**Celebrex Capsules**

**(Celecoxib)**

**NDA 20-998**

**Medical Officer Review**

**Submission Date:** June 29, 1998

**Received Date:** June 30, 1998

**Review Date:** July 8, 1998

**Drug Name:** Celebrex

**Generic Name:** celecoxib

**Applicant:** G.D. Searle & Co.

4901 Searle Parkway

Skokie, IL 60077

**Pharmacologic category:** COX-2 inhibitor

**Proposed Indication:** Management of:

-   pain

-   rheumatoid arthritis

-   osteoarthritis

    **Dosage forms and route:** Oral capsule, 100 and 200 mg

    **Submission type:** Original NDA

    Orig NDA \# 20-998

    HFD-550/Div File

    HFD-550/PM/Lutwak

    HFD-550/Pharm/Yang
    \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

    HFD-550/Chem/Bhavnagri (James Witter, M.D., Ph.D. Medical Officer)

    HFD-550/Biopharm/Bashaw

    HFD-550/Statistics/Lin

    HFD-550/MO/Witter

####### Celecoxib Executive Summary {#celecoxib-executive-summary .unnumbered}

**Significant Issues**

-   If approved, celecoxib would be the first so-called "COX-2
    selective" agent approved in the U.S. In fact, as noted below, it is
    suggested that celecoxib be called a "specific" COX-2 inhibitor. The
    biological and clinical implications of this designation are, at
    present, not fully characterized.

-   Although the single-dose, dental pain trials have established that
    celecoxib is efficacious compared to placebo, the other postsurgical
    pain trials did not confirm the analgesic properties of the proposed
    doses.

-   Because serum bicarbonates were not measured, the NDA database
    cannot exclude an adverse effect of celecoxib on acid-base balance.

-   Celecoxib is efficacious in the treatment of the signs and symptoms
    of osteoarthritis and rheumatoid arthritis at the proposed doses.

    **Highlights**

-   Endoscopic data with celecoxib have found that it is associated with
    significantly fewer endoscopically-defined ulcers as compared to
    studies with ibuprofen and naproxen. However, celecoxib was
    associated with fewer ulcers in only one of two such endoscopic
    studies with diclofenac. However, these ulceration rates are not
    equivalent to placebo.

-   The overall safety profile of celecoxib suggests at this time that
    it is generally more comparable to NSAIDs (ibuprofen, diclofenac,
    naproxen) than to placebo.

-   Randomized and open-label trials, to date, suggest the rate for
    clinically relevant upper gastrointestinal events is less with
    celecoxib than that of traditional NSAIDs.

-   If approved, celecoxib would be the first compound with properties
    similar to currently understood NSAIDs to successfully employ the
    Western Ontario and McMaster Universities (WOMAC) Osteoarthritis
    Index as well as the American College of Rheumatology (ACR-20)
    Responder Index for rheumatoid arthritis in a New Drug Application.

    **BACKGROUND AND OVERVIEW:**

    ***Celecoxib (Cx)*** is the USAN name for
    4-\[5-(methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl\]benzenesulfonamide
    which is a diarylsubstituted pyrazole compound. The trade name for
    this same compound is ***Celebrex*** while the code name is
    ***SC-58635.*** Cx was originally developed as a "selective"
    prostaglandin G/H synthase-2 (i.e. ***COX-2***) inhibitor. However,
    during the development of this compound, Cx is now presented as a
    "specific" COX-2 inhibitor (SCI). According to current thinking,
    such "SCI inhibitors" at therapeutic doses would inhibit COX-2 and
    would be maximally effective in treating inflammation and pain, but
    would not inhibit COX-1 activity involved in normal physiologic
    function (see below). Many regard this compound as a new class of
    anti-inflammatory and analgesic agents. In fact, the WHO has
    recently changed the ATC classification of Cx to "COX-2 specific
    inhibitors".

    From studies dating back only to the late 1980's and early 1990's,
    it became clear that there must be another isoform of human
    cyclooxygenase (COX), the enzyme which catalyzes the rate-limiting
    step in converting arachidonic acid to prostaglandins (PG),
    thromboxanes, and leukotrienes. For example, early experiments with
    endotoxin-treated monocytes showed that the significant increase in
    PGE~2~ was inhibited by dexamethasone, this corticosteroid is not
    known to alter the transcription of COX-1. Subsequently, the theory
    has evolved that COX-1 and COX-2 may subserve different roles in the
    body. Originally, COX-1 was postulated to be a constitutive form of
    COX involved in "house-keeping" functions, such as maintenance of
    the gastrointestinal (GI) tract mucosal integrity, normal platelet
    function, and renal function while COX-2 represented the inducible
    form of COX involved in inflammation and pain. Similarly, it was
    postulated early that COX-1 was present in all cells (and, most
    importantly, in platelets) while COX-2 was only distributed at sites
    of inflammation, such as arthritic joints; COX-2 was not present in
    platelets (since they lack the transcriptional machinery necessary
    to produce this inducible enzyme).

    Currently, it is appreciated that the COX story is much more
    complicated, and potentially much more interesting. For example, it
    is now accepted that COX-2 can also be constitutively expressed in
    areas like the kidney and brain whereas previously these areas were
    felt to be devoid of any significant COX-2. The situation of whether
    COX-2 is present in the human GI tract has also rapidly evolved in
    the last few years. Early on, it was felt that COX-2 was not present
    in the human GI tract. It is now clear that this enzyme is not only
    present in the lower GI tract, it is a target for prophylactic
    therapy of colonic cancer. Similarly, COX-2 is also recognized to be
    increased in the upper GI tract in situations of ulcer healing or
    infection with Helicobacter pylori infection. Conversely, there is
    an understanding that COX-1 can also be inducible under certain
    experimental systems and COX-1 may be upregulated in situations when
    COX-2 is absent or blocked; animals models have been particularly
    illustrative in this regard. Finally, it is becoming evident that
    COX-2 may also play important roles in Alzheimer's disease,
    cardiovascular disease, angiogenesis, along with their already
    recognized important roles in inflammation, pain and pyrexia.

    While on the surface, NDA 20-998 might appear to represent just
    another drug to review, in reality one could easily argue it
    represents a test to the various hypotheses of the proposed roles of
    COX-2 in human health and disease. While reviewing this NDA, the
    reader is therefore encouraged to constantly question whether we are
    testing a drug, a theory, or both with this compound? It will be of
    interest to see where this NDA positions itself in the future in
    terms of helping to address some of these very important biological
    and clinical questions.

    A total of 51 trials were submitted to support NDA 20-998. As
    detailed in the Table 1 below, these 51 trials have been divided by
    the Sponsor into three basic types of studies (Phase 1, Arthritis,
    Postsurgical Analgesia):

#### Table 1. Studies Included in NDA 20-998 {#table-1.-studies-included-in-nda-20-998 .unnumbered}

+---------------------+------------+-----------------------------------+
| Type of Study       | No. of     | Study Numbers                     |
|                     | Studies    |                                   |
+---------------------+------------+-----------------------------------+
| Phase 1             | 9          | 001, 006, 009, 018, 019, 037,     |
|                     |            | 044, 084, 088                     |
| Single dose         |            |                                   |
+---------------------+------------+-----------------------------------+
| Multiple dose       | 11         | 003, 004, 010, 014, 015, 026,     |
|                     |            | 032, 033, 043, 065, 069           |
+---------------------+------------+-----------------------------------+
| Drug Interaction    | 7          | 017, 038, 039, 040, 050, 051, 072 |
+---------------------+------------+-----------------------------------+
| Hepatic Impairment  | 1          | 016                               |
+---------------------+------------+-----------------------------------+
| Renal Impairment    | 1          | 038                               |
+---------------------+------------+-----------------------------------+
| Arthritis           | 5          | 020, 021, 054, 060, 087           |
|                     |            |                                   |
| OA                  | 3          | 042, 013, 047                     |
|                     |            |                                   |
| Pivotal Efficacy    |            |                                   |
|                     |            |                                   |
| Supportive          |            |                                   |
+---------------------+------------+-----------------------------------+
| RA                  | 2          | 022, 023                          |
|                     |            |                                   |
| Pivotal Efficacy    | 2          | 041, 012                          |
|                     |            |                                   |
| Supportive          |            |                                   |
+---------------------+------------+-----------------------------------+
| OA/RA combined      | 2          | 062, 071                          |
+---------------------+------------+-----------------------------------+
| Long-term open      | 1          | 024                               |
| label               |            |                                   |
+---------------------+------------+-----------------------------------+
| Postsurgical        | 3          | 025, 027, 070                     |
| Analgesia           |            |                                   |
|                     | 1          | 005                               |
| Dental pain         |            |                                   |
|                     |            |                                   |
| Pivotal Efficacy    |            |                                   |
|                     |            |                                   |
| Supportive          |            |                                   |
+---------------------+------------+-----------------------------------+
| Surgical Pain       | 1          | 028                               |
|                     |            |                                   |
| Pivotal Efficacy    | 2          | 029, 080                          |
|                     |            |                                   |
| Supportive          |            |                                   |
+---------------------+------------+-----------------------------------+
| Total               | 51         |                                   |
+---------------------+------------+-----------------------------------+

Reviewer's comment: To facilitate review of the clinical aspect of this
NDA, several different Divisions within CDER have been engaged as
follows:

Mickey Averbuch, M.D. Pain trials

Lawrence Goldkind, M.D. UGI safety

Douglas Throckmorton, M.D. Renal Safety

Lourdes Villalba, M.D. General Safety

Lilia Talarico, M.D. Platelet Safety

While these other reviews have addressed the safety and efficacy of Cx,
the consultant reviews outside the Division have focused on platelet
effect and function, along with the effects of Cx on the GI tract and
kidneys. This review will attempt to integrate the highlights of all
these critically important consultant reviews but the interested reader
is referred to the original reviews for in-depth details.

**Integrated Summary of Safety:**

This ISS is not intended to be the only review of the safety of Cx; it
is more of a supplement and overview. This relates to the nature of the
compound and how the review of this NDA was divided. Celecoxib was
developed primarily to address the issue of the UGI safety of NSAIDs. It
is well known that NSAIDs are a significant source of UGI morbidity and
death. For example, recently updated numbers from the ARAMIS
Postmarketing Surveillance Program at Stanford University (Am. J. Med.,
Vol. 105, \[1b\] p. 31-38S; July 27, 1998) state that: "Conservative
calculations estimate that **approximately 107,000 patients are
hospitalized** annually for nonsteroidal anti-inflammatory drug
(NSAID)-related gastrointestinal (GI) complications and **at least
16,500 NSAID-related deaths occur each year among arthritis patients
alone."** This is stated in another way in the NSAID GI warning template
for the Agency which states:

"It has been demonstrated that upper GI ulcers, gross bleeding or
perforation, caused by NSAIDs, appear in approximately 1% of patients
treated for 3-6 months, and in about 2-4% of patients for one year".
Therefore, the safety review of the this NDA has been addressed as
follows and the interested reader should also see these other reviews:

Maria Lourdes Villalba, M.D. Celecoxib Safety Review

Larry Goldkind, M.D. UGI Safety Review

Lilia Talarico, M.D. Platelet Safety Review

Douglas Throckmorton, M.D. Renal/Cardiovascular Safety Review

**Renal Safety:**

Reviewer's comment: For a detailed examination of the results of Cx on
renal function and safety, the interested reader is encouraged to read
the cardiorenal consult.

Experimental and clinical evidence demonstrates that NSAIDs reduce renal
function

when renal perfusion is dependent on prostaglandin formation. Patients
at risk for acute

ischemic renal failure (renal decompensation) include those with a
variety of renal

diseases, congestive heart failure, cirrhosis with ascites, volume
depletion and diuretic

use. These effects are normally readily reversible upon withdrawal of
the drug. NSAIDs

can also produce fluid retention leading to edema formation, interfere
with the blood

pressure-lowering effects of certain antihypertensive medication and
rarely lead to

chronic renal injury such as interstitial nephritis or papillary
necrosis.

Cyclooxygenase activity can be found throughout the kidney although
enzyme activity is

most abundantly expressed in four discrete sites; the glomerular
afferent and efferent

arterioles, the glomerulus, the interstitial cells of the renal medulla
and the medullary

collecting ducts. It remains unclear how much of renal prostaglandin
synthesis is

normally mediated by COX-1 or COX-2 at these various sites. COX-2 may be
needed for normal development of the kidney during embryogenesis because
homozygous COX-2 knockout mice develop kidneys with abnormal nephrons
containing hypotrophic glomeruli and dysplastic tubules. Several studies
have detected apparent constitutive expression of COX-2 within the
kidney at the following level locations:

-   macula densa

-   interstitial cells of the papillae

-   medullary interstitial cells

-   epithelial cells of the thick ascending loop of Henle

-   glomerular podocytes

These findings suggest COX-2 has a role in handling sodium and in the
regulation of both

glomerular filtration and fluid balance. However, it is also highly
likely that COX-1, more

ubiquitously distributed in the kidney, plays a significant role in all
of these processes too.

Whether COX-2 inhibitors would avoid many of the common NSAID-associated

renal toxicities was examined in this NDA.

The three clinical pharmacology studies outlined in table 31, were
conducted in selected groups of subjects and patients felt to be at risk
for adverse renal hemodynamic effects or excretory changes related to
use of NSAIDs.

#### Table 31. Studies to Assess Effects on Renal Function in NDA 20-998

+-----+--------+---------------------------+--------+----------------+
| **S | **     | **Treatment Groups and**  | *      | **Outcome      |
| tud | Popula |                           | *Treat | Measures**     |
| y** | tion** | **Regimens**              | ment** |                |
|     |        |                           |        |                |
|     |        |                           | **Pe   |                |
|     |        |                           | riod** |                |
+-----+--------+---------------------------+--------+----------------+
| *   | **Hea  | **- Celecoxib 200/400 mg  | **10   | **Glomerular   |
| *01 | lthy** | BID**                     | days** | filtration     |
| 0** |        |                           |        | rate, urinary  |
|     | **eld  | **- Naproxen 500 mg BID** |        | PGE2 and**     |
| *   | erly** |                           |        |                |
| *(n |        | **Celecoxib 200 mg BID    |        | **6-keto-PGF1  |
| =29 | **subj | for five days followed by |        | excretion**    |
| )** | ects** | 400 mg BID for 4.5 days,  |        |                |
|     |        | or naproxen 500 mg**      |        |                |
|     |        |                           |        |                |
|     |        | **BID for 9.5 days; after |        |                |
|     |        | 7 day washout, crossover  |        |                |
|     |        | to opposite treatment**   |        |                |
+-----+--------+---------------------------+--------+----------------+
| *   | **So   | **- Placebo**             | **6.5  | **Glomerular   |
| *03 | dium** |                           | days** | filtration     |
| 3** |        | **- Celecoxib 200 mg      |        | rate, urinary  |
|     | **depl | BID**                     |        | PGE2 and       |
| *   | eted** |                           |        | 6-keto-PGF1    |
| *(n |        | **- Celecoxib 400 mg      |        | excretion,     |
| =42 | **h    | BID**                     |        | renal blood    |
| )** | ealthy |                           |        | flow, plasma   |
|     | male** | **- Naproxen 500 mg BID** |        | renin          |
|     |        |                           |        | activity,      |
|     | **subj |                           |        | plasma         |
|     | ects** |                           |        | aldosterone,   |
|     |        |                           |        | plasma atrial  |
|     |        |                           |        | natriuretic    |
|     |        |                           |        | peptide, serum |
|     |        |                           |        | TxB2,          |
|     |        |                           |        | fractional     |
|     |        |                           |        | sodium,        |
|     |        |                           |        | potassium and  |
|     |        |                           |        | lithium        |
|     |        |                           |        | excretion**    |
+-----+--------+---------------------------+--------+----------------+
| *   | **Pa   | **- Placebo**             | **6.5  | **Glomerular   |
| *03 | tients |                           | days** | filtration     |
| 6** | with** | **- Celecoxib 200 mg      |        | rate**         |
|     |        | BID**                     |        |                |
| *   | **c    |                           |        | **(inulin),    |
| *(n | hronic | **- Naproxen 500 mg BID** |        | urinary PGE2   |
| =75 | r      |                           |        | and**          |
| )** | enal** |                           |        |                |
|     |        |                           |        | **6-keto-PGF1D |
|     | **ins  |                           |        | excretion,**   |
|     | uffici |                           |        |                |
|     | ency** |                           |        | **plasma renin |
|     |        |                           |        | activity,      |
|     |        |                           |        | urinary        |
|     |        |                           |        | 1              |
|     |        |                           |        | 1-dehydro-TxB2 |
|     |        |                           |        | excretion,     |
|     |        |                           |        | serum TxB2,    |
|     |        |                           |        | creatinine     |
|     |        |                           |        | clearance,     |
|     |        |                           |        | fractional     |
|     |        |                           |        | sodium and     |
|     |        |                           |        | potassium      |
|     |        |                           |        | excretion**    |
+-----+--------+---------------------------+--------+----------------+

**From Text Table 121, ISS.**

Principal outcome measures in these studies included glomerular
filtration rate (GFR, determined using Glofil, sinistrine, or inulin,
and measurement of urinary prostaglandins). Creatinine clearance
measurements were also performed as part of two other studies
Measurement of prostaglandins in urine has gained general acceptance as
a marker of

renal prostaglandin production following the original report suggesting
their renal origin

in healthy women, although a number of methodologic as well as biologic
variables can

affect urinary prostaglandin measurements in humans. Urine
concentrations of PGE2 and

6-keto-PFG1 were determined using a combination of chromatographic and

GC/ENCI/MS/MS analyses (sensitivity limit of 10 pg/mL) in Studies 010,
036 and 033.

Adequate pre-study control assays were conducted to determine accuracy,
specificity,

sensitivity, and reproducibility of assays. Urine samples were analyzed
for 11-dehydro-TxB2 concentrations using radioimmunoassay competition
binding assays. The range of calibration was 10 pg/mL to 1000 pg/mL.

The data suggest that COX-2 is present in the human kidney and so
represent a potential and plausible candidate to explain any observed
clinical toxicity. Cardiac and renal safety was examined in both the
short-term, controlled NA trials and in the longer, open-label trial
involving approximately 7400 patients with OA and RA. As part of the
safety database, the sponsor collected AEs related to both clinical and
laboratory measurements. In addition, serial laboratory measurements
were obtained from a subset of patients.

**The results (safety, pharmacodynamic) of these trials can be
summarized as follows (see cardiorenal consult for details):**

1.  **No measurements of acid-base balance (e.g. serum bicarbonate,
    arterial pH) performed as part of any trial in the NDA. Therefore,
    an adverse effect of Cx on acid-base balance cannot be excluded,
    particularly in the context of the observed increase in
    hyperchloremia (see below).**

2.  **Both Cx and comparator NSAIDs (in short-term trials) inhibited
    prostaglandin PGE~2~ and 6-keto-PFG1 excretion by the kidney to more
    or less the same extent. Both had significant inhibitory effects on
    the excretion of urinary prostaglandins when compared to placebo. Cx
    caused slightly less of a decrease in GFR in one study (010). Both
    Cx and naproxen inhibited serum renin and urinary (11-dehydro-TxB2­­) ­
    ­ ­thromboxane levels.**

3.  **There was an association between Cx administration and the
    development of clinically significant edema (especially peripheral
    edema), similar to comparator NSAIDs, and clearly distinguished from
    placebo. Both naproxen and Cx cause sodium retention. There was no
    statistically significant association between 1 kg weight gain and
    the occurrence of 'peripheral edema\' in a subset of patients with
    edema as an AE, although a higher % of both the Cx and active
    control group patients had both.**

4.  **There was an association between Cx administration and the
    development of worsened hypertension in susceptible individuals,
    again similar to NSAIDs, and clearly distinguished from placebo.**

5.  **There is a definite association between Cx use and an increased
    incidence of hypophosphatemia, and hyperchloremia compared to
    placebo and similar to active controls. There was no increase in
    bony fractures in those individuals with these abnormalities, as
    might be expected if there is a change in the acid-base balance. An
    increase in bony fractures has been seen with other drugs with
    prominent renal tubular toxicities resulting in renal tubular
    acidosis. The controlled trials were also too short to examine the
    rate of renal stone formation, which might also increase during
    renal tubular acidosis. The clinical consequences of these changes
    remain to be determined.**

6.  **There was a trend towards an increase incidence of elevated serum
    creatinine values and elevated BUN with proteinuria in both the Cx
    and active control groups relative to placebo. These surrogates for
    renal toxicity suggest, but do not confirm, a link between Cx use
    and clinically relevant nephrotoxicity similar to NSAIDs.**

7.  **There is no evidence to suggest that Cx has unique renal
    toxicities not shared by NSAIDs, or evidence of a renal toxicity
    caused by NSAIDs that occurs at a significantly higher incidence
    rate with Cx.**

8.  **The pattern of AEs reported in both the controlled and the
    long-term trials is similar to that expected for NSAIDs.**

9.  **There were several individuals taking Cx who were withdrawn from
    the long-term trials because or renal AEs including acute renal
    failure, edema and worsened hypertension.**

10. **While there were no clear cut cases of Cx-induced renal failure
    requiring dialysis, it remains to be determined whether severe renal
    injury will occur at the same rate that is seen with NSAIDs.**

11. **The renal effects of Cx are clearly distinguished from placebo.**

12. **The NDA does not reveal a strong signal pointing towards
    substantial clinically serious renal disease (i.e. large numbers of
    patients with acute renal failure requiring dialysis, nephrotic
    syndrome, papillary necrosis, interstitial neprhritis). This will
    require a larger database.**

####### 

####### Cardiovascular Safety

Reviewer's comment: For a detailed examination of the results of Cx on
cardiovascular safety, the interested reader is encouraged to read the
cardiorenal consult.

The association of COX inhibitors with cardiovascular disease is based
on their effects

upon prostaglandins, primarily in the kidney, but also to a lesser
extent, in platelets and in

vascular endothelium. It had been hypothesized that these effects are
mostly due to inhibition of COX-1, resulting in fluid retention and
hypertension. However, as noted in the cardiorenal consult, Cx is also
associated with edema and worsened hypertension. As discussed in one of
the consults from the Division of GI and Coagulation Drug Products, Cx
does not seem to affect platelet function (aggregation) at, and above,
therapeutic doses

This cardiovascular effects of Cx were addressed by following
W.H.O.a.r.t. body systems: General Cardiovascular Disorders, Heart Rate
and Rhythm Disorders, Myo/Endo/Pericardial and Valve Disorders and
Vascular (Extracardiac Disorders). In addition, pertinent adverse events
from other body systems, such as hypertension, were reviewed. Serious
cardiovascular events, the effects of medical histories and concurrent
medications, pertinent vital sign and laboratory data were also
reviewed.

Adverse Events

Table 42 below presents the cardiovascular adverse events for which
there was a 1%

incidence in the NA arthritis trials.

**^Table\ 42.\ Cardiovascular\ AEs:\ Incidence\ 1%\ in\ North\ American\ arthritis\ trials1^**

  ------------------ ------------- ------------- ---------- --------- ---------- --------- -----------
                                   **Celecoxib                                             
                                   (mg)**                                                  

  **Adverse Event**  **Placebo**   **50 BID**    **100      **200     **200      **400     **Active
                                                 BID**      QD**      BID**      BID**     Control**

  **No. Treated**    **1864**      **690**       **1779**   **453**   **1914**   **615**   **2098**

  **Any event**      **53 (3.0)**  **27 (3.9)**  **74       **22      **123      **39      **120
                                                 (4.2)**    (4.9)**   (6.4)**    (6.3)**   (5.7)**

  **Edema            **21 (1.1)**  **15 (2.2)**  **27       **13      **49       **15      **45
  peripheral**                                   (1.5)**    (2.9)**   (2.6)**    (2.4)**   (2.1)**

  **Hypertension**   **5 (0.3)**   **2 (0.3)**   **11       **1       **20       **3       **14
                                                 (0.6)**    (0.2)**   (1.0)**    (0.5)**   (0.7)**
  ------------------ ------------- ------------- ---------- --------- ---------- --------- -----------

**1. From Table 32.1.1 (ISS). Includes trials 012, 013, 020, 021, 022,
023, 047, 054, 060, 062, 071, and 087.**

As can be seen, peripheral edema was the most common cardiovascular
adverse event. There is no obvious dose-response relationship; overall
incidence with Cx appears similar to the active control. Further
analysis, (Text Table 154, ISS) revealed there was no statistically
significant difference in incidence of peripheral edema between

Cx and active control, but there was between Cx and placebo (p=0.007).
The peripheral edema associated with Cx was reported as mild to moderate
in severity in 97% of cases, and in only 17% was judged to be "probably
related" by the Investigator. Of note, generalized edema, a potentially
more meaningful indication of clinically important fluid retention
(which was coded only when CRF text stated "generalized" or "body"
edema), was significantly more frequent in patients receiving active
controls than in

Cx patients (active control 0.5% vs. 0.1% for Cx, p=0.031). The
differences in the incidence of hypertension between treatment groups
(in this comparison) was not statistically significant for Cx vs.
placebo or for Cx vs. active control. A related, but less frequent,
adverse event, "hypertension aggravated" also was also not significantly

different in incidence between Cx and placebo, or Cx and active control
in these comparisons. There were no events for which there was a 1%
incidence in any treatment group for patients who withdrew due to a
cardiovascular adverse event.

The next table (from Text Table 155, ISS) summarizes the incidences of
cardiovascular AEs by body systems and by time interval in the
long-term, open-label trial (024).

**^Table\ 43.\ Cardiovascular\ AEs:\ Incidence\ 1%\ in\ Long-Term\ Trial\ (024)1^**

+--------------------+---------+-----+----+------+-----+-----+-----+
| **Adverse Events** |         | **  |    |      |     |     |     |
|                    |         | Dos |    |      |     |     |     |
|                    |         | ing |    |      |     |     |     |
|                    |         | Int |    |      |     |     |     |
|                    |         | erv |    |      |     |     |     |
|                    |         | als |    |      |     |     |     |
|                    |         | (D  |    |      |     |     |     |
|                    |         | ays |    |      |     |     |     |
|                    |         | )** |    |      |     |     |     |
+--------------------+---------+-----+----+------+-----+-----+-----+
|                    | *       | **  | ** | **1  | **  | **  | **  |
|                    | *No.(%) | 1-9 | 91 | 81-2 | 271 | 361 | 451 |
|                    | of Pts  | 0** | -1 | 70** | -36 | -45 | -54 |
|                    | with    |     | 80 |      | 0** | 0** | 0** |
|                    | Event** |     | ** |      |     |     |     |
+--------------------+---------+-----+----+------+-----+-----+-----+
| **No. treated**    | *       | **  | ** | **23 | **  | *   | *   |
|                    | *4499** | 449 | 35 | 73** | 157 | *97 | *29 |
|                    |         | 9** | 45 |      | 6** | 0** | 4** |
|                    |         |     | ** |      |     |     |     |
+--------------------+---------+-----+----+------+-----+-----+-----+
| **Adverse Event**  | **77    | *   | *  | **0  | *   | *   | *   |
|                    | (1.7)** | *0. | *0 | .6** | *0. | *0. | *0. |
| **Hypertension**   |         | 8** | .5 |      | 5** | 4** | 0** |
|                    | **172   |     | ** | **0  |     |     |     |
| **Edema            | (3.8)** | *   |    | .7** | *   | *   | *   |
| peripheral**       |         | *2. | *  |      | *0. | *0. | *0. |
|                    |         | 6** | *0 |      | 7** | 1** | 0** |
|                    |         |     | .9 |      |     |     |     |
|                    |         |     | ** |      |     |     |     |
+--------------------+---------+-----+----+------+-----+-----+-----+
| **WHO art body     | **29    | *   | *  | **0  | *   | *   | *   |
| system/disorder**  | (0.6)** | *0. | *0 | .2** | *0. | *0. | *0. |
|                    |         | 2** | .2 |      | 5** | 0** | 0** |
| **Cardiovascular,  | **65    |     | ** | **0  |     |     |     |
| general**          | (1.4)** | *   |    | .4** | *   | *   | *   |
|                    |         | *0. | *  |      | *0. | *0. | *0. |
| **Heart            | **58    | 8** | *0 | **0  | 4** | 3** | 0** |
| rate/rhythm        | (1.3)** |     | .4 | .4** |     |     |     |
| disorders**        |         | *   | ** |      | *   | *   | *   |
|                    | **57    | *0. |    | **0  | *0. | *0. | *0. |
| **M                | (1.3)** | 6** | *  | .6** | 5** | 3** | 0** |
| yo/end/pericardial |         |     | *0 |      |     |     |     |
| and**              |         | *   | .5 |      | *   | *   | *   |
|                    |         | *0. | ** |      | *0. | *0. | *0. |
| **valvular         |         | 5** |    |      | 3** | 2** | 0** |
| disorders**        |         |     | *  |      |     |     |     |
|                    |         |     | *0 |      |     |     |     |
| **Vascular         |         |     | .4 |      |     |     |     |
| (extracardiac)**   |         |     | ** |      |     |     |     |
+--------------------+---------+-----+----+------+-----+-----+-----+

**1. From Tables 9.2 and 9.5 (ISS).**

As with many other adverse events in this trial, the highest incidence
of peripheral edema

occurred in the first 90 days of dosing with celecoxib, during which
time the patients

were seen more frequently than in later intervals. Peripheral edema was,
however, the only cardiovascular adverse event for which there appeared
to be a temporal

relationship to the onset of dosing. The prevalence of peripheral edema
remained

essentially constant at 2.6% throughout the first year in the trial, and
fell slightly to 1.7%

at 451-540 days. The cases of peripheral edema resulted in a low
incidence of withdrawals (\<0.1%) for all treatment intervals (Table
9.6, ISS).

The only cardiovascular-related AEs that occurred in 1% in the
international arthritis trials were hypertension and peripheral edema
(hypertension, 0.9-1.2% with Cx vs. 0.0-1.5% with active controls:
peripheral edema, 2.0-3.4% with Cx vs. 1.5-2.3% with active controls).

Reviewer's comment: Serious adverse events, withdrawals and deaths
related to the cardiovascular system as well as potential interactions
with various drugs classes (i.e. ACE inhibitors, beta blockers, etc.)
are discussed in detail in the cardiorenal consult.

Comparison of increases in BUN and creatinine (Cr) have been useful
screens to help evaluate the overall potential for a drug to cause
damage (reversible or not) to the kidney. In the NDA, evaluation of
increases of these laboratory values has resulted in the following
(Table 44):

**^Table\ 44.\ BUN\ (mmol/L)\ by\ Creatinine\ (Cr\ -mol/L)\ Contingency\ Tablea^**

+----------------------+-----+------------------+---------+-----------+
| Increase of:         | P   |                  |         | O         |
|                      | erc |                  |         | pen-Label |
|                      | ent |                  |         |           |
|                      | of  |                  |         |           |
|                      | Pat |                  |         |           |
|                      | ien |                  |         |           |
|                      | ts: |                  |         |           |
|                      | C   |                  |         |           |
|                      | ont |                  |         |           |
|                      | rol |                  |         |           |
|                      | led |                  |         |           |
|                      | Tri |                  |         |           |
|                      | als |                  |         |           |
|                      | ^b^ |                  |         |           |
|                      | (n) |                  |         |           |
+----------------------+-----+------------------+---------+-----------+
|                      | **C | **Active         | **Plc** | **Cx**    |
|                      | x** | Control**        |         |           |
|                      |     |                  | **(     | *         |
|                      | *   | **(2025)**       | 1786)** | *(4404)** |
|                      | *(5 |                  |         |           |
|                      | 538 |                  |         |           |
|                      | )** |                  |         |           |
+----------------------+-----+------------------+---------+-----------+
| **Cr \< 159 and BUN  | *   | **0.2**          | **0**   | **0.2**   |
| 14.3**               | *0. |                  |         |           |
|                      | 3** |                  |         |           |
+----------------------+-----+------------------+---------+-----------+
| **Cr 159 and BUN     | **  | **0.15**         | *       | **0.18**  |
| 14.3**               | 0.0 |                  | *0.06** |           |
|                      | 4** |                  |         |           |
+----------------------+-----+------------------+---------+-----------+

a.  **Data from Table 4.1 (N49-98-17-819)**

b.  **Includes studies 012, 013, 020, 021, 022, 023, 041, 042, 047, 054,
    060, 062, 071 and 087.**

These results are consistent with that of the other renal safety results
which suggest that, overall, event rates for potentially serious events
are low but that Cx is more like the active control than placebo in this
regard.

The overall cardiovascular safety profile of Cx is mostly unremarkable.
However, the increased rate of peripheral edema compared to placebo
(2.1% vs.1.1%) are real and are similar to the incidence seen with
active control (2.1%). This edema was generally mild, and usually not
attributed to treatment by the Investigator. The edema did not appear to
be significantly associated with or exacerbated by preexisting
cardiovascular disease or use of concomitant cardiovascular medications.

**In conclusion**, as noted under the "Deaths" section of this review,
and in the cardiorenal consult, myocardial infarction was noted to occur
at a higher rate in Cx than placebo patients. In the long-term trial,
the predominate (90%+) cause of death for patients taking Cx at any dose
was cardiovascular. The majority of these deaths represented progression
of previously known CV disease. The demographics of the subjects in the
controlled trials, as estimated from ICD-9 codes, reveals that about
35-40% of the subjects had hypertension, 15% had a history of
significant cardiac disease (i.e. MI, angina pectoris), 7-8% were
diabetic, 7-10% were hyperlipidemic, and 3-4% had significant renal
disease. No information about smoking history is available. Examination
of the Kaplan-Meier survival curves (see cardiorenal consult) for both
the controlled and long-term trials, suggests there is no apparent
relationship between any given duration of exposure to Cx and increased
mortality.

Nonetheless, there may are suggestions of a dose-response relationship
between CV mortality and Cx use although the database is not sufficient
to answer this question either way. It is interesting to remember,
however, that Cx is not associated with antiplatelet effects. Therefore,
it seems reasonable to remind physicians that Cx does not provide
cardiovascular prophylaxis. Cardiovascular serious adverse events,
withdrawals, vital signs and clinical laboratory test parameters
abnormalities were unremarkable with Cx and did not seem to indicate any
pattern of drug association.

The administration of Cx cannot be linked to any rare or unusual cardiac
toxicities based on the available data. For some AEs, including
arrhythmias and overall CV mortality, the data are inadequate to either
exclude or confirm and adverse effect of Cx. The available data do
suggest the effects of Cx are similar to NSAIDs with regard to the
"cardiac" effects of hypertension and edema (see Renal Safety section).

#### Deaths:

***Reviewer's comment: Interested readers should read the extensive
discussion of this topic in the cardiorenal consult.***

In the Cx program to date, which includes the 120 day safety update
(letter date: October 28, 1998, cutoff date of update: July 24, 1998)),
there have been a total of 44 deaths which are summarized in table 52.

**Table 52. Disposition of Deaths in the ISS and Safety Update**

+---------------------+------+---------+------+-------+-------+-------+
|                     | #    |         | *    |       | #     |       |
|                     | #### |         | *New |       | ##### |       |
|                     | #### |         | Rep  |       | ### C |       |
|                     |  Rep |         | orts |       | umula |       |
|                     | orte |         | in   |       | tive  |       |
|                     | d in |         | Sa   |       | Total |       |
|                     |  ISS |         | fety |       |       |       |
|                     |      |         | Upda |       |       |       |
|                     |      |         | te** |       |       |       |
+---------------------+------+---------+------+-------+-------+-------+
|                     | #### | **A     | **   | **A   | *     | **A   |
|                     | #### | ctive** | Cx** | ctive | *Cx** | ctive |
|                     | # Cx |         |      | Cont  |       | Cont  |
|                     |      | **Co    |      | rol** |       | rol** |
|                     |      | ntrol** |      |       |       |       |
+---------------------+------+---------+------+-------+-------+-------+
| **Controlled        | *    | **4**   | *    | **0** | **4** | **4** |
| arthritis trials**  | *4** |         | *0** |       |       |       |
+---------------------+------+---------+------+-------+-------+-------+
| #### Pain Studies   | *    | **0**   | *    | **    | **0** | **1** |
|                     | *0** |         | *0** | 1\*** |       |       |
+---------------------+------+---------+------+-------+-------+-------+
| **Long-term open    | **   | **-**   | *    | **-** | *     | **-** |
| label study**       | 18** |         | *6** |       | *24** |       |
+---------------------+------+---------+------+-------+-------+-------+
| ######### On        | *    | **1\*** | *    | **0** | **1** | **0** |
| going/other studies | *1** |         | *0** |       |       |       |
|                     |      | **0**   |      | *     | *     | *     |
| **Surgical pain     | *    |         | **   | *1b** | *1b** | *1b** |
| 075**               | *0** | **1\*** | 1b** |       |       |       |
|                     |      |         |      | **-** | **-** | **-** |
| **Surgical pain     | *    | **-**   | *    |       |       |       |
| 082**               | *0** |         | *-** | **-** | **1** | **-** |
|                     |      | **6b**  |      |       |       |       |
| **Open label 058**  | *    |         | *    | *     | *     | *     |
|                     | *1** | **1b**  | *-** | *2b** | *8b** | *8b** |
| **Alzheimer's       |      |         |      |       |       |       |
| 1Q5-001**           | **   |         | **   | **-** | *     | *     |
|                     | 6b** |         | 2b** |       | *1b** | *1b** |
| **Chemoprevention   |      |         |      |       |       |       |
| 1Q4-001**           | **   |         | *    |       |       |       |
|                     | 1b** |         | *-** |       |       |       |
+---------------------+------+---------+------+-------+-------+-------+
| **Subtotal**        | **   | **5**   | *    | **0** | *     | **5** |
|                     | 23** |         | *6** |       | *29** |       |
+---------------------+------+---------+------+-------+-------+-------+
| **Blinded (b)**     | *    |         | *    |       | *     |       |
|                     | *7** |         | *3** |       | *10** |       |
+---------------------+------+---------+------+-------+-------+-------+
| **Grand Total**     | **   |         | *    |       | *     |       |
|                     | 35** |         | *9** |       | *44** |       |
+---------------------+------+---------+------+-------+-------+-------+

**\* This death in study 082 was reported as a death in an ongoing study
in the ISS; it is now counted as a death in a completed surgical pain
study, but not added to the total of new reports in the Safety Update.**

As can be seen, although 35 deaths were reported in the ISS, 26 of them
are described further both below and/or in the renal safety
consultation. Of the 9 new deaths reported in the Safety Update, six
will be described briefly. Since the cutoff date for the Safety Update
was July 24, 1998, there were three additional deaths noted in Text
Table 18 of the Safety Update that occurred during the treatment between
July 25, 1998 and September 11, 1998. These patients are summarized as
follows:

-   **Pt number (024-US0007-007051); DER Number (970912-CL896). 63 y/o
    female taking Cx 300 mg BID on 67. Cause of death listed as
    carcinoma.**

-   **Pt number (024-US0090-090028); DER Number (980917-CL561). 61 y/o
    male taking Cx 100 mg BID on day 327. Cause of death listed as MI.**

-   **Pt number (024-US121-121022); DER number (980910-CL790). 63 y/o
    male taking Cx 400 mg BID on day 496. Cause of death listed as
    unknown.**

-   **Pt number (024-US0015-0150041); DER number (980527-CL495). 58 y/o
    female taking Cx 400 mg BID on day 614. Cause of death listed as
    ventricular fibrillation/aortic stenosis.**

-   **Pt number (024-US0211-2110005); DER number (980702-CL081). 65 y/o
    male taking Cx 200 mg BID on day 244. Cause of death listed as
    CHF.**

-   **Pt number (0870092). 75 y/o male taking 300 mg BID on day 414.
    Cause of death listed as cancer.**

***Reviewer's comment: Therefore, it appears that the total number of
deaths in patients taking Cx as of the writing of this review is 29.
Eighteen (18) were in study 024, four (4) in the controlled trials and
one (1) in the other studies listed- all of these 23 patients were
reported in the ISS. The six (6) additional deaths were in the Safety
Update and they are listed above in the bulleted items.***

As noted in table 52, six of these new deaths occurred in the long-term,
open label study and three occurred in two ongoing (blinded) trials.

Is should be noted that NONE of these deaths were considered by the
Searle Safety Monitor or the panel of safety consultants to have been
related to study medication.

There were 26 deaths in patients who participated in studies included in
the NDA. A narrative listing of all of the deaths is to be found in
Appendix two of this consult. A total of eight subjects who enrolled in
controlled arthritis trials died. Six deaths occurred during controlled
arthritis studies, and two following discontinuation of study drug. Four
of the individuals in the controlled arthritis group who died received
celecoxib, while four received active control drug. The individuals in
bold letters died of cardiovascular disease.

**Table 53. Deaths: Controlled Trials in the NDA 20-998^a^**

+-------------------+--------+----------+---------+-------------------+
| **Subject \#**    | **Age/ | **Tre    | **D     | **Cause of        |
|                   | Sex**  | atment** | uration | Death**           |
|                   |        |          | of Tx** |                   |
+-------------------+--------+----------+---------+-------------------+
| **Deaths During   |        |          |         |                   |
| Study Drug        |        |          |         |                   |
| Administration**  |        |          |         |                   |
+-------------------+--------+----------+---------+-------------------+
| 041-BE0002-0010   | 70/M   | C        | 81      | Gallbladder       |
|                   |        | elecoxib |         | carcinoma with    |
|                   |        |          |         | liver metastasis  |
|                   |        | 200 mg   |         |                   |
|                   |        | BID      |         |                   |
+-------------------+--------+----------+---------+-------------------+
| **062-            | **     | **Na     | **63**  | **Brain-stem      |
| US0117-46761235** | 68/M** | proxen** |         | infarct**         |
|                   |        |          |         |                   |
|                   |        | **500 mg |         |                   |
|                   |        | BID**    |         |                   |
+-------------------+--------+----------+---------+-------------------+
| 07                | 78/M   | I        | 29      | Obstructive       |
| 1-US0382-65811310 |        | buprofen |         |                   |
|                   |        |          |         | pulmonary disease |
|                   |        | 800 mg   |         |                   |
|                   |        | TID      |         |                   |
+-------------------+--------+----------+---------+-------------------+
| **071-            | **     | **Dicl   | **1**   | **Hypertensive    |
| US0333-46521451** | 53/F** | ofenac** |         | cardiovascular    |
|                   |        |          |         | disease**         |
|                   |        | **75 mg  |         |                   |
|                   |        | BID**    |         |                   |
+-------------------+--------+----------+---------+-------------------+
| 021-US0191-1334   | 67/M   | Naproxen | 47      | Pulmonary embolus |
|                   |        |          |         |                   |
|                   |        | 500 mg   |         |                   |
|                   |        | BID      |         |                   |
+-------------------+--------+----------+---------+-------------------+
| **                | **     | **Cel    | **30**  | **A               |
| 087-US0021-0182** | 56/M** | ecoxib** |         | rteriosclerotic** |
|                   |        |          |         |                   |
|                   |        | **200 mg |         | **Cardiovascular  |
|                   |        | QD**     |         | disease**         |
+-------------------+--------+----------+---------+-------------------+
|                   |        |          |         |                   |
+-------------------+--------+----------+---------+-------------------+
| # Deat            |        |          |         |                   |
| hs After Drug D/C |        |          |         |                   |
+-------------------+--------+----------+---------+-------------------+
| 020-US0052-0683   | 62/F   | C        | 26/ 54  | Pulmonary         |
|                   |        | elecoxib |         | carcinoma         |
|                   |        | 100 mg   |         |                   |
|                   |        | BID      |         |                   |
+-------------------+--------+----------+---------+-------------------+
| **                | **     | **C      | *       | **MI**            |
| 020-US0033-0768** | 80/F** | elecoxib | *6/45** |                   |
|                   |        | 200 mg   |         |                   |
|                   |        | BID**    |         |                   |
+-------------------+--------+----------+---------+-------------------+

a.  Data from Integrated Safety Summary, Text Table 67. Table shows all
    deaths from controlled trials, including

> those that occurred after the study drug was discontinued. For those
> two subjects, the \# of days
>
> after drug discontinuation for the death is shown after the day of
> death.

Ten deaths occurred during the long-term open-label study prior to the
database cutoff date (November 21, 1997), and are summarized in table 54
below. The duration of treatment ranged from 15 to 273 days, with a
final regimen of 200 mg BID for four patients, 300 mg BID for two
patients and 400 mg BID for four patients. The subjects in bold letters
(9/10, 90%) died of cardiovascular disease.

**Table 54. Deaths in the Long-Term Trial Prior to NDA Cutoff Date^a^**

  -------------------------- ---------- --------------- --------- ------------------------
  **Subject \#**             **Age/     **Treatment**   **Day of  **Cause of Death**
                             Sex**                      Death**   

  **024-US0001-0010053**     **65/F**   **Celecoxib 400 **196**   **Myocardial rupture
                                        mg BID**                  post-MI**

  **024-US0023---0230020**   **76/M**   **Celecoxib 200 **45**    **MI, cardiac failure**
                                        mg BID**                  

  **024-US0024---0240004**   **58/M**   **Celecoxib 400 **273**   **MI**
                                        mg BID**                  

  **024-US0052---0520043**   **83/F**   **Celecoxib 300 **193**   **Coronary thrombosis**
                                        mg BID**                  

  **024-US0053---0530001**   **80/M**   **Celecoxib 200 **159**   **Massive coronary**
                                        mg BID**                  

  **024-US0058---0580018**   **59/M**   **Celecoxib 200 **246**   **Ischemic heart
                                        mg BID**                  disease**

  024-US0066---0660004       60/M       Celecoxib 400   155       Adenocarcinoma
                                        mg BID                    

  **024-US0073---0730060**   **84/F**   **Celecoxib 400 **243**   **Respiratory failure,
                                        mg BID**                  CHF**

  **024-US0121---1210052**   **52/M**   **Celecoxib 300 **114**   **MI**
                                        mg BID**                  

  **024-CA0139---139009**    **57/F**   **Celecoxib 200 **15**    **Subarachnoid
                                        mg BID**                  hemorrhage**
  -------------------------- ---------- --------------- --------- ------------------------

a\. Data from Integrated Safety Summary, Text Table 66.

There were also five deaths in the long-term, open-label study between
the database cutoff (November 21, 1997) date and May 1, 1998. These
deaths are listed in table 55 below; all were due to cardiovascular
disease (and are shown in bold letters).

**Table 55. Deaths: Long-Term Open-Label Trial After NDA Cutoff** ^a^.

+------------------+--------+------------+-----------+---------------+
| **Subject \#**   | **Age/ | **T        | **Day of  | **Cause of    |
|                  | Sex**  | reatment** | Death**   | Death**       |
+------------------+--------+------------+-----------+---------------+
| **024-           | **     | **C        | **336**   | **Heart       |
| US0001-0010076** | 74/M** | elecoxib** |           | block**       |
|                  |        |            |           |               |
|                  |        | **400 mg   |           |               |
|                  |        | BID**      |           |               |
+------------------+--------+------------+-----------+---------------+
| **024-           | **     | **C        | **32**    | **Coronary    |
| US0024-0240024** | 71/M** | elecoxib** |           | artery        |
|                  |        |            |           | disorder**    |
|                  |        | **400 mg   |           |               |
|                  |        | BID**      |           |               |
+------------------+--------+------------+-----------+---------------+
| **024-           | **     | **C        | **37**    | **MI**        |
| US0073-0730189** | 71/F** | elecoxib** |           |               |
|                  |        |            |           |               |
|                  |        | **400 mg   |           |               |
|                  |        | BID**      |           |               |
+------------------+--------+------------+-----------+---------------+
| **024-           | **     | **C        | **471**   | **MI**        |
| US0110-1100006** | 61/F** | elecoxib** |           |               |
|                  |        |            |           |               |
|                  |        | **400 mg   |           |               |
|                  |        | BID**      |           |               |
+------------------+--------+------------+-----------+---------------+
| **024-           | **     | **C        | **88**    | **Aortic      |
| US0116-1160042** | 78/F** | elecoxib** |           | Aneurysm**    |
|                  |        |            |           |               |
|                  |        | **200 mg   |           |               |
|                  |        | BID**      |           |               |
+------------------+--------+------------+-----------+---------------+

> a\. Data from Integrated Safety Summary, Text Table 67.

Finally, there were five deaths that occurred more than 28 days after
the last dose in any study reported in this NDA (note that the two
patients in the 020 trial are included in the table above) and are
summarized in table 56. Two of these patients died after participation
in trial 020 and three died following participation in Study 024. Of the
five celecoxib subjects in this group, two died of cardiovascular
disease (40%).

**Table 56. Deaths That Occurred More than 28 Days After Last Dose^a^**.

+------------------+-------+----------+------+--------+---------------+
| **Subject \#**   | *     | **Tre    | *    | **Days | **Cause of    |
|                  | *Age/ | atment** | *Day | after  | Death**       |
|                  | Sex** |          | of   | Last   |               |
|                  |       |          | Dea  | Dose** |               |
|                  |       |          | th** |        |               |
+------------------+-------+----------+------+--------+---------------+
| 020-US0052-0683  | 62/F  | **Cel    | 26   | 54     | Pulmonary     |
|                  |       | ecoxib** |      |        | carcinoma     |
|                  |       |          |      |        |               |
|                  |       | **100 mg |      |        |               |
|                  |       | BID**    |      |        |               |
+------------------+-------+----------+------+--------+---------------+
| **0              | **8   | # C      | *    | **45** | **MI**        |
| 20-US0033-0768** | 0/F** | elecoxib | *6** |        |               |
|                  |       |          |      |        |               |
|                  |       | **200 mg |      |        |               |
|                  |       | BID**    |      |        |               |
+------------------+-------+----------+------+--------+---------------+
| **024-US0027-    | **6   | **Cel    | **3  |        | **Anterior    |
| 0270004**        | 6/M** | ecoxib** | 34** |        | MI**          |
|                  |       |          |      |        |               |
|                  |       | **400 mg |      |        |               |
|                  |       | BID**    |      |        |               |
+------------------+-------+----------+------+--------+---------------+
| 02               | 66/M  | **Cel    | 173  | 29     | Sepsis,       |
| 4-CA0087-0870100 |       | ecoxib** |      |        | pneumonitis   |
|                  |       |          |      |        |               |
|                  |       | **200 mg |      |        |               |
|                  |       | BID**    |      |        |               |
+------------------+-------+----------+------+--------+---------------+
| 024-US0042-      | 77/F  | **Cel    | 111  | 36     | Pulmonary     |
| 0420004          |       | ecoxib** |      |        | carcinoma     |
|                  |       |          |      |        |               |
|                  |       | **200 mg |      |        |               |
|                  |       | BID**    |      |        |               |
+------------------+-------+----------+------+--------+---------------+

a.  Data from Integrated Safety Summary, Text Tables 66 and 68.

**[Total Mortality]{.underline}**

Depending on the population used for the denominator, mortality can be
calculated in two ways using the information from the Cx database,
summarized in table 57 and 58 below.

The first way uses the number of subjects exposed to the drug in each
treatment group, independent of the duration of that exposure (Table
57).

> **Table 57. Deaths per Patients Exposed in NDA 20-998^a^**.

+------------------------------+---------+--------------+--------------+
| **Population**               | *       | **Number of  | **Crude      |
|                              | *Number | Exposed      | Mortality    |
|                              | of      | Subjects**   | Incidence**  |
|                              | D       |              |              |
|                              | eaths** |              |              |
+------------------------------+---------+--------------+--------------+
| ***Controlled North American |         |              |              |
| OA/RA Trials***              |         |              |              |
+------------------------------+---------+--------------+--------------+
| ### **Deaths during Trial**  |         |              |              |
+------------------------------+---------+--------------+--------------+
| ###### Placebo               | 0       | 1864         | 0%           |
+------------------------------+---------+--------------+--------------+
| **Celecoxib**                | 2       | 6376^e^      | 0.03%        |
+------------------------------+---------+--------------+--------------+
| **Active Control**           | 4       | 2768         | 0.14%        |
+------------------------------+---------+--------------+--------------+
|                              |         |              |              |
+------------------------------+---------+--------------+--------------+
| **[All known                 |         |              |              |
| deaths^b^]{.underline}**     |         |              |              |
+------------------------------+---------+--------------+--------------+
| **Placebo**                  | 0       | 1864         | 0%           |
+------------------------------+---------+--------------+--------------+
| **Celecoxib**                | 4       | 6376^e^      | 0.06%        |
+------------------------------+---------+--------------+--------------+
| **Active Control**           | 4       | 2768         | 0.14%        |
+------------------------------+---------+--------------+--------------+
|                              |         |              |              |
+------------------------------+---------+--------------+--------------+
| ***Long-term, Open-label     |         |              |              |
| Trial***                     |         |              |              |
+------------------------------+---------+--------------+--------------+
| ### **                       | 10      | 5155         | 0.19%        |
| Deaths before cut-off date** |         |              |              |
+------------------------------+---------+--------------+--------------+
| **[Known deaths during       | 15^d^   | 5155         | 0.29%        |
| celecoxib use]{.underline}** |         |              |              |
+------------------------------+---------+--------------+--------------+
| **[All known                 | 18      | 5155         | 0.35%        |
| deaths^c^]{.underline}**     |         |              |              |
+------------------------------+---------+--------------+--------------+

> a\. Data from Integrated Safety Summary, including Text Tables 65-68
> and Summary table 2.9. Confirmed with the sponsor.

b\. Includes one death in the active control group and two deaths in the
celecoxib group after trial completion. These deaths occurred \>28 days
after last dose of study medication.

c\. For all patients who received celecoxib. Includes five deaths that
occurred during celecoxib administration, reported after the cut-off
date for the ongoing trial (11.21.97). Also includes three deaths that
occurred \>28 days after last reported use of celecoxib (see tables
above).

d\. Includes five deaths that occurred during celecoxib administration,
reported after the cut-off date for the ongoing trial.

e\. Number equals the total number of individual patients in the OA and
RA trials (4151 and 2086, see earlier tables).

It is also fruitful to calculate mortality using the data on
patient-years of exposure as the denominator as in the table 58 below.

Table 58. Mortality Rate: Deaths per Patient-Years of Exposure

+----------------------------+------------+------------+--------------+
| **Population**             | **Number   | **P        | **Mortality  |
|                            | of**       | atient-yrs | Rate**       |
|                            |            | of         |              |
|                            | **Deaths** | Exp        |              |
|                            |            | osure^e^** |              |
+----------------------------+------------+------------+--------------+
| ***Controlled N.A. OA/RA   |            |            |              |
| Trials***                  |            |            |              |
+----------------------------+------------+------------+--------------+
| **[Deaths during           |            |            |              |
| Trial]{.underline}**       |            |            |              |
+----------------------------+------------+------------+--------------+
| **Placebo**                | 0          | 208        | 0.00%        |
+----------------------------+------------+------------+--------------+
| **Celecoxib**              | 2          | 1020       | 0.19%        |
+----------------------------+------------+------------+--------------+
| **Active Control**         | 4          | 535        | 0.75%        |
+----------------------------+------------+------------+--------------+
|                            |            |            |              |
+----------------------------+------------+------------+--------------+
| **[All known               |            |            |              |
| deaths^b^]{.underline}**   |            |            |              |
+----------------------------+------------+------------+--------------+
| **Placebo**                | 0          | 208        | 0.00%        |
+----------------------------+------------+------------+--------------+
| **Celecoxib**              | 4          | 1020       | 0.39%        |
+----------------------------+------------+------------+--------------+
| **Active Control**         | 4          | 535        | 0.74%        |
+----------------------------+------------+------------+--------------+
|                            |            |            |              |
+----------------------------+------------+------------+--------------+
| ***Long-term, Open-label   |            |            |              |
| Trial***                   |            |            |              |
+----------------------------+------------+------------+--------------+
| **[Deaths before cut-off   | 10         | 2672       | 0.37%        |
| date]{.underline}**        |            |            |              |
+----------------------------+------------+------------+--------------+
| **[Known deaths during     | 15^d^      | 4274       | 0.35%        |
| celecoxib                  |            |            |              |
| use]{.underline}**         |            |            |              |
+----------------------------+------------+------------+--------------+
| **[All known               | 18         | 4274       | 0.42%        |
| Deaths^c^]{.underline}**   |            |            |              |
+----------------------------+------------+------------+--------------+

> a\. Data from Integrated Safety Summary, including Text Tables 65-68.
>
> b\. Includes one death in the active control group and two deaths in
> the celecoxib group after trial completion. These deaths occurred \>28
> days after last dose of study medication.

**[Mortality Rate due to Cardiovascular (CV) Disease and for Total
Mortality]{.underline}**

As noted table 59 below, the crude rates of death due to CV disease in
both the Cx and active control groups were higher than placebo:

**^Table\ 59.\ Cardiovascular\ Mortality\ Rates:\ North\ American\ Arthritis\ Trials^**1

+-------------------+-------+----------+---------+---------+--------+
|                   | **No. | **No.    | **P     | **Mort  | *      |
|                   | dea   | E        | t-years | ality** | *Morta |
|                   | ths** | xposed** | of      |         | lity** |
|                   |       |          | Exp     | **Inci  |        |
|                   |       |          | osure** | dence** | **     |
|                   |       |          |         |         | Rate** |
+-------------------+-------+----------+---------+---------+--------+
| **[Cardiac deaths | **0** | **1864** | **208** | **      | **0    |
| in                |       |          |         | 0.00%** | .00%** |
| tri               | **1** | **6376** | *       |         |        |
| al]{.underline}** |       |          | *1020** | **      | **0    |
|                   | **2** | **2768** |         | 0.02%** | .10%** |
| **Placebo**       |       |          | **535** |         |        |
|                   |       |          |         | **      | **0    |
| **Celecoxib**     |       |          |         | 0.07%** | .37%** |
|                   |       |          |         |         |        |
| **Active          |       |          |         |         |        |
| control**         |       |          |         |         |        |
+-------------------+-------+----------+---------+---------+--------+
| **[All known      | **0** | **1864** | **208** | **      | **0    |
| cardiac           |       |          |         | 0.00%** | .00%** |
| deaths^           | **2** | **6376** | *       |         |        |
| 2^]{.underline}** |       |          | *1020** | **      | **0    |
|                   | **2** | **2768** |         | 0.03%** | .20%** |
| **Placebo**       |       |          | **535** |         |        |
|                   |       |          |         | **      | **0    |
| **Celecoxib**     |       |          |         | 0.07%** | .37%** |
|                   |       |          |         |         |        |
| **Active          |       |          |         |         |        |
| control**         |       |          |         |         |        |
+-------------------+-------+----------+---------+---------+--------+

**1. Data from Text Tables 65-65, ISS.**

1.  **Includes one death in active control group and two deaths in the
    Cx group after trial completion. These deaths occurred \>28 days
    after last dose of study medication.**

It should be noted that these relationships between treatment groups and
CV deaths when analyzed by Kaplan-Meier plots (see cardiorenal consult
for more details).

Of interest, table 60 compares the rates of CV mortality in patients
arranged according to highest dose of Cx received in the long-term
trial.

**Table 60. Cardiovascular Mortality Rates by Increasing Dose: Long-Term
Trial^1,2^**

+-----------------+-----------------+-----------------+-----------------+
| **Cx dose       | **No. deaths**  | **Patient-years | **Crude         |
| (BID)**         |                 | of              | Mortality       |
|                 |                 | exposure^4^**   | Rate^3^**       |
+-----------------+-----------------+-----------------+-----------------+
| **100 mg**      | **0**           | **519**         | **0%**          |
|                 |                 |                 |                 |
| **200 mg**      | **4**           | **1271**        | **0.31%**       |
|                 |                 |                 |                 |
| **300 mg**      | **2**           | **340**         | **0.59%**       |
|                 |                 |                 |                 |
| **400 mg**      | **3**           | **465**         | **0.64%**       |
+-----------------+-----------------+-----------------+-----------------+

1.  **Data from Text Tables 65-68, ISS.**

2.  **Deaths occurred prior to cutoff of Nov. 21, 1997.**

3.  **Mortality in deaths/pt-years (x100)**

4.  **Data from Appendix Table 4.3, ISS.**

**Conclusions regarding deaths due to cardiovascular causes:**

It appears that most of the deaths in both the controlled trials and the
open-label extension are from CV causes. Combined with the apparent
relationship with Cx dose (Table 60), this suggests that there is some
association between Cx use and cardiovascular mortality. As has been
noted elsewhere in this review, the lack of effect of Cx on platelets
may help to explain these results compared to active control (probably
not to placebo). However, the rates with Cx appear to be lower those
seen with active controls (Table 59) suggesting this is not a good
explanation.

It would appear that any adequate interpretation of these results is
confounded by a number of factors. The population studied is generally
older (with a substantial percentage of geriatric patients) with their
associated increased CV risks factors (i.e. increased use of meds, more
diabetes, hypertension, etc.). The number of events is small making
adequate statistical conclusions difficult since a few deaths in the
placebo group (for example) can dramatically change results. Also, in
the long-term study of Cx, there are no control groups which forces
reliance on the use of other large databases which may not properly
mimic the subjects in these trials.

Therefore, it is not possible to conclude that use of Cx is associated
with excess CV mortality. However, it is also not possible to rule it
out. The "large and simple" trials currently underway looking at GI
endpoints, along with post-marketing use should clarify this issue.

**[Conclusions Regarding Cx Safety:]{.underline}**

The safety of Cx was addressed throughout NDA 20-998. This NDA
represents not only a new molecular entity in Cx, it also would appear
to represent the first compound with properties sufficient to
distinguish itself as "selective" or "specific" for COX-2. Therefore, it
is appreciated that a discussion of the safety of Cx may, or may not,
represent a discussion regarding the theoretical advantages of COX-2
selective or specific. Only time, and more compounds of similar
characteristics, will answer these questions.

**Overall, and as a conclusion, Cx has demonstrated that it is a safe
compound when given in the range of doses studied in the analgesic and
arthritis trials of this NDA. Particular safety issues are summarized as
follows:**

1.  **Considering both the controlled North American and International
    arthritis trials, along with the placebo- and active control
    patients added to the long-term, safety trial, there were 8044 (4223
    OA, 2098 RA, 1723 open-label) unique patients exposed to Cx at the
    time of the NDA database cutoff. By adding in the Phase 1 and Pain
    subjects, this number increases to 9574 patients/subjects to Cx at
    any dose. This number further increases to 10,704 patients/subjects
    by adding the new patients in the 120-Day Safety Update.**

2.  **Compared to placebo, Cx does not affect platelet function as
    demonstrated by *ex vivo* platelet aggregation to collagen or
    arachidonate and TxB~2~ levels, even when given at supratherapeutic
    doses. Celecoxib also did not significantly increase bleeding times
    when compared to placebo; technical variability limits
    interpretation. Serum TxB~2~ levels were not reduced by Cx to
    sufficiently enough affect platelet function. Adverse event and
    clinical laboratory data indicated that Cx use was not associated
    with hemorrhagic events related to platelet function. Thrombotic
    events, including MIs, occurred. Consequently, patients that require
    thromboprophylaxis may still require low dose aspirin or other
    antiplatelet agents.**

3.  **The multiple studies convincingly show that Cx, used at the
    proposed dosages of 100 to 200 mg BID, was associated with a
    statistically significantly lower incidence of gastroduodenal ulcers
    and gastric erosions compared to naproxen 500 mg BID in all three
    pivotal studies. The one study comparing Cx 200 mg BID to ibuprofen
    800 mg TID revealed robust support for the safety claims related to
    gastroduodenal lesions.**

4.  **The data comparing Cx to diclofenac were inconclusive. Study 041
    suggested endoscopic superiority over diclofenac but study 071
    showed no significant differences. However, study 071 had a larger
    evaluable endoscopy cohort and ulcer-free baseline endoscopy giving
    a better picture of the *de novo* and drug related ulcer incidence.
    On the other hand, study 041 was a study of longer duration. The 4%
    ulcer incidence at 4 weeks and 7% final cumulative ulcer rate at 12
    weeks in study 071 was within the range of ulcer rates on Cx in the
    other studies over 12-24 weeks.**

5.  **None of the GI studies were designed to address the issue of
    comparability to placebo.**

6.  **The lack of consistent association between H. pylori and ulcer
    incidence across all treatment was seen regardless of the
    methodology used to detect this infection.**

7.  **When data from the five pivotal endoscopic studies are combined,
    there is a statistically significant ulcerogenic effect of low-dose
    aspirin in the Cx group. This aspirin enhanced rate, however, was
    still lower than the ulcer rate among the NSAID groups. There was no
    effect of aspirin in the active NSAID comparators when taken as a
    whole. Nonetheless, these trials were not designed to analyze the
    role of aspirin co-administration. The risk of ulceration of Cx and
    aspirin use, however, remains lower than the risk of gastroduodenal
    ulcers associated with the use of naproxen or ibuprofen.**

8.  **Endoscopically-defined ulcers have been defined as the surrogate
    of choice in this NDA. Future studies need to address the true
    clinically meaningful endpoints to corroborate the assumption that
    the development or presence of endoscopic ulcers correlates with
    adverse clinical outcomes and to quantify this relationship, if
    possible. The lack of standardization of definitions and procedures
    is of concern for such future studies.**

9.  **No measurements of acid-base balance (e.g. serum bicarbonate,
    arterial pH) performed as part of any trial in the NDA. Therefore,
    an adverse effect of Cx on acid-base balance cannot be excluded,
    particularly in the context of the observed increase in
    hyperchloremia.**

10. **Both Cx and comparator NSAIDs (in short-term trials) inhibited
    prostaglandin PGE~2~ and 6-keto-PFG1 excretion by the kidney to more
    or less the same extent. Both had significant inhibitory effects on
    the excretion of urinary prostaglandins when compared to placebo. Cx
    caused slightly less of a decrease in GFR in one study (010). Both
    Cx and naproxen inhibited serum renin and urinary (11-dehydro-TxB2­­) ­
    ­ ­thromboxane levels.**

11. **There was an association between Cx administration and the
    development of clinically significant edema (especially peripheral
    edema), similar to comparator NSAIDs, and clearly distinguished from
    placebo. Both naproxen and Cx cause sodium retention. There was no
    statistically significant association between 1 kg weight gain and
    the occurrence of 'peripheral edema\' in a subset of patients with
    edema as an AE, although a higher % of both the Cx and active
    control group patients had both.**

12. **There was an association between Cx administration and the
    development of worsened hypertension in susceptible individuals,
    again similar to NSAIDs, and clearly distinguished from placebo.**

13. **There is a definite association between Cx use and an increased
    incidence of hypophosphatemia, and hyperchloremia compared to
    placebo and similar to active controls. There was no increase in
    bony fractures in those individuals with these abnormalities, as
    might be expected if there is a change in the acid-base balance. An
    increase in bony fractures has been seen with other drugs with
    prominent renal tubular toxicities resulting in renal tubular
    acidosis. The controlled trials were also too short to examine the
    rate of renal stone formation, which might also increase during
    renal tubular acidosis. The clinical consequences of these changes
    remain to be determined.**

14. **There was a trend towards an increase incidence of elevated serum
    creatinine values and elevated BUN with proteinuria in both the Cx
    and active control groups relative to placebo.**

15. **The laboratory surrogates for renal toxicity suggest, but do not
    confirm, a link between Cx use and clinically relevant
    nephrotoxicity similar to NSAIDs.**

16. **There is no evidence to suggest that Cx has unique renal
    toxicities not shared by NSAIDs, or evidence of a renal toxicity
    caused by NSAIDs that occurs at a significantly higher incidence
    rate with Cx.**

17. **The pattern of AEs reported in both the controlled and the
    long-term trials is similar to that expected for NSAIDs.**

18. **There were several individuals taking Cx who were withdrawn from
    the long-term trials because or renal AEs including acute renal
    failure, edema and worsened hypertension.**

19. **While there were no clear cut cases of Cx-induced renal failure
    requiring dialysis, it remains to be determined whether severe renal
    injury will occur at the same rate that is seen with NSAIDs.**

20. **The renal effects of Cx are clearly distinguished from placebo.**

21. **The NDA does not reveal a strong signal pointing towards
    substantial clinically serious renal disease (i.e. large numbers of
    patients with acute renal failure requiring dialysis, nephrotic
    syndrome, papillary necrosis, interstitial neprhritis). This will
    require a larger database.**

22. **The endocrine/metabolic safety profile of Cx is certainly no worse
    than the active controls.**

23. **Analysis of the data from the elderly population demonstrates that
    Cx is safe and well tolerated in the elderly, and poses no apparent
    additional safety considerations which do not apply to the younger
    age group.**

24. **Myocardial infarction was noted to occur at a higher rate in Cx
    than placebo patients. In the long-term trial, the predominate
    (90%+) cause of death for patients taking Cx at any dose was
    cardiovascular. The majority of these deaths represented progression
    of previously known CV disease. There is no apparent relationship
    between any given duration of exposure to Cx and increased
    mortality. The administration of Cx cannot be linked to any rare or
    unusual cardiac toxicities based on the available data. The
    available data do suggest the effects of Cx are similar to NSAIDs
    with regard to the "cardiac" effects of hypertension and edema.**

25. **Rashes and related cutaneous reactions were among the more
    frequently noted AEs associated with Cx treatment. The rashes were
    generally mild in severity, and often associated with urticaria or
    pruritus. Rash was the single most common reason for withdrawal from
    study treatment. There was an increase in incidence of rash**

> **at higher Cx doses (maximal with the 400 mg BID dose) suggesting a
> dose-response relationship. Importantly, there were no serious
> cutaneous reactions associated with Cx treatment.**

26. **In view of the possible etiologic link to sulfonamide sensitivity,
    physicians should exercise caution in prescribing CX to patients
    with a known history of systemic sulfa reaction.**

27. **Respiratory events were common in all treatment groups and
    occurred at similar incidence, suggesting that the high frequency
    simply reflected the common nature of these disorders in the general
    population. Bronchitis and associated bronchospasm are not apparent
    to be exacerbated by celecoxib.**

28. **Review of the data regarding central and peripheral nervous system
    and psychiatric AEs does not reveal a pattern suggestive of
    deleterious effects from Cx use.**

29. **The available data does not suggest that Cx is associated with an
    increased risk of infection.**

30. **The most frequent adverse events were headache, dyspepsia, upper
    respiratory tract infection, diarrhea, and nausea.**

31. **Events that were frequent in occurrence (\>1%) and associated with
    significantly greater incidences or withdrawal rates for Cx than
    placebo included GI complaints, rashes or itching, peripheral edema,
    pharyngitis, and upper respiratory tract infection.**

32. The rate of withdrawal for adverse events for all doses of Cx
    appears better than comparators but NOT equivalent to placebo.

#### None of the serious adverse events that have occurred in NDA 20-998 appear to be obviously related to use of Cx.

33. **No outstanding safety issues have been demonstrated during the
    clinical trials conducted to investigate the treatment of pain.**

34. **The data indicate that there was not an increased risk of
    neoplasms or malignancies for**

> **patients taking Cx.**

35. **None of the data suggest that Cx is associated with deleterious
    effects on the musculoskeletal system, including increases in the
    incidence of fractures.**

**Overall Discussion/Conclusions Regarding Celecoxib:**

It has been argued that Cx represents a compound that is "selective" or
"specific" for COX-2. The exact definition of a COX-2 selective agent,
and as to whether it is moderately or highly selective or specific has
yet to be adequately addressed. Of note, the number of peer-reviewed
articles on this topic is increasing and the WHO has recently declared
Cx to be in a unique therapeutic class based upon its mechanism of
action (MOA). Therefore, in this review, it could be asked how much are
we testing the drug, the theory of the drug, or both?

Although the exposure to Cx in this NDA has been large, this is still a
"NDA" look at the drug, not a post-marketing look. Many of the questions
(regarding both safety and efficacy) that need to be answered, can not
be adequately addressed until Cx has been in the market and accumulated
the exposures with such marketing. For example, one of these issues
includes what will happen with widespread exposure in patients who are
not aware or adequately questioned about having allergies to
sulfonamide-containing products. This is a universal problem of
extrapolating results from clinical trials where patients are "included"
or "excluded" from the experience in "all comers" once a compound is
approved.

Regarding safety, many would argue that since non-selective NSAIDs also
inhibit COX-2, any safety concerns from this perspective should already
be obvious from the numerous compounds approved and widely used to date.
Others would argue that we do not know the consequences of "long-term,
high-grade" inhibition of COX-2 and what types of compensatory
mechanisms may come into play in this situation. It must be noted that
the distribution and molecular biology of COX-2 is rapidly evolving.

Therefore, when considering the safety of COX-2 agents from a MOA
standpoint, it may really depend on the particular tissue/target and
whether or not COX-2 is present, and under what conditions. For example,
the safety of COX-2 agents would theoretically be different in a target
such as platelets which are widely assumed not to have COX-2 (because
they have no nuclear machinery to make an inducible enzyme); from the
safety profile in an organ where COX-2 is present, such as the kidney.
Intermediate between these "clear-cut" extremes would be a organ such as
the stomach which may only have significant levels of COX-2 during a
"diseased" state such as infection with Helicobacter pylori or during
the healing phase of an ulcer's natural history.

It must also be noted here that, from a safety perspective, COX-2 agents
may not behave like non-selective agents because of nature of the
target, COX-2. In the early understanding of COX-2, drugs such as Cx
were thought to target only an inducible enzyme. Even though it is now
appreciated that COX-2 is expressed constitutively in some areas (like
kidney, brain, pancreas), COX-2 (unlike COX-1) is inducible. This would
suggest that the body has a mechanism to overcome inhibition of COX-2,
this does not appear to be the case with COX-1. That there may be such
"upregulation" of COX-2 is suggested by the "dose-creep" phenomenon
noted in the open-label, long-term trials with OA and RA (see below).

The following patient summary, taken from the 120-Day Safety Update
represents many of the issues surrounding Cx and COX-2 agents:

> **Patient 024-US0130-1300010 was a 47-year-old female with a history
> of RA, sinusitis, tuberculosis, hysterectomy, osteoporosis,
> gastroduodenal ulcers, gastrointestinal bleeding, and gastrointestinal
> NSAID intolerance. Concomitant medications included azathioprine,
> methotrexate, prednisone, calcium, etidronate disodium, folic acid,
> and diphenhydramine hydrochloride. After successfully completing Study
> 022 in which the patient was randomized to celecoxib 100 mg BID, she
> was immediately entered into the long-term open label study and began
> taking celecoxib 200 mg BID. The dosage was increased to 300 mg BID 42
> days later, and to 400 mg BID 67 days after that. Sixty-seven days
> after the last dose adjustment, the patient vomited two times, filling
> the commode with frank blood. She also complained of black, tarry
> stools and gnawing stomach pain after the episodes of hematemesis. She
> discontinued study medication on her own and started taking sucralfate
> on the same day. Vital signs were not recorded on that day, but the
> patient saw her private physician two days later. At that time, blood
> pressure was 94/60 mmHg, pulse was 76 bpm, and temperature was 97.8F.
> An endoscopy was performed that same day, which revealed gastric and
> esophageal ulcers. The patient was continued on sucralfate and started
> on omeprazole. The patient did not resume celecoxib treatment and was
> terminated early from the study. Laboratory results taken the day
> after endoscopy were hemoglobin 10.1 g/dL, hematocrit 31.0% (decreased
> from a Baseline hematocrit of 40.0%; she also tested positive for
> [H]{.underline}. [pylori]{.underline} antibody by FlexSure test). The
> patient has recovered. The Investigator felt this event was related to
> study**

Clearly, this patient developed a "clinically relevant" UGI event and
she was in a risk group to have such an event. It could be argued that
she was at a greater risk because she increased her dose of Cx, but she
increased this dose for a reason, apparently she and her physician felt
she needed it.

While most (70%) patients with OA or RA in the open-label, long-term
studies increased their dose of Cx, most did not an event similar to
this patient. This "dose creep" is recognized to occur with other drugs,
including NSAIDs. It could be argued that this creep seems to occur for
both the "analgesic" and "anti-inflammatory" doses of Cx since it did
occur in patients with both OA and RA. However, the end doses appear
higher in patients with RA vs. patients with OA; the latter is
considered to have less of an inflammatory component than RA.

**In conclusion, Celebrex had demonstrated that is generally safe and
effective for treating the signs and symptoms of OA and RA. Trials for
analgesia were not adequate enough to conclude that Celebrex is an
analgesic but this is expected with ongoing trials. Similarly, the
clinical significance of the lower rates of endoscopic ulcers associated
with Celebrex has yet to be established. In organs where COX-2 is
present, such as the kidney, Celebrex looks more like a traditional
NSAID. On the other hand, in targets where COX-2 is absent (such as
platelets), Celebrex looks more like placebo. Overall, Celebrex is
comparable to (or better than) active control NSAIDs while tending to be
worse than (or, at times, comparable to) placebo.**

####### 

####### 

####### 

####### Appendices

#### [Deaths in NDA 20-998]{.underline}

**Reviewer's comment: The following section is from the Appendix of the
Cardiorenal Review**

> **[Deaths in the Celecoxib NDA Database]{.underline}**

**9.1.1 Deaths in patients who enrolled in a controlled arthritis
trial**

A total of eight subjects who enrolled in controlled arthritis trials
died. Five deaths occurred during controlled arthritis studies, and
three following discontinuation of study drug. The narratives for those
subjects who died while receiving study drug are in the first section
below. The narratives for the subjects who died after discontinuation of
study drug are found in section 9.1.2 below.

Five of the individuals in the controlled arthritis group who died
received celecoxib, while three received active control drug.

Table 9.1.1.1 Deaths during controlled trials in the NDA 20-998
database^a^.

+-------------------+----------+---------+-------+--------------------+
| **Subject \#**    | **Age/   | **Trea  | **Day | **Cause of Death** |
|                   | Sex**    | tment** | of    |                    |
|                   |          |         | De    |                    |
|                   |          |         | ath** |                    |
+-------------------+----------+---------+-------+--------------------+
| **Deaths During   |          |         |       |                    |
| Study Drug        |          |         |       |                    |
| Administration**  |          |         |       |                    |
+-------------------+----------+---------+-------+--------------------+
| 041-BE0002-0010   | 70/M     | Ce      | 81    | Gallbladder        |
|                   |          | lecoxib |       | carcinoma          |
|                   |          |         |       |                    |
|                   |          | 200mg   |       | with liver         |
|                   |          | BID     |       | metastasis         |
+-------------------+----------+---------+-------+--------------------+
| 062-US0117-       | 68/M     | N       | 63    | Brain-stem infarct |
|                   |          | aproxen |       |                    |
| 46761235          |          |         |       |                    |
|                   |          | 500mg   |       |                    |
|                   |          | BID     |       |                    |
+-------------------+----------+---------+-------+--------------------+
| 071-US0382-       | 78/M     | Ib      | 29    | Obstructive        |
|                   |          | uprofen |       | pulmonary          |
| 65811310          |          |         |       |                    |
|                   |          | 800mg   |       | disease            |
|                   |          | TID     |       |                    |
+-------------------+----------+---------+-------+--------------------+
| 071-US0333-       | 53/F     | Dic     | 1     | Hypertension CV    |
|                   |          | lofenac |       | disease            |
| 46521451          |          |         |       |                    |
|                   |          | 75 mg   |       |                    |
|                   |          | BID     |       |                    |
+-------------------+----------+---------+-------+--------------------+
| 087-US0021-0182   | 56/M     | Ce      | 30    | Arteriosclerotic   |
|                   |          | lecoxib |       |                    |
|                   |          |         |       | cardiovascular     |
|                   |          | 200mg   |       | disease            |
|                   |          | QD      |       |                    |
+-------------------+----------+---------+-------+--------------------+
| # Deat            |          |         |       |                    |
| hs After Drug D/C |          |         |       |                    |
+-------------------+----------+---------+-------+--------------------+
| 020-US0052-0683   | 62/F     | Ce      | 26/   | Pulmonary          |
|                   |          | lecoxib | 54    |                    |
|                   |          |         |       | carcinoma          |
|                   |          | 100mg   |       |                    |
|                   |          | BID     |       |                    |
+-------------------+----------+---------+-------+--------------------+
| 020-US0033-0768   | 80/F     | Ce      | 6/ 45 | MI                 |
|                   |          | lecoxib |       |                    |
|                   |          |         |       |                    |
|                   |          | 200mg   |       |                    |
|                   |          | BID     |       |                    |
+-------------------+----------+---------+-------+--------------------+
| 021-US0191-1334   | 67/M     | N       | 47/   | Pulmonary          |
|                   |          | aproxen | NA    |                    |
|                   |          |         |       | embolus            |
|                   |          | 5       |       |                    |
|                   |          | 00mgBID |       |                    |
+-------------------+----------+---------+-------+--------------------+

a.  Data from Integrated Safety Summary, Text Table 67. Table shows all
    deaths from controlled trials, including those that occurred after
    the study drug was discontintued. For those three subjects, the \#
    of days after drug discontinuation for the death is shown after the
    day of death.

**1. Patient No. BE0002-0010** (Carcinoma--Gallbladder to Liver) was a
70 year old male with a past history including cardiomyopathy, pulmonary
hypertension, COPD, hyperthyroidism, cholelithiasis,
hypercholesterolemia, hypergammaglobulinemia, and an enlarged liver was
admitted to study and randomized to the celecoxib 200 mg BID treatment
group. Patient began taking study medication on 5 February 1997. Seventy
nine days after the start of dosing on 26 April 1997 the patient stopped
taking study medication because of nausea. On 11 May 1997 he saw his
general practitioner because of sudden nausea, vomiting and intermittent
diffuse abdominal pain. The patient was hospitalized on for further
investigation. His bilirubin and liver enzymes were elevated. He was
found to have carcinoma of the gallbladder with metastases to the liver.
He also had mild macrocytic anemia with no evidence of bleeding.
Laboratory work included:

Hgb 10.3, Hct 31, WBC and Diff Normal, during hospitalization ECHO and
CT , alpha-fetoprotein (0-12) 38, CEA (0-3) \>90, Total Bilirubin 4.5,
Indirect Bilirubin 2.7, SGOT 230, SGPT 111, LDH 4257, Alk Phos 360, and
Gamma GT 442. The patient died on due to the carcinoma. No autopsy was
performed.

**2. Patient No. US0117-46761235** (Cerebrovascular Disorder) was a 68
year old male with a history of tonsillectomy, bilateral otitis externa,
herpes zoster, post-herpatic neuralgia, arteriosclerotic cardiovascular
disease, bilateral claudication, hypertension, removal of abdominal
aortic aneurism, appendectomy, hemorrhoidectomy, right great toe
fracture, mild scoliosis, hypercholesterolemia, and OA. The patient was
enrolled into the study on 14 July 1997 and randomized to receive
naproxen 500 mg BID. After 63 days of treatment, the patient could not
get out of bed. He had right-sided weakness and felt he would fall if he
tried to stand. He felt "very funny" and had blurred vision and slurred
speech. He was taken to the emergency room where his blood pressure was
elevated at 192/90. Central nervous system examination revealed slurred
speech, blurred vision, mild vertical nystagmus, and abnormal right
upper extremity finger-to-nose. Other physical examination was normal.
Initial lab data was unremarkable. A CT scan of the head did not reveal
any acute hemorrhage. Chest x-ray revealed mild cardiomegaly. Brain stem
evoked potential was suggestive of acute brain stem infarct. The patient
was admitted to the hospital and intravenous enalapril maleate was
initiated. He was also treated with metoprolol tartrate and sublingual
nifedipine. His speech and coordination improved somewhat the following
day, but later that day he developed focal seizures and became
unresponsive. He was treated with intravenous diazepam and phenytoin but
remained unresponsive. His blood pressure was 167/90 and it was felt
that he had probably had an extension of his initial brain stem
cerebrovascular accident. He was intubated and was started on
intravenous antibiotics. Blood cultures were negative. The patient died
four days later. No autopsy was performed. Concomitant medications
included quinapril, metoprolol succinate SR, doxepin, and atrovastatin.

**3. Patient No. US0382-65811310** (Sudden Death) was a 78 year old male
with a history of osteoarthritis, hearing loss, sinus congestion,
hypertension and emphysema. The patient was enrolled into the study on 8
September 1997 and randomized to receive ibuprofen 800 mg TID. After 35
days of treatment, the patient experienced edema in his ankles and was
withdrawn from the study. This subsided an unknown number of days after
stopping study medication. Twenty four days later, the patient
experienced severe abdominal pain. While getting into his car to go to
the doctor, he collapsed and expired. The patient had previously been
diagnosed with a urinary tract infection and was being treated by his
primary physician. No autopsy was performed. Concomitant medications at
the Early Termination Visit included nifedipine, metaproterenol sulfate
and triamcinolone acetonide.

**4. Patient No. US0333-46521451** (Arteriosclerosis) was a 53 year old
female with a history of hypertension, hysterectomy, allergy to codeine,
and osteoarthritis. The patient was enrolled into the study on 25 August
1997 and randomized to receive diclofenac 75 mg BID. On , the patient
was found dead at home by her daughter. Since the patient's family never
returned the study medication containers, compliance or length of study
medication cannot be determined. Her daughter stated the patient had "
probably been dead for about one hour" when she was found. She also
stated that the coroner's report listed the cause of death as
"hypertensive cardiovascular disease." Concomitant medications included
fluoxetine hydrochloride, buspirone hydrochloride, and losartan
potassium.

**5. Patient No. US0021-0182** (Coronary artery disorder) was a 56 year
old male with a history of seasonal allergies, corrective lenses,
presbyopia, asthma, benign inflamed lymph node in the groin area,
diabetes mellitus type II, obesity, allergies to dust, mold, grass and
cat hair, and osteoarthritis. The patient was enrolled into the study on
February 9, 1998, and randomized to celecoxib 200 mg QD. After
twenty-nine days of treatment, the patient was out of town at a
basketball game and collapsed and due to arteriosclerotic cardiovascular
disease while getting into his car. Concomitant medications included
regular insulin, NPH insulin, metformin hydrochloride, epinepherine,
albuterol, beclomethasone dipropionate, albuterol sulfate, and
multivitamins. Study medication was continued up until the time of
death.

**9.1.2 Deaths during the Open-Label Uncontrolled, Long-term
Administration of Celecoxib**

Ten deaths occurred during the long-term open-label study prior to the
database cutoff date (November 21, 1997), and are summarized below. The
duration of treatment ranged from 15 to 273 days, with a final regimen
of 200 mg BID for four patients, 300 mg BID for two patients and 400 mg
BID for four patients.

> Table 9.1.2.1 Deaths During the Long-Term Open Label Trial
>
> Prior to Database Cutoff Date of November 21, 1997^a^.

  -------------------------- ---------- --------------- --------- -----------------------
  **Subject \#**             **Age/     **Treatment**   **Day of  **Cause of Death**
                             Sex**                      Death**   

  **024-US0001-0010053**     **65/F**   **Celecoxib 400 **196**   **Natural causes**
                                        mg BID**                  

  **024-US0023\--0230020**   **76/M**   **Celecoxib 200 **45**    **MI, cardiac failure**
                                        mg BID**                  

  **024-US0024\--0240004**   **58/M**   **Celecoxib 400 **273**   **MI**
                                        mg BID**                  

  **024-US0052\--0520043**   **83/F**   **Celecoxib 300 **193**   **Coronary thrombosis**
                                        mg BID**                  

  **024-US0053\--0530001**   **80/M**   **Celecoxib 200 **159**   **Massive coronary**
                                        mg BID**                  

  **024-US0058\--0580018**   **59/M**   **Celecoxib 200 **246**   **Ischemic heart
                                        mg BID**                  disease**

  **024-US0066\--0660004**   **60/M**   **Celecoxib 400 **155**   **Adenocarcinoma**
                                        mg BID**                  

  **024-US0073\--0730060**   **84/F**   **Celecoxib 400 **243**   **Respiratory failure,
                                        mg BID**                  CHF**

  **024-US0121\--1210052**   **52/M**   **Celecoxib 300 **114**   **MI**
                                        mg BID**                  

  **024-CA0139\--139009**    **57/F**   **Celecoxib 200 **15**    **Subarachnoid
                                        mg BID**                  hemorrhage**
  -------------------------- ---------- --------------- --------- -----------------------

**a. Data from Integrated Safety Summary, Text Table 66.**

There were also five deaths in the long-term open label study between
the database cutoff date and May 1, 1998. Their narratives are included
below.

Table 9.1.2.2Deaths During the Long-Term Open Label Trial After Database
Cutoff Date of November 21, 1997^a^.

  ------------------------ ---------- ------------------- --------- --------------------
  **Subject \#**           **Age/     **Treatment**       **Day of  **Cause of Death**
                           Sex**                          Death**   

  **024-US0001-0010076**   **74/M**   **Celecoxib 400 mg  **336**   **Heart block**
                                      BID**                         

  **024-US0024-0240024**   **71/M**   **Celecoxib 400 mg  **32**    **Coronary artery
                                      BID**                         disorder**

  **024-US0073-0730189**   **71/F**   **Celecoxib 400 mg  **37**    **MI**
                                      BID**                         

  **024-US0110-1100006**   **61/F**   **Celecoxib400 mg   **471**   **MI**
                                      BID**                         

  **024-US0116-1160042**   **78/F**   **Celecoxib 200 mg  **88**    **Aneurysm**
                                      BID**                         
  ------------------------ ---------- ------------------- --------- --------------------

a\. Data from Integrated Safety Summary, Text Table 67.

Finally, there were six deaths that occurred more than 28 days after
last dose in any study reported in this New Drug Application. Two of
these patients died after participation in trial 020, one died after
participation in Study 021, and three died following participation in
Study 024. The narratives for these subjects are also included below.

Table 9.1.3 Deaths That Occurred More than 28 Days After Last Dose^a^.

+--------------+--------+------------+-------+--------+--------------+
| Subject \#   | Age/   | Treatment  | Day   | Days   | Cause of     |
|              | Sex    |            | of    | after  | Death        |
|              |        |            | Death | Last   |              |
|              |        |            |       | Dose   |              |
+--------------+--------+------------+-------+--------+--------------+
| 020          | 62/F   | Celecoxib  | 26    | 54     | Pulmonary    |
| -US0052-0683 |        |            |       |        |              |
|              |        | 100 mg BID |       |        | carcinoma    |
+--------------+--------+------------+-------+--------+--------------+
| 020          | 80/F   | Celecoxib  | 6     | 45     | MI           |
| -US0033-0768 |        |            |       |        |              |
|              |        | 200 mg BID |       |        |              |
+--------------+--------+------------+-------+--------+--------------+
| 021          | 67/M   | Naproxen   | 47    |        | Pulmonary    |
| -US0191-1334 |        |            |       |        |              |
|              |        | 500 mg BID |       |        | embolus      |
+--------------+--------+------------+-------+--------+--------------+
| 024-US0027-  | 65/M   | Celecoxib  | 334   |        | Anterior MI  |
|              |        |            |       |        |              |
| 0270004      |        | 400 mg BID |       |        |              |
+--------------+--------+------------+-------+--------+--------------+
| 024-CA0087-  | 66/M   | Celecoxib  | 173   | 29     | Sepsis,      |
|              |        |            |       |        |              |
| 0870100      | \-     | 200 mg BID |       |        | pneumonitis  |
+--------------+--------+------------+-------+--------+--------------+
| CL004        | 77/F   | Celecoxib  | 111   | 36     | Pulmonary    |
|              |        |            |       |        |              |
| 024-US0042-  |        |            |       |        |              |
+--------------+--------+------------+-------+--------+--------------+

a\. Data from Integrated Safety Summary, Text Tables 66 and 68.

**1. Patient No. US0033-0768** (Myocardial Infarction) was an
80-year-old female with a history of OA, hypertension, borderline
diet-controlled diabetes, hysterectomy, appendectomy, cholecystectomy,
lumbar laminectomy, anterior cervical decompression and fusion, cataract
surgery and rectal surgery for fistulas. The patient was enrolled into
the study on 18 October 1996 and randomized to receive celecoxib 200 mg
BID. After five days on treatment, the patient experienced severe chest
pain lasting three hours which was associated with vomiting, diaphoresis
and shortness of breath. She was hospitalized for an inferior wall
myocardial infarction. It was noted that the patient had experienced
intermittent chest pain for three days prior to hospital admission and
had complained of anginal symptoms which occurred both with activity and
at rest for six months prior to enrollment into the study. Treatment
included aspirin, tissue plasminogen activator or a novel plasminogen
activator under investigation. Additional treatment included morphine,
intravenous heparin, intravenous nitroglycerin, ticlopidine and
metoprolol. An ECG demonstrated ST fullness in the inferior leads with
T-wave inversion and ST elevation with right-side ECG in V4-V6. A chest
x-ray showed cardiomegaly and an atherosclerotic aorta with no other
acute abnormalities. Emergency left heart catheterization was performed
showing 100% occlusion of the mid-right coronary artery. Percutaneous
transluminal coronary angioplasty was performed with suboptimum blood
flow; therefore, a coronary stent was deployed which was successful.
Concomitant medication included triamterene/hydrochlorothiazide,
diphenoxylate/atropine and alprazolam. Study medication was discontinued
and the patient was terminated early from the study. The patient was
discharged from the hospital and reported feeling well. The patient was
unable to schedule the Early Termination visit. Forty-five days
following onset of the event, the patient expired in her sleep. No
autopsy was performed. The death certificate listed immediate cause of
death probable myocardial infarction due to coronary artery disease and
congestive heart failure.

**2. Patient No. US0052-0683** (Pulmonary Carcinoma) was a 62-year-old
female with a history of tobacco use, no taste or smell, hysterectomy,
pneumonia, hypertension, arthroscopy, fibromyalgia, degenerative disc
disease and OA. The patient was enrolled into the study on 19 September
1996 and randomized to receive celecoxib 100 mg BID. Eight days after
treatment began, the patient was referred to a pulmonologist for
increased dyspnea. Chest x-ray revealed a right upper lung nodular
density. On Study Day 12, a CT scan of the patient's chest showed a 2.2
cm spiculated right upper lobe mass, consistent with a carcinoma.
Bronchoscopy was performed thirteen days later and bronchoalveolar
lavage cytology report showed atypical cells that were non-diagnostic.
Study medication was discontinued at this time and the patient was
withdrawn from the study. Thirty-four days later the patient was
admitted for a right upper lobe lung mass. A thoracotomy with right
upper and middle lobectomy was performed. No evidence of metastatic
disease was found. The patient developed post-operative atelectasis with
possible pneumonia three days later which advanced to adult respiratory
distress syndrome (origin unknown) ending in death sixteen days after
onset. No autopsy was performed. Other concomitant medications included
nifedipine, fluoxetine, estradiol, cephalexin and minocycline.

**3. Patient No. US0191-1334** (Gallbladder Disorder, Death from
Myocardial Infarction or Massive Pulmonary Embolism) was a 68 year old
male with a history of OA, deep venous thrombosis following a tractor
accident and pulmonary emboli. The patient has previously participated
in celecoxib clinical trial #N49-96-02-047 for three days. One hundred
and thirty four days later after Early Termination from this study due
to treatment failure, the patient was enrolled into the current study (3
June 1997) and randomized to receive naproxen 500 mg BID. After forty
six days of treatment the patient was on an out-of-town trip when he
began experiencing heartburn. The heartburn progressed and became severe
and was accompanied by nausea and vomiting. After returning home, he was
hospitalized the following day. Physical examination revealed abdominal
tenderness. He had an elevated white blood cell count. An
electrocardiogram revealed some changes, including left bundle branch
block, but the patient was cleared for surgery by cardiology consult who
felt there were no acute changes or evidence of acute myocardial injury.
Laparoscopic cholecystectomy was initially attempted but because of
severe gangrenous and inflammatory changes in and around the
gallbladder, it was necessary to do an open cholecystectomy. An
operative cholangiogram was within normal limits. The gallbladder was
found to have sludge and stones with a stone impacted in the neck of the
gallbladder along with a possible common bile duct stone. The patient
was maintained on intravenous fluids, intravenous antibiotics, and
subcutaneous heparin postoperatively. The patient was unable to tolerate
oral feedings and five days after surgery nausea and vomiting increased.
An ultrasound of the abdomen showed a suspected fluid collection in the
right upper quadrant. CT scan showed a large periduodenal hematoma. The
patient's white blood cell count and amylase were elevated and some
degree of pancreatitis was also suspected. A central line was placed,
the patient was started on total parenteral nutrition and anticoagulant
therapy was discontinued. The patient then developed some hallucinations
and erratic behavior and bizarre complaints, and eight days after
surgery, apparently suffered a cardiopulmonary arrest. The patient was
resuscitated and was transferred to intensive care. His ECG at that time
showed tachycardia with left bundle branch block. Shortly after transfer
to the unit, he developed an idioventricular rhythm and was pulseless.
Resuscitation attempts were unsuccessful and the patient was pronounced
dead. It was the opinion of the cardiologist who attended the event that
he had either suffered a massive myocardial infarction or massive
pulmonary embolus. An autopsy was not done. No other concomitant
medications were being taken. Study medication was interrupted during
hospitalization.

**4. Patient No. US0001-0053** (Death) was a 66 year old female with a
history of cataracts, appendectomy, hemorrhoidectomy, postmenopause,
fibrocystic breast disease, bilateral mastectomy, bilateral breast
implant, squamous cell carcinoma, iron deficient anemia, multiple drug
allergies, and RA. The patient had previously participated in the
N49-96-02-022 clinical trial during which she had received placebo.
After successfully completing this study, she was entered into the
long-term safety study and began taking celecoxib 200 mg BID on 25
February 1997. Dosage was increased to 300 mg BID 42 days later on 8
April 1997. Nine days after that on , the patient had a basal cell
carcinoma removed from the right side of her nose. One hundred and
thirty three days later (on 28 August 1997), dosage was increased to 400
mg BID. Approximately 12 days later, on or about , the patient died of
"natural causes." Concomitant medications included prednisone,
methotrexate sodium, folic acid, and ferrous sulfate.

**5. Patient No. US0001-0076** (Heart Block, Hypoglycemia,Hyperglycemia)
was a 74 year old male with a history of seasonal allergies,
pericarditis,prostate surgery for benign prostatic hypertrophy,
bilateral ankle fusion, psoriasis, snoring, hypertension, chronic
obstructive pulmonary disease, and rheumatoid arthritis. The patient
previously participated in celecoxibclinical trial #N49-96-02-022,
during which the patient had received either placebo, celecoxib 100 mg
BID, 200 mg BID, 400mg BID or naproxen 500 mg BID. After being withdrawn
early due to treatment failure, he was entered into the long-term safety
study, N49-96-02-024, and began taking SC-58635200 mg BID on April 23,
1997. Dosage was adjusted to 300 mg BID 5 days later, on April 28, 1997
and to 400 mg BID 4 days later, on May 2, 1997. Three hundred and
twenty-seven days later, on , the patient was wheeled into the doctor's
office and was cyanotic and lethargic. The patient was incubated and
taken to the emergency room where he was pronounced dead. The patient
was diagnosed as being in total heart block, hypoglycemic (blood sugar
of 16), and hyperkalemic (potassium was 9.0). Amphetamines and
antidepressants were detected in the patient's urine. The patient had
gone to see his primary care physician one day prior to this event, on ,
and the physician said the patient was "OK". Concomitant medications
included prednisone, pencillamine, trinallin and amlodipine. The date of
last dose is unknown at this time.

**6. Patient No. US0023-0020** (Myocardial Infarction, Cardiac Failure)
was a 76 year old male with a history of appendectomy, testicle cyst
(removed), malaria, diabetes, sinusitis, insomnia, fractures of foot,
shoulder and nose, hyperlipidemia, hypertension and RA. The patient had
previously participated in the N49-96-02-023 clinical trial during which
he had received naproxen 500 mg BID. After terminating early from this
study due to treatment failure, the patient entered into the long term
safety study and began taking celecoxib200 mg BID on 1 April 1997. After
23 days of treatment, on , the patient was hospitalized for a previously
scheduled total hip replacement. After 39 days of treatment, on , the
patient was hospitalized for a right deep venous thrombosis. Seven days
after discharge, on , the patient was seen in the emergency room for
constant anterior chest pain, which had began approximately two days
earlier and was not associated with radiation, diaphoresis,or dyspnea.
The patient was then hospitalized the following day, on , with a
myocardial infarction of the anterior wall. Treatment included
intravenous nitroglycerin and heparin sodium, oxygen, and monitoring and
evaluation of cardiac status. Lab work revealed glucose of 227 and CK of
52. Repeat CKs were 456, 784, and 687 with MBs of 82.6, 150.1, and
121.7. Ventilation-perfusion lung scan performed due to an episode of
shortness of breath showed a low probability of a pulmonary embolus.
Portable chest x-ray showed no acute cardiopulmonary disease.
Echocardiogram showed normal left ventricular contractility, ejection
fraction of approximately 52%, normal intracardiac chambers, and normal
valvular function. Cardiac catheterization performed six days later, on
, showed coronary artery disease with 20% left main proximal stenosis,
100% left circumflex distal stenosis, left anterior descending with
someplaquing in the midportion but no focal stenosis more than 50%, 90%
mid right coronary artery stenosis, and left ventricular ejection
fraction of 50-55%. The patient was then transferred to another hospital
that same day, where he underwent a percutaneous transluminal coronary
angioplasty with stenting of the right coronary artery. Nine days after
transfer and approximately one week after discharge, on , the patient
developed a sudden onset of chest pain which was not relieved by three
sublingual nitroglycerin. The patient was taken to the emergency room
and was intubated and cardioverted after experiencing sustained
ventricular tachycardia, ventricular fibrillation, and cardiac arrest.
The patient was then admitted for an acute inferior wall myocardial
infarction probably due to acute closure of the right coronary stent
placed two weeks prior to admission, complicated by cardiogenic shock,
hypotension with systolic blood pressure 60-70, and bradycardia with
heart rate in the 30\'s. Electrocardiogram confirmed an acute inferior
infarct showing acute ST segment elevation, severe bradycardia, and
third degree heart block. Despite being on warfarin sodium, his protime
was only 15 and INR was 1.3. Treatment included a temporary pacemaker as
well as intravenous fluids, oxygen, morphine sulfate, Levophed,
thrombolytic therapy, heparin sodium, and dopamine hydrochloride. The
patient expired the following day, on , due to cardiogenic shock and
acute myocardial infarction after an unsuccessful resuscitation attempt
for pulseless ventricular fibrillation. Other concomitant medications
included Centrum, multivitamins, metformin hydrochloride and
nisoldipine.

**7. Patient No. US0024-0024** (Coronary Artery Disorder) was a 71 year
old male with a history of hypertension, myocardial infraction,
peripheral bilateral edema due to cardiovascular disease, removal of
ganglion cyst on left elbow, dentures, not-fasting hyperglycemia,
hypercholesterolmia, hypertriglycaridemia, hypocalcemia, macular
degeneration of right eye, right inguinal hernia repair, urinary tract
infection, and rheumatoid arthritis. The patient had previously
participated in celecoxib clinical trial #N49-96-02-023, during which
the patient had received celecoxib 100 mg BID, 200 mgBID, 400 mg BID,
naproxen 500 mg or placebo BID. After the patient successfully completed
this study, he was entered into the long-term safety study and began
taking celecoxib 200 mg BID on February 6, 1997. Dosage was adjusted to
300 mg BID 42 days later, on March 20 1997, and again adjusted to 400 mg
BID 49 days later, on May 8,1997. Three hundred six days after last dose
adjustment, on , the patient expired in his home due to cardiopulmonary
arrest as a consequence of coronary artery disease. Concomitant
medications included methotrexate sodium, multivitamin, folic acid,
diltiazem hydrochloride, inadapamide, mononitrate, and baby aspirin.
Study medication was continued until the time of death.

**8. Patient No. US0024-0004** (Myocardial Infarction) was a 59 year old
male with a history of cardiomegaly, lumbar and cervical spine surgery,
umbilical hernia repair, peripheral edema, hypertension, hip
replacement, spinal stenosis, muscle spasm, elevated creatine
phosphokinase, two pack per day smoker, obesity and RA. The patient had
previously participated in the N49-96-02-012 clinical trial during which
he received celecoxib 400 mg BID for four weeks. One hundred and forty
days after successfully completing this study, the patient was entered
into the long-term safety study and began taking celecoxib 200 mg BID on
31 July 1996. Dosage was increased to 300 mg BID 42 days later, on 11
September 1996, and to 400 mg BID 21 days later on 2 October 1996. Two
hundred and nine days after the last adjustment, on , the patient
suddenly collapsed while at a horse race track. Following an
unsuccessful resuscitation attempt, the patient was subsequently
pronounced dead in the emergencyroom as a result of an acute myocardial
infarction due to hypertensive heart disease. Examination on the body
after death revealed distinguishable earlobe creasing and edema to the
ankles. There was no indication of injury. No autopsy was
performed.Concomitant medications included aurothioglucose, prednisone
and lisinopril. (The Searle Medical Monitor elected to code this event
as "sudden death" until more information about the evidence of M.I. was
available).

**9. Patient No. US0027-0004** (Anterior Myocardial Infarction) was a
66year old male with a history of tinnitus, hypertension, benign
prostatic hypertrophy, mechanical low back pain, Baker's cyst, right
knee arthrotomy, lipoma of the right shoulder, cholelithiasis, exogenous
obesity, anemia, choroidal nevus, and RA. The patient had previously
participated in the N49-96-02-012 clinical trial during which he had
received placebo. After successfully completing this study, he was
entered the long-term safety study and began taking celecoxib 200 mg BID
on 18 July 1996. Dosage was increased to 300 mg BID thirteen days later
on 31 July 1996, and again increased to 400 mg BID twenty eight days
later on 28 August 1996. Two hundred and eighty five days after the last
adjustment on , the patient developed chest pressure while at rest with
associated diaphoresis that persisted for one hour. He went to the
emergency room where an electrocardiogram was negative. Treatment
included sublingual nitroglycerin and nitroglycerin paste with relief of
his pain. Subsequent electrocardiogram revealed possible non-specific
anterolateral T wave change and he was admitted for further evaluation
on . On admission, his blood pressure was120/80 and pulse was 76 with no
abnormalities noted on physical examination. A cardiac catheterization
performed that same day revealed significant disease of the left
anterior descending coronary artery, 90% discrete stenosis, followed by
a large first diagonal that had a 75% stenosis (apical stenosis 70%).
Left ventriculography revealed moderately severe anterolateral
hypokinesis with an ejection fraction around 45 to 50% overall. One day
later on , the patient underwent a percutaneous transluminal coronary
angioplasty with implantation of a JR II intracoronary stent in the
first diagonal and a J & J intracoronary stent in the left anterior
descending. There were no residual stenoses. Post procedure, when his
sheath was pulled, he developed some sinus bradycardia and associated
hypotension, which was treated with no further sequelae. The patient had
no further complaints of chest pain or shortness of breath and was
discharged two days later on . Treatment included ticlopidine,
acetylsalicylic acid, atenolol, andranitidine. Study medication was
discontinued, and the patient was terminated early from the study on 17
June 1997 due to taking the above medications. The patient was started
on diclofenac that same day. On the night of (sixty-three days later
after terminating from the study) the patient developed chest pressure.
This persisted and he went to the emergency room early the following
morning on . Electrocardiogram showed acute anterior ST elevation. He
was treated with thrombolytics. The chest pain continued and he was
subsequently transferred to another hospital for further cardiac
evaluation. On admission, lung sounds were diminished and heart rate and
rhythm were regular with S1, S2, and S4 gallop. Peak creatine
phosphokinase was 6581 with an MB of greater than 300. Potassium was
2.2, which was corrected to 4.5. Magnesium was 1.5. Following admission
the patient underwent an emergency left heart catheterization with
coronary angiography due to continued chest pain. This showed hazy
proximal left anterior descending with subtotal occlusion of diagonal
and thrombus in the distal left anterior descending. The patient was
started on abciximab and an intra-aortic balloon pump was then inserted.
He developed a wide complete tachycardia requiring intubation and
subsequent CPR. The patient was resuscitated. In the cath lab the
patient vomited approximately 200 cc of bright red blood and a
gastroenterology consult was obtained. An acute GI hemorrhage was
suspected either due to a Mallory-Weiss tear versus diclofenac induced
surgery. It was also felt that anticoagulant therapy had contributed to
the blood loss. Neurologically, the patient did not arouse post-code and
developed mild clonic activity. On consultation, the neurologist felt
that symptoms were indicative of a moderate to severe intracranial
hypoxic event. The patient did not regain consciousness. He died the
following day on . Concomitant medications included folic acid,
methotrexate, hydroxychloroquine, and verapamil.

**10. Patient No. US0042-0004** (Pulmonary Carcinoma) was a 77 year old
female with a history of cardiomegaly, periodontal disease, hearing
loss, hemorrhoids, breast cyst, myopia, chronic obstructive lung
disease, smoker, pneumonia, shortness of breath and osteoarthritis. The
patient had previously participated in celecoxibclinical trial
#N49-96-02-022, during which she had received either placebo, celecoxib
50 mg BID, 100 mg BID, 200 mg BID or naproxen 500 mg BID. After
successfully completing this study, she immediately entered into the
long-term safety study and began taking celecoxib 100 mg BID on November
19, 1996. Dosage was adjusted to 200 mg BID 168 days later, on May 6,
1997. After another 288 days of treatment, on February 18, 1998, she was
seen for her month 15 visit with complaints of increased shortness of
breath and cough. She had completed a regimen of cefprozil on this same
date. Chest x-ray was performed and showed a large infiltrate mass in
the left lung. Computed tomography performed 5 days later, on confirmed
alarge left hilar mass which appeared to have mediastinal invasion. Nine
days later, on , a diagnostic bronchoscopy with endobronchial biopsy was
performed and was suggestive of a bronchogenic neoplasm with secondary
atelectasis. Pathology report of the left upper lobe bronchial biopsies
showed non small cell carcinoma (possible large cell undifferentiated
carcinoma) of the left upper lobe of her lung. Study medication was
discontinued on March 10, 1998, and the patient was withdrawn from the
study on March 12, 1998. Twelve days later, on , the patient was
admitted for an exudative pleural effusion and a new onset of atrial
fibrillation. She was treated with insertion of a chest tube and
warfarin sodium. She was subsequently discharged on . Eleven days later,
on , the patient was readmitted withincreasing shortness of breath. She
was noted to have complete white out of her left lung. A chest tube was
inserted, and 2 liters of fluid were removed. Other treatment included
pain medication, antibiotics, steroids, breathing treatments, a
radiation substantially, and she expired 4 days later, on . Concomitant
medications included triamcinolone acetonide, albuterol and calcium
carbonate.

**11. Patient No. US0052-0043** (Coronary Thrombosis) was an 84 year old
female with a history of hypertension, coronary artery disease,
cigarette smoking, occasional indigestion, atherosclerosis,
hyperlipidemia, adult onset diabetes mellitus, anxiety attack,
bronchitis, depression, and RA. The patient had previously participated
in the N49-96-02-023 clinical trial during which she received celecoxib
400 mg BID. After being withdrawn early from this study due to a
nosebleed, the patient was entered into the long-term safety study and
began taking celecoxib 200 mg BID on 10 April 1997. Dosage was increased
to 300 mg BID 14 days later, on 24 April 1997. One hundred and seventy
nine days later, on , the patient died of a coronary thrombosis; a
contributing cause of death was considered to be chronic obstructive
pulmonary disease. Concomitant medications included alprazolam,
ipratropium, albuterol, salmeterol xinafoate, vitamin E, baby aspirin,
glipizide, Triavil, pentoxifylline, enalapril maleate, and lovastatin.
The Investigator was uncertain of the association of the event with the
study drug.

**12. Patient No. US0053-0001** (Ventricular Fibrillation, Myocardial
Infarction, Coronary Artery Disease) was an 80 year old male with a
history of cataracts, spinal stenosis, cardiomyopathy, cardiac
arrhythmia, angina, mild congestive heart failure, pneumonia, colon
polyps, irritable bowel syndrome, constipation, hyperlipidemia,
gastroduodenal ulcer, benign prostatic hypertrophy, meniscectomy,
hypothyroidism, gout, hypertension, depression and OA. The patient had
previously participated in the N49-96-02-020 clinical trial during which
he received celecoxib 100 mg BID. After withdrawing early from this
study due to treatment failure, the patient was entered into the
long-term safety study and began taking celecoxib 100 mg BID on 11
September 1996. Dosage was increased to 200 mg BID 14 days later, on 25
September 1996. One hundred and thirty days later, on , the patient woke
up " not feeling well". After eating breakfast, the patient left the
table, collapsed and died. Death certificate reveals cause of death to
be cardiorespiratory arrest due to ventricular fibrillation, acute
myocardial infarction and coronary artery disease. Concomitant
medications included methylcellulose, levothyroxine, allopurinol,
propoxyphene, gemfibrozil, furosemide, digoxin, diltiazem, potassium
chloride, losartan, sertraline and psyllium.

**13. Patient No. US0058-0018** (Coronary Artery Disorder) was a 60 year
old female with a history of allergic rhinitis, nasal congestion,
refraction disorder, bilateral middle finger numbness, asthma,
hemorrhoids, stress incontinence, cystocele,total abdominal hysterectomy
and bilateral salpingo-oophorectomy, post-menopausal, intermittent back
pain, right great toe fracture, lumbar laminectomy, bilateral calcaneal
spurs, intermittent eczema, hypercholesterolemia, exogenous obesity,
allergies to adhesive tape and amoxicillin, inhalant allergies, and OA.
The patient had previously participated in the N49-96-02-021 clinical
trial during which she received celecoxib mg BID. After successfully
completing this study, the patient was entered into the long-term safety
study and began taking celecoxib 100 mg BID on 20 February 1997. Dosage
was increased to 200 mg BID 14 days later on 6 March 1997. One hundred
and forty six days later, on the patient was found dead by her son. An
autopsy performed one day later, on 31 July 1997, revealed
arteriosclerotic cardiovascular disease with severe narrowing of the
left anterior descending coronary, right coronary artery by
atherosclerosis, and severe atherosclerosis of the aorta. No evidence of
a recent or old myocardial infarction was noted. Hashimoto's thyroiditis
and cholesterolosis of the gallbladder were also seen on autopsy. The
death certificate shows the patient died of ischemic heart disease.
Concomitant medications included Naldecon, pravastatin, estrogen,
calcium carbonate, and allergy injection.

**14. Patient No. US0066-0004** (Respiratory Insufficiency, Pulmonary
Carcinoma, Treatment Emergent Surgery) was a 60 year old male with a
history of tonsillectomy, seasonal allergies, sleep apnea, hypertension,
appendectomy, cholecystectomy, obesity, peripheral edema, adult onset
diabetes mellitus, skin rash, proteinuria/gold therapy, excision of
eyelid polyps, toe surgery, allergy to penicillin, excoriated insect
bites, hyperlipidemia, hypothyroidism, chronic obstructive lung disease,
tobacco use and RA. The patient had previously participated in the
N49-96-02-023 clinical trial during which he received placebo. After
being withdrawn early from this study due to treatment failure, the
patient was entered into the long-term safety study and began taking
celecoxib 200 mg BID on 11 November 1996. Dosage was increased to 300 mg
BID 15 days later, on 27 December 1996. Eighty three days later, on ,
the patient complained of chest pain. The Investigator referred the
patient to his primary physician, who started the patient on
clarithromycin for possible pneumonia and did a chest x-ray. Twenty six
days later, on , the patient was hospitalized for a lung mass which was
seen on the chest x-ray. Three days following hospital admission, on ,
4000 cc of fluid was aspirated from the patient's lungs. Cell
differential of this fluid returned cancer cells. The diagnosis of
adenocarcinoma of the lung was made and a scan showed metastasis of the
liver. Thirteen days following admission, on , a thoracotomy was
performed. The patient was mechanically ventilated postoperatively.
Seven days later, on , the patient expired due to respiratory failure
secondary to carcinoma of the left lung. Concomitant medications
included diltiazem, glipizide, gemfibrozil, levothyroxine, docusate,
terfenadine, methotrexate, phentermine, fenfluramine, anti-fungal cream
and continuous positive airway pressure oxygen. Study drug was
discontinued on 15 April 1997. The patient never recovered

**15. Patient No. US0073-0060** (Respiratory Insufficiency, Cardiac
Failure) was an 85 year old female with a history of removal of benign
throat tumor, hypertension, peptic ulcer disease, cholecystectomy,
cigarette smoking, post-menopause, osteoporosis, right hip replacement,
hypothyroidism, bilateral cataracts, lens implants,and RA. The patient
had previously participated in the N49-96-02-023 clinical trial during
which she received placebo. After being withdrawn early from this study
due to treatment failure, the patient was entered into the long-term
safety study and began taking celecoxib 200 mg BID on 10 March 1997.
Dosage was increased to 300 mg BID four days later, on 14 March 1997 and
to 400 mg BID 11 days later, on 25 March 1997. Twohundred and twenty
eight days after dose adjustment, on 8 November 1997, the patient was
hospitalized for unknown reasons. The patient died 12 days later, on of
respiratory secondary to congestive heart failure. Concomitant
medications included sulfasalazine, levothyroxine sodium, alendronate
sodium, lisinopril, furosemide, and potassium chloride. Study drug was
interrupted during hospitalization.

**16. Patient No. US0073-0189** (Myocardial Infarction) was a 71 year
old female with a history of sleep disturbance, hypertension, irregular
heart rate, cholecytecomy, appendectomy, ovarian cyst removed, benign
breast cyst removed, cataracts, post-menopausal, anemia, hyperglycemia,
hypercholesterolmia, hyperuricemia, and rheumatoid arthritis. The
patient had previously participated in celecoxibclinical trial
#N49-96-02-022, during which the patient had received either placebo,
celecoxib 100 mg BID, 200 mg BID, 400 mg BID or naproxen 500 mg BID.
After terminating early due to treatment failure, she was entered into
the long-term safety study and began taking celecoxib 200 mg BID on
November 21, 1997. Seventeen days later, on December 8, 1997, dosage was
adjusted to 400 mg BID. Seventeen days later, on , the patient began
experiencing jaw pain that radiated to the chest. The patient was
hospitalized with a possible myocardial infarction. Initial cardiac
enzymes were elevated. An electrocardiogram revealed septal and lateral
wall changes. Treatment included subcutaneous heparin sodium,
nitroglycerin, metoprolol tartrate, and warfarin sodium. Three days
after admission, , the patient died due to complications from a
myocardial infarction. Concomitant medications included methotrexate,
folic acid, enalapril, calcium carbonate, vitamin E, lorazepam,
multivitamin, digoxin, and prednisolone acetate.

**17. Patient No. US0087-0100** (Sepsis, Pneumonitis, Respiratory
Insufficiency) was a 66 year old male with a history of hypertension,
gastrointestinal upset related to anti-inflammatory medications, reflux
esophagitis, gastritis, benign cyst on left hip, osteoporosis,
dermatitis, heat rash, diabetes, positive Helicobacter pylori, right
medial menisectomy, crush injury to left hand and remote history of
peptic ulcer disease, allergy to penicillin, and rheumatoid arthritis.
The patient had previously participated in celecoxibclinical trial
#N49-97-02-023, during which the patient had received celecoxib 100 mg
BID, 200 mg BID, 400 mg BID, naproxen 500 mg BID or placebo BID. After
terminating early from this study due to treatment failure, he was
entered into the long-term safety study, N49-96-02-024, and began taking
celecoxib 200 mg BID on May 6, 1997. Dosage was increased to 300 mg BID,
14 days later, on May 20, 1997 and increased again to 400 mg BID, 4 days
after that, on May 24, 1997. One hundred and seventy-four days after
dose adjustment , the patient was admitted to the intensive care unit
for complaints of shortness-of-breath, dyspnea, left sided weakness and
elevated blood pressure. A CAT scan of the lungs showed alveolar edema,
chest x-ray revealed peripheral pulmonary fibrosis, presumably secondary
to rheumatoid arthritis or long-term methotrexate therapy, and changes
consistent with pulmonary edema. And electrocardiogram revealed sinus
tachycardia with ST and T sagging in the lateral leads, and a suggestion
of left atrial hypertrophy. A CAT scan of the head was negative. Blood
cultures revealed enterococcal species. Physical exam was remarkable for
crackles in bilateral lung fields almost to the scapular level and
slight left arm and leg weakness with slightly diminished reflexes
bilaterally. According to the study coordinator, the patient\'s blood
pressure had been elevated to at least 176/86 at his past few visits and
he had been advised to see his primary physician. The patient was
started on enalapril maleate, furosemide, and digoxin. Additional
treatment for this event included Humulin Insulin, multiple antibiotics,
Ventolin, Atrovent, Heparin and famotidine, tracheostomy and mechanical
ventilation. The patient died 29 days later, on . The cause of death was
determined to be respiratory failure, overwhelming sepsis and the
interstitial pneumonitis. Concomitant medications included
hydroxychloroquine sulfate, folic acid, glyburide, omeprazole, metformin
hydrochloride, calcium and methotrexate. Study medication was
interrupted during hospitalization.

**18. Patient No. US0110-0006** (Myocardial Infarction) was a 61 year
old female with a history of fluid retention, hyperlipidemia, coronary
artery disease, congestive heart failure, chronic obstructive pulmonary
disease, tobacco use, triple bypass surgery, arrhythmia, abdominal
aortic aneurysm, hysterectomy, thrombocytosis and rheumatoid arthritis.
The patient had previously participated in Searle study #N49-96-02-022,
during which she received either placebo, celecoxib 100 mg BID, 200 mg
BID, 400 mg BID or naproxen 500 mg BID. After successfully completing
this study, on December 17, 1996, the patient was entered into the
long-term safety study and began taking celecoxib 200 mg BID. Dosage was
adjusted to 300 mg BID 17 days later, on January 3, 1997, and again to
400 mg BID 35 days after that, on February 7, 1997. Two hundered and
twenty days after the last dose adjustment, on , the patient underwent
femoral bypass surgery due to a foot ulcer that was caused by poor
circulation. The patient was discharged 3 days later, on . Eleven days
later, on , the patient was re-hospitalized with complaints of chest
pain. The patient underwent cardiac catheterization and angioplasty with
stent placement. The patient was discharged 31 days later, on .
Seventy-seven days later, on , the patient suffered a myocardial
infarction and died. The patient\'s brother had died earlier in the
week. Concomitant medications included prednisone, digoxin, pravastatin
sodium, acetylsalicylic acid, furosemide, pentoxifylline, and
multivitamins.

**19. Patient No. US0116-0042** (Arterial Dissection, Aneurysm) was a 78
year old female with a history of cataracts, lens implants,
hypertension, supraventricular tachycardia, angioplasty, appendectomy,
hiatal hernia, post-menopause, bilateral metatarsophalangeal repair,
allergies to piroxicam and gold, and rheumatoid arthritis. The patient
had previously participated in celecoxib clinical trial \# N49-96-02-
022, during which the patient had received either placebo, celecoxib200
mg BID on September 25, 1997. After 88 days of treatment, on , the
patient was hospitalized with an ascending aortic aneurysm and developed
a dissection which was confirmed on repeat CT scanning. Preoperative
echocardiogram revealed moderately severe aortic stenosis with a peak
gradient of 42. On , the patient underwent an aortic valve replacement
with a 21mm St. Jude Mechanical heart valve and ascending aorta and
hemi-arch replacement with 24mm Hemashield graft utilizing circulatory
arrest and hypothermia. During the procedure, the patient began bleeding
from the anterior portion of the proximal anastomosis and developed left
ventricular aortic discontinuity from this area. Massive bleeding
ensued. Attempts to repair this were unsuccessful and the patient was
pronounced dead. The death certificate revealed the cause of death as
type I ascending (aortic) arch dissection, artherosclerotic coronary
artery disease and critical aortic stenosis. Concomitant medications
included sulfasalazine, diltiazem hydrochloride-sustained release,
thyroid, Ascriptin, medroxyprogescerone acetate, conjugated estrogens,
and digoxin. Study medication was interrupted one day prior to
hospitalization.

**20. Patient No. US0121-0052** (Sepsis, Pneumonia, Myocardial
Infarction) was a 52 year old male with a history of tinnitus, recurring
sore throats, decreased hearing, sinus trouble, sores in mouth, glasses,
pain behind eyes, depression, headaches, vertigo, fainting spells,
occasional chest pain, influenza, cough, chronic obstructive airway
disease, pneumonia, obesity, hernia repair, appendectomy, H. pylori,
hemorrhoids, gastritis, pedal edema, leg cramps, bursitis, brittle
nails, skin rash, hypoglycemia, diabetes mellitus, allergies to
penicillamine and cyclosporin, and RA. The patient had previously
participated in the N49-96-02-022 clinical trial during which he had
received celecoxib 100 mg BID. After successfully completing this study,
he was entered into the long-term safety study and began taking
celecoxib 200 mg BID on 29 September 1997. Fourteen days later, on 13
October 1997, dosage was increased to 300 mg BID. Four days after that
on , the patient presented with shortness of breath which had been
present for one month, and had become significantly worse, and was
admitted with respiratory distress. Physical examination revealed a
blood pressure of 107/50 on dopamine, respiratory rate of 15, which was
decreased from 36 previously, and a temperature of 99°F. Lung
auscultation revealed crackles in the left base, and a trace of bipedal
pitting edema. Pleural fluid and sputum grew Acinetobacter "pneumoniae."
White blood cell count was 10.5 on admission. Complete blood
differential count revealed a left shift with 54 bands. The patient's
blood urea nitrogen was 24 and creatinine was 3.3 on admission and rose
to 35 and 4.7, respectively, one day after admission. Potassium rose
from 4.7 to 6.9 in just a few hours. Aspartate transaminase, which was
initially normal, rose to 649. Alanine transaminase rose to 309 and
lactate dehydrogenase to 3,272; CK-MB index was 7.9%. Arterial blood
gasses were pH 7.06, pC02 of 67, and p02 of 58 on a 7 liter oxygen mask.
Pleural fluid showed 14,000 nucleated cells with neutrophilic
predominance and glucose of 70 with pH of 7.2. Blood cultures grew a
bacillus species. Electrocardiogram revealed sinus tachycardia with an
incomplete right bundle branch block and small Q wave in lead III with
anterolateral ST changes consistent with possible ischemia. Chest x-ray
showed cardiomegaly and a possible pleural effusion on the left.
Treatment included intubation and subsequent ventilator support,
thoracentesis, insertion of a Swan-Ganz, central venous pressure line,
arterial line and Vas-Cath, dopamine in increasing doses, rescue doses
of steroids, ceftriaxone, sodium, fluid replacement for dehydration and
sepsis, phenylephrine hydrochloride drip, amikacin, and ofloxacin. The
patient was found to have gram negative sepsis and pneumonia and
subsequently expired one day later on . According to the death
certificate, the patient died of an acute myocardial infarction. No
autopsy was done. Concomitant medications included methotrexate,
prednisone, and folic acid as well as nasal continuous positive airway
pressure. Study medication was continued up until the time of death.

**21. Patient No. US0139-0009** (Subarachnoid Hemorrhage) was a 57 year
old female with a history of dyspepsia, hysterectomy, lumbar spinal
fusion, and RA. The patient had previously participated in the
N49-96-02-022 clinical trial during which she had received placebo.
After successfully completing this study, she was entered into the
long-term safety study and began taking celecoxib 200 mg BID on 26
August 1997. Twenty three days later on , the patient was admitted with
a grade V subarachnoid hemorrhage. On admission her right pupil was
fixed and dilated and she had decerebrate posturing. Apparently, this
had occurred at 4:30 in the morning, with onset of emesis and loss of
consciousness at that time. She was subsequently intubated and received
mannitol and was transferred by ambulance to the hospital. On
examination her initial blood pressure was 200/80 and nitroglycerin
paste was given to help lower this. Her Glasgow Coma Scale at the time
of admission was 4T. A computerized tomography scan revealed diffuse
subarachnoid hemorrhage with a large right sided temporal lobe clot;
intraventricular hemorrhage; right to left shift; and extensive midbrain
compression and swelling. The patient deteriorated and was pronounced
brain dead later that same day. Concomitant medications included
methotrexate, folic acid, sulfasalazine, and estrogen.