+-----------------+----------------------------------------------------+
| #### MEMORANDUM | **DEPARTMENT OF HEALTH AND HUMAN SERVICES**        |
|                 |                                                    |
|                 | **PUBLIC HEALTH SERVICE**                          |
|                 |                                                    |
|                 | **FOOD AND DRUG ADMINISTRATION**                   |
|                 |                                                    |
|                 | **CENTER FOR DRUG EVALUATION AND RESEARCH**        |
+-----------------+----------------------------------------------------+

DATE:

FROM: Renan Bonnel, Pharm. D., M.P.H, Safety Evaluator

> Claudia B. Karwoski, Pharm.D., Team Leader

Division of Drug Risk Evaluation I, HFD-430

THROUGH: Julie Beitz, M.D., Director

Division of Drug Risk Evaluation I, HFD-430

TO: Jonca Bull, M.D. Acting Director

### Division of Antiinflammatory and Ophthalmic Drug Products, HFD-550

SUBJECT: OPDRA Postmarketing Safety Review

Drugs: Rofecoxib (Vioxx, NDA 21-042, 21-052),

Celecoxib (Celebrex, NDA 20-998, 21-156)

Etodolac (Lodine, NDA 18-922, 20-584)

Reaction: Thrombotic Vascular Events

**[EXECUTIVE SUMMARY]{.underline}**

This document summarizes our evaluation of 223 US cases of thrombotic or
embolic events possibly associated with rofecoxib (99), celecoxib (102),
and etodolac (22). These events include myocardial infarction (MI),
cerebrovascular events, pulmonary embolism (PE) and deep venous
thrombosis (DVT), and miscellaneous thrombotic events. Etodolac, a
non-selective NSAID, was chosen for review because it is a relatively
new antiinflammatory agent with similar indications.

There were several common characteristics in these cases noted for all
three products. In general, the patients were elderly and the mean ages
for rofecoxib, celecoxib and etodolac were 67, 69, and 65 years old,
respectively. For all three products, females made up slightly greater
than 65% of the cases. Most cases reported a dose within the recommended
labeled range. This information, however, was not always consistently
reported. Risk factors or precipitating factors such as past medical
history, underlying disease, concomitant medications, or acute
concurrent adverse events were present in many of the cases.

#### Rofecoxib

There were a total of 99 cases reviewed that were possibly associated
with the use of rofecoxib. These events include 26 of MI, 19 of PE or
DVT, 43 cerebrovascular events, and 14 miscellaneous thrombotic vascular
events. The numbers of events (102) slightly exceed the number of cases
because one case reported both MI and a PE and two cases reported PE/DVT
and CVA. Seven of the 26 patients who experienced an MI did not have
apparent precipitating factors or cardiovascular risk factors. Two of
the seven were greater than 65 years of age, and in three cases there
was extremely poor documentation. Of the 19 patients who were possibly
at an increased risk, two had a single cardiovascular risk factor and 17
had at least two cardiovascular risk factors, past medical history,
and/or a major concurrent event that may have contributed to the MI.

Ten of the 19 patients who experienced a PE or DVT may have been at
increased risk. Risk factors noted include obesity, history of DVT/PE,
concurrent CHF or MI, and/or concomitant suspect medications labeled for
thromboembolic events (including hormone replacement therapy (HRT) and
oral contraceptives (OC)). There were no apparent risk factors in the
remaining nine patients. Twenty-six of the 43 patients who experienced a
cerebrovascular event had precipitating risk factors or concurrent
medical conditions that may have contributed to the cerebrovascular
event. Hypertension was the most frequently reported underlying medical
condition. The remaining 17 cases lacked detailed clinical information.
We reviewed 14 miscellaneous thrombotic or embolic vascular events
possibly related to the use of rofecoxib. The events include arterial
thrombosis (1), portal vein thrombosis (1), ocular vascular
occlusion/embolism/clot (4), and intestinal vascular
insufficiency/ischemic colitis (8).

**Celecoxib**

There were a total of 102 cases reviewed that were temporally associated
with the use of celecoxib. These events include 37 of MI, 27 of PE or
DVT, 31 cerebrovascular events, and 10 miscellaneous thrombotic vascular
events. The numbers of events (105) slightly exceed the number of cases
because two cases reported both MI and a CVA and one case reported
PE/DVT and CVA. Six of the 37 patients who experienced an MI did not
appear to have precipitating factors or cardiovascular risk factors for
MI. Two of the six were greater than 65 years of age and the other four
were poorly documented. Of the 31 patients who were possibly at an
increased risk, three had a single cardiovascular risk factor and 28 had
at least two cardiovascular risk factors, past medical history, and/or a
major concurrent event that may have contributed to the MI.

Seventeen of the 27 patients who experienced a PE or DVT may have been
at increased risk. Risk factors noted include obesity, history of
thrombosis, anticardiolipin antibody, malignancy, SLE, recent surgery,
concurrent events (SBO, ARDS, and CHF), and/or concomitant suspect
medications labeled for thromboembolic events (including HRT). There
were no apparent risk factors in the remaining 10 patients. None of the
10 cases were very well documented. Twenty-five of the 31 patients who
experienced a cerebrovascular event had precipitating risk factors or
concurrent medical conditions that may have contributed to the
cerebrovascular event. Hypertension was the most frequently reported
underlying medical condition. The remaining six cases lacked detailed
clinical information. We reviewed 10 miscellaneous thrombotic vascular
events possibly related to the use of celecoxib. The events were ocular
vein occlusion (3), digital ischemia /occlusive thrombosis/limb embolism
(5), and ischemic colitis (2).

#### Etodolac

There were a total of 22 cases reviewed that were temporally associated
with the use of etodolac. These include seven cases of MI, six cases of
PE or DVT, seven cases involving cerebrovascular events, and two
miscellaneous thrombotic vascular events. Only one of the seven patients
who experienced an MI did not have apparent precipitating factors or
cardiovascular risk factors for an MI. The age and past medical history
of this patient was not reported. Of the six patients at an increased
risk, one had a single cardiovascular risk factor, two had no risk
factors but a single concurrent event, and the remaining three had at
least two risk factors, past medical history, and/or a major concurrent
event that may have contributed to the MI.

Four of the six patients who experienced a PE or DVT may have been at
increased risk. Risk factors noted include HRT use, history of CHF,
probable immobility secondary to hospitalization, and concurrent
eosinophilic pneumonia and interstitial nephritis. There were no
apparent risk factors in the remaining two patients, however these two
cases were not well documented. We reviewed seven cases of
cerebrovascular events possibly related to the use of etodolac. Four of
the seven patients had possible predisposing factors (hypertension- 4,
DM-2, smoker-1, and HRT-1) for the cerebrovascular events. Two patients
had more than one risk factor. We reviewed two miscellaneous thrombotic
vascular events possibly related to the use of etodolac. The events were
retinal vein thrombosis (1) and digital thrombosis (1).

**In conclusion**, this document describes the US cases of thrombotic
vascular events possibly related to rofecoxib, celecoxib, and etodolac
use. Because many of these patients were older and/or had possible
predisposing factors or underlying disease, it is difficult to determine
the role of each of the products in causing the event. Although certain
thrombotic events are mentioned in the product labeling, the continued
existence of the thrombotic events particularly in high-risk populations
is an important finding since the actual number of cases may in fact be
higher due to the underreporting of adverse events in passive
surveillance systems.

####### 

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| # |   |   |                                                    | age |
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+---+---+---+----------------------------------------------------+-----+
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+---+---+---+----------------------------------------------------+-----+
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| # |   |   |                                                    | # 6 |
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+---+---+---+----------------------------------------------------+-----+
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| # | # |   |                                                    | ### |
| # | # |   |                                                    | # 6 |
| # | # |   |                                                    |     |
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+---+---+---+----------------------------------------------------+-----+
| # | # |   |                                                    | #   |
| # | # |   |                                                    | ### |
| # | # |   |                                                    | # 7 |
| # | # |   |                                                    |     |
| # | # |   |                                                    |     |
|   |   |   |                                                    |     |
|   | C |   |                                                    |     |
|   | a |   |                                                    |     |
|   | s |   |                                                    |     |
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|   | d |   |                                                    |     |
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|   | d |   |                                                    |     |
|   |   |   |                                                    |     |
|   | i |   |                                                    |     |
|   | n |   |                                                    |     |
|   |   |   |                                                    |     |
|   | r |   |                                                    |     |
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|   | w |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # |   |   |                                                    | #   |
| # |   |   |                                                    | ### |
| # |   |   |                                                    | # 7 |
| # |   |   |                                                    |     |
| # |   |   |                                                    |     |
|   |   |   |                                                    |     |
| S |   |   |                                                    |     |
| u |   |   |                                                    |     |
| m |   |   |                                                    |     |
| m |   |   |                                                    |     |
| a |   |   |                                                    |     |
| r |   |   |                                                    |     |
| y |   |   |                                                    |     |
|   |   |   |                                                    |     |
| o |   |   |                                                    |     |
| f |   |   |                                                    |     |
|   |   |   |                                                    |     |
| C |   |   |                                                    |     |
| a |   |   |                                                    |     |
| s |   |   |                                                    |     |
| e |   |   |                                                    |     |
| s |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # |                                                    | #   |
| # | # | # |                                                    | ### |
| # | # | # |                                                    | # 8 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
|   | 1 | R |                                                    |     |
|   | . | o |                                                    |     |
|   |   | f |                                                    |     |
|   |   | e |                                                    |     |
|   |   | c |                                                    |     |
|   |   | o |                                                    |     |
|   |   | x |                                                    |     |
|   |   | i |                                                    |     |
|   |   | b |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Myocardial Infarction                        | #   |
| # | # | # |                                                    | ### |
| # | # | # |                                                    | # 8 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | #                                                  | #   |
| # | # | # | #### Pulmonary Embolism and Deep Venous Thrombosis | ### |
| # | # | # |                                                    | # 9 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Cerebrovascular Events                       | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  10 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Miscellaneous Thrombotic Events              | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  12 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # |                                                    | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  14 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
|   | 2 | C |                                                    |     |
|   | . | e |                                                    |     |
|   |   | l |                                                    |     |
|   |   | e |                                                    |     |
|   |   | c |                                                    |     |
|   |   | o |                                                    |     |
|   |   | x |                                                    |     |
|   |   | i |                                                    |     |
|   |   | b |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Myocardial Infarction                        | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  14 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | #                                                  | ##  |
| # | # | # | #### Pulmonary Embolism and Deep Venous Thrombosis | ### |
| # | # | # |                                                    |  15 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Cerebrovascular Events                       | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  16 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Miscellaneous Thrombotic Events              | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  18 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # |                                                    | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  19 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
|   | 3 | E |                                                    |     |
|   | . | t |                                                    |     |
|   |   | o |                                                    |     |
|   |   | d |                                                    |     |
|   |   | o |                                                    |     |
|   |   | l |                                                    |     |
|   |   | a |                                                    |     |
|   |   | c |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Myocardial Infarction                        | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  20 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | #                                                  | ##  |
| # | # | # | #### Pulmonary Embolism and Deep Venous Thrombosis | ### |
| # | # | # |                                                    |  20 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Cerebrovascular Events                       | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  21 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # | # | # | ##### Miscellaneous Thrombotic Events              | ##  |
| # | # | # |                                                    | ### |
| # | # | # |                                                    |  21 |
| # | # | # |                                                    |     |
| # | # | # |                                                    |     |
|   |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # |   |   |                                                    | ##  |
| # |   |   |                                                    | ### |
| # |   |   |                                                    |  22 |
| # |   |   |                                                    |     |
| # |   |   |                                                    |     |
|   |   |   |                                                    |     |
| C |   |   |                                                    |     |
| o |   |   |                                                    |     |
| n |   |   |                                                    |     |
| c |   |   |                                                    |     |
| l |   |   |                                                    |     |
| u |   |   |                                                    |     |
| s |   |   |                                                    |     |
| i |   |   |                                                    |     |
| o |   |   |                                                    |     |
| n |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+
| # |   |   |                                                    | ##  |
| # |   |   |                                                    | ### |
| # |   |   |                                                    |  22 |
| # |   |   |                                                    |     |
| # |   |   |                                                    |     |
|   |   |   |                                                    |     |
| R |   |   |                                                    |     |
| e |   |   |                                                    |     |
| f |   |   |                                                    |     |
| e |   |   |                                                    |     |
| r |   |   |                                                    |     |
| e |   |   |                                                    |     |
| n |   |   |                                                    |     |
| c |   |   |                                                    |     |
| e |   |   |                                                    |     |
| s |   |   |                                                    |     |
+---+---+---+----------------------------------------------------+-----+

## **[INTRODUCTION]{.underline}**

Reports of serious thrombotic vascular events with the use of rofecoxib
and celecoxib were noted during the routine postmarketing surveillance
of these products. Simultaneously, a written consult from the Division
of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products requested
a review of serious thrombotic cardiovascular adverse events associated
with celecoxib and rofecoxib since their approval. This consult request
prompted a review of all thrombotic and embolic vascular events for
these products in the Adverse Event Reporting System (AERS) database.

Rofecoxib was approved in 1999 for the treatment of osteoarthritis,
management of acute pain, and treatment of primary dysmenorrhea.
Celecoxib was approved in 1998 for relief of the signs and symptoms of
osteoarthritis and rheumatoid arthritis in adults and to reduce the
number of adenomatous colorectal polyps in familial adenomatous
polyposis (FAP), as an adjunct to usual care. Etodolac was approved in
1991 for acute and long-term use in the management of signs and symptoms
of osteoarthritis and pain.

Nonselective NSAIDs (such as etodolac) and the COX-2 selective NSAIDs
(celecoxib and rofecoxib) induce potent analgesic and anti-inflammatory
effects via the inhibition of cyclooxygenase (COX) enzymes in arthritic
patients. The inhibition of COX enzymes decreases the production of
prostaglandins and thromboxane. COX-2 (the inducible form) is primarily
found in inflamed tissue, brain, reproductive organs, and the kidney;
very little COX-2 is found in normal tissue. COX-1 (the constitutive
form) is expressed in most tissues, primarily in GI tract, kidney, and
platelets. It is involved in the production of protective prostaglandins
that are responsible for the maintenance of normal GI mucosa, and the
production of thromboxane A2, which promotes platelet aggregation.
Because selective COX-2 inhibitors (rofecoxib and celecoxib) do not
block COX-1 mediated platelet aggregation, there is a theoretical
increased risk of thrombotic vascular events in certain patients at risk
for such events.

# **LABELING**

The current labeling contains the following information regarding
thrombotic events:

**Rofecoxib (Vioxx)**

> ADVERSE REACTIONS (Cardiovascular): In the osteoarthritis studies, the
> following events occurred in \>0.1% to 1.9% of patients treated with
> Vioxx regardless of causality: cerebrovascular accident, deep venous
> thrombosis, myocardial infarction, pulmonary embolism, transient
> ischemic attacks, and unstable angina.
>
> DRUG INTERACTIONS: Aspirin - At steady-state, Vioxx 50 mg once daily
> had no effect on the anti-platelet activity of low-dose (81 mg once
> daily) aspirin, as assessed by *ex vivo* platelet aggregation and
> serum TBX~2~ generation in clotting blood. Vioxx is not substituted
> for aspirin for cardiovascular prophylaxis.

**Celecoxib (Celebrex)**

> ADVERSE REACTIONS (Cardiovascular): Angina pectoris, coronary artery
> disorder, myocardial infarction, pulmonary embolism, cerebrovascular
> accident, peripheral gangrene, thrombophlebitis.
>
> DRUG INTERACTIONS: Aspirin - Because of its lack of platelet effects,
> Celebrex is not a substitute for aspirin for cardiovascular
> prophylaxis. Celebrex can be used with low dose aspirin.

**Etodolac (Lodine)**

ADVERSE REACTIONS (Cardiovascular): Myocardial infarction,
cerebrovascular accident.

# **DRUG USE**

Total prescriptions since marketing approval will be presented for
Vioxx, Celebrex, and Lodine.

# **MEDICAL LITERATURE **

A MEDLINE search of the medical literature for thrombotic adverse event
case reports was performed using the MESH terms rofecoxib, celecoxib,
etodolac, cardiovascular adverse events, myocardial infarction,
pulmonary embolism, cerebrovascular accident, and thrombosis. The search
resulted in one relevant article of interest ^6.^ The article reported
thrombosis occurring during celecoxib therapy in four female patients.
All four cases were submitted to the FDA and all are summarized with the
other cases in the document.

# **SELECTION OF CASES**

An October 12, 2000 AERS search was conducted for rofecoxib, celecoxib,
and etodolac utilizing the following MedDRA Terms: central nervous
system hemorrhages and cerebral accidents (HLT), coronary artery
occlusion (PT), coronary artery embolism (PT), myocardial infarction
(PT), gastrointestinal occlusion and infarction (HLT), and embolism,
thrombosis, and stenosis (HLGT). The AERS search was limited to US cases
only. The search resulted in 144 unduplicated cases for celecoxib, 159
for rofecoxib, and 25 for etodolac.

# 

# **Cases Excluded from Review** 

# Forty-two celecoxib cases, 60 rofecoxib cases, and three etodolac cases were excluded from review for one or more of the following reasons:

-   No systemic thrombotic or embolic adverse event reported -- These
    include reports of superficial phlebitis, GI bleeds with mucosal
    blood clot formation, hematoma, epistaxis, hemorrhagic colitis,
    aortic valve regurgitation, retrobulbar hemorrhage, and reports of
    patients that ruled out for thrombotic or embolic events.

-   Hemorrhagic strokes in cases with an INR, PT, or PTT above the upper
    limit of normal range. The therapeutic INR for most conditions is 2
    to 3. In individuals with a mechanical valve or recurrent systemic
    embolism, the recommended INR is 3-4.5. So based on the upper limit
    of 4.5, we excluded cases with INRs above this value. If the INR
    value was not available then those with a PT or PTT value greater
    than 2 times of control were excluded.

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-   Events not included in this review -- Thrombocytopenic Purpura, DIC,
    mediastinal tumor with superior vena cava syndrome, and temporal
    arteritis.

-   Consumer or second hand reports with no confirmed diagnosis of a
    thrombotic event -- These reports refer to consumer or "hearsay"
    reports with no medical confirmation of diagnosis. An example
    includes the following:

-   By HCP - A pharmacist reported that another pharmacist told her that
    his mother-in-law was taking Celebrex for a couple of weeks before
    she died. The reporting pharmacist knew nothing further about the
    Celebrex case. She did not know the prescribing physician or the
    patient.

-   By consumer -- Unnamed consumer reports that a female patient
    started on Celebrex and developed severe intestinal cramps and then
    had a heart attack.

-   No actual adverse event report -- just request for information,
    initially interpreted by company as an ADR

-   Not clear if the patient was receiving the product (celecoxib,
    rofecoxib, or etodolac) or the thrombotic event was not temporally
    related to product -- in these cases, the use of either celecoxib or
    rofecoxib prior to the event was questionable.

-   No actual patient -- physician reported that an unspecified number
    of patients (NOS) experienced DVT and MI.

-   Study reports

# **Cases Included in Review**

-   Cases with events that were temporally related to the use of the
    product -- Cases lacking this information were excluded.

-   Cases with reported diagnosis of a systemic thrombotic or embolic
    event -- these events include myocardial infarction (MI), pulmonary
    embolism (PE), deep vein thrombosis (DVT), cerebrovascular accidents
    (CVA), and other miscellaneous systemic thrombotic or embolic
    events. This review did not include cases of varying degrees of
    angina or chest pain. Cases were included in the following two
    circumstances:

-   If a HCP reported a diagnosis of any of the above events with no
    supporting clinical data, the diagnosis was taken at face value.

-   If a consumer (patient or family member) reported the event with
    enough specific details regarding the event, these were taken at
    face value.

-   Cases that met the following clinical definitions^4,5^ -- but did
    not provide a diagnosis were included if the following case
    definitions were met:

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-   Myocardial infarction (MI) - The presence of two of the following
    criteria was used to identify MI cases: (1) a history of prolonged
    chest discomfort or anginal equivalent, (2) ECG changes consistent
    with ischemia or necrosis, (3) elevated cardiac enzymes, or (4)
    serious outcome attributed to MI in the report. Cases with a
    diagnosis of myocardial ischemia or angina were not included in this
    review unless they met the criteria above.

-   Pulmonary embolism (PE) - The presence of two or more of the
    following criteria was used to identify PE cases: (1) clinical
    symptoms including dyspnea, pleuritic chest pain, apprehension,
    cough, tachypnea, and tachycardia, (2) antecedent or concurrent
    DVT, (3) positive ventilation-perfusion (V/Q) lung scan, (4)
    positive pulmonary angiography (5) serious outcome attributed to PE
    in the report, and (5) PE on autopsy. If a case reported a diagnosis
    of PE with no supporting clinical data, the diagnosis was taken at
    face value.

-   Cerebrovascular Events - The presence of one of the following
    criteria was used to identify cerebrovascular events: (1) clinical
    symptoms and functional deficits confirmed by neurologic
    examination (2) positive diagnostic tests including MRI, CT Scan,
    Carotid Doppler, and Transthoracic Two-dimensional Echocardiography
    (TTE) to confirm the cerebrovascular event or, (3) serious outcome
    attributed to "stroke" in the report. If a case reported a diagnosis
    of cerebrovascular accident, stroke, or transcient ischemic attack
    with no supporting clinical data, the diagnosis was taken at face
    value.

##### [SUMMARY OF CASES]{.underline}

##### 

We reviewed the thrombotic vascular events for rofecoxib, celecoxib, and
etodolac. These events include myocardial infarction, cerebrovascular
events, pulmonary embolism and deep venous thrombosis, and miscellaneous
thrombotic events. The cerebrovascular events include the following
events or reported terms: stroke, cerebrovascular accident (CVA),
transient ischemic attacks (TIA), and cerebrovascular hemorrhage. The
miscellaneous thrombotic events involved ocular, gastrointestinal, and
peripheral circulatory systems.

1\. ROFECOXIB

There were a total of 99 cases reviewed that were temporally associated
with the use of rofecoxib. These events include 26 of MI, 19 of PE or
DVT, 43 cerebrovascular events, and 14 other thrombotic vascular events.
The numbers of events (102) slightly exceed the number of cases (99)
because one case reported both MI and a PE and two cases reported PE/DVT
and CVA.

+---------------+------------------------------------------------------+
|               | **Rofecoxib (N = 99)**                               |
+---------------+------------------------------------------------------+
| **Event**     | Myocardial Infarction-26, PE/DVT-19,Cerebrovascular  |
|               | Events-43                                            |
|               |                                                      |
|               | Miscellaneous thrombotic events-14 (arterial         |
|               | thrombosis-1, portal vein thrombosis-1, ocular       |
|               | events-4, ischemic colitis-8)                        |
+---------------+------------------------------------------------------+
| **Age**       | Range 19-91 years, mean-67.1, median-69 (unknown in  |
|               | 17)                                                  |
+---------------+------------------------------------------------------+
| **Gender**    | Female-59, Male-35, (unknown in 5)                   |
+---------------+------------------------------------------------------+
| **Outcome     | Death-15, Hospitalization-64, Disability-10, Outcome |
| \***          | not specified-22                                     |
+---------------+------------------------------------------------------+
| **Time to     | Range 1-300 days, mean-44, median-22 (n=58)          |
| onset**       |                                                      |
+---------------+------------------------------------------------------+
| **Dose**      | At labeled range-59, outside of labeled range-2      |
|               | (unknown in 38)                                      |
+---------------+------------------------------------------------------+
| **Reporter**  | HCP-75, Non-HCP-24                                   |
+---------------+------------------------------------------------------+

\* A case may have more than one reported outcome.

#### 

#### [Myocardial Infarction]{.underline} 

We reviewed 26 cases of myocardial infarction (MI) possibly related to
the use of rofecoxib. In one case, there was also a diagnosis of
pulmonary embolism so this case is also summarized in that section of
the document. The cases involved 11 females, 11 males, and four whose
gender was not specified. The patients' ages ranged from 50 to 87 years
of age with a mean and median of 71 and 73years, respectively. Sixteen
patients were \> 65 years of age. The mean and median time to onset (n=
16) was 42 and 13 days, respectively with a range of 1 day to 5 months.
The dose of rofecoxib was within the recommended range in 14 patients
and not reported in the remaining 12 patients. Twenty patients required
hospitalization, and six patients eventually died. The outcome in five
cases was not reported.

In 19 of the 26 cases, the patients may have been at increased risk for
an MI because of past medical history, the presence of cardiovascular
risk factors, and/or a recent major concurrent event. Six patients had a
prior history of coronary heart disease as evidenced by past history of
previous MI (2), coronary artery bypass graft (CABG) (3), percutaneous
coronary angioplasty (1), and/or history of coronary artery disease (4).
One or more cardiovascular risk factors were reported in 13 patients and
include hypertension (9), diabetes (6), hyperlipidemia (7), obesity (2),
hormone replacement therapy (3), and smoking (2). Additionally, the MI
in 11 patients may have been precipitated by a major concurrent event.
The major events included gastrointestinal hemorrhage (4), recent
surgery (2), renal failure (2), congestive heart failure (3), and
unspecified hemorrhage (1).

A total of six patients were on ASA therapy at the time of the MI. One
of the six was also on Advil. Of the five patients with a prior history
of coronary heart disease, only one was receiving ASA. Neither of the
two patients with a previous MI was on ASA, however one was on
concomitant warfarin for an unknown indication.

Overall, only 7 of the 26 patients did not have apparent precipitating
factors or cardiovascular risk factors for a MI. Two of the seven were
greater than 65 years of age, and in three cases there was extremely
poor documentation including no information regarding a past medical
history or risk factors. Of the 19 patients previously mentioned at an
increased risk, two had a single cardiovascular risk factor (diabetes-1,
hypertension-1). The remaining 17 had at least two risk factors, past
medical history, and/or a major concurrent event that may have
contributed to the MI.

#### [Pulmonary Embolism and Deep Venous Thrombosis]{.underline}

We reviewed 19 cases of pulmonary embolism (PE) and deep venous
thrombosis (DVT) possibly related to the use of rofecoxib. In three
cases, there was also a diagnosis of cerebrovascular accident (2) and
myocardial infarction (1) and these cases are again summarized in those
respective sections of this document. Rofecoxib was the only suspect
medication in 14 cases. In five cases, Enbrel (1), estrogen (2),
celecoxib (1), and olanzapine (1) were listed as co-suspect and were
temporally associated with the event.

The cases involved 11 females, seven males, and one whose gender was not
specified. The mean and median ages were was 51 and 54, respectively
with a range of 19 to 74 years old. Five patients were [\>]{.underline}
65 years of age. For rofecoxib therapy, the mean and median time to
onset (n= 14) was 40 and 15.5 days, respectively with a range of 5 to
165 days. The dose of rofecoxib was within the recommended range in 15
patients and not reported in the remaining four patients. Eleven
patients required hospitalization, and four patients died. The death in
two patients was secondary to PE, in the third patient was secondary to
endocarditis (diagnosed after PE), and in the fourth is not clear but
may have been secondary to PE.

Because of the complexity and range of severity of these cases, brief
descriptions of these events are presented below to hopefully provide
more clarity.

-   Seven patients suffered lower extremity (6) or upper extremity (1)
    DVTs.

-   Three patients developed lower extremity DVT that progressed to PE.

-   One patient suffered lower extremity DVT that was felt by the
    reporting physician to have embolized in her right middle cerebral
    artery and caused a stroke.

-   Four patients presented with PE with no mention of DVT.

-   Two patients were diagnosed with PE at autopsy (one also diagnosed
    with subarachnoid hemorrhage at autopsy).

-   One patient presented with MI, possibly anaphylaxis, and PE that
    might have been diagnosed on autopsy. The specific time course of
    these events is not clear.

-   One patient presented with PE and CHF.

In 10 of the 19 cases, the patients may have been at increased risk of
PE or DVT. The following risk factors were noted in six patients:
obesity (4) and history of DVT/PE (2). Two patients reported concurrent
events (CHF-1, MI-1) however it is not clear if these events may have
precipitated a PE. Two of the 10 patients were on chronic warfarin at
the time they experienced their PE, although it is not clear if they had
a therapeutic INR. One was on warfarin for chronic atrial fibrillation
and the other patient had a history of DVT and PE and was positive for
anticardiolipin antibodies. Seven patients were on concomitant or
co-suspect medications labeled for thromboembolic diseases. These
medications include HRT or OC use (5), Enbrel (1), and paroxetine (1)
listed as co-suspect and were temporally associated with the event.
There were no apparent risk factors in the remaining nine patients. Two
representative cases are presented below:

#### ISR 3396968, MFR# WAES 99102156, NC, 1999

A 50-year-old male physician with no significant medical history or
concomitant medication began to experience right leg pain approximately
five days after starting rofecoxib 25mg per day for chronic back pain.
An unspecified flow study revealed a right DVT and he was subsequently
hospitalized and treated with heparin and warfarin. He did not receive
rofecoxib during hospitalization, but was restarted on rofecoxib on
discharge. Two days after discharge, he began to experience similar
symptoms in his left leg. He underwent another flow study, which
revealed a DVT in his left leg. He was readmitted and treated with
heparin. He was also treated for a petechial rash felt to be related to
rofecoxib. He was eventually discharged home on warfarin and enoxaparin.

ISR 3595541, direct, KY, 2000

A 30-year-old female with no significant medical history died of
multiple pulmonary emboli approximately one month after starting
rofecoxib 50mg daily for knee pain. Concomitant medication included
Estrosten Fe (an oral contraceptive) for 10 months. She had previously
used other oral contraceptives without problems. One month after
initiation of rofecoxib, she experienced severe dyspnea and agitation.
She was admitted to the ER in respiratory arrest and expired after 2
hours of cardiopulmonary resuscitation. The autopsy findings were as
follows: bilateral multiple pulmonary emboli, subarachnoid hemorrhage,
and negative post-mortem blood toxicology.

#### [Cerebrovascular Events]{.underline}

##### 

We reviewed 43 cases of cerebrovascular events possibly related to the
use of rofecoxib. Rofecoxib was the primary suspect in 41 cases and the
secondary suspect in two cases. In two cases, there was also a diagnosis
of pulmonary embolism so these cases are also summarized in that section
of the document. Celecoxib, aspirin, warfarin, Premarin, Naprosyn,
captopril, Estrogen Fe, and Kenalog injection were co-suspect
medications in eight cases. The quality of data in the reports varied
from good (7) to adequate (17), and poor (19). The majority of the
reports lacked detailed clinical information.

The cases involved 27 females and 16 males. The mean age was 71 years
old (n=32) with a range of 30 to 91 years. The mean and median time of
onset (n=21) was 44 and 18 days, respectively with a range of 1 to 300
days after starting rofecoxib therapy. The dose was within the
recommended range in 26 patients, outside of the recommended range in
one patient, and not reported in 16 patients. Twenty-eight patients were
hospitalized, seven reported disability, and 15 reported the event as
life threatening. Seven cases had a reported positive dechallenge and
six had a reported negative dechallenge upon discontinuation of the
drug. There were six fatalities. The cause of death was secondary to
cerebral hemorrhage in three patients, possible acute renal failure in
one patient, PE and subarachnoid hemorrhage in one patient, and was
undetermined in one patient.

Twenty-six cases had one or more possible predisposing factors for
stroke (hypertension-18, hormone replacement therapy (HRT)-7,
hyperlipidemia-6, diabetes mellitus (DM)-3, malignancy-2, obesity-2,
smoking-1, and illicit drug use-1). There were four patients who
suffered hemorrhagic stroke that were receiving warfarin at the time. In
addition, 11 of the 26 patients had concurrent medical conditions such
as immobility/paraplegia, deep vein thrombosis, gram negative sepsis,
severe migraine, severe epistaxis, atherosclerosis, acute GI bleeding
with severe blood loss, multiorgan failure, carotid artery disease, and
cardiac valve replacement that may have played a contributory role in
the events. Many patients had more than one risk factor. Two patients
had an indication for cardioprotective aspirin therapy (h/o TIA and CVA)
and neither was receiving chronic aspirin therapy. Eighteen patients had
diagnostic work-ups including neuroimaging (MRI or CT scan) studies in
13 patients to confirm the diagnosis of the cerebrovascular event.

The types of stroke were thrombotic (2), embolic (2), hemorrhagic (9)
and indeterminate (30).

The case involving the thrombotic event was reported as "blood clot in
the brain" and cerebral thrombosis. This case was poorly documented. A
CT scan confirmed the second thrombotic stroke case. The patient was an
84-year-old female with a previous history of HTN, MI, and obesity that
may have contributed to the event. She suffered left-sided hemiplegia.
There were two well-documented cases involving embolic events. One of
the patients, with hypercholesterolemia, small vessel disease, and mild
hypertension, presented with a TIA. The small vessel disease and mild
hypertension were thought to be contributory to the event. The second
patient had concurrent deep vein thrombosis and hypertension that
resulted in right middle cerebral artery stroke and persistent severe
hemiparesis.

There were 30 cases that merely included the terms "stroke", CVA or
infarcts. These cases were classified as "indeterminate" because they
lacked specific information regarding the type of lesion (hemorrhagic vs
ischemic). Fifteen of the 30 cases were confounded by risk factors for
stroke such as hypertension (12), hyperlipidemia (5), HRT (5), DM(2), or
malignancy (1) at the time of the event. Nine patients had more than one
risk factor.

There were nine cases involving hemorrhagic cerebrovascular events. The
majority of the cases were well documented and had neuroimaging (CT or
MRI) studies or an autopsy to confirm the location of the hemorrhage.
Five patients may have had an increased risk for the event. Uncontrolled
hypertension was a possible contributory risk factor in three patients.
Other risk factors include HRT/OC use (2), obesity (1), and DM (1).
Concomitant aspirin (325 mg) and warfarin use was reported in four
patients. However, normal or slightly elevated (3.9) INR lab values did
not support the role of warfarin in these cases. Although cerebral
hemorrhages may have resulted from rupture of an arteriosclerotic vessel
by uncontrolled arterial hypertension, the possibility of local thrombus
formation and ischemia prior to cerebral hemorrhage cannot be excluded.

Overall, in 26 of the 43 cases, the patients had precipitating risk
factors or concurrent medical conditions that may have contributed to
the cerebrovascular event. Hypertension was the most frequently reported
underlying medical condition. The remaining 17 cases lacked detailed
clinical information. The following are representative cases of
thrombotic cerebrovascular events:

ISR \# 3483702 (MFG \# WAES 00031937) (US, 2000)

A 75-year-old female with a history of hyperlipidemia, GERD,
osteoporosis, DJD, compression fractures and s/p bilateral knee
replacement, suffered a stroke during treatment with rofecoxib 25mg
daily for osteoarthritis. Other than hyperlipidemia, the patient had no
other known risk factors. The patient's blood pressure had always been
within the normal range. Concomitant medications included baby aspirin
and vitamins. Two days after initiation of rofecoxib, she developed
blurred vision, dizziness, and vertigo and rofecoxib was discontinued.
The symptoms cleared and the family suspected a stroke at the time of
this event. Three weeks after discontinuation of rofecoxib, she
presented with left lower leg weakness, facial droop, mild left-sided
paresis and another episode of blurred vision. She was hospitalized and
CT scan showed enlarging lacunar infarcts. The carotid studies were
unremarkable and EKG was negative for left atrial enlargement or left
ventricular hypertrophy. The patient has not fully recovered as of the
time of the report. Presently, she is being treated in a rehabilitation
hospital and has a persistent left hemiparesis.

ISR \# 3444499 (MFG \# WAES 99101748) (US, 2000)

A 59-year-old male with a history of hypercholesterolemia, mild
hypertension, BPH, and bilateral knee replacement, suffered a TIA during
treatment with rofecoxib 25 mg daily for arthritis. Concomitant therapy
included finasteride and doxazosin (dose and duration unknown). Six
weeks after initiating rofecoxib, he noted acute onset of weakness in
his right hand, numbness, and clumsiness of the hand while golfing. He
was admitted to the ER. On admission his BP was 155/90 and physical
examination was unremarkable other than his neurologic symptoms, which
disappeared after 2 --1/2 hours. A CT scan (without contrast) showed
abnormal appearance of both orbits and densities were present
anteriorly. No previous scan was available for comparison. The carotids,
EKG, lab values were normal. The diagnosis of transient ischemic attack
was made and he was placed on therapy with Aggrenox.

#### [Miscellaneous Thrombotic Vascular Events]{.underline}

We reviewed 14 other or miscellaneous thrombotic or embolic vascular
events possibly related to the use of rofecoxib. The events include
arterial thrombosis (1), portal vein thrombosis (1), ocular vascular
occlusion/embolism/clot (4), and intestinal vascular
insufficiency/ischemic colitis (8).

######### Arterial Thrombosis/Digital Ischemia

A case of arterial thrombosis (MFR \# WAES 99070971) was temporally
related to rofecoxib therapy. The patient was a 51-year-old female who
developed severe digital vasospasm of all five fingers on the left hand
and acrocyanosis after four days of rofecoxib (unknown dose) therapy for
arthritis. Her past medical history was unknown. Concomitant medications
included Premarin, Prozac, and Ritalin. Therapy with rofecoxib was
immediately discontinued. She was found to have a thrombosis of the
proximal ulnar artery. The patient was hospitalized and treated with
t-PA and surgical measures. At the time of the report, the patient
remained hospitalized and continued to have digital ischemia in two
fingers.

######### Portal Vein Thrombosis

One case of (ISR# 3576870) portal vein thrombosis involved a 59-year-old
male patient who developed portal vein thrombosis while using rofecoxib
on an "as needed" basis. The patient had concurrent pancreatic neoplasm,
hepatic veno-occlusive disease, and portal hypertension that may have
contributed to the event. Rofecoxib use was deemed unlikely to be the
etiology for the event.

######### Ocular Vascular Events

There were four cases of ocular vascular occlusion, embolism, or clot
formation temporally associated with rofecoxib therapy. All four
patients were elderly females. Two of the patients had hypertension or
concurrent essential thrombocythemia that might have contributed to
ophthalmic thrombotic events.These cases are described below.

-   (ISR#3557980) A 72-year-old female with a history of retinal
    hemorrhage (1998) who developed "a second episode of retinal vein
    thrombosis" of the left eye about one month after starting rofecoxib
    25 mg daily for osteoarthritis. The patient had a history of
    hemorrhagic gastric ulcer and was on concurrent lansoprazole. She
    had no history of hypertension, glaucoma, or other systemic
    coagulopathies. Other concomitant meds included alendronate and
    hormone replacement therapy. Rofecoxib was discontinued. No further
    information was expected.

-   (ISR# 3535108) A 70-year-old female developed retinal vein branch
    occlusion after receiving rofecoxib (unknown dose and duration).
    Concomitant therapy included levothyroxine, Dyazide, raloxifene and
    atorvastatin. The report was lacking clinical detailed information.

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-   (ISR #3536521) A 76-year-old female with a history of hypertension
    developed an ophthalmic vascular disorder, loss of blood pressure
    control, "clot", blind spot and visual loss five days after starting
    rofecoxib 12.5 mg daily.

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-   (ISR# 3548936) A 72-year-old female developed essential
    thrombocythemia (platelet count 926,000) and thrombocyte embolus of
    the eye five weeks after starting rofecoxib. Her baseline
    thrombocyte count was 283,000. Upon discontinuation of rofecoxib,
    the platelet count normalized. The patient was treated with
    anagrelide.

***Intestinal Vascular Insufficiency or Ischemic Colitis***

We reviewed eight cases of intestinal vascular insufficiency or ischemic
colitis with rofecoxib use. The patients' ages ranged from 49 to 86
years with a mean of 67 years old. Five patients received the
recommended dose for 7 days to 5 months. The onset of the event was 4 to
106 days after initiation of therapy. Three cases may have been
confounded by recent major multiple illness, aspirin use, erosive
esophagitis, previous history of gastrointestinal distress, and
concomitant ibuprofen (1800 mg daily) therapy. One patient reported a
history of colectomy for an unspecified reason. Five cases reported
positive dechallenge upon discontinuation of therapy. Six patients
reported recovery, one patient remained in the hospital at the time of
the report and one patient died as a result of GI hemorrhage with
ischemic bowel disease. There was one compelling case (MFR# WAES
00010660) involving a 53-year-old female with no known predisposing
factors who developed intestinal vascular insufficiency, colitis, and
intestinal ischemia while on rofecoxib therapy. An extensive evaluation
did not reveal predisposing factors or an underlying process promoting
ischemia or any evidence of ischemic arterial disease. She was
hospitalized, had a bowel resection, and recovered.

##### 

##### 2. CELECOXIB

There were a total of 102 cases reviewed that were temporally associated
with the use of celecoxib. These events include 37 of MI, 27 of PE or
DVT, 31 cerebrovascular events, and 10 other thrombotic vascular events.
The numbers of events (105) slightly exceed the number of cases (102)
because two cases reported both MI and a CVA and one case reported
PE/DVT and CVA.

+-----------------+----------------------------------------------------+
|                 | **Celecoxib (N= 102)**                             |
+-----------------+----------------------------------------------------+
| **Event**       | Myocardial Infarction-37, PE/DVT- 27,              |
|                 | Cerebrovascular Events-31                          |
|                 |                                                    |
|                 | Miscellaneous thrombotic events-10 (ocular         |
|                 | events-3, digital ischemia-5, ischemic colitis-2)  |
+-----------------+----------------------------------------------------+
| #### Age        | Range 24-95 years , mean-69, median-74 (unknown in |
|                 | 17)                                                |
+-----------------+----------------------------------------------------+
| **Gender**      | Female-64, Male-31 (unknown in 7)                  |
+-----------------+----------------------------------------------------+
| **Outcome \***  | Death-15, Hospitalization-78, Disability-7,        |
|                 | Outcome not specified-17                           |
+-----------------+----------------------------------------------------+
| **Time to       | Range 1-565 days, mean-55, median-27.5 (n=76)      |
| onset**         |                                                    |
+-----------------+----------------------------------------------------+
| **Dose**        | At labeled range-81 (unknown in 21)                |
+-----------------+----------------------------------------------------+
| **Reporter**    | HCP-78, Non-HCP-18 (unknown in 6)                  |
+-----------------+----------------------------------------------------+

\* A case may have more than one reported outcome.

#### [Myocardial Infarction]{.underline}

We reviewed 37 cases of MI possibly related to the use of celecoxib. In
two cases, there was also a diagnosis of cerebrovascular accident and
these are again summarized in the cerebrovascular events section of this
document. The cases involved 19 females, 17 males, and one whose gender
was not specified. The mean and median ages were was 73 and 75,
respectively with a range of 39 to 92 years old. Twenty-seven patients
were [\>]{.underline} 65 years of age. The mean and median time to onset
(n= 32) was 53 and 24 days, respectively with a range of 1 day to 1.5
years. The dose of celecoxib was within the recommended range in 32
patients and not reported in the remaining five patients. Thirty-one
patients required hospitalization, and nine patients died. The outcome
in four cases was not reported.

In 31 of the 37 cases, the patients may have been at increased risk for
an MI because of past medical history, the presence of cardiovascular
risk factors, and/or a recent major concurrent event. Eleven patients
had prior history of coronary heart disease as evidenced by past history
of previous MI (3), percutaneous coronary angioplasty (1), and/or
history of coronary artery disease, angina, or chest pain (9). One or
more cardiovascular risk factors were reported in 24 patients and
include hypertension (14), diabetes (7), hyperlipidemia (5), obesity
(6), hormone replacement therapy (3), and smoking (2). Additionally, the
myocardial infarction in 16 patients may have been precipitated by a
major concurrent event. The major events include gastrointestinal
hemorrhage (9), renal failure (1), congestive heart failure (3),
hemolytic anemia (1), pericarditis (1), and pancreatitis (1).

A total of eight patients were on ASA therapy at the time of the MI. Of
the eight patients with a prior history of coronary heart disease, three
were receiving ASA. Two of the three patients with a previous MI were on
ASA.

Overall, six of the 37 patients did not appear to have precipitating
factors or cardiovascular risk factors for MI. Two of the six were
greater than 65 years of age (70 and 90yo). Four of the six were also
poorly documented cases. Of the 31 patients previously mentioned at an
increased risk, three had a single cardiovascular risk factor
(hypercholesteremia-1, diabetes-1, hormone replacement therapy-1). The
remaining 28 had at least two risk factors, past medical history, and/or
a major concurrent event that may have contributed to the MI.

There was one profound case involving a 39-year-old female on long term
estrogen and methyltestosterone who suffered a "massive" MI
approximately three weeks after initiating therapy with celecoxib. She
was put on celecoxib 200mg per day for anterior cruciate joint
inflammation of her shoulder. About one week after starting therapy she
developed nausea and vomiting and temporarily stopped celecoxib for four
days, but she suffered the MI about 10 days after restarting it. Other
than hormone replacement therapy she had no other risks for heart
disease.

##### 

#### [Pulmonary Embolism and Deep Venous Thrombosis]{.underline}

##### 

We reviewed 27 cases of pulmonary embolism (PE) and deep venous
thrombosis (DVT) possibly related to the use of celecoxib. In one case,
there was also a diagnosis of cerebrovascular accident and this case is
again summarized in the cerebrovascular event section of this document.
Celecoxib was the only suspect medication in 23 cases. In four cases,
heparin (1), warfarin (1), and aspirin (2) were listed as co-suspect.
Three of these listed a concurrent hemorrhagic adverse event.

The cases involved 19 females, five males, and three whose gender was
not specified. The mean and median ages were was 65 and 64, respectively
with a range of 39 to 95 years old. Ten patients were [\>]{.underline}
65 years of age. The mean and median time to onset (n=21) was 56 and 25
days, respectively with a range of 2 to 565 days. The dose of celecoxib
was within the recommended range in 23 patients and not reported in the
remaining three patients. Twenty-four patients required hospitalization,
and one patient died. The cause of death was unknown in an elderly
patient who experienced a DVT two weeks prior.

Because of the complexity and range of severity of these cases, brief
descriptions of these events are presented below to hopefully provide
more clarity.

-   Eleven patients suffered lower extremity (5) or unspecified (6)
    DVTs.

-   Two patients developed lower extremity DVT that progressed to PE.

-   Two patients developed PE during hospitalization for GI hemorrhage.

-   Two patients were diagnosed with subclavian thrombosis.

-   Seven patients were diagnosed with PE with no mention of prior DVT.

-   One patient developed CVA and DVT during admission for GI
    hemorrhage.

-   One patient developed hemolytic anemia, DIC, and PE felt to be
    related to gallbladder CA.

-   One patient on chronic warfarin developed an extension of her DVT
    while on celecoxib.

In 17 of the 27 cases, the patients may have been at increased risk of
PE or DVT. The following possible risk factors were noted in 12
patients: obesity (3), history of DVT (1), history of ulnar artery
thrombosis (1), history of carotid artery occlusion (1), anticardiolipin
antibody (2), malignancy (3), SLE (1), unspecified circulatory problems
(1), recent surgery (2), total knee replacement (1), and bedridden (1).
Four of the 16 also reported concurrent events (CHF-1, hemolytic anemia
and DIC --1, Small bowel obstruction and ARDS-1, GI bleed and CVA-1)
however it is not clear if these events may have precipitated the
thromboembolic event. Five patients were on concomitant medications
labeled for thromboembolic disease. These medications include HRT (3),
tamoxifen (1), gabapentin (1), methotrexate (1), and fluoxetine (1).
None of these medications were listed as co-suspect.

Two patients were on warfarin at the time they experienced their event.
One was receiving warfarin for a DVT and had an INR of 6.48. She
developed progression of her DVT despite a supratherapeutic INR. Another
patient was on warfarin for anticardiolipin syndrome and previous ulnar
artery thrombus. Her INR was maintained between 2 to 2.5. There were
another four cases with warfarin listed as a concomitant but the
indications were not specified.

There were no apparent risk factors in the remaining 10 patients. None
of these cases were very well documented. One physician reported four
cases of DVT occurring in elderly nursing home patients who were on
celecoxib from 1 to 3 months. The patients past medical history and
concomitant medications were not reported

##### 

#### [Cerebrovascular Events]{.underline}

We reviewed 31 cases of cerebrovascular events possibly related to the
use of celecoxib. In three cases, there was also a diagnosis of MI (2)
and PE/DVT (1) these are summarized in those sections of the document.
Celecoxib was the primary suspect in 27 cases and methotrexate, warfarin
(5), metaxalone, and hydrochlorothiazide were co-suspect in eight cases.
In the majority of the cases, the quality of data was adequate for
evaluation, but 11 cases were poorly documented.

The cases involved 19 females, 10 males, and two whose gender was not
specified. The mean age (n=24) was 75 years old with a range of 24 to 92
years. The mean time of onset (n=20) was 53 days with a range of 1 to
300 days after starting celecoxib therapy. The dose was within the
recommended range in 22 cases and not reported in nine cases.
Twenty-three patients were hospitalized, six reported disability, and
seven reported the event as life threatening. Seven patients reported
positive dechallenges and two patients reported negative dechallenge
upon discontinuation of the drug. There were six fatalities. The cause
of death was secondary to cerebral hemorrhage in two patients,
multiorgan failure in two patients, and myocardial infarction in two
patients.

Seventeen cases had one or more predisposing factors (hypertension-14,
HRT-4, hyperlipidemia-3, DM-6, obesity-1) that might have contributed to
the cerebrovascular event. In addition, five patients had concurrent
medical conditions such as chronic renal failure with dialysis, carotid
endarterectomy, cardiomyopathy/mitral valve regurgitation/sepsis,
pancytopenia, severe vascular disease, and GI bleeding that might have
played a contributory role in the cerebrovascular event. As with the
rofecoxib cases, many patients had more than one risk factor. Five
patients had an indication for cardioprotective aspirin therapy (h/o TIA
and CVA) and only one was receiving chronic aspirin therapy. Ten
patients had a diagnostic work-up, including a CT scan in six to confirm
the diagnosis of the cerebrovascular events.

The types of stroke were thrombotic (1), hemorrhagic (13) and
indeterminate (17). The case involving the thrombotic event was reported
as "thrombotic infarction-stroke" and affected the left middle cerebral
artery. The event occurred six weeks after starting celecoxib therapy
and left the patient with aphagia and hemiplegia. This obese patient had
hyperlipidemia and hypertension that might have contributed to the
event.

There were 17 reports of "stroke" and CVA that lacked the specific
information to determine the type of the lesion. They were classified as
"indeterminate" for the purpose of this evaluation. Eight of the
patients had hypertension, one had hyperlipidemia, and two were on
hormone replacement therapy at the time of the event that might have
contributed to events.

There were 13 cases involving hemorrhagic cerebrovascular events. The
majority of the reports had adequate information and four cases had
CTscans to confirm the intracranial hemorrhage. Five patients were
receiving warfarin at the time of the event, however the INR was within
the normal range in one patient and was unknown in the other four. Five
patients had hypertension that might have contributed to event. Although
the cerebral hemorrhages may have resulted from rupture of an
arteriosclerotic vessel by uncontrolled arterial hypertension, the
possibility of local thrombus formation and ischemia prior to cerebral
hemorrhage cannot be excluded.

Overall, 25 of 31 patients had precipitating factors or concurrent
medical conditions that may have contributed to the cerebrovascular
event. Hypertension was the most frequently reported medical condition.
The remaining six cases lacked detailed clinical information. The
following are representative cases of the cerebrovascular events:

## ISR \# 3274994, Direct, US, 1999

A 77-year-old female in excellent health received celecoxib 200 mg daily
for arthritic trigger finger. After two doses, she experienced rash and
increased temperature followed by a right-sided deficit that included
speech impairment and inability to walk and use her hand. She
discontinued celecoxib without clinical improvement. In the ER, she was
diagnosed with "stroke" in progress. The patient was hospitalized and
required long-term rehabilitation. Although progress was being made, she
had not fully recovered at the time of this report.

ISR #3358036,MFG \# SKEL0319990003, US, 1999

A 92-year-old female started taking celecoxib 100 mg twice a day in 1999
for osteoarthritis of the neck. On 7/1/1999 after 2-3 doses of
celecoxib, she suffered an acute left-sided cerebrovascular accident
while attending mass. She presented with right-sided weakness, and
aphagia. Concomitant medications included Skelexin ½ tab (strength
unknown) twice daily, nitroglycerin, digoxin, potassium supplement,
paroxetine, quinine, klonopin, VitE, Cozaar, and a Ca supplement. The
strength and the duration of all concomitant medications were unknown. A
CT scan was negative for hemorrhage. The rheumatologist indicated
celecoxib and Skelaxin as suspect medications

#### [Miscellaneous Thrombotic Vascular Events]{.underline}

We reviewed 10 miscellaneous thrombotic vascular events possibly related
to the use of celecoxib. The events were ocular vein occlusion (3),
digital ischemia /occlusive thrombosis/limb embolism (5), and ischemic
colitis (2).

**Ocular Vein Occlusion**

There were three cases of ocular vein occlusion with celecoxib therapy.
These cases included two females, both 50 years of age, and one male
whose age was not reported. Two patients received a recommended dose of
celecoxib, and one patient received an unspecified dose. The three
patients developed ocular vein occlusion 2 days, 3 months, and 6 months
after initiation of celecoxib therapy. One patient had a sulfa allergy
and she developed hives, pruritus, facial swelling, and retinal
occlusion within two days of celecoxib therapy. None of the patients had
documented hypertension, elevated intraocular pressure, carotid
occlusive disease, retinal vasculitis, or systemic coagulopathies. One
patient had a history of deep vein thrombosis and one patient had a
history of cataract surgery. Concomitant medications included HRT
therapy (2), torsemide (1) and unspecified herbal extracts (1). It is
unclear what if any role these concomitant medications might have had in
this event. One patient reported a positive dechallenge.

######### Digital ischemia, occlusive thrombosis, or limb embolism

There were five cases of digital ischemia, occlusive thrombosis, or limb
embolism temporally associated with celecoxib therapy. Three cases were
interesting and are described in the literature**^6^**. These three
events occurred during celecoxib therapy in women aged 37, 41, and 42.
All patients received celecoxib  400mg/day as required for arthritis.
All of the women had a history of, or had conditions that predisposed
them to thrombosis including Raynaud's phenomenon (RP), previous history
of thrombosis, systemic lupus erythematosus (SLE), and lupus
anticoagulant (LAC). These cases are described below:

-   A 42-year-old female with RP began developing acute ischemic changes
    to the left foot after 2 doses of celecoxib. The angiography
    confirmed thromboembolic disease. Her concomitant medications were
    prednisone and hydroxychloroquine. She was treated with
    methylprednisolone and heparin. Two weeks after starting celecoxib,
    she was hospitalized with diminished posterior tibial and dorsalis
    pedis pulses. Thrombolytic therapy failed and she underwent an
    embolectomy. Her arterial blood flow was partially restored and
    warfarin therapy was started. One month later, the arterial flow to
    her foot remained reduced and she developed gangrene in her left
    great toe and the dorsum of her foot.

-   A 37-year-old female with a history of SLE, cerebritis, Raynaud's
    and Sjogren's syndrome developed pain, cyanosis, swelling of her
    toes within 2 weeks of celecoxib use. She discontinued celecoxib and
    was hospitalized and treated with methyprednisolone and aspirin.
    After she failed to improve clinically she was treated with a single
    dose of cyclophosphamide. Her ulceration had improved 2 weeks later,
    but digital ischemia persisted.

-   A 41-year-old female with a history of SLE, RP and LAC developed
    occlusive thrombosis involving the proximal right anterior tibial,
    proximal peroneal, and proximal posterior tibial arteries 5 months
    after starting celecoxib. Symptoms of pain, discoloration, and ulcer
    formation attributed to vasculitis 2 months after initiation of
    therapy in this patient may, in retrospect, have been due to
    thrombosis. There was no evidence of atherosclerotic disease.
    Concomitant medications included methotrexate and prednisone. She
    received thrombolytic infusion therapy resulting in some
    improvement. An embolectomy was performed to restore blood flow and
    she was discharged on warfarin therapy.

The remaining two cases had minimal information stating that the
patients developed emboli in the toes or the feet after starting
celecoxib. One patient was a 79-year-old female who developed
thromboembolism of the toes after two weeks of celecoxib use. The event
occurred two weeks after stopping the drug and the hematologist in the
case felt the event was unrelated to celecoxib.

######### Ischemic colitis

There were two cases of ischemic colitis in two females, ages 64 and 77
years old. One patient had a history of diverticulitis and developed
ischemic colitis (per reporter) while on celecoxib. The dose and
duration of celecoxib was unknown. She was hospitalized and a
colonoscopy was positive for GI hemorrhage. The second patient had no
significant GI history but developed ischemic colitis after taking
celecoxib for one day. She presented with rectal hemorrhage and
leukocytosis. Aspirin and estrogen were co-suspect medications. A
colonoscopy confirmed the diagnosis of severe colitis. The patient
recovered and was discharged. Both cases were confounded by the past
medical history or concomitant NSAID use.

##### 

##### C. ETODOLAC

There were a total of 22 cases reviewed that were temporally associated
with the use of etodolac. These include seven cases of MI, six cases of
PE or DVT, seven cases involving cerebrovascular events, and two other
thrombotic vascular events.

+-------------+--------------------------------------------------------+
|             | **Etodolac (N= 22)**                                   |
+-------------+--------------------------------------------------------+
| **Event**   | Myocardial Infarction-7, PE/DVT-6, Cerebrovascular     |
|             | Events-7, Miscellaneous thrombotic events-2 (Retinal   |
|             | Vein thrombosis-1,Digital thrombosis-1)                |
+-------------+--------------------------------------------------------+
| **Age**     | Range 24-81 years , mean-65, median-70 (unknown in 4)  |
+-------------+--------------------------------------------------------+
| **Gender**  | Female-15, Male-7                                      |
+-------------+--------------------------------------------------------+
| **Outcome   | Death-6, Hospitalization-17, Disability-2              |
| \***        |                                                        |
+-------------+--------------------------------------------------------+
| **Time to   | Range 1-210 days, mean-36.5, median-13 (n=14)          |
| onset**     |                                                        |
+-------------+--------------------------------------------------------+
| **Dose**    | At labeled range-17, (unknown in 5)                    |
+-------------+--------------------------------------------------------+
| *           | ## HCP-17, Non-HCP-5                                   |
| *Reporter** |                                                        |
+-------------+--------------------------------------------------------+

\* A case may have more than one reported outcome.

#### 

#### [Myocardial Infarction]{.underline} 

We reviewed seven cases of MI possibly related to the use of etodolac.
The cases involved four females and three males. The patient's ages
ranged from 50 to 81 years of age with a mean and median of 69 and 70
years, respectively. Five patients were \> 65 years of age. The time to
onset (n= 4) ranged from 1 to 28 days. The dose of etodolac was within
the recommended range in five patients and not reported in the remaining
two patients. Five patients required hospitalization, and two patients
died.

In 6 of the 7 cases, the patients may have been at increased risk of MI
because of past medical history, the presence of cardiovascular risk
factors, and/or a recent major concurrent event. One patient had a
history of previous MI. One or more cardiovascular risk factors were
reported in four patients and include hypertension (2), diabetes (1),
hormone replacement therapy (1), and smoking (2). Additionally, the MI
in four patients may have been precipitated by a major concurrent event.
The major events include gastrointestinal hemorrhage and ventricular
thrombus (1), anaphylaxis (1), anemia (1), and aortic valve disorder
(1). No patients were on ASA at the time of the MI, however there was
one patient who had years of Naprosyn treatment prior to switching to
etodolac.

Overall, only 1 of the 7 patients did not have apparent precipitating
factors or cardiovascular risk factors for an MI. The age and past
medical history of this patient was not reported. Of the six patients
previously mentioned at an increased risk, one had a single
cardiovascular risk factor (smoking-1), and two only had the concurrent
event (anemia-1, aortic valve disorder-1) but no reported risk factors
or past coronary disease. The remaining three patients had at least two
risk factors, past medical history, and/or a major concurrent event that
may have contributed to the MI.

#### [Pulmonary Embolism and Deep Venous Thrombosis]{.underline}

We reviewed six cases of pulmonary embolism (PE) and deep venous
thrombosis (DVT) possibly related to the use of etodolac. The cases
involved four females and two males. The mean and median ages were 52
and 70, respectively with a range of 24 to 77 years old. Four patients
were [\>]{.underline} 65 years of age. The time to onset reported in
four cases was 11 days, 1, 2, and 7 months. The dose of etodolac was
within the recommended range in all six patients. Five patients required
hospitalization, and three patients died. The death was secondary to
right heart thromboembolism in one patient, adult respiratory distress
syndrome in the second patient, and PE in the third patient. Brief
descriptions of these events are presented below.

-   One patient was diagnosed with right heart thromboembolism on
    autopsy.

-   Three patients developed lower extremity DVT.

-   One patient was diagnosed with PE.

-   One patient was diagnosed with eosinophilic pneumonia, multifocal
    thromboemboli, and microinfarction of the lung.

In four of the six cases, the patients may have been at increased risk
of PE or DVT. The following risk factors were noted in four patients:
HRT or OC use (2), congestive heart failure (1), and probable immobility
secondary to hospitalization (1). Two patients reported concurrent acute
events (eosinophilic pneumonia-1, interstitial nephritis-1) however it
is not clear if these events may have precipitated a PE. There were no
apparent risk factors in the remaining two patients, however these two
cases were not well documented.

#### [Cerebrovascular Events]{.underline}

We reviewed seven cases of cerebrovascular events possibly related to
the use of etodolac. The reports dated back to the early 1990's and in
general lacked detailed clinical information. The cases involved five
females and two males. The mean age (n=24) was 75 years old with a range
of 24 to 92 years. The mean age was 64 with a range of 47 to 74 years.
The time of onset (n=4) was 38.5 days with a range of 3 to 120 days. The
dose of etodolac was within the recommended range in four patients and
was not reported in three.

Four patients had possible predisposing factors (hypertension- 4, DM-2,
smoker-1, and HRT-1) for the cerebrovascular events. Two patients had
more than one risk factor. Three patients had imaging (MRI or CT scan)
studies and two had confirmed middle artery occlusion and lacunar
infarct. All patients were hospitalized and one reported disability as
an outcome. There were no reported deaths. The following is a
representative case of thrombotic cerebrovascular event:

ISR #936131, MFG \# 8-93062-001S, US, 1993

A 73-year-old female with a history of Bell's Palsy presented with
stroke-like symptoms while receiving etodolac 900 mg for DJD for
unspecified length of time. Concomitant medications included lisinopril,
amoxicillin, and Trental. During hospitalization, she developed acute
renal failure (BUN/SCr: 135/5.3) in addition to stroke. A CT scan
revealed middle cerebral occlusion. Etodolac was discontinued. The
patient's clinical condition improved. The adverse events resulted in
prolonged hospitalization.

**[Miscellaneous Thrombotic Vascular Events]{.underline}**

We reviewed two miscellaneous thrombotic vascular events possibly
related to the use of etodolac. The events were retinal vein thrombosis
(1) and digital thrombosis (1).

The case (MFR#8-96239-007S, 1996) of retinal vein thrombosis occurred
after five days of etodolac at 300mg twice daily. Six days after
discontinuation of etodolac therapy, a female (age unknown) presented
with foot pain, swelling, red-purple rash on her lower extremities,
headache, and blurred vision. The diagnosis of cryoglobulinemia
associated with leukocytoclastic vasculitis was made. The patient
suffered permanent damage to her eye due to retinal vein thrombosis. The
reporter stated that the ocular event resulted from leukocytoclastic
vasculitis and cryoglobulinemia.

The case of digital thrombosis (MFR# 8-92120-0110A, 1992) occurred in a
female patient who developed hypersensitivity vasculitis with necrosis
and thrombosis of fingertips after taking etodolac for two weeks. The
patient was thought to have lupus and a coagulopathy was felt to
represent evidence of anticardiolipin antibodies as a manifestation of
lupus erythematosis.

# 

######## CONCLUSION

## We have reviewed 223 US cases of thrombotic vascular events possibly associated with celecoxib, rofecoxib and etodolac. In general, the patients were elderly. For all cases and all three products approximately 65% of the patients [\>]{.underline} 65 years of age (of the cases that provided age information). Females made up slightly greater than 65% of the cases. This was not surprising since rheumatoid arthritis occurs more in females (3:1)**^7^**. 

Risk factors or precipitating factors such as past cardiovascular
medical history, underlying disease, concomitant medications, or acute
concurrent adverse events were present in many of the cases. It is
plausible that the elderly, particularly those with preexisting
cardiovascular risk factors would be more susceptible to developing
thrombotic vascular events. The thrombotic events did not appear to be
dose related as the majority of the patients received the recommended
daily dose. The quality of the reports was overall adequate but some
cases lacked detailed clinical information and many were potentially
confounded.

Although, certain thrombotic events such as CVA, MI, PE, venous
thrombosis, and TIA are mentioned in the product labeling, the continued
existence of thrombotic events in high-risk population in post-marketing
phase is an important finding. The actual number of thrombotic adverse
events may in fact be higher due to the underreporting of adverse events
in passive surveillance systems.

**[REFERENCES]{.underline}**

1\. Vioxx Product labeling. Merck & Co., Inc. 1999

2\. Celebrex Product labeling. G.D. Searle & Co, 1999

3.  Lodine Product labeling. Wyeth-Ayerst, 1998

4.  Carey, Lee, Woeltje. Manual of Medical Therapeutics. The Washington
    Manual. 29 th Edition. Lippincott, Williams& Wilkins.

5.  The Merck Manual. Sixteenth Edition. 1992

6.  Crofford LJ, Oates JC, McCune WJ, Gupta S, Kaplan MJ,
    Caltella-Lawson F, Morrow JD, McDonagh KT, Schmaier AH. Thrombosis
    in patients with connective tissue diseases treated with specific
    cyclooxygenase 2 inhibitors. A report of four cases. Arthritis &
    Rheumatism 43: 1891-1896, Aug 2000

7.  Gregory Gardner. Therapy of the Rheumatic Diseases: Past, Present ,
    Future. Annual Scientific Meeting of the American College of
    Rheumatology, Philadelphia, Pennsylvania, Oct 31, 2000

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

Renan A. Bonnel, Pharm.D., M.P.H

Post-Marketing Safety Evaluator

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

Claudia B. Karwoski, Pharm.D.

Team Leader

Cc:

NDA \# 21042, 21052, 20998,21156, 18922,20584)

HFD-430: Beitz /Trontell/Karwoski /Bonnel /Guinn

HFD-550: NDA 2104221052, NDA 20998, 21156, NDA 18922,20584 / Goldkind/
Villalba/ Folkandt

HFD-2/MedWatch

Bonnel/thrombotic CV.COX-2.AC

####