# FDA Advisory Committee Briefing Document

# 

# NDA 21-042, s007 

# VIOXX Gastrointestinal Safety

# 

# February 8, 2001

+------------------------------------------------------------+----+---+
| ### NDA \# 21-042 & 21-052, s007 -- VIOXX GI safety        | Pa |   |
|                                                            | ge |   |
| Advisory Committee Briefing Document                       |    |   |
|                                                            |    |   |
| February 8, 2001                                           |    |   |
|                                                            |    |   |
| Table of contents                                          |    |   |
+------------------------------------------------------------+----+---+
| ########                                                   | 3  |   |
| # Section I. Overall Safety (Maria Lourdes Villalba, M.D.) |    |   |
|                                                            | 4  |   |
| ######### Background                                       |    |   |
|                                                            | 7  |   |
| ######### Data reviewed in this submission                 |    |   |
|                                                            | 7  |   |
| 1.  New studies                                            |    |   |
|                                                            | 15 |   |
|     1.  VIGOR (088c)                                       |    |   |
|                                                            | 16 |   |
|     2.  Studies 085 and 090                                |    |   |
|                                                            | 19 |   |
|     3.  Study 102                                          |    |   |
|                                                            | 20 |   |
| 2.  Data from original NDA (069, 058)                      |    |   |
|                                                            | 21 |   |
| 3.  Post-marketing data                                    |    |   |
|                                                            | 22 |   |
| ```{=html}                                                 |    |   |
| <!-- -->                                                   | 24 |   |
| ```                                                        |    |   |
| 1.  Conclusions                                            |    |   |
|                                                            |    |   |
| 2.  Recommendations                                        |    |   |
|                                                            |    |   |
| 3.  Appendix 1. Listing of deaths                          |    |   |
+------------------------------------------------------------+----+---+
| **Section II. Gastrointestinal Safety (Lawrence Goldkind,  | 2  |   |
| M.D. )**                                                   |    |   |
|                                                            | 5  |   |
| ######### Background                                       |    |   |
|                                                            | 5  |   |
| VIGOR study (088c)                                         |    |   |
|                                                            | 10 |   |
| > Study design and reviewer comments                       |    |   |
| >                                                          | 11 |   |
| > Conclusions regarding study design                       |    |   |
| >                                                          | 11 |   |
| > Results                                                  |    |   |
| >                                                          | 14 |   |
| > Demographics                                             |    |   |
| >                                                          | 21 |   |
| > GI outcome results                                       |    |   |
| >                                                          | 28 |   |
| > Subgroup analysis                                        |    |   |
|                                                            | 29 |   |
| Overall conclusions                                        |    |   |
|                                                            |    |   |
| Appendix 1. Protocol provisions                            |    |   |
+------------------------------------------------------------+----+---+
| **Section III. Cardiovascular Safety (Shari Targum,        | 3  |   |
| M.D.)**                                                    |    |   |
|                                                            | 4  |   |
| ######### Background                                       |    |   |
|                                                            | 26 |   |
| ######### VIGOR study (088c)                               |    |   |
|                                                            | 31 |   |
| Study 085                                                  |    |   |
|                                                            | 36 |   |
| Study 090                                                  |    |   |
|                                                            |    |   |
| Issues and comments                                        |    |   |
+------------------------------------------------------------+----+---+
| **Section IV. Statistics (Qian Li, Sc. D.)**               | 1  |   |
|                                                            |    |   |
| I. Introduction                                            | 1  |   |
|                                                            |    |   |
| II\. Design and Statistical Methodology                    | 5  |   |
|                                                            |    |   |
| III\. Results                                              | 14 |   |
|                                                            |    |   |
| IV\. Conclusions                                           |    |   |
+------------------------------------------------------------+----+---+

# NDA 21-042/052, s007 

# Rofecoxib Overall Safety

# 

#  

# 1. [Background]{.underline} 

VIOXX (rofecoxib) is a non-steroidal anti-inflammatory drug (NSAID) with
selective cyclooxygenase 2 (COX-2) inhibitory properties. It was
approved for marketing in the U.S. in May 1999 for the treatment of
acute pain in adults, dysmenorrhea and the signs and symptoms of
osteoarthritis (OA).

Based on the safety profile demonstrated in the original NDA database
VIOXX carries the Warnings and Precautions section of the NSAID class,
including the risk of gastrointestinal (GI) bleeding, as follows:

##### WARNINGS

> Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and
> Perforation:
>
> Serious gastrointestinal toxicity such as bleeding, ulceration, and
> perforation of the stomach, small intestine or large intestine, can
> occur at any time, with or without warning symptoms, in patients
> treated with nonsteroidal anti‑inflammatory drugs (NSAIDs). Minor
> upper gastrointestinal problems, such as dyspepsia, are common and may
> also occur at any time during NSAID therapy. Therefore, physicians and
> patients should remain alert for ulceration and bleeding, even in the
> absence of previous GI tract symptoms. Patients should be informed
> about the signs and/or symptoms of serious GI toxicity and the steps
> to take if they occur. The utility of periodic laboratory monitoring
> has not been demonstrated, nor has it been adequately assessed. Only
> one in five patients who develop a serious upper GI adverse event on
> NSAID therapy is symptomatic. It has been demonstrated that upper GI
> ulcers, gross bleeding or perforation, caused by NSAIDs, appear to
> occur in approximately 1% of patients treated for 3-6 months, and in
> about 2-4% of patients treated for one year. These trends continue
> thus, increasing the likelihood of developing a serious GI event at
> some time during the course of therapy. However, even short-term
> therapy is not without risk.

In addition to the above paragraph, the VIOXX label states: It is
unclear, at the present time, how the above rates apply to VIOXX (see
CLINICAL STUDIES, Special Studies, *Upper Endoscopy in Patients with
Osteoarthritis*). Safety data from two endoscopic studies in which
ibuprofen was the active comparator are included under the Clinical
Studies section of the label.

> *(Of note, the estimates of perforations, ulcers and bleeding that
> appear in the GI warning section of NSAID labels include ulcers
> associated with pain alone without the more serious complications.)*

The FDA and the sponsor agreed that evidence was needed regarding
clinically meaningful upper GI events as well as a large controlled
database for overall safety assessment.

Based on the results of the present submission the sponsor proposes to
remove the NSAID-class GI Warnings. By doing so, VIOXX would distance
itself from the NSAIDs class. The sponsor proposes to include a brief
paragraph describing GI risk under the Precautions section of the label.

FDA has concerns with:

-   The generalizability of the findings of the VIGOR study to the
    general population and to NSAIDs other than the one included as an
    active comparator in this study.

```{=html}
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```
-   Remaining GI risk as evidenced by ongoing occurrence of serious
    complicated GI events associated with rofecoxib use in this review
    and in post-marketing surveillance.

```{=html}
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```
-   Cardiovascular safety issues raised during this review.

*(Reviewer's comments in this review will appear in italics.)*

**2. [Data reviewed in this submission]{.underline}**

Studies reviewed under NDA 20-042/052 supplement 007 included 3 new
studies and data provided in the original NDA submission. These studies
are summarized in Tables 1 and 2. An additional study conducted under
this NDA is summarized in Table 3.

Table 1. NDA 21-042/S007. New studies in this submission

+-----------+-------------------+----+---------------+--------+------+
|           | Design            | D  | Treatment     | N      | ASA  |
|           |                   | z. | (mg/day)      |        |      |
|           |                   |    |               |        | all  |
|           |                   |    |               |        | owed |
+-----------+-------------------+----+---------------+--------+------+
| Study     | "Large and        | RA | Rofecoxib 50  | 4027   | #    |
| 088c      | simple"           |    |               |        | # NO |
| "VIGOR"   | Multicenter,      |    | Naproxen 1000 | 4049   |      |
|           | double-blind,     |    |               |        |      |
|           | randomized,       |    |               |        |      |
|           |                   |    |               |        |      |
|           | active            |    |               |        |      |
|           | controlled,       |    |               |        |      |
|           |                   |    |               |        |      |
|           | median 9 months   |    |               |        |      |
|           | f.u.              |    |               |        |      |
+-----------+-------------------+----+---------------+--------+------+
| Study 085 | Multicenter,      | OA | Rofecoxib     | 424    | ##   |
|           | double-blind,     |    | 12.5          |        |  YES |
|           | randomized,       |    |               | 410    |      |
|           | placebo and       |    | Nabumetone    |        | 10   |
|           | a                 |    | 1000          | 208    | -15% |
|           | ctive-controlled, |    |               |        |      |
|           | six- week         |    | Placebo       |        |      |
|           | duration          |    |               |        |      |
+-----------+-------------------+----+---------------+--------+------+
| Study 090 |                   |    | Rofecoxib     | 390    |      |
|           |                   |    | 12.5          |        |      |
|           |                   |    |               | 392    |      |
|           |                   |    | Nabumetone    |        |      |
|           |                   |    | 1000          | 196    |      |
|           |                   |    |               |        |      |
|           |                   |    | Placebo       |        |      |
+-----------+-------------------+----+---------------+--------+------+
| Table 2.  |                   |    |               |        |      |
| Data from |                   |    |               |        |      |
| original  |                   |    |               |        |      |
| NDA       |                   |    |               |        |      |
| s         |                   |    |               |        |      |
| ubmission |                   |    |               |        |      |
| (         |                   |    |               |        |      |
| December, |                   |    |               |        |      |
| 1998)     |                   |    |               |        |      |
+-----------+-------------------+----+---------------+--------+------+
|           | Design            | D  | Treatment     | N      | ASA  |
|           |                   | z. | (mg/day)      |        |      |
|           |                   |    |               |        | all  |
|           |                   |    |               |        | owed |
+-----------+-------------------+----+---------------+--------+------+
| 069       | Pooled studies of | OA | Rofecoxib     | 3357   | #    |
|           | 6 to 86 weeks     |    | 12.5, 25 and  |        | # NO |
|           | duration,         |    | 50 (pooled)   | 1564   |      |
|           | including two     |    |               |        |      |
|           | 6-month           |    |               | 514    |      |
|           | endoscopic        |    |               |        |      |
|           | studies.          |    |               |        |      |
|           |                   |    |               |        |      |
|           | Most patients     |    |               |        |      |
|           | exposed \<6       |    |               |        |      |
|           | months.           |    |               |        |      |
+-----------+-------------------+----+---------------+--------+------+
|           |                   |    | Ibuprofen     |        |      |
|           |                   |    | 2400          |        |      |
|           |                   |    | Diclofenac    |        |      |
|           |                   |    | 150           |        |      |
|           |                   |    | Nabumetone    |        |      |
|           |                   |    | 1000          |        |      |
|           |                   |    |               |        |      |
|           |                   |    | (pooled)      |        |      |
+-----------+-------------------+----+---------------+--------+------+
|           |                   |    | Placebo (6    |        |      |
|           |                   |    | weeks)        |        |      |
+-----------+-------------------+----+---------------+--------+------+
| 058       | Same as 085 and   | OA | Rofecoxib     | 56     | ##   |
|           | 090               |    | 12.5          |        |  YES |
|           |                   |    |               | 118    |      |
|           | but in Elderly    |    | Rofecoxib 25  |        | 60   |
|           | 65 years         |    |               | 115    | -70% |
|           |                   |    | Nabumetone    |        |      |
|           |                   |    | 1000          | 52     |      |
|           |                   |    |               |        |      |
|           |                   |    | Placebo       |        |      |
+-----------+-------------------+----+---------------+--------+------+
| ##        |                   |    |               |        |      |
|           |                   |    |               |        |      |
| Table 3.  |                   |    |               |        |      |
| A         |                   |    |               |        |      |
| dditional |                   |    |               |        |      |
| study     |                   |    |               |        |      |
+-----------+-------------------+----+---------------+--------+------+
| Study     | Multicenter,      | OA | Rofecoxib 25  | 2799   | ##   |
| 102\*     | double-blind,     |    |               |        | YES  |
|           | randomized,       |    | Naproxen 1000 | 2789   |      |
| "A        | active            |    |               |        | 12   |
| dvantage" | controlled,       |    |               |        | -13% |
|           |                   |    |               |        |      |
|           | 12-week duration  |    |               |        |      |
+-----------+-------------------+----+---------------+--------+------+

\* This study had been completed by March 2000 but not submitted as part
of this supplement. Preliminary results of serious GI and CV events were
submitted at FDA request.

**2.1 New studies**

**2.1.1 Study 088c. VIOXX Gastrointestinal Outcomes Research study
(VIGOR).**

The objective of the VIGOR study was to determine whether VIOXX, a
selective COX-2 inhibitor, would result in significant reduction in the
incidence of clinically relevant GI events relative to therapy with
naproxen, a non-selective COX inhibitor. The study involved
approximately 4000 patients per treatment arm followed for a median time
of 9 months. The use of low dose ASA for cardiovascular prophylaxis was
not allowed in this study.

Rofecoxib 50 mg/day dose is the dose recommended for the treatment of
acute pain and twice the highest recommended dose in osteoarthritis
(OA). The dose of naproxen (500 mg bid) is the highest recommended dose
for chronic use in OA and RA.

> *The exclusion of low dose ASA users seriously limits the
> generalizability of this study to that segment of the population.*
>
> *VIGOR was not an efficacy study. Standard RA efficacy endpoints were
> not measured. The efficacy of VIOXX in RA is yet to be demonstrated.*

There were no substantial differences in the baseline demographics and
clinical characteristics of each treatment group. Similar number of
patients used concomitant corticosteroids (approximately 56%) and
methotrexate (also approximately 56%) in the rofecoxib and naproxen
group, respectively).

> *The FDA has asked the sponsor to provide mean and median doses of
> corticosteroids used in each treatment group.*

**2.1.1.1 Safety results**

**1. [Deaths]{.underline}**

There were a total of 22 deaths in the rofecoxib group and 15 in the
naproxen group. A listing deaths is presented in Appendix 1.

There were 14 cardiovascular deaths, (nine and five in rofecoxib and
naproxen groups, respectively). Most of the cardiovascular deaths were
in patients with known cardiovascular risks.

Eight patients died of pneumonia: five in the rofecoxib group (two of
them complicated with bacterial sepsis - one of them in the setting of
aplastic anemia-) and three in the naproxen group.

There were five deaths due to worsening interstitial/RA lung disease
(four and one in rofecoxib and naproxen groups, respectively).

Four patients died of gastrointestinal complications (3 on rofecoxib --
one of them a patient with gastric carcinoma - and one on naproxen).

One patient receiving naproxen died of hepatic necrosis right after
completing the study. This patient was receiving concomitant
methotrexate (MTX) three times a week.

Although there were more deaths in the rofecoxib group, the small number
of cases does not allow statistical comparisons.

**2. [Serious Adverse Experiences (SAE's)]{.underline}**

There were no substantial differences in the overall incidence of SAE's
(9.3% and 7.8% for rofecoxib and naproxen, respectively). Body systems
with the highest incidence of SAE's were the Gastrointestinal,
Cardiovascular and Musculoskeletal systems.

Table 4. Serious adverse experiences and discontinuations due to adverse
experiences by body system (incidence 0.2%)

+----------------------------+---------+---------+----------+---------+
|                            | Ro      |         | Naproxen |         |
|                            | fecoxib |         |          |         |
|                            |         |         | (N=4029) |         |
|                            | (       |         |          |         |
|                            | N=4047) |         | n (%)    |         |
|                            |         |         |          |         |
|                            | n (%)   |         |          |         |
+----------------------------+---------+---------+----------+---------+
| Number (%) of patients     | Serious | D       | Serious  | D       |
| with one or                |         | ropouts |          | ropouts |
|                            | 378 (   |         | 315 (    |         |
| more adverse experience    | 9.3)    | 643 (   | 7.8)     | 635     |
|                            |         | 15.9)   |          | (15.8)  |
+----------------------------+---------+---------+----------+---------+
| Body As A Whole/Site       | 51      | 100     | 35 (0.9) | 107     |
| Unspecified                | (1.3)   | (2.5)   |          | (2.7)   |
|                            | 101     |         | 46 (1.1) |         |
| Cardiovascular System      | (2.5)   | 109     |          | 33 (0.8 |
|                            |         | (2.7)   | 97 (2.4) | ) 392   |
| Digestive System           | 48      |         |          | (9.7)   |
|                            | (1.2)   | 292     | 4 (0.1)  |         |
| Eyes, Ears, Nose, And      |         | (7.2)   |          | 11      |
| Throat                     | 13      |         | 7 (0.2)  | (0.3)   |
|                            | (0.3)   | 20      |          |         |
| Hemic And Lymphatic System |         | (0.5)   | 8 (0.2)  | 9 (0.2) |
|                            | 8 (0.2) |         |          |         |
| Hepatobiliary System       |         | 4 (0.1) | 70 (1.7) | 2 (0.0) |
|                            | 11      |         |          |         |
| Musculoskeletal System     | (0.3)   | 10      | 7 (0.2)  | 27      |
|                            |         | (0.2)   |          | (0.7)   |
| Nervous System             | 83      |         | 3 (0.1)  |         |
|                            | (2.1)   | 29      |          | 24      |
| Psychiatric Disorder       |         | (0.7)   | 39 (1.0) | (0.6)   |
|                            | 14      |         |          |         |
| Respiratory System         | (0.3)   | 44      | 20 (0.5) | 10      |
|                            |         | (1.1)   |          | (0.2)   |
| Skin And Skin Appendages   | 7 (0.2) |         | 23 (0.6) |         |
|                            |         | 3 (0.1) |          | 13      |
| Urogenital System          | 52      |         |          | (0.3)   |
|                            | (1.3)   | 23      |          |         |
|                            |         | (0.6)   |          | 37      |
|                            | 31      |         |          | (0.9)   |
|                            | (0.8)   | 42      |          |         |
|                            |         | (1.0)   |          | 9 (0.2) |
|                            | 32      |         |          |         |
|                            | (0.8)   | 17      |          |         |
|                            |         | (0.4)   |          |         |
+----------------------------+---------+---------+----------+---------+

Source: Modified from appendix 4.17.4 and 4.17.2 of 088c study report.
Patients may appear under more than one category, but only once within
one category.

> *As seen in Table 4, less than 25% of the events leading to
> discontinuations in the GI body system were defined as serious AE's,
> while most discontinuations in the CV system were defined as serious
> AE's. This observation raises concerns about the possible overall
> safety conclusions that could be extrapolated from the GI specific
> results.*
>
> *Of note, an effective dose has not been established for RA. The
> safety profile of the 50 mg dose may be relevant, as the organ
> specific GI safety profile may be interpreted by some as generalizable
> to overall safety and allowing for dose creep.*

1.  **Serious Gastrointestinal events**

Serious AE's related to the digestive system were observed in 48 (1.2%)
and 97 (2.4%) of patients in the rofecoxib and naproxen groups,
respectively.

The sponsor successfully demonstrated a risk reduction of clinically
relevant GI adverse events for rofecoxib compared to naproxen.

Table 5. PUB's^1^ and **complicated** PUB's^2^ confirmed by the CRC^3^
in the VIGOR study

+----------+----+----------+-------+------+--------+---+---------+-------+
|          | N  | Events   | P     | Rat  | Re     |   |         |       |
|          |    |          | YR^4^ | e^5^ | lative |   |         |       |
|          |    | n (%)    |       |      | r      |   |         |       |
|          |    |          |       |      | isk^6^ |   |         |       |
+----------+----+----------+-------+------+--------+---+---------+-------+
|          |    |          |       |      | Es     |   | 95%CI   | p-    |
|          |    |          |       |      | timate |   |         | value |
+----------+----+----------+-------+------+--------+---+---------+-------+
| PUB's    |    |          |       |      |        |   |         |       |
+----------+----+----------+-------+------+--------+---+---------+-------+
| R        | 40 | 56       | 2697  | 2.08 | 0.46   |   | 0.33,   | \<    |
| ofecoxib | 47 | (1.38)   |       |      |        |   | 0.64    | 0.001 |
|          |    |          | 2694  | 4.49 |        |   |         |       |
| Naproxen | 40 | 121      |       |      |        |   |         |       |
|          | 49 | (3.0)    |       |      |        |   |         |       |
+----------+----+----------+-------+------+--------+---+---------+-------+
| Com      |    |          |       |      |        |   |         |       |
| plicated |    |          |       |      |        |   |         |       |
| PUB's    |    |          |       |      |        |   |         |       |
+----------+----+----------+-------+------+--------+---+---------+-------+
| R        | 40 | 16 (0.4) | 2699  | 0.59 | 0.43   | 0 |         | 0.005 |
| ofecoxib | 47 |          |       |      |        | . |         |       |
|          |    | 37       | 2698  | 1.37 |        | 2 |         |       |
| Naproxen | 40 | (0.92)   |       |      |        | 4 |         |       |
|          | 49 |          |       |      |        | , |         |       |
|          |    |          |       |      |        | 0 |         |       |
|          |    |          |       |      |        | . |         |       |
|          |    |          |       |      |        | 7 |         |       |
|          |    |          |       |      |        | 8 |         |       |
+----------+----+----------+-------+------+--------+---+---------+-------+

^1^ Perforations, [symptomatic]{.underline} ulcers and GI bleedings.
^2^Excludes uncomplicated ulcers. ^3^Adjudicated by the Case Review
Committee. ^4^Patient-years at risk. ^5^Per 100 PYR. ^6^Relative risk of
rofecoxib compared to naproxen. Source: sponsor's tables 22, 23, 24, 26
and 31 of 088c study report.

The cumulative incidence of PUB's (perforations,
[symptomatic]{.underline} ulcers and GI bleedings) was 2.08% and 4.49%
for rofecoxib and naproxen, respectively (relative risk 0.46, p\<0.001)
(Primary endpoint of the study).

> *The percentage of PUB's observed in the study is very close to the
> risk referred to in the NSAID-class label in the general population
> (2-4% in patients treated for one year).*

The cumulative incidence of **complicated** PUB's was 0.59% and 1.37% in
the rofecoxib and naproxen groups, respectively (relative risk, 0.43,
p=0.005) (Secondary endpoint of the study). **Complicated** PUB's
include serious events of perforation, obstruction and bleeding (also
referred as to POB's).

> *Symptomatic ulcers do not represent the same severity of endpoint as
> complicated PUBs. Only a small fraction of ulcers are thought to
> result in a clinically serious outcome. Therefore, time to event plot
> for **complicated** PUB's is presented in Figure 1.*
>
> *For a detailed GI safety review, the reader is referred to Dr.
> Goldkind's review.*
>
> Figure 1. Confirmed **complicated** PUB's in the VIGOR study
> (secondary endpoint). Time to event plot (all patients randomized).
>
> ![](media/image1.png){width="5.999305555555556in"
> height="4.125694444444444in"}
>
> Source: sponsor's Figure 5, s007 submission)

2.  **Serious Cardiovascular events**

Serious cardiovascular events with the highest incidence were CV
thrombotic, HTN-related and CHF-related events.

The cumulative risk of developing serious CV thrombotic events was 1.7%
in the rofecoxib group compared to 0.7% in the naproxen group. (Data
include eleven patients submitted with the four-month safety update).

The protocol mandated that patients with recent or significantly active
cardiovascular disease be excluded from the protocol. Patients with
recent MI (\<1 year) or TIA/stroke (\<2 years) and patients deemed by
the investigator to require prophylactic ASA or anticoagulation at the
time of enrollment were excluded from the study. Patients on low dose
ASA were not to stop therapy in order to enter the study.

The sponsor retrospectively identified 321 patients enrolled in this
study with past medical history of cerebrovascular accident, transient
ischemic attack, myocardial infarction, unstable angina, stable angina,
coronary artery bypass surgery or percutaneous coronary intervention who
might have benefited from the use of low dose ASA.

> *The validity of this retrospective identification of patients is
> unclear. By protocol, patients with active cardiovascular disease were
> excluded. The investigator's clinical judgement at the time of
> enrollment appears to be more relevant than a retrospective chart
> review.*

An analysis in this subgroup of patients retrospectively identified by
the sponsor as candidates for low dose ASA showed that the risk of
developing CV thrombotic events was five times higher in the rofecoxib
group compared to the naproxen group (14.3% and 2.9% respectively). For
those patients in whom neither prospective nor retrospective chart
review suggested need for low dose ASA use, the risk was still twice in
the rofecoxib group compared to the naproxen group (1.2% and 0.6%,
respectively).

Table 6. Adjudicated thrombotic cardiovascular serious adverse
experiences. Subgroup analyses by sponsor's retrospective identification
of patients who may have benefited from low dose ASA.

+-----------------+----+---------+-----+-----+------+---------+-----+
|                 | N  | P       | PYR | Ra  | Rela |         |     |
|                 |    | atients | ^2^ | tes | tive |         |     |
|                 |    | with    |     | ^3^ | ris  |         |     |
|                 |    | ev      |     |     | k^4^ |         |     |
|                 |    | ents^1^ |     |     |      |         |     |
|                 |    |         |     |     |      |         |     |
|                 |    | ^(%)^   |     |     |      |         |     |
+-----------------+----+---------+-----+-----+------+---------+-----+
|                 |    |         |     |     | 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^Thrombotic cardiovascular serious adverse experiences confirmed by
Adjudication Committee. ^2^ Patient-years at risk. ^3^ 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, stats reviewer).

A summary of adjudicated Thrombotic Cardiovascular serious adverse
events in the VIGOR study is presented in Appendix 2a and 2b.

> ![](media/image2.png){width="5.979166666666667in"
> height="4.302083333333333in"}Figure 2. Confirmed Thrombotic CV serious
> adverse experiences in the VIGOR study. Time to event plot (all
> patients randomized).
>
> Source: sponsor's Figure 1 of safety update.
>
> *The sponsor explanation for the excess of cardiovascular thrombotic
> events in the VIGOR study is the potent antiplatelet aggregation
> effect of naproxen. However, unopposed thromboxane production leading
> to an increase in CV thrombotic events can not be discarded as a
> potential explanation of the VIGOR findings.*
>
> *There are several arguments against the beneficial naproxen effect
> being the sole explanation for these findings.*

a)  *There are no prospective placebo-controlled trials with naproxen to
    support to support the assumption that naproxen transient inhibition
    of platelet aggregation is effective in decreasing the risk of
    cardiovascular events.*

b)  *The effect size of naproxen in reducing CV thrombotic events
    relative to rofecoxib in the VIGOR study (58%) exceeds the effect
    size of ASA compared to placebo in other trials (25-30%).*

c)  *The absence of a meaningful prothombotic signal in the original NDA
    may be explained by the short duration and low doses of rofecoxib
    used in the majority of the OA database.*

> *As shown in Figure 2., the cumulative incidence of CV thrombotic AE's
> for rofecoxib and naproxen start to diverge at approximately 3 months,
> but the difference increases after 8 months of follow up. Furthermore,
> RA is recognized as a disease associated with twice the risk of CV
> disease compared with OA. The population in VIGOR may be a more
> sensitive model for detecting the potential thrombogenic effects of
> selective COX-2 inhibition than a population with predominance of OA.*

d)  *Several other studies (085, 090 and 102) to be noted later in this
    review, suggest trends towards higher rates of myocardial infarction
    in the rofecoxib group compared to active control groups. Of note,
    these studies involved lower doses and duration of exposure to
    rofecoxib than the VIGOR trial and allowed the use of low dose ASA.*

In addition to the difference in cardiovascular thrombotic events,
serious HTN-related and CHF-related events were higher in the rofecoxib
group. Ten (0.2%) and one patients (0%) had a serious
hypertension-related adverse experience in the rofecoxib and naproxen
groups, respectively. Sixteen patients developed serious CHF-related
events: 13 (0.3%) in the rofecoxib group and 3 (0.1%) in the naproxen
group. Additionally, two and one patient developed pulmonary edema in
the rofecoxib and naproxen group respectively.

> *For a detailed CV review the reader is referred to Dr. Targum's
> review.*

1.  **Serious Musculoskeletal related AE's**

Serious Musculoskeletal related AE's were relatively high in both
treatment groups. They were observed in 83 (2.1%) and 70 (1.7%) of
patients in the rofecoxib and naproxen groups respectively.
Musculoskeletal system includes fractures, worsening RA and trauma.
There were 41 (1%) and 29 (0.7%) fractures (all sites) in the rofecoxib
and naproxen groups, respectively.

> *This is a population at increased risk for fractures. The study was
> not powered to detect differences in the incidence of fractures.
> Therefore, the difference between treatment groups may be not
> relevant. However, COX-2 is involved in regulation of bone metabolism
> and concerns have been raised about long-term effects of some NSAIDs
> in the skeletal system. The sponsor is conducting a study to address
> the issue of long-term effects of rofecoxib in bone metabolism.*

2.  **Other serious adverse experiences**

Other than GI and CV safety differences, the safety profile of rofecoxib
and naproxen showed a similar pattern and were consistent with those of
the NSAID class. Serious AE's were consistently higher in the rofecoxib
group, except for the GI system (Table 4).

3.  **[Discontinuations due to pre-specified adverse
    events]{.underline}**

Discontinuations due to NSAID-related AE's such as renal, liver, HTN and
edema-related AE's were numerically higher (and some statistically
significantly higher) in the rofecoxib group. CHF-related adverse events
(also pre-specified) were also higher in the rofecoxib group.

Table 7: Results of pre-specified safety analyses involving
NSAID-related adverse events.

+-------------------+-------+----+-----+-----+------+---------+-----+
| Type of Adverse   | Trea  | N  | Eve | Ra  | Rela |         |     |
| Experience        | tment |    | nts | tes | tive |         |     |
|                   |       |    |     |     | Risk |         |     |
+-------------------+-------+----+-----+-----+------+---------+-----+
|                   |       |    |     |     | Esti | 95%CI   | p   |
|                   |       |    |     |     | mate |         | -va |
|                   |       |    |     |     |      |         | lue |
+-------------------+-------+----+-----+-----+------+---------+-----+
| Discontinued due  | rofe  | 40 | 25  | 0   | 1.92 | (0.9    | 0.  |
| to edema-related  | coxib | 47 |     | .93 |      | 8,3.75) | 057 |
| AEs               |       |    | 13  |     |      |         |     |
|                   | nap   | 40 |     | 0   |      |         |     |
|                   | roxen | 29 |     | .48 |      |         |     |
+-------------------+-------+----+-----+-----+------+---------+-----+
| Discontinued due  | rofe  | 40 | 28  | 1   | 4.67 | (1.93,  | \   |
| to                | coxib | 47 |     | .04 |      | 11.28)  | <0. |
| hyp               |       |    | 6   |     |      |         | 001 |
| ertension-related | nap   | 40 |     | 0   |      |         |     |
| AEs               | roxen | 29 |     | .22 |      |         |     |
+-------------------+-------+----+-----+-----+------+---------+-----+
| CHF AEs           | rofe  | 40 | 19  | 0   | 2.11 | (0.96,  | 0.  |
|                   | coxib | 47 |     | .70 |      | 4.67)   | 065 |
|                   |       |    | 9   |     |      |         |     |
|                   | nap   | 40 |     | 0   |      |         |     |
|                   | roxen | 29 |     | .33 |      |         |     |
+-------------------+-------+----+-----+-----+------+---------+-----+
| Discontinued due  | rofe  | 40 | 10  | 0   | 3.33 | (0.92,  | 0.  |
| to hepatic        | coxib | 47 |     | .37 |      | 12.11)  | 067 |
| disease AEs       |       |    | 3   |     |      |         |     |
|                   | nap   | 40 |     | 0   |      |         |     |
|                   | roxen | 29 |     | .11 |      |         |     |
+-------------------+-------+----+-----+-----+------+---------+-----+
| Discontinued due  | rofe  | 40 | 8   | 0   | 1.14 | (0.41,  | 0.  |
| to renal-related  | coxib | 47 |     | .30 |      | 3.15)   | 796 |
| AE's\*            |       |    | 7\* |     |      |         |     |
|                   | nap   | 40 |     | 0   |      |         |     |
|                   | roxen | 29 |     | .26 |      |         |     |
+-------------------+-------+----+-----+-----+------+---------+-----+

Source: Modified from sponsor's tables 66 to 72, 088c study report.

> *\* It is unclear to this reviewer whether patients AN 1824 and 2720
> on naproxen were included in this analysis. These two patients had
> abnormal renal function in the setting of obstructive uropathy.*

4.  **[Laboratory data]{.underline}**

Four hundred fourteen (10.4%) and 368 (9.2%) patients presented one or
more laboratory adverse experience in the rofecoxib and naproxen groups
respectively. Of those, 22 patients discontinued due to laboratory AE's
in the rofecoxib group compared with 12 in the naproxen group. There
were only two cases of serious laboratory AE's: one case of neutropenia
and one of leukopenia and platelet decrease, both in the rofecoxib
group. Both patients were taking concomitant MTX.

Of the 90 (2.2%) and 49 (1.2%) patients with liver-related (clinically
and laboratory) adverse experiences in the rofecoxib and naproxen groups
respectively few patients exceeded pre-defined limits of change for
laboratory liver related adverse events. Four patients exceeded limits
for serum ALT and 1 patient for AST (all in the rofecoxib group),
defined as: in patients with normal baselines, consecutive values \>3
times the ULN or 1 value \>3 times the ULN associated with study drug
discontinuation; in patients with abnormal baselines, consecutive values
that are \>2 times the baseline value and \>3 times the ULN or 1 value
\>3 times the ULN associated with study drug discontinuation).

In this study, 0.5 and 0.3% of patients on rofecoxib and 0.2 and 0.3% of
patients on naproxen had at least 1 single (nonconsecutive) AST and ALT
value \>3 times the ULN, respectively.

Only 4 and 3 patients in the rofecoxib and naproxen group respectively
met predefined limits of change for serum creatinine (defined as
consecutive values with an actual increase of 0.5 mg/dL and \>ULN or 1
value with an increase of 0.5 mg/dL and \>ULN that was associated with
study drug discontinuation).

These criteria for LFT and creatinine predefined limit of change are
more stringent than the ones used in the original NDA. In the original
NDA the definition for AST and ALT predefined limit of change was a
single value increased by x2 and \>ULN; for creatinine it was a single
value increased by 0.5 mg/dL and \>ULN. Additional analyses have been
requested to the sponsor.

In general, analyses of laboratory predefined limits of change not
associated with pre-specified adverse events showed no significant
differences between groups. Of note, changes in sodium (hyponatremia and
hypernatremia) were relatively high in both groups. The difference in
the incidence of hyponatremia between rofecoxib and naproxen was
statistically significant: 39 on rofecoxib (1%) and 20 on naproxen
(0.5%).

5.  **[MTX and non-MTX users]{.underline}**

In this study, approximately 60% of patients were on MTX in each
treatment group. The overall incidence of clinical adverse experiences,
drug-related clinical adverse experiences, or serious clinical adverse
experiences was similar for patients who took or did not take
concomitant methotrexate for treatment of RA.

There were no significant differences in the overall incidence of
adverse events by body system between MTX and non-MTX users for each
treatment.

The only two serious laboratory events observed in the study (one of
neutropenia and one leukopenia + platelet decrease) and one case of
pneumonia in the setting of aplastic anemia (a patient who died)
occurred in patients taking refecoxib concomitantly with MTX.

> *This preliminary observation suggests that despite lack of apparent
> PK interaction between rofecoxib and MTX, rofecoxib may have increased
> the potential for MTX bone marrow toxicity.*

Table 8. Adverse experience summary in MTX users and non-MTX users

+----------------------+----------+-----------+-----------+-----------+
|                      | MTX      |           | MTX       |           |
|                      | Users    |           | Non-users |           |
+----------------------+----------+-----------+-----------+-----------+
|                      | R        | Naproxen  | Rofecoxib | Naproxen  |
|                      | ofecoxib | 1000      | 50        | 1000      |
|                      | 50       |           |           |           |
|                      |          | N = 2387  | N = 1662  | N = 1642  |
|                      | N = 2385 | %         | %         | %         |
|                      | %        |           |           |           |
+----------------------+----------+-----------+-----------+-----------+
| Clinical AE's        |          |           |           |           |
+----------------------+----------+-----------+-----------+-----------+
| With one or more     | 1716     | 1701      | 1156      | 1123      |
| AE's                 | (71.9)   | (71.3)    | (69.6)    | (68.4)    |
|                      |          |           |           |           |
| With serious AE's    | 223      | 190 (8.0) | 155 (9.3) | 125 (7.6) |
|                      | (9.4)    |           |           |           |
| Who died             |          | 10 (0.4)  | 7 (0.4)   | 5 (0.3)   |
|                      | 15 (0.6) |           |           |           |
| Discontinued due to  |          | 345(14.5) | 281       | 290       |
| AE's                 | 362      |           | (16.9)    | (17.7)    |
|                      | (15.2)   | 74 (3.1)  |           |           |
| Discontinued due to  |          |           | 59 (3.5)  | 53 (3.2)  |
| SAE's                | 84 (3.5) | 39 (1.6)  |           |           |
|                      |          |           | 16 (1.0)  | 29 (1.8)  |
| Discontinued due to  | 39 (1.6) |           |           |           |
| serious drug-related |          |           |           |           |
| AE's                 |          |           |           |           |
+----------------------+----------+-----------+-----------+-----------+
| Laboratory AE's      |          |           |           |           |
+----------------------+----------+-----------+-----------+-----------+
| With one lab test    | 2372     | 2374      | 1634      | 1625      |
| post baseline        |          |           |           |           |
|                      | 257      | 240       | 161 (9.9) | 128 (7.9) |
| With one or more     | (10.8)   | (10.1)    |           |           |
| AE's                 |          |           | 9 (0.6)   | 6 (0.4)   |
|                      | 13 (0.5) | 6 (0.3)   |           |           |
| Discontinued due to  |          |           |           |           |
| adverse experiences  |          |           |           |           |
+----------------------+----------+-----------+-----------+-----------+

AE's: adverse experience. SAE: serious adverse experience. Source
Appendix 4.21, Study 088c, s007.

1.  **Efficacy results**

The efficacy of rofecoxib in RA remains to be demonstrated in placebo
controlled studies designed for that purpose.

VIGOR was not an efficacy study. Patients were not required to meet RA
flare criteria and changes in DMARD and corticosteroid therapy were
allowed without restriction during the study. Standard RA efficacy
endpoints such as swollen joints and tender joints were not measured.

The efficacy parameters in this study were Patient's and Investigator's
Global Assessment of Disease Status, measured on the Likert scale from 0
to 4, the modified HAQ consisting of 8 questions measured on a scale of
0 to 3, and discontinuations due to lack of efficacy. There were no
differences in these efficacy parameters between rofecoxib 50 mg/day and
naproxen 1000 mg/day.

**2.1.2. Studies 085 and 090**

Studies 085 and 090 were six-week, placebo controlled studies in
patients with OA. The dose of rofecoxib used in the studies was the
lowest dose approved for the treatment of OA (12.5 mg/day). The dose of
nabumetone (1000 mg/day) was the lowest recommended dose for OA and RA.
Both studies used a 2:2:1 randomization scheme (rofecoxib/
nabumetone/placebo). Each active treatment arm involved approximately
400 patients. The studies were designed to support the efficacy of
rofecoxib in patients with OA.

There were no substantial differences in the demographic and clinical
characteristics at baseline in each treatment group, in each study. The
studies allowed the use of prophylactic ASA. Approximately 12% of
patients used ASA in these studies. The most common concomitant
condition was cardiovascular; and approximately 40 % of patients had a
history of HTN.

Table 9. Clinical AE summary of studies 085 and 090

+-------------------------------+------------+------------+------------+
| Number (%) of patients:       | Rofecoxib  | Nabumetone | Placebo    |
|                               |            |            |            |
| with one or more adverse      | 12.5 mg    | 1000 mg    | (N=404)    |
| experiences                   |            |            |            |
|                               | (N=814)    | (N=802)    |            |
| with serious adverse          |            |            |            |
| experiences                   |            |            |            |
|                               |            |            |            |
| discontinued due to an        |            |            |            |
| adverse experience            |            |            |            |
|                               |            |            |            |
| discontinued due to a serious |            |            |            |
| AE                            |            |            |            |
+-------------------------------+------------+------------+------------+
|                               | n (%)      | n (%)      | n (%)      |
+-------------------------------+------------+------------+------------+
|                               | 432 (53)   | 390 (48.6) | 188 (46.5) |
|                               |            |            |            |
|                               | 13 (1.6)   | 10 (1.2)   | 2 (0.5)    |
|                               |            |            |            |
|                               | 53 (6.5)   | 41 (5.1)   | 13 (3.2)   |
|                               |            |            |            |
|                               | 10 (1.2)   | 4 (0.5)    | 1 (0.3)    |
+-------------------------------+------------+------------+------------+

(Source: pooled data from Table 33 and 34 of studies 085 and 090). †
Considered by the investigator to be possibly, probably, or definitely
drug-related.

1\. Deaths. There were no deaths.

2\. Serious Adverse Events (SAE's):

The rates of SAE's similar between the active comparators. There were
three serious gastrointestinal complications: one lower GI bleeding in
the nabumetone group and two cases of cholecystitis, one in each active
treatment group. There were no PUB's.

There were six cases of serious cardiovascular events in the rofecoxib
group (4 MI and 2 CVA's); three in the nabumetone group (1 MI, 1
coronary artery disease and 1 CHF) and one coronary artery occlusion in
the placebo group.

3.  Discontinuations due to AE's

The incidence of discontinuations due to clinical and laboratory AE's
were similar. Discontinuations by body system are presented in the
following table.

Table 10. Discontinuations due to clinical AEs in study 085 and 090

+------------------------------+------------+------------+------------+
| Body As A Whole/Site         | Rofecoxib  | Nabumetone | Placebo    |
| Unspecified                  |            |            |            |
|                              | 12.5 mg    | 1000 mg    | (N=404)    |
| Cardiovascular System        |            |            |            |
|                              | (N=814)    | (N=802)    |            |
| Digestive System             |            |            |            |
|                              |            |            |            |
| Musculoskeletal System       |            |            |            |
|                              |            |            |            |
| Nervous System               |            |            |            |
|                              |            |            |            |
| Respiratory System           |            |            |            |
|                              |            |            |            |
| Skin And Skin Appendages     |            |            |            |
|                              |            |            |            |
| Urogenital System            |            |            |            |
+------------------------------+------------+------------+------------+
|                              | n (%)      | n (%)      | n (%)      |
+------------------------------+------------+------------+------------+
|                              | 13 (1.6)   | 11 (1.4)   | 4 (1)      |
|                              |            |            |            |
|                              | 10 (1.2)   | 3 (0.4)    | 1 (0.2)    |
|                              |            |            |            |
|                              | 19 (2.3)   | 18 (2.2)   | 0          |
|                              |            |            |            |
|                              | 5 (0.6)    | 9 (1.1)    | 3 (0.7)    |
|                              |            |            |            |
|                              | 6 (0.7)    | 4 (0.5)    | 0          |
|                              |            |            |            |
|                              | 2 (0.2)    | 2 (0.2)    | 1 (0.2)    |
|                              |            |            |            |
|                              | 6 (0.7)    | 2 (0.2)    | 3 (0.7)    |
|                              |            |            |            |
|                              | 0          | 1 (0.2)    | 1 (0.2)    |
+------------------------------+------------+------------+------------+

Although a patient may have had 2 or more clinical adverse experiences,
the patient is counted only once within a category. The same patient may
appear in different categories.

Discontinuations in the Digestive system were similar in both active
groups and higher than placebo. Discontinuations in the CV system were
twice in the rofecoxib 12.5 mg dose than in nabumetone 1000 mg dose.

4.  Laboratory AE's

Two patients in the rofecoxib 25 mg group, one in the nabumetone 1000 mg
group and one patient on placebo discontinued due to laboratory AE's

> *Population size, dose and duration limit the value of these studies
> in assessing the safety of chronic rofecoxib use. However, there were
> 6 cardiovascular thrombotic events in the rofecoxib group and two in
> the nabumetone group. The number of events is small to allow
> statistical comparisons but results appear to follow the pattern
> observed in the VIGOR study for CV thrombotic events.*

3.  **Study 102**

Study 102 ("ADVANTAGE") was a 12-week, randomized, double blind active
controlled study of rofecoxib 25 mg/day and naproxen 1000 mg/day in
approximately 5500 patients with OA who were allowed low dose ASA (81 to
325 mg/day). Patients taking low dose ASA were 12.1% and 12.8% in the
rofecoxib and naproxen treatment group, respectively.

> *This study was completed in March 2000. Unfortunately this large
> database was not included with this supplement submission. The short
> duration of the study is noted. At the FDA request, preliminary data
> on GI and CV events were submitted in 12/21/00. Baseline demographics
> by treatment arm have not been provided.*

[a. Serious GI: Preliminary Results]{.underline}

There were 6 clinical upper GI events in the rofecoxib 25 mg group and
12 in the naproxen 1000 mg group.

The small number of serious GI events and the relatively short duration
of treatment do not allow statistical comparisons. However, there is a
trend in favor of rofecoxib

[b. Serious CV events: Preliminary results.]{.underline}

There were 6 myocardial infarctions (MI) in the rofecoxib 25 mg group
and one MI in the naproxen 1000 mg group. Of the 6 MI in the rofecoxib
group, 3 were in patients taking low ASA for cardiovascular prophylaxis.
The patient with MI in the naproxen group was a non-ASA user.

> *A trend towards an excess of MI's in the rofecoxib 25 mg group in a
> 12 week study is noted. This observation is consistent with the
> pattern seen in VIGOR.*

**2. 2 Data from the original NDA.**

In addition to the new studies, this supplement refers to study 058 and
069 from the original NDA.

Study 058 was a double-blind, randomized, placebo-controlled, 6-week
study of rofecoxib 12.5 and 25 mg/day and nabumetone 1000 mg/day in
elderly patients with OA. Seventy percent of patients were taking
prophylactic ASA.

> *Because of the small size and short duration, this study is
> inadequate to detect differences in clinically relevant adverse events
> between rofecoxib and nabumetone.*

Study 069 was a pooled analysis of gastrointestinal events from all OA
studies conducted under the original NDA. The analysis compared PUB's
between rofecoxib -- pooled doses, despite the evidence of dose-related
adverse events -- and other NSAIDs (pooled data from ibuprofen 2400
mg/day, diclofenac 150 mg/day and nabumetone 1000 mg/day, each one with
different risk of GI bleeding). These studies were of different duration
(from 6 weeks to 86 months). Most patients were exposed for less than 6
months.

> *The Division has serious concerns with a combined analysis of studies
> of different length and dosing regimens. Furthermore, combining
> multiple different drugs within a single comparator arm may not be
> reflective of the risk of any one drug. These concerns were discussed
> extensively during the Advisory Committee Meeting of April 20, 1999.*

Similarly, the sponsor conducted a meta-analysis of CV thrombotic events
in the OA database.

> *This database overall included short term, low doses of rofecoxib.
> Most of the exposure for more than 6 months was at the 12.5 and 25 mg
> QD doses. Two hundred and seventy two patients received 50 mg QD for 
> 6 months (265 in OA trials); the rest of the exposure to 50 mg was in
> short-term studies. The Division has requested a meta-analysis based
> on dose and duration.*
>
> *None of the studies were powered to detect differences in serious CV
> thrombotic events compared to the active comparator, but more
> important, the studies involved a different population.*
>
> *Patients with RA have been recently reported to have twice the risk
> of cardiovascular events compared with OA. There is increasing
> evidence that ongoing inflammation is a risk factor for coronary
> disease (plaque unstability). It is likely that the RA population is a
> very sensitive model for detecting differences in the beneficial or
> deleterious effects of any drug on cardiovascular risk.*

**2.3 Post-marketing data**

#### From May 1999 to October 25, 2000, thirty-seven deaths after experiencing GI bleeding, perforation or obstruction have been reported to the FDA AERS system in association with the use of rofecoxib. 

Table 11. Summary of deaths due to GI complications reported to FDA AERS
in association with the use of rofecoxib (May 1999 to October 1999).

+----------------+-----------------------------------------------------+
| Age in years   | Mean 76, median 80, range 28 to 93                  |
+----------------+-----------------------------------------------------+
| Gender         | Male (14), Female (22), Unknown (1)                 |
+----------------+-----------------------------------------------------+
| Year           | 1999 (3), 2000 (34)                                 |
+----------------+-----------------------------------------------------+
| Indication     | Osteoarthritis (14), Acute pain (6), Unspecified    |
|                | arthritis (6), Other (6), Unknown (5)               |
+----------------+-----------------------------------------------------+
| Time to onset  | Mean 43, median 21 (range, 0 to 131) days           |
+----------------+-----------------------------------------------------+
| Dose           | At or below labeled range (24), Higher than labeled |
|                | range (1), Unknown (12)                             |
+----------------+-----------------------------------------------------+
| GI event       | Hemorrhage (23), Perforation (7), Melena (4),       |
|                | Hematemesis (6), Erosions (1), Stenosis/Obstruction |
|                | (1), Other (10)                                     |
+----------------+-----------------------------------------------------+
| Location       | Gastric (13), Duodenal (5), Large intestine (2),    |
|                | Other (2), Unknown (15)                             |
+----------------+-----------------------------------------------------+
| Pertinent PMH  | Anemia (1), ASA allergy (1), sulfa allergy (1),     |
|                | Crohn\'s disease (1), CVA (1), Diabetes (1),        |
|                | Diverticulitis (1), Functional intestinal disorder  |
|                | (1), Gastrostomy (1), Previous GI bleed (1),        |
|                | Irritable bowel syndrome (1), Hepatic dysfunction   |
|                | (1), PUD (4)                                        |
+----------------+-----------------------------------------------------+
| Major event    | Metastatic gastric cancer (1), Pancreatitis,        |
| preceding      | hepatitis (1), Shock (1)                            |
| bleed          |                                                     |
|                | Surgery (3)                                         |
+----------------+-----------------------------------------------------+
| Significant    | ASA (8), Clopidogril (2), Corticosteroid (2),       |
| concomitant    | Warfarin (6)                                        |
| meds.          |                                                     |
|                | Antacid, H2 blocker, or PPI (4)                     |
+----------------+-----------------------------------------------------+

Source: Joyce Weaver, Pharm.D., Safety Evaluator. Office of
Post-marketing Drug Risk Assessment.

*Inherent limitations to the spontaneous report system are the lack of
known denominator (number of patients at risk), the under-reporting of
events and the multiple confounding variables. Despite these
limitations, post marketing surveillance does inform in the evaluation
of the safety profile of a drug.*

*The risk of serious gastrointestinal complications with rofecoxib is
still a concern. Risk factors associated with serious gastrointestinal
bleeding with rofecoxib are the same as for other NSAIDS: age, prior
history of ulcer disease, concomitant use of ASA, warfarin or
antiplatelet agents and corticosteroids.*

> *Other NSAID class related adverse events such as anaphylactoid
> reactions, interstitial nephritis, papillary necrosis and clinically
> significant drug interactions with coumadin were reported within a few
> months of post-marketing surveillance. An analysis of post-marketing
> CV thrombotic events is currently being conducted.*
>
> **3. [Conclusions]{.underline}**

1.  The sponsor has demonstrated a statistically significant reduction
    associated with the use of rofecoxib compared to naproxen in PUBs
    and complicated PUB's, in this population of patients not taking low
    dose ASA. The cumulative incidence of PUB's was 2.08% and 4.49% for
    rofecoxib and naproxen, respectively. The cumulative incidence of
    **complicated** PUB's was 0.59% and 1.37% in the rofecoxib and
    naproxen groups, respectively. The cumulative risk of PUB's in both
    groups is similar to the rate range for one year that appears in the
    current GI warning section of NSAID labels (2 to 4%).

2.  *This risk reduction in relevant GI events did not translate into an
    overall safety benefit of rofecoxib over naproxen. GI safety must be
    assessed within the overall safety profile of a drug. Evaluation of
    safety by routine parameters showed no advantage of rofecoxib over
    naproxen:*

+-------------------------+---------------------+---------------------+
|                         | Rofecoxib 50 mg     | Naproxen 1000 mg    |
|                         |                     |                     |
|                         | N=4047 (%)          | N=4029 (%)          |
+-------------------------+---------------------+---------------------+
| a\. Deaths              | 22 (0.5)            | 15 (0.4)            |
|                         |                     |                     |
| b\. Serious AEs         | 378 ( 9.3)          | 315 ( 7.8)          |
|                         |                     |                     |
| c\. Dropouts due to AEs | 643 ( 15.9)         | 635 (15.8)          |
|                         |                     |                     |
| d\. Serious lab AEs     | 2 (0)               | 0 (0)               |
|                         |                     |                     |
| e\. Dropouts due to lab | 22 (0.5)            | 12 (0.3)            |
| AEs                     |                     |                     |
+-------------------------+---------------------+---------------------+

Other than GI and CV, the safety profile of rofecoxib and naproxen
showed a similar pattern and was consistent with that of the NSAID
class. NSAID-related (liver, renal, HTN and edema-related AE's) were
consistently higher in the rofecoxib group.

3.  The relative risk of cardiovascular thrombotic events was twice in
    rofecoxib compared with naproxen. Cumulative risk was 1.67% and 0.7%
    for rofecoxib and naproxen, respectively (mainly due to the higher
    risk of MI). In addition to CV thrombotic events, rofecoxib had a
    higher incidence of discontinuations due to HTN- and CHF related
    events compared with naproxen. These differences were statistically
    significant.

> Safety profiles must be carefully analyzed based on events of
> comparable severity and seriousness. In the VIGOR study the potential
> advantage of decreasing the risk of complicated PUB's was paralleled
> by the increased risk of developing cardiovascular thrombotic events.

4.  The sponsor recommends that patients with known cardiovascular risk
    should be on

prophylactic ASA, however, outstanding issues are:

a.  Whether any of the cardiovascular effects potentially associated
    with rofecoxib will be prevented by ASA

b.  Whether the addition of ASA will decrease or abolish the GI
    advantage of rofecoxib over naproxen.

There are no data available to answer these questions. The sponsor
proposes that studies 085, 090 and 058 support the safety of the
concomitant use of rofecoxib and ASA. Each of these three studies was
designed as an efficacy trial and neither the size nor the duration was
adequate to detect differences in serious gastrointestinal events. The
doses of rofecoxib used in these studies were one fourth and one half of
the dose used in the VIGOR study.

> Study 102 compared rofecoxib (25 mg/day) and naproxen (1000 mg/day)
> for 12 weeks and allowed the use of low dose ASA. Preliminary results
> of GI clinical events in this study showed a trend in favor of
> rofecoxib. However, it also showed a pattern of myocardial infarctions
> consistent with the VIGOR study.

5.  Despite a substantial risk reduction compared to naproxen in the
    VIGOR study, the risk of serious GI complications with rofecoxib is
    still a concern. From May 1999 to October 2000, the FDA
    post-marketing AER system received 37 unduplicated reports of death
    due to gastrointestinal complications associated with the use of
    rofecoxib. Risk factors associated with serious GI complications are
    similar to those associated with conventional NSAIDs: age, prior
    history of ulcer disease, concomitant use of ASA, coumadin or other
    antiplatelet agents, and corticosteroids.

**4. [Recommendations]{.underline}**

1.  The NSAID-class GI warning should not be removed from the VIOXX
    label.

2\. Information regarding cardiovascular thrombotic events should be
added to the

VIOXX label.

3\. Additional studies may be needed to optimally clarify outstanding
questions.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

> Maria Lourdes Villalba, M.D.,
>
> Medical Officer, DAAODP

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

> Lawrence Goldkind, M.D.,

Team Leader, DAAODP

Appendix 1. VIGOR. Deaths in patients treated with Rofecoxib 50 mg.

+-------+----+----+--------------------------+----------+------------+
| ID/   | Ag | Re | Serious adverse event    | Other RA | Medical    |
|       | e/ | l^ |                          | meds     | history    |
| Study |    | 1^ |                          |          |            |
|       | Ge |    |                          |          |            |
|       | nd | (d |                          |          |            |
|       | er | ay |                          |          |            |
|       |    | s) |                          |          |            |
+-------+----+----+--------------------------+----------+------------+
| 32    | 69 | 1  | Ventricular              | MTX      | HTN        |
| 4/088 | F  | 74 | fibrillation/sudden      |          |            |
|       |    |    | death                    | MTX,     | HTN, pulm  |
| 22    | 70 | 1  |                          | HCQ,     | fibrosis   |
| 9/088 | F  | 32 | Adult respiratory        | Pred     |            |
|       |    |    | distress syndrome        |          | Pulmonary  |
| 73    | 77 | 2  |                          | MTX      | fibrosis   |
| 1/088 | F  | 54 | Pneumonia                |          |            |
|       |    |    |                          | MTX      | GI         |
| 256   | 78 | 41 | Penetrating duodenal     |          | bleeding,  |
| 0/088 | M  |    | ulcer, pneumonia,        | Gold,    | COPD       |
|       |    | 26 |                          | Pr       |            |
| 266   | 62 |    | septic shock.            | ednisone | COPD,      |
| 2/088 | F  | 46 |                          |          | smoker     |
|       |    |    | Perforating hemorrhagic  | Gold,    |            |
| 122   | 68 | 2  | gastric ulcer,           | Pr       | Smoker,    |
| 4/088 | F  | 05 |                          | edinsone | gout       |
|       |    |    | subphrenic abcess,       |          |            |
| 92    | 68 | 94 | septic shock.\*          | MTX,     | HTN,       |
| 0/088 | F  |    |                          | Pr       | chol, GI  |
|       |    | 2  | Myocardial infarction,   | ednisone | ulcer      |
| 275   | 69 | 83 | multiple organ failure.  |          |            |
| 9/088 | M  |    |                          | MTX,     | chol,     |
|       |    | 69 | Cerebrovascular          | Pred, CQ | family hx  |
| 568   | 53 |    | accident; complete heart |          | CAD        |
| 7/089 | M  | 1  | block.                   | MTX,     |            |
|       |    | 01 |                          | Pr       | HTN, CAD,  |
| 728   | 71 |    | Myocardial infarction.   | ednisone | pulm fibr. |
| 5/089 | M  | 3  |                          |          |            |
|       |    | 09 | Gastric neoplasm.        | Pr       | Pulm       |
| 810   | 57 |    |                          | ednisone | fibr.,     |
| 4/089 | M  | 90 | Pneumonia.               |          | gastritis  |
|       |    |    |                          | MTX,     |            |
| 530   | 75 | 3  | Gastrointestinal         | Pr       | HTN, Pulm  |
| 5/089 | F  | 02 | bleeding.                | ednisone | fibr., MI  |
|       |    |    |                          |          |            |
| 531   | 80 | 31 | Cardiac arrest. Sudden   | MTX, CQ, | HTN, MI,   |
| 6/089 | M  |    | death.                   | Pred     | dyspepsia  |
|       |    | 2  |                          |          |            |
| 802   | 84 | 06 | Interstitial lung        | MTX,     | HTN        |
| 1/089 | F  |    | disease.                 | Pr       |            |
|       |    | 3  |                          | ednisone | Interst    |
| 762   | 55 | 40 | Hip fracture, pneumonia, |          | p          |
| 0/089 | F  |    | respiratory failure      | MTX,     | neumonitis |
|       |    | 25 |                          | Pred, CQ |            |
| 559   | 51 |    | Dissecting aortic        |          | HTN,       |
| 1/089 | F  | 1  | aneurism                 | Pre      | gammopathy |
|       |    | 47 |                          | dnisone, |            |
| 610   | 65 |    | Cerebrovascular          | CQ       | Asthma     |
| 3/089 | F  | 28 | accident.                |          |            |
|       |    |    |                          | Pre      | HTN, DM    |
| 746   | 56 | 1  | Worsening rheumatoid     | dnisone, |            |
| 1/089 | F  | 33 | arthritis (lung).        | HCQ      |            |
|       |    |    |                          |          |            |
| 797   | 71 | 2  | Pulmonary infection.     | MTX      |            |
| 3/089 | M  | 06 | Bacterial sepsis.        |          |            |
|       |    |    |                          | MTX      |            |
| 755   | 51 |    | Myocardial infarction.   |          |            |
| 3/089 | F  |    |                          | MTX,     |            |
|       |    |    | CHF? Unknown cause of    | Pr       |            |
| 1007  | 54 |    | death.                   | ednisone |            |
| 8/089 | F\ |    |                          |          |            |
|       | 60 |    | Aplastic anemia.         | MTX,     |            |
| 768   | F  |    | Pneumonia. Sepsis.       | Pr       |            |
| 9/089 |    |    |                          | ednisone |            |
|       |    |    | Sudden death. \*\*       |          |            |
+-------+----+----+--------------------------+----------+------------+

Source Table 54 of 088c study report; medical reviewer's review of
narratives and CRFs. \* Cause of death listed as pneumonia but patient
died as a septic complication after GI surgery. \*\* Cause of death
listed as Aortic Valve Stenosis but there is no documentation of A.S. in
the autopsy.

Appendix 1. cont. NDA 21-042/s007. VIGOR. Deaths in patients treated
with Naproxen 1000 mg.

+------+----+----+-------------------------+----------+-------------+
| ID/  | Ag | Re | Serious adverse event   | Other RA | Medical     |
|      | e/ | l^ |                         | meds     | history     |
| S    |    | 1^ |                         |          |             |
| tudy | Ge |    |                         |          |             |
|      | nd | (d |                         |          |             |
|      | er | ay |                         |          |             |
|      |    | s) |                         |          |             |
+------+----+----+-------------------------+----------+-------------+
| 923  | 60 | 1  | Cerebrovascular         | MTX,     | HTN, CAD,   |
| /088 | M  | 64 | accident; myocardial    | HCQ,     | smoker, GI  |
|      |    |    | infarction?; aortic     | Pred     | ulcer,      |
| 815  | 72 | 1  | thrombosis.             |          | prior       |
| /088 | M  | 33 |                         | MTX,     | carotid sx. |
|      |    |    | Metastatic neoplasm of  | Pr       |             |
| 3097 | 78 | 9- | unknown primary         | ednisone | HTN,        |
| /088 | F  | 29 |                         |          | lymphoma    |
|      |    |    | Perforating gastric     | MTX,     |             |
| 981  | 66 | 1  | ulcer, septic shock.    | Pr       | HTN,        |
| /088 | F  | 2- |                         | ednisone | dyspepsia,  |
|      |    | 28 | Respiratory failure.    |          | COPD        |
| 2632 | 70 |    | Pneumonitis. RA lung.   | CQ,      |             |
| /088 | F  | 17 |                         | Pr       | HTN, MI,    |
|      |    |    | Sudden death\*\*        | ednisone | DM, chol   |
| 2229 | 79 | 2  |                         |          |             |
| /088 | F  | 47 | Cerebrovascular         | MTX,     | HTN, renal  |
|      |    |    | accident. Intracraneal  | Pred, CQ | insuff.     |
| 7732 | 62 | 61 | hemorrage.              |          |             |
| /089 | M  |    |                         | MTX,     | HTN, Atrial |
|      |    | 2  | Unknown cause of death/ | Pred, CQ | fibrillatio |
| 7769 | 58 | 66 | sudden death\*\*.       |          |             |
| /089 | M  |    |                         | MTX      | Gastritis   |
|      |    | 2  | Sudden death.\*\*       | **^1^**, |             |
| 1    | 58 | 53 |                         | APAP, CQ | HTN, DM,    |
| 0100 | F  |    | Pneumonia.              |          | dyspepsia   |
| /089 |    | 2  |                         | AZA,     |             |
|      | 55 | 15 | Pneumonia. Electrolyte  | Pred,    | HTN, gout   |
| 5590 | F  |    | imbalance.              | SSZ      |             |
| /089 |    | 2  |                         |          | Gastric     |
|      | 62 | 60 | Hepatic necrosis.       | MTX      | ulcer,      |
| 9191 | F  |    |                         |          | depression  |
| /089 |    | 44 | Lung malignant          | MTX,     |             |
|      | 51 | -1 | neoplasm.               | Pr       |             |
| 6030 | M  | 06 |                         | ednisone |             |
| /089 |    |    | Sudden death.\*\*       |          |             |
|      | 60 | 2  |                         | MTX,     |             |
| 6057 | M  | 00 | Intracranial hemorrhage | HCQ,     |             |
| /089 |    |    |                         | Pred     |             |
|      | 53 | 2  | Pneumonia.              |          |             |
| 6703 | F  | 05 |                         |          |             |
| /089 |    |    |                         |          |             |
|      | 76 | 52 |                         |          |             |
| 6912 | F  |    |                         |          |             |
| /089 |    |    |                         |          |             |
+------+----+----+-------------------------+----------+-------------+

Source Table 54 of 088c study report; medical reviewer's review of
narratives and CRFs. \*\* Cause of death listed as myocardial infarction
but there were no documented MI in the CRF. **^1^** MTX three times a
week.

![](media/image3.png){width="5.510416666666667in"
height="4.979166666666667in"}

Appendix 2.a. Adjudicated Thrombotic Cardiovascular Serious Adverse
Experiences in VIGOR (updated application data) (Source: sponsor's
table)

Appendix 2.b. Summary of Analysis of Confirmed Adjudicated Thrombotic
Cardiovascular Serious Adverse Experiences in VIGOR study. (Source:
sponsor's Table 5, updated application data).

![](media/image4.png){width="8.996527777777779in"
height="3.6993055555555556in"}