         |     |
|                 |    | with    |     | ^2^ | ris  |         |     |
|                 |    | events  |     |     | k^3^ |         |     |
|                 |    |         |     |     |      |         |     |
|                 |    | ^(%)^   |     |     |      |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+
|                 |    |         |     |     | Esti | 95%CI   | p   |
|                 |    |         |     |     | mate |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+
| All patients    |    |         |     |     |      |         |     |
| randomized      |    |         |     |     |      |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+
| Rofecoxib       | 40 | 45      | 2   | 1   | 2.37 | 1.39 -- | 0.0 |
|                 | 47 | (1.1%)  | 697 | .67 |      | 4.06    | 016 |
| Naproxen        |    |         |     |     |      |         |     |
|                 | 40 | 19      | 2   | 0   |      |         |     |
|                 | 29 | (0.5%)  | 698 | .70 |      |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+
| Potential       |    |         |     |     |      |         |     |
| candidate for   |    |         |     |     |      |         |     |
| low dose ASA^5^ |    |         |     |     |      |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+
| Rofecoxib       | 1  | 15      | 105 | 14  | 4.89 | 1.41 -  | 0.0 |
|                 | 70 | (8.8%)  |     | .29 |      | 16.88   | 122 |
| Naproxen        |    |         | 102 |     |      |         |     |
|                 | 1  | 3 (2.0  |     | 2   |      |         |     |
|                 | 51 | %)      |     | .94 |      |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+
| Not candidate   |    |         |     |     |      |         |     |
| for low dose    |    |         |     |     |      |         |     |
| ASA             |    |         |     |     |      |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+
| Rofecoxib       | 38 | 30      | 2   | 1   | 1.88 | 1.03 -- | 0.  |
|                 | 77 | (0.8%)  | 592 | .16 |      | 3.45    | 041 |
| Naproxen        |    |         |     |     |      |         |     |
|                 | 38 | 16      | 2   | 0   |      |         |     |
|                 | 38 | (0.4%)  | 596 | .62 |      |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+

^1^ Patient-years at risk. ^2^ Per 100 patients years. ^4^ Relative risk
of rofecoxib with respect to naproxen. ^5^ Patients with past medical
history of cerebrovascular accident, transient ischemic attack,
myocardial infarction, unstable angina, stable angina, coronary artery
bypass surgery or percutaneous coronary intervention. (Source: modified
from sponsor's Table 9 of the safety update, Estimate calculated by Dr.
Qian Li, FDA statistician).

VIGOR study. Myocardial Infarctions. Subgroup analyses by sponsor's
retrospective identification of patients who may have benefited from low
dose ASA.

**Appendix 5.c.** VIGOR. Investigator reported and adjudicated (CV
committee confirmed) serious CV thrombotic events. (Source: NDA
21-042/007, SUR 10/3/01 submission).

+-----------------------+----------+-----------+-----------+-----------+
|                       | Number   |           | Number of |           |
|                       | of       |           | patients  |           |
|                       | patients |           | with      |           |
|                       | with     |           |           |           |
|                       | Inve     |           | CV        |           |
|                       | stigator |           | Committee |           |
|                       | reported |           | confirmed |           |
|                       | serious  |           | serious   |           |
|                       | CV       |           | CV-t      |           |
|                       | th       |           | hrombotic |           |
|                       | rombotic |           | events    |           |
|                       | events   |           |           |           |
+-----------------------+----------+-----------+-----------+-----------+
|                       | R        | Naproxen  | Rofecoxib | Naproxen  |
|                       | ofecoxib |           |           |           |
|                       |          | (N= )     | (N=       | (N= )     |
|                       | (N= )    |           |           |           |
+-----------------------+----------+-----------+-----------+-----------+
|                       | **64**   | **32**    | **47**    | **20**    |
+-----------------------+----------+-----------+-----------+-----------+
| **CV death**          | **7**    | **7**     | **6**     | **6**     |
|                       |          |           |           |           |
| Fatal acute MI        | 3        | 4         | 2         | \-        |
|                       |          |           |           |           |
| Fatal hemorrhagic     | \-       | \-        | 1         | 1         |
| stroke                |          |           |           |           |
|                       | 2        | 1         | \-        | 1         |
| Fatal Ischemic stroke |          |           |           |           |
|                       | 2        | \-        | 3         | 4         |
| Sudden cardiac death  |          |           |           |           |
|                       | \-       | 2         | \-        | \-        |
| Intracranial          |          |           |           |           |
| hemorrhage            | **36**   | **19**    | **28**    | **10**    |
|                       |          |           |           |           |
| **Cardiac events**    | 23       | 8         | 20        | 4         |
| (fatal & nonfatal)    |          |           |           |           |
|                       | 6        | 7         | 3         | 4         |
| MI                    |          |           |           |           |
|                       | 1        | \-        | 5         | 3         |
| Angina                |          |           |           |           |
|                       | 1        | \-        | \-        | \-        |
| Vent fib              |          |           |           |           |
|                       | 2        | 3         | \-        | \-        |
| Cardiac arrest        |          |           |           |           |
|                       | 2        | 1         | \-        | \-        |
| Coronary art          |          |           |           |           |
| disease/oclusion      | **20**   | **11**    | **13**    | **9**     |
|                       |          |           |           |           |
| Ischemic heart dz.    | 15       | 6         | \-        | \-        |
|                       |          |           |           |           |
| **Cerebrovascular**   | \-       | \-        | 2         | 1         |
| (fatal& nonfatal)     |          |           |           |           |
|                       | \-       | 3         | 9         | 8         |
| CVA                   |          |           |           |           |
|                       | 2        | \-        | 2         | \-        |
| Hemorrhagic stroke    |          |           |           |           |
|                       | 1        | \-        | \-        | \-        |
| Ischemic cerebr.vasc  |          |           |           |           |
| stroke                | 1        | 2         | \-        | \-        |
|                       |          |           |           |           |
| TIA                   | 1        | 2         | \-        | \-        |
|                       |          |           |           |           |
| Carotid artery        | **8**    | **2**     | **6**     | **1**     |
| obstruction           |          |           |           |           |
|                       | 1        | 1         | 1         | \-        |
| Cerebrovascular       |          |           |           |           |
| disorder              | 5        | 1         | 5         | 1         |
|                       |          |           |           |           |
| Intracranial          | 1        | \-        | \-        | \-        |
| hemorrhage            |          |           |           |           |
|                       | 1        | \-        | \-        | \-        |
| **Peripheral**        |          |           |           |           |
|                       |          |           |           |           |
| Arterial thrombosis   |          |           |           |           |
|                       |          |           |           |           |
| Venous thrombosis     |          |           |           |           |
|                       |          |           |           |           |
| Peripheral vascular   |          |           |           |           |
| disorder              |          |           |           |           |
|                       |          |           |           |           |
| Arterial embolism     |          |           |           |           |
+-----------------------+----------+-----------+-----------+-----------+

**Appendix 6.** a. Deaths in Alzheimer's protocol \# 091

+-----------------------------------------------------------------------+
| Rofecoxib 25 mg (14)                                                  |
|                                                                       |
| > \*AN 332 - Cardiac arrest , fatal MI: 78 M, 1 day off drug,         |
| > relative day 328                                                    |
| >                                                                     |
| > \*AN 601 -- Sudden death: 75 M, 1 day off drug, relative day 228    |
| >                                                                     |
| > \*AN 831 -- CVA: 85 W M, relative day 296                           |
| >                                                                     |
| > AN 915 - CHF and pneumonia: 79 F, relative day 260 []{.mark}        |
| >                                                                     |
| > AN 964 - Dizziness, CVA, respiratory failure: 86 F, taking          |
| > conjugated estrogens,                                               |
| >                                                                     |
| > developed CVA approx. 1 month into the study. Drug stopped. Patient |
| > died                                                                |
| >                                                                     |
| > on relative day 58. Not adjudicated due to insufficient data.       |
| >                                                                     |
| > AN 3 - Pneumonia: 91 F day 260                                      |
| >                                                                     |
| > AN 42 - Endocarditis/pneumonia: 83 M, day 303                       |
| >                                                                     |
| > AN 282 -- Lung cancer: 71 F, day 165                                |
| >                                                                     |
| > AN 376 - Burn/fungemia/anuria: 62 M, day 173                        |
| >                                                                     |
| > AN 382 - Lung and brain malignant neoplasm: 77 F, relative day 123  |
| >                                                                     |
| > AN 542 - Hypercalcemia, acute renal failure: 82 F 7 days off drug;  |
| > relative day 188                                                    |
| >                                                                     |
| > AN 691 - Esophageal malignant neoplasm: 86 M, relative day onset    |
| > 390                                                                 |
| >                                                                     |
| > AN 835 - Interstitial lung disease, pneumonia, cardiac arrest: 82   |
| > M, day 269                                                          |
| >                                                                     |
| > AN 891 - Fever, sepsis. 88 F, day 76                                |
|                                                                       |
| Placebo (8)                                                           |
|                                                                       |
| > \*AN 784 -- Sudden death: 70 F, day 458                             |
| >                                                                     |
| > AN 394 - Metastatic neoplasm, unknown primary: 68 M, day 452        |
| >                                                                     |
| > AN 613 - COPD/ aspiration pneumonia: 88 M, day 131                  |
| >                                                                     |
| > AN 664 - Alzheimer's/Pneumonia: 84 M, day 417                       |
| >                                                                     |
| > AN 827 - Intracranial hemorrhage: 74 M, day 70 (CV                  |
| > non-thromboembolic)                                                 |
| >                                                                     |
| > AN 830 - Acute myelogenous leukemia: 79 F, day 99                   |
| >                                                                     |
| > AN 832 - Pneumonia, cardiac arrest secondary to aspiration/sepsis:  |
| > 82 M, day 461                                                       |
| >                                                                     |
| > AN 956 - Ruptured aortic aneurysm: 81 M, day 16 (CV                 |
| > non-thromboembolic)                                                 |
+-----------------------------------------------------------------------+

\* Case confirmed by Cardiovascular Adjudication Committee

**Appendix 6b**. Deaths in Alzheimer's protocol \# 078 (from WAES
database)

+-----------------------------------------------------------------------+
| Rofecoxib 25 mg (15)                                                  |
|                                                                       |
| \*AN 248 -- Sudden death, unknown cause of death: 71 F, day 747       |
|                                                                       |
| \*AN 359 - Sudden death, hypertension: 68 M, day 624                  |
|                                                                       |
| \*AN 737 - Sudden death, cardiac arrest: 84 M, day 185                |
|                                                                       |
| \*AN 799 - Sudden death, cardiac arrest: 85 M, day 312                |
|                                                                       |
| \*AN1025 -- Acute Myocardial infarction: 83 M, day 138                |
|                                                                       |
| AN 205 - Postop complication, hip fracture, pulmonary embolism: 85 M, |
| day 496 (CV)                                                          |
|                                                                       |
| AN 583 - Pulmonary embolism/ pancreatic ca: 70 M, day 357 (CV)        |
|                                                                       |
| AN 352 - Hemorragic duodenal ulcer; small cell ca; 67 M, day 322      |
|                                                                       |
| AN 762 - Metastatic prostate ca, renal failure; 87 M, day 707         |
|                                                                       |
| AN 821 - Head trauma: 85 M, day 271                                   |
|                                                                       |
| AN 935 - Trauma: 75 M, day 106                                        |
|                                                                       |
| AN 1097 -- Electric shock: 69 M , day 248                             |
|                                                                       |
| AN 1453 -- Chest trauma: 83 M, day 611                                |
|                                                                       |
| AN1453 -- Bacterial sepsis, acute myelogenous leukemia: 80 M, day 53  |
|                                                                       |
| Placebo (8):                                                          |
|                                                                       |
| \*AN 1256 -- Sudden death: 82 F, day 674                              |
|                                                                       |
| \*AN 1378 -- Sudden death: 74 M, day 392                              |
|                                                                       |
| AN 539 - Hypertension: 72 M, day 243 (CV).                            |
|                                                                       |
| AN 264 -- Colon ca: 76 M, day 430                                     |
|                                                                       |
| AN 294 - malignant melanoma: 77 M, day 556                            |
|                                                                       |
| AN 308 - myelogenous lukemia, pneumonia, acute renal failure: 85 M,   |
| day 407                                                               |
|                                                                       |
| AN 1144 - Pancreatic carcinoma: 94 F, day 469                         |
|                                                                       |
| AN 1350 - bladder carcinoma: 79 F, day 708                            |
|                                                                       |
| AN 1547 - metastatic neoplasm of unknown origin: 82 M, day 96         |
+-----------------------------------------------------------------------+

Deaths in Alzheimer's protocol #126

+-----------------------------------------------------------------------+
| Rofecoxib (4)                                                         |
|                                                                       |
| AN 125 - GI (large intestine) perforation: 86 F, day 214              |
|                                                                       |
| AN 466 - Hip fracture, dyspnea (PE?): 86 M, day 190 NOT REFERRED x    |
| adjudication                                                          |
|                                                                       |
| AN 532 - Hemorragic CVA (confirmed)                                   |
|                                                                       |
| AN 743 - Intracranial hemorrhage (confirmed)                          |
|                                                                       |
| Placebo (3)                                                           |
|                                                                       |
| \*AN 661 - Myocardial infarction, related to major stressor:          |
| meningitis: 77 M, day 236                                             |
|                                                                       |
| AN 257 - Trauma: 79 M, day 82                                         |
|                                                                       |
| AM 635 - Lymphoma, GI bleeding, sepsis: 78 F, day 216                 |
+-----------------------------------------------------------------------+

\* Confirmed as cardiovascular thrombotic event by CV Adjudication
Committee*.* Of note, mean exposure in this study was 5 months only.