Celebrex Capsules

**(Celecoxib)**

# NDA 20-998/S-009

# Medical Officer Review

**Submission Date:** June 12, 2000

**Received Date:** June 14, 2000

**Review Date:** September 20, 2000

**Drug Name:** Celebrex

**Generic Name:** celecoxib

**Chemical Name:**
4-\[5-(4-methylphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl\]
benzenesulfonamide

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

**Related Reviews:** Statistics, Cardio-Renal, Gastrointestinal
(HFD-550)

**Pharmacologic category:** COX-2 inhibitor

**Proposed Indication:** Label changes

-Warnings (Clinically Significant UGI Events)

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

**Submission type:** Supplemental NDA

**Materials Reviewed:** Primary-document N49-00-06-035_102

Orig NDA \# 20-998

HFD-550/Div File

HFD-550/PM/Kong

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/Goldkind

# 

# 

# 

# 

# CLASS Executive Summary

**Significant Issues/Highlights**

-   The Celecoxib Long-term Arthritis Safety Study (CLASS) represented
    the combination of two large safety studies (protocols N49-98-02-035
    and N49-98-02-102) which addressed primarily the UGI clinical
    outcomes of celecoxib, a COX-2 selective agent, as compared to more
    traditional NSAIDs. In particular, the incidence of clinically
    significant UGI events (CSUGIEs) associated with celecoxib was
    compared to that associated with ibuprofen or diclofenac during
    chronic administration in patients with OA or RA. Patients were
    allowed to take aspirin (ASA) for cardiovascular prophylaxis. The
    term "CSUGIE" represented a composite end point comprised of UGI
    bleeding, perforation, or gastric outlet obstruction. Those
    symptomatic UGI events deemed not to be CSUGIEs, were referred to as
    gastroduodenal ulcers (GDU).

-   Data in the CLASS trial included information on serum bicarbonates
    and other estimates of potential effects on acid-base balance. This
    new data represented a fulfillment of a phase 4 commitment to study
    these issues since serum bicarbonates had not been measured in the
    original NDA.

-   Overall, the CLASS trial represented a robust test of the safety of
    celecoxib as compared to the "traditional" NSAIDs of ibuprofen and
    diclofenac. The latter two compounds were at their "usual"
    therapeutic doses while celecoxib was given at a "2X" dose which
    represent twice the currently approved dosing for rheumatoid
    arthritis. This supratherapeutic dose is the also the currently
    recommended dose for the labeled indication of familial adenomatous
    polyposis (FAP).

# 

-   Celecoxib did not demonstrate statistical superiority to NSAIDs
    (pooled) or either comparator (diclofenac and ibuprofen) with
    regards to the primary safety endpoint of CSUGIEs at any point in
    the trial although there were trends (noted below) that favored
    celecoxib. When the subgroup of non-aspirin users was considered, or
    the definition of the UGI endpoints was expanded to include ulcer
    events not deemed to be CSUGIEs (i.e. GDUs), celecoxib did
    demonstrate superiority to pooled NSAIDs, and to ibuprofen (only),
    during this trial. This superiority was not a pre-specified efficacy
    endpoint and was not corrected statistically for multiplicity.
    Celecoxib did not demonstrate statistical superiority to diclofenac
    regardless of selection of study endpoint or aspirin use during any
    point in the trial.

-   Aspirin use appears to influence event rates for gastrointestinal,
    renal and possibly cardiac outcomes. However, owing to the nature of
    this trial, particularly that use of aspirin would indicate a higher
    level of pre-existing cardiovascular disease and aspirin use was not
    stratified, it is unclear how aspirin impacts these outcomes among
    the treatment groups evaluated in this trial.

-   The CLASS trial data do not support an apparent adverse effect of
    celecoxib on cardiovascular mortality or on serious adverse events
    related to thrombosis relative to either diclofenac or ibuprofen.
    The data do not exclude a less apparent effect, reflected in the
    relative rates of cardiac adverse events related to ischemia.

-   The CLASS trial data do not support an apparent adverse effect of
    celecoxib on renal or cardiac adverse events relative to either
    diclofenac or ibuprofen. This includes adverse events reported by
    investigators (*e.g.*, hypertension, uremia) and those detected
    through routine laboratory or blood pressure measurements (*e.g.*,
    increased BUN/ serum creatinine or systolic blood pressure).

-   Overall safety, as defined by the endpoints of deaths, serious
    adverse events and withdrawals due to adverse events did not appear
    to be meaningfully or consistently different among the three
    treatment groups.

**[Clinical Background (Section 6):]{.underline}**

**Relevant Human Experience (Section 6.1):**

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat
chronic arthritic diseases such as osteoarthritis (OA) and rheumatoid
arthritis (RA). An important mechanism through which these agents are
thought to act is via inhibition of the enzyme cyclooxygenase (COX).
This enzyme is now known to exist in two isoforms: a mostly constitutive
form (COX-1) and a mostly inducible form (COX-2). However, it is now
appreciated that COX-2 can also be constitutively expressed in certain
areas in the body. COX-1 is thought to be widely distributed throughout
most body tissues and mediates synthesis of prostaglandins that have a
diverse array of homeostatic physiological functions. One of these
important functions is thought to include the maintenance of mucosal
integrity in the upper gastrointestinal (UGI) tract. In contrast, COX-2
in most areas of the body, is thought to be expressed in low levels in
tissues but is rapidly and highly induced at sites of inflammation.

Since "traditional" NSAIDs nonspecifically inhibit both COX isoforms, it
has been postulated that their anti-inflammatory and analgesic benefits
result from inhibition of COX-2 while the increased rate of UGI ulcers
and complications commonly associated with NSAIDs result from inhibition
of COX-1. The principal manifestations of ulcer complications are UGI
bleeding, perforation, and gastric outlet obstruction. The UGI toxicity
of NSAIDs has been well documented. For example, observational analysis
of the Arthritis, Rheumatism, and Aging Medical Information System
(ARAMIS) database suggests that in a large population receiving NSAIDs
over 10,600 patient-years, GI-related hospitalizations or deaths
occurred at a rate of 1.3% per year. Most studies in this area, such as
the one cited, have been observational cohort or retrospective
case-control studies. In the only large, randomized, prospective trial
of NSAID-related UGI ulcer complications (the MUCOSA trial), the
annualized incidence was approximately 1.9% in 8843 RA patients followed
for six months; the risk of UGI ulcer complications did not seem to
diminish with continuing exposure.

This risk of UGI complications noted for NSAIDs resulted in the
formation of a GI paragraph which has been included in the labeling of
approved NSAIDs. The current labeling for Celebrex is as follows:

***WARNINGS***

***Gastrointestinal (GI) Effects- Risk of GI Ulceration, Bleeding, and
Perforation:***

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

*It is unclear, at the present time, how the above rates apply to
CELEBREX. (See CLINICAL STUDIES-Special Studies.) Among 5285 patients
who received CELEBREX in studies of 1 to 6 months duration, at a daily
dose of 200 mg or more in controlled clinical trials, 2 (0.04%)
experienced significant upper GI bleeding at 14 and **22** days after
initiation of dosing. Approximately **40%** of these 5285 patients were
in studies that required them to be free of ulcers by endoscopy at study
entry. (Thus this study population may have been at lower risk for
significant gastrointestinal complications**.**) **Thus it is unclear if
this study is representative of the general population.** Prospective,
long-term studies required to compare the occurrence of serious
clinically significant upper GI adverse events in patients taking
CELEBREX vs. comparator NSAID products have not been performed.*

*NSAIDs should be prescribed with extreme caution in those with a prior
history of ulcer disease or gastrointestinal bleeding. Most spontaneous
reports of fatal GI events are in elderly or debilitated patients and
therefore special care should be taken in treating this population. **To
minimize the potential risk for an adverse GI event, the lowest
effective dose should be used for the shortest possible duration.** For
high risk patients, alternate therapies that do not involve NSAIDs
should be considered.*

*Studies have shown that patients with a prior history of peptic ulcer
disease and/or gastrointestinal bleeding and who use NSAIDs, have a
greater than 10-fold **higher** risk for developing a GI bleed than
patients with neither of these risk factors. In addition to a past
history of ulcer disease, pharmacoepidemiological studies have
identified several other co-therapies or co-morbid conditions that may
increase the risk for GI bleeding such as: treatment with oral
corticosteroids, treatment with anticoagulants, longer duration of NSAID
therapy, smoking, alcoholism, older age, and poor general health
status.*

An important hypothesis for development of selective inhibitors of COX-2
has been that they, by avoiding inhibition of COX-1, would spare the UGI
tract toxicity while maintaining analgesic and anti-inflammatory
efficacy. A corollary to this has been the impression that COX-2 agents
may also be safer, overall, as compared to traditional NSAIDs. The
original NDA for Celebrex included data on endoscopically-defined UGI
endpoints, but insufficient data on clinical UGI outcomes to allow for
any substantial modification of the GI Warning paragraph. **This sNDA,
which consists basically of two large safety studies (protocols
N49-98-02-035 and N49-98-02-102), seeks to address primarily the UGI
clinical outcomes of celecoxib, a COX-2 selective agent, as compared to
more traditional NSAIDs.** In particular, the incidence of clinically
significant UGI events (CSUGIEs) associated with celecoxib was compared
to that associated with ibuprofen or diclofenac during chronic
administration (at least six months) in patients with OA or RA. The term
"CSUGIE" represents a composite end point comprised of UGI bleeding,
perforation, or gastric outlet obstruction. It should be noted that
these companion protocols were prospectively designed with the intent to
combine the results into a single study, pooling the celecoxib patients
from both protocols into a single treatment group.

***Safety evaluation***:

All patients who took at least one dose of study medication were
included in all safety analyses. Adverse events (AE) were coded using
W.H.O.a.r.t. terminology. The incidences of treatment-emergent adverse
events were tabulated by treatment group and body system, and compared
pairwise between treatment groups using Fisher's Exact test. Events
occurring more than 28 days after the last dose of study medication were
excluded from all analyses.

Adverse events causing withdrawal were similarly analyzed. Serious
adverse events were tabulated by treatment group and body system, but no
statistical analysis was performed. The incidences of treatment-emergent
adverse events were also tabulated by severity and by the Investigator's
attribution of the cause of the event.

Because of the long treatment period in this study, a separate analysis
was performed in which adverse events were summarized by 90-day
intervals (1 to 90 days, 91 to 180 days, 181 to 270 days, 271 to 360
days, 361 to 450 days, and 451 to 540 days). In this analysis,
incidences and prevalences were summarized separately for each adverse
event. Within each interval, events were counted under prevalence if
they were new in that interval or continued from a previous interval,
whereas incidence values included only events that were new within that
interval.

For selected GI adverse events, time-to-event analyses were performed to
assess the rates of the events by pre-specified time intervals (1, 4,
13, 26, 39, 52, and 65 weeks). The log-rank test was used to compare the
time-to-event curves between celecoxib 400 mg BID and the two NSAIDs
combined, as well as between celecoxib and each of the NSAIDs
separately. Each test was performed at the alpha level of 0.05.

Times to withdrawal due to adverse events were analyzed using the
log-rank test. In this analysis, patients who withdrew for other reasons
were censored at the time of withdrawal; those who did not withdraw at
any time were censored at the final scheduled visit.

Changes from baseline in clinical laboratory values at weeks 4, 13, 26,
39, 52, and the final visit were summarized as means and standard
deviations (SD). The changes were compared among treatment groups by
ANCOVA using pairwise treatment contrasts with baseline value as the
covariate.

Incidences of extreme laboratory (and vital signs) values during the
study were summarized by treatment group and compared among groups using
Fisher's exact test. The values representing upper and lower extremes
for each laboratory test were determined before the initiation of study
conduct through discussions with external safety consultants, and were
listed (Table 6.d, N49-00-06-035-102, p. 52/24295) and were utilized to
construct shift tables. Contingency tables were also prepared showing
numbers of patients whose post-treatment laboratory results met certain
criteria for combinations of values or changes in values that might
indicate hematologic, hepatobiliary, or renal effects. These criteria
represented: decreases in both hemoglobin and hematocrit; increases in
both creatinine and BUN; increases in both AST and ALT; increases in
both alkaline phosphatase and total bilirubin; increases in both ALT and
alkaline phosphatase; and increases in both ALT and total bilirubin.
These tables showed numbers of patients shifting among various
categories of increases and decreases according to predetermined cutoff
values.

**[Other Serious Adverse Events:]{.underline}**

A total of 500 patients experienced **serious adverse events (SAE)**
during or 28 days after study participation:

-   270 patients in the celecoxib group

-   111 patients in the diclofenac group

-   119 patients in the ibuprofen group

The most common SAEs are summarized in **Table 41**. As can be seen, the
difference between any two treatment groups was no more than 0.6 per 100
patient-years. The highest rate seen for

any serious adverse event was 0.8 per 100 patient-years, seen in at
least one treatment group for myocardial infarction, coronary artery
disorder, accidental fracture, cardiac failure, and back pain. Although
the results are similar to those shown for general adverse events, the
patterns suggested by the general adverse events were not replicated
exactly in the serious adverse events. This difference in pattern may
reflect the fact that there were smaller numbers of serious events than
general adverse events.

**^Table\ 41:\ Summary\ of\ Serious\ Adverse\ Events-Entire\ Study\ Period1^**

+----------------------+-----------------+-------------+--------------+
| **Adverse Event**    | **Celecoxib**   | **D         | *            |
|                      |                 | iclofenac** | *Ibuprofen** |
|                      | **(n=3987)**    |             |              |
|                      |                 | *           | **(n=1985)** |
|                      | **2320.4        | *(n=1996)** |              |
|                      | pt-yrs**        |             | **1122.5     |
|                      |                 | **1080.5    | pt-yrs**     |
|                      |                 | pt-yrs**    |              |
+----------------------+-----------------+-------------+--------------+
| Any serious event    | 270 (11.6)      | 111 (10.3)  | 119 (10.6)   |
+----------------------+-----------------+-------------+--------------+
| Abdominal pain       | 6 (0.3)         | 6 (0.6)     | 2 (0.2)      |
|                      |                 |             |              |
| Accidental fracture  | 10 (0.4)        | 4 (0.4)     | 9 (0.8)      |
|                      |                 |             |              |
| Accidental injury    | 3 (0.1)         | 4 (0.4)     | 7 (0.6)      |
|                      |                 |             |              |
| Angina pectoris      | 4 (0.2)         | 5 (0.5)     | 6 (0.5)      |
|                      |                 |             |              |
| Atrial fibrillation  | 9 (0.4)         | 2 (0.2)     | 3 (0.3)      |
|                      |                 |             |              |
| Back pain            | 15 (0.6)        | 3 (0.3)     | 9 (0.8)      |
|                      |                 |             |              |
| Cardiac failure      | 9 (0.4)         | 2 (0.2)     | 9 (0.8)      |
|                      |                 |             |              |
| Cellulitis           | 8 (0.3)         | 1 (\<0.1)   | 1 (\<0.1)    |
|                      |                 |             |              |
| Cerebrovascular      | 4 (0.2)         | 6 (0.6)     | 6 (0.5)      |
| disorder             |                 |             |              |
|                      | 11 (0.5)        | 5 (0.5)     | 7 (0.6)      |
| Chest pain           |                 |             |              |
|                      | 19 (0.8)        | 5 (0.5)     | 5 (0.4)      |
| Coronary artery      |                 |             |              |
| disorder             | 7 (0.3)         | 5 (0.5)     | 1 (\<0.1)    |
|                      |                 |             |              |
| Deep                 | 7 (0.3)         | 2 (0.2)     | 1 (\<0.1)    |
| thrombophlebitis     |                 |             |              |
|                      | 19 (0.8)        | 4 (0.4)     | 9 (0.8)      |
| GI hemorrhage        |                 |             |              |
|                      | 14 (0.6)        | 5 (0.5)     | 5 (0.4)      |
| Myocardial           |                 |             |              |
| infarction           | 5 (0.2)         | 4 (0.4)     | 3 (0.3)      |
|                      |                 |             |              |
| Pneumonia            | 8 (0.3)         | 4 (0.4)     | 0            |
|                      |                 |             |              |
| Syncope              |                 |             |              |
|                      |                 |             |              |
| Unstable angina      |                 |             |              |
+----------------------+-----------------+-------------+--------------+

1.  From Table 10.g (p 184); N49-00-06-035-102. Owing primarily to the
    unequal randomization, results are displayed as normalized for
    length of exposure, rather than crude incidence rates. Table
    includes any event experienced by a total of at least 10 patients
    across the three treatment groups.

> *Reviewer's comment: Generally, these normalized incidences do not
> seem to suggest any important differences or obvious trends of
> specific target organ or organ-system involvement by any treatment
> group.*

# Renal Effects

Table 50 shows the incidences of selected renal adverse events occurring
throughout the entire study period. In general, the incidences were low
in all treatment groups, not suggesting any pronounced renal effects of
any of these treatments. However, patients receiving ibuprofen
experienced more edema and hypertension than celecoxib or diclofenac
patients; these differences were statistically significant. Adverse
events relating to increases in renal function laboratory values (BUN
increased and NPN increased) were more frequent for diclofenac than for
celecoxib. The differences were statistically significant when examined
in the six-month analysis, but not over the entire treatment period.

**^Table\ 50:\ Selected\ Adverse\ Events\ Relating\ to\ Renal\ Function:\ Entire\ Study\ Period1^**

+--------------------------------+-----------+-----------+------------+
| **Adverse Event**              | **        | **D       | **I        |
|                                | Celecoxib | iclofenac | buprofen** |
|                                | (         | (         |            |
|                                | n=3987)** | n=1996)** | **         |
|                                |           |           | (n=1985)** |
+--------------------------------+-----------+-----------+------------+
| Hypertension                   | 2.0       | 2.0       | 3.1\*      |
|                                |           |           |            |
| Hypertension aggravated        | 0.8       | 0.6       | 1.2        |
|                                |           |           |            |
| Edema generalized              | 0.5       | 0.6       | 1.0\*      |
|                                |           |           |            |
| Edema peripheral               | 3.7       | 3.5       | 5.2 \*     |
|                                |           |           |            |
| Cardiac failure                | 0.3       | 0.2       | 0.5        |
|                                |           |           |            |
| BUN increased                  | 1.1       | 1.7       | 0.9        |
|                                |           |           |            |
| NPN increased                  | 1.3       | 1.9       | 1.2        |
|                                |           |           |            |
| Renal failure acute            | 0.0       | \<0.1     | 0.0        |
|                                |           |           |            |
| Renal function abnormal        | \<0.1     | \<0.1     | 0.1        |
+--------------------------------+-----------+-----------+------------+

1.  From Table 10.q (p 201); N49-00-06-035-102. All numbers are
    percentages of patients. (\*) =p\<0.05 vs. celecoxib.

Reviewer's comment: For a more detailed analysis of the cardiovascular
and renal effects of celecoxib and the comparator groups in this trial,
the reader is referred to the review by Douglas Throckmorton, M.D.

**Table 51** shows group mean changes and extreme changes in BUN and
creatinine. Although the meaning is unclear, the results suggest an
effect of diclofenac on mean creatinine values, and of celecoxib on BUN
as compared to ibuprofen. Few patients experienced an extreme BUN value;
the incidence appeared higher for ibuprofen than for the other two
groups, but the difference was not statistically significant. When the
extreme creatinine threshold of 265 µmol/L was used, only one patient in
the entire study period experienced an extreme value. However, as noted
above for the renal contingency tables, when the lower threshold of 159
µmol/L for creatinine with or without BUN changes was utilized, percent
increases of 1.3 for celecoxib, 2.1 for diclofenac, and 1.4 for
ibuprofen were noted. The difference between celecoxib and diclofenac
was statistically significant.

Not shown in Table 51 was that between celecoxib and ibuprofen in
elevated potassium levels: 0.3% of celecoxib patients and 0.0% of
ibuprofen patients had a maximum potassium value above 6.0 mmol/L
(p=0.021; Table 45.1,p. 535). Five of these 11 cases of extreme
potassium levels in celecoxib patients were isolated increases that were
bracketed by values within the normal range, and may be artifactual
(i.e., due to hemolysis). One additional case was an isolated value
drawn four days after discontinuation of study medication and is of
uncertain clinical significance.

**^Table\ 51:\ Mean\ Changes\ from\ Baseline\ to\ Final\ Visit/Extreme\ Values\ in\ Specific\ Renal\ Laboratory\ Values1^**

+-------------------------------+-------------+------------+-----------+
| **Laboratory Test**           | **          | **Di       | **Ib      |
|                               | Celecoxib** | clofenac** | uprofen** |
+-------------------------------+-------------+------------+-----------+
| **Group Mean Changes from     |             |            |           |
| Baseline (Mean \[SE\])**      |             |            |           |
+-------------------------------+-------------+------------+-----------+
| BUN, mmol/L                   | 0.66        | 0.58       | 0.52      |
|                               | (0.027)     | (0.041)    | (         |
| Creatinine, µmol/L            |             |            | 0.039)^1^ |
|                               | 0.8 (0.22)  | 2.4        |           |
|                               |             | (0.33)^1^  | 1.5       |
|                               |             |            | (0.33)    |
+-------------------------------+-------------+------------+-----------+
| **Incidence of Extreme Values |             |            |           |
| (No./total \[%\])**           |             |            |           |
+-------------------------------+-------------+------------+-----------+
| BUN (\>14.3 mmol/L)           | 17/3692     | 8/1849     | 12/1786   |
|                               | (0.5)       | (0.4)      | (0.7)     |
| Final visit                   |             |            |           |
|                               | 31/3692     | 20/1849    | 16/1786   |
| Maximum value                 | (0.8)       | (1.1)      | (0.9)     |
+-------------------------------+-------------+------------+-----------+
| Creatinine (\>265.2 µmol/L)   | 0/3692      | 0/1850     | 0/1786    |
|                               | (0.0)       | (0.0)      | (0.0)     |
| Final visit                   |             |            |           |
|                               | 1/3692      | 0/1850     | 0/1786    |
| Maximum value                 | (\<0.1)     | (0.0)      | (0.0)     |
+-------------------------------+-------------+------------+-----------+

1.  From Table 10.r (p 202); N49-00-06-035-102. P\<0.05 vs. celecoxib.

# Vascular (Cardiac and Noncardiac) Effects

The incidences of cardiac and noncardiac vascular adverse events
throughout the entire study period are shown in Table 52. The table
shows that vascular events were rare in all treatment groups, and
incidences were similar between celecoxib and the two NSAIDs. The only
statistically significant difference in incidences was for
cerebrovascular disorder between celecoxib (0.2%) and ibuprofen (0.5%).

**^[Table\ 52:\ Incidences\ of\ Selected\ Cardiac/Noncardiac\ Vascular\ Adverse\ Events:\ Entire\ Study\ Period1]{.underline}^**

+--------------------------+---------------+-------------+-----------+
| **Adverse Event**        | **Celecoxib** | *           | **Ib      |
|                          |               | *Diclofenac | uprofen** |
|                          | **(n=3987)**  | (n=1996)**  |           |
|                          |               |             | **(       |
|                          |               |             | n=1985)** |
+--------------------------+---------------+-------------+-----------+
| Angina pectoris          | 0.6           | 0.5         | 0.6       |
|                          |               |             |           |
| Arteriosclerosis         | \<0.1         | 0.0         | \<0.1     |
|                          |               |             |           |
| Atherosclerosis          | \<0.1         | \<0.1       | 0.1       |
|                          |               |             |           |
| Carotid bruit            | \<0.1         | 0.1         | \<0.1     |
|                          |               |             |           |
| Carotid stenosis         | \<0.1         | 0.0         | 0.0       |
|                          |               |             |           |
| Cerebrovascular disorder | 0.2           | 0.5         | 0.5^1^    |
|                          |               |             |           |
| Coronary artery disorder | 0.6           | 0.4         | 0.3       |
|                          |               |             |           |
| Embolism                 | \<0.1         | 0.0         | 0.0       |
|                          |               |             |           |
| Embolism pulmonary       | 0.1           | \<0.1       | 0.1       |
|                          |               |             |           |
| Myocardial infarction    | 0.5           | 0.3         | 0.5       |
|                          |               |             |           |
| Myocardial ischemia      | \<0.1         | 0.1         | 0.0       |
|                          |               |             |           |
| Peripheral gangrene      | \<0.1         | 0.0         | 0.0       |
|                          |               |             |           |
| Peripheral ischemia      | 0.1           | 0.0         | 0.1       |
|                          |               |             |           |
| Peripheral vascular      | \<0.1         | 0.0         | \<0.1     |
| disease                  |               |             |           |
|                          | \<0.1         | 0.0         | \<0.1     |
| Phlebitis                |               |             |           |
|                          | \<0.1         | 0.0         | \<0.1     |
| Thrombophlebitis         |               |             |           |
|                          | \<0.1         | 0.0         | \<0.1     |
| Thrombophlebitis arm     |               |             |           |
|                          | 0.3           | 0.3         | \<0.1     |
| Thrombophlebitis deep    |               |             |           |
|                          | 0.0           | \<0.1       | \<0.1     |
| Thrombophlebitis leg     |               |             |           |
|                          | \<0.1         | \<0.1       | 0.0       |
| Thrombophlebitis leg     |               |             |           |
| deep                     | \<0.1         | \<0.1       | 0.0       |
|                          |               |             |           |
| Thrombophlebitis leg     | 0.3           | 0.2         | 0.1       |
| superficial              |               |             |           |
|                          |               |             |           |
| Unstable angina          |               |             |           |
+--------------------------+---------------+-------------+-----------+

1.  From Table 10.s (p 204); N49-00-06-035-102. Numbers are percentages.
    P\<0.05 vs. celecoxib.

***Reviewer's comment: There does not appear to be any clinically or
statistically significant trend with celecoxib to suggest additional
cardiovascular risks over the comparator drugs.***

Incidences of the same group of adverse events are shown and
statistically analyzed by aspirin status in **Table 53**. Patients in
the two NSAID groups were pooled for this analysis. As might be
expected, incidences of the cardiovascular-related events were higher in
the patients taking aspirin, since these patients were more likely to
have a significant cardiovascular medical history than the overall study
population. The absence of statistical significance for any of the
events suggest that the differences between celecoxib and NSAID were not
markedly altered by the use of aspirin.

**^[Table\ 53:\ Incidences\ of\ Selected\ Cardiac/Noncardiac\ Vascular\ Adverse\ Events\ with/without\ Aspirin\ Use:\ Entire\ Study1]{.underline}^**

+-----------------------+--------+--------+-----+-------+-------+---+
|                       | **With |        |     | **Wi  |       |   |
|                       | Asp    |        |     | thout |       |   |
|                       | irin** |        |     | Aspi  |       |   |
|                       |        |        |     | rin** |       |   |
+-----------------------+--------+--------+-----+-------+-------+---+
|                       | *      | **NS   | **  | **C   | **NSA | * |
|                       | *Celec | AIDs** | RD\ | eleco | IDs** | * |
|                       | oxib** |        | *** | xib** |       | R |
|                       |        | **(n=  |     |       | **    | D |
|                       | **(n=  | 857)** |     | **    | (n=31 | \ |
|                       | 882)** |        |     | (n=31 | 24)** | * |
|                       |        |        |     | 05)** |       | * |
|                       |        |        |     |       |       | * |
+-----------------------+--------+--------+-----+-------+-------+---+
| ######### Any         | 6.1    | 5.7    | 0.4 | 1.5   | 1.2   | 0 |
| thromboembolic event  |        |        |     |       |       | . |
|                       |        |        |     |       |       | 3 |
+-----------------------+--------+--------+-----+-------+-------+---+
| Angina pectoris       | 1.5    | 1.6    | -   | 0.3   | 0.3   | 0 |
|                       |        |        | 0.2 |       |       | . |
| Arteriosclerosis      | 0.2    | 0.1    |     | 0.0   | 0.0   | 0 |
|                       |        |        | \-  |       |       |   |
| Atherosclerosis       | 0.1    | 0.2    |     | \<0.1 | \<0.1 | \ |
|                       |        |        | -   |       |       | - |
| Carotid bruit         | 0.0    | 0.1    | 0.1 | \<0.1 | \<0.1 |   |
|                       |        |        |     |       |       | 0 |
| Carotid stenosis      | 0.1    | 0.0    | -   | 0.0   | 0.0   | . |
|                       |        |        | 0.1 |       |       | 0 |
| Cerebrovascular       | 0.6    | 1.2    |     | \<0.1 | 0.3   |   |
| disorder              |        |        | \-  |       |       | 0 |
|                       | 1.7    | 0.9    |     | 0.3   | 0.2   | . |
| Coronary artery       |        |        | -   |       |       | 0 |
| disorder              | 0.0    | 0.0    | 0.6 | \<0.1 | 0.0   |   |
|                       |        |        |     |       |       | \ |
| Embolism              | 0.1    | 0.0    | 0.8 | \<0.1 | \<0.1 | - |
|                       |        |        |     |       |       |   |
| Embolism pulmonary    | 1.5    | 1.2    | \-  | 0.2   | 0.1   | - |
|                       |        |        |     |       |       | 0 |
| Myocardial infarction | 0.1    | 0.2    | 0.1 | \<0.1 | 0.0   | . |
|                       |        |        |     |       |       | 2 |
| Myocardial ischemia   | 0.0    | 0.0    | 0.3 | \<0.1 | 0.0   |   |
|                       |        |        |     |       |       | 0 |
| Peripheral gangrene   | 0.3    | 0.1    | -   | \<0.1 | \<0.1 | . |
|                       |        |        | 0.1 |       |       | 2 |
| Peripheral ischemia   | 0.1    | 0.0    |     | \<0.1 | \<0.1 |   |
|                       |        |        | \-  |       |       | \ |
| Peripheral vascular   | 0.0    | 0.0    |     | \<0.1 | \<0.1 | - |
| disease               |        |        | 0.2 |       |       |   |
|                       | 0.0    | 0.0    |     | \<0.1 | \<0.1 | 0 |
| Phlebitis             |        |        | 0.1 |       |       | . |
|                       | 0.0    | 0.0    |     | \<0.1 | \<0.1 | 0 |
| Thrombophlebitis      |        |        | \-  |       |       |   |
|                       | 0.3    | 0.4    |     | 0.3   | \<0.1 | 0 |
| Thrombophlebitis arm  |        |        | \-  |       |       | . |
|                       | 0.0    | 0.0    |     | 0.0   | \<0.1 | 1 |
| Thrombophlebitis deep |        |        | \-  |       |       |   |
|                       | 0.0    | 0.0    |     | \<0.1 | \<0.1 | 0 |
| Thrombophlebitis leg  |        |        | 0.0 |       |       | . |
|                       | 0.0    | 0.1    |     | \<0.1 | 0.0   | 0 |
| Thrombophlebitis leg  |        |        | \-  |       |       |   |
| deep                  | 0.9    | 0.6    |     | \<0.1 | \<0.1 | \ |
|                       |        |        | \-  |       |       | - |
| Thrombophlebitis leg  |        |        |     |       |       |   |
| superficial           |        |        | -   |       |       | 0 |
|                       |        |        | 0.1 |       |       | . |
| Unstable angina       |        |        |     |       |       | 0 |
|                       |        |        | 0.3 |       |       |   |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       | . |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       | . |
|                       |        |        |     |       |       | 2 |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       | . |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       | . |
|                       |        |        |     |       |       | 0 |
+-----------------------+--------+--------+-----+-------+-------+---+

1.  From Table 10.t (p 205); N49-00-06-035-102. Numbers are percentages.
    RD indicates risk reduction. None of the differences were
    statistically significant at p\<0.05.

**Table 54** (from Cardiorenal review, Doug Throckmorton, M.D.) shows
selected cardiac adverse events reported during the trial according to
aspirin use. For anginal disorders (especially the combined disorders),
there seems to be a trend toward more events in those patients receiving
celecoxib, regardless of aspirin use. However, for edema, there appears
to be a trend toward more events in those patients receiving ibuprofen.

**Table 54: Selected Cardiac Adverse Events Reported During CLASS
According to ASA Use^a^**.

+-----------------------------------------+---------+--------+---------+
| **Adverse Event**                       | **Cele  | **     | **Ibup  |
|                                         | coxib** | Diclof | rofen** |
|                                         |         | enac** |         |
|                                         | **400   |        | **800   |
|                                         | mg      | **75   | mg      |
|                                         | BID**   | mg     | TID**   |
|                                         |         | BID**  |         |
+-----------------------------------------+---------+--------+---------+
| **[ASA-Users]{.underline}**             | N=882   | N=445  | N=412   |
+-----------------------------------------+---------+--------+---------+
| Edema                                   |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Edema peripheral                      | 35      | 17     | **23    |
|                                         | (4.0%)  | (3.8%) | (       |
|                                         |         |        | 5.6%)** |
+-----------------------------------------+---------+--------+---------+
| > Edema (pooled reporting)^b^           | 38      | 20     | **28    |
|                                         | (4.3%)  | (4.5%) | (       |
|                                         |         |        | 6.8%)** |
+-----------------------------------------+---------+--------+---------+
| Angina                                  |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Unstable Angina                       | 8       | 4      | 1       |
|                                         | (0.9%)  | (0.9%) | (0.2%)  |
+-----------------------------------------+---------+--------+---------+
| > Angina Pectoris                       | 13      | 8      | 6       |
|                                         | (1.5%)  | (1.8%) | (1.5%)  |
+-----------------------------------------+---------+--------+---------+
| > Coronary Artery Disorder              | 15      | 3      | 5       |
|                                         | (1.7%)  | (0.7%) | (1.2%)  |
+-----------------------------------------+---------+--------+---------+
| > **Combined Anginal Disorders^c^**     | **36    | **15   | **12    |
|                                         | (       | (3     | (       |
|                                         | 4.1%)** | .4%)** | 2.9%)** |
+-----------------------------------------+---------+--------+---------+
| Myocardial Ischemia                     | 1       | 2      | 0 (0%)  |
|                                         | (0.1%)  | (0.4%) |         |
+-----------------------------------------+---------+--------+---------+
| Myocardial Infarction                   | 13      | 3      | 7       |
|                                         | (1.5%)  | (0.7%) | (1.7%)  |
+-----------------------------------------+---------+--------+---------+
| Hypertension                            | 24      | 14     | 19      |
|                                         | (2.7%)  | (3.1%) | (4.6%)  |
+-----------------------------------------+---------+--------+---------+
| Hypertension Aggravated                 | 12      | 2      | 7       |
|                                         | (1.4%)  | (0.4%) | (1.7%)  |
+-----------------------------------------+---------+--------+---------+
| Thrombophlebitis                        |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Thrombophlebitis, Deep                | 3       | 2      | 1       |
|                                         | (0.2%)  | (0.4%) | (0.2%)  |
+-----------------------------------------+---------+--------+---------+
| > Thrombophebitis, Combined^d^          | 3       | 3      | 1       |
|                                         | (0.2%)  | (0.4%) | (0.2%)  |
+-----------------------------------------+---------+--------+---------+
| Vasculitis                              | 1       | 0 (0%) | 0 (0%)  |
|                                         | (0.1%)  |        |         |
+-----------------------------------------+---------+--------+---------+
| **[Non-ASA Users]{.underline}**         | N=3105  | N=1551 | N=1573  |
+-----------------------------------------+---------+--------+---------+
| > Edema peripheral                      | 111     | 53     | **81    |
|                                         | (3.6%)  | (3.4%) | (       |
|                                         |         |        | 5.1%)** |
+-----------------------------------------+---------+--------+---------+
| > Edema (pooled reporting)^b^           | 127     | 61     | **96    |
|                                         | (4.1%)  | (3.9%) | (       |
|                                         |         |        | 6.1%)** |
+-----------------------------------------+---------+--------+---------+
| Angina                                  |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Unstable Angina                       | 2       | 0 (0%) | 1       |
|                                         | (       |        | (       |
|                                         | \<0.1%) |        | \<0.1%) |
+-----------------------------------------+---------+--------+---------+
| > Angina Pectoris                       | 9       | 2      | 6       |
|                                         | (0.3%)  | (0.1%) | (0.4%)  |
+-----------------------------------------+---------+--------+---------+
| > Coronary Artery Disorder              | 10      | 4      | 1       |
|                                         | (0.3%)  | (0.3%) | (       |
|                                         |         |        | \<0.1%) |
+-----------------------------------------+---------+--------+---------+
| > **Combined Anginal Disorders^c^**     | **21    | **6    | **8     |
|                                         | (0      | (0.    | (0      |
|                                         | .67%)** | 38%)** | .51%)** |
+-----------------------------------------+---------+--------+---------+
| Myocardial Ischemia                     | 1       | 0 (0%) | 0 (0%)  |
|                                         | (       |        |         |
|                                         | \<0.1%) |        |         |
+-----------------------------------------+---------+--------+---------+
| Myocardial Infarction                   | 6       | 2      | 2       |
|                                         | (0.2%)  | (0.1%) | (0.1%)  |
+-----------------------------------------+---------+--------+---------+
| Hypertension                            | 54      | 26     | 42      |
|                                         | (1.7%)  | (1.7%) | (2.7%)  |
+-----------------------------------------+---------+--------+---------+
| Hypertension Aggravated                 | 20      | 10     | 17      |
|                                         | (0.6%)  | (0.6%) | (1.1%)  |
+-----------------------------------------+---------+--------+---------+
| Thrombophlebitis                        |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Thrombophlebitis, Deep                | 9       | 3      | 0 (0%)  |
|                                         | (0.3%)  | (0.2%) |         |
+-----------------------------------------+---------+--------+---------+
| > Thrombophlebitis, Combined^d^         | 14      | 5      | 4       |
|                                         | (0.45%) | (0.3%) | (0.25%) |
+-----------------------------------------+---------+--------+---------+
| Vasculitis                              | 1       | 0 (0%) | 1       |
|                                         | (       |        | (       |
|                                         | \<0.1%) |        | \<0.1%) |
+-----------------------------------------+---------+--------+---------+

1.  Data from electronic submission, NDA 20-998 supplement S-009, Table
    T41.1.

b\. Includes edema, edema generalized, and edema peripheral.

c\. Includes unstable angina, angina pectoris and coronary artery
disorder.

d\. Includes AEs reported under the following terms: phlebitis,
thrombophlebitis, thrombophlebitis arm, thrombophlebitis deep,
thrombophlebitis leg, thrombophlebitis leg deep, thrombophlebitis leg
superficial.

**Table 55** (from Cardiorenal review, Doug Throckmorton, M.D.) shows
serious cardiac adverse events reported during the trial according to
aspirin use. In the non-aspirin users, there appears to be a slight
trend toward more events in those patients receiving celecoxib for
combined atrial and anginal disorders; this does not appear to be the
case for aspirin users.

**Table 55: Serious Adverse Events (SAEs) per 100 Pt-Yrs Reported During
CLASS by ASA Use^a^**.

+---------------------------------------+---------+---------+---------+
| **Adverse Event**                     | **Cele  | **Diclo | **Ibup  |
|                                       | coxib** | fenac** | rofen** |
|                                       |         |         |         |
|                                       | **400   | **75 mg | **800   |
|                                       | mg      | BID**   | mg      |
|                                       | BID**   |         | TID**   |
+---------------------------------------+---------+---------+---------+
| ######### ASA Users                   | N=882   | N=445   | N=412   |
|                                       |         |         |         |
|                                       | 517     | N=239   | 249     |
|                                       | Pt-Yrs  | Pt-Yrs  | Pt-Yrs  |
+---------------------------------------+---------+---------+---------+
| Cardiac SAEs                          |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Atrial Arrhythmias                  |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Arrhythmia Atrial                   | 2       | 0 (0%)  | 1       |
|                                       | (0.4%)  |         | (0.4%)  |
+---------------------------------------+---------+---------+---------+
| > Bradycardia                         | 0 (0%)  | 0 (0%)  | 0 (0%)  |
+---------------------------------------+---------+---------+---------+
| > Fibrillation Atrial                 | 4       | 1       | 3       |
|                                       | (0.8%)  | (0.4%)  | (1.2%)  |
+---------------------------------------+---------+---------+---------+
| > Tachycardia Supraventricular        | 1       | 0 (0%)  | 0 (0%)  |
|                                       | (0.2%)  |         |         |
+---------------------------------------+---------+---------+---------+
| > Combined Atrial SAEs^b^             | 7       | 1       | 4       |
|                                       | (1.4%)  | (0.4%)  | (1.6%)  |
+---------------------------------------+---------+---------+---------+
| > Angina                              |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Unstable Angina                     | 6       | 4       | 0 (0%)  |
|                                       | (1.2%)  | (1.7%)  |         |
+---------------------------------------+---------+---------+---------+
| > Angina Pectoris                     | 3       | 5       | 4       |
|                                       | (0.6%)  | (2.1%)  | (1.6%)  |
+---------------------------------------+---------+---------+---------+
| > Coronary Artery Disorder            | 11      | 2       | 5       |
|                                       | (2.1%)  | (0.8%)  | (2.0%)  |
+---------------------------------------+---------+---------+---------+
| > Combined Anginal Disorders^c^       | 20      | 11      | 8       |
|                                       | (3.9%)  | (4.6%)  | (3.2%)  |
+---------------------------------------+---------+---------+---------+
| > Myocardial Infarction               | 13      | 2       | 7       |
|                                       | (2.5%)  | (0.8%)  | (2.8%)  |
+---------------------------------------+---------+---------+---------+
| > Thrombophlebitis Combined^d^        | 0 (0%)  | 2       | 1       |
|                                       |         | (0.8%)  | (0.4%)  |
+---------------------------------------+---------+---------+---------+
| ######### Non-ASA Users               | N=3105  | N=1551  | N=1573  |
|                                       |         |         |         |
|                                       | 1804    | 841     | 874     |
|                                       | Pt-Yrs  | Pt-Yrs  | Pt-Yrs  |
+---------------------------------------+---------+---------+---------+
| Cardiac SAEs                          |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Atrial Arrhythmias                  |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Arrhythmia Atrial                   | 0 (0%)  | 0 (0%)  | 0 (0%)  |
+---------------------------------------+---------+---------+---------+
| > Bradycardia                         | 2       | 0 (0%)  | 0 (0%)  |
|                                       | (0.1%)  |         |         |
+---------------------------------------+---------+---------+---------+
| > Fibrillation Atrial                 | 5       | 1       | 0 (0%)  |
|                                       | (0.3%)  | (0.1%)  |         |
+---------------------------------------+---------+---------+---------+
| > Tachycardia Supraventricular        | 2       | 0 (0%)  | 0 (0%)  |
|                                       | (0.1%)  |         |         |
+---------------------------------------+---------+---------+---------+
| > **Combined Atrial SAEs^b^**         | **6     | **1     | **0     |
|                                       | (       | (       | (0%)**  |
|                                       | 0.3%)** | 0.1%)** |         |
+---------------------------------------+---------+---------+---------+
| > Angina                              |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Unstable Angina                     | 2       | 0 (0%)  | 0 (0%)  |
|                                       | (0.1%)  |         |         |
+---------------------------------------+---------+---------+---------+
| > Angina Pectoris                     | 1       | 0 (0%)  | 2       |
|                                       | (       |         | (0.2%)  |
|                                       | \<0.1%) |         |         |
+---------------------------------------+---------+---------+---------+
| > Coronary Artery Disorder            | 8       | 3       | 0 (0%)  |
|                                       | (0.4%)  | (0.4%)  |         |
+---------------------------------------+---------+---------+---------+
| > **Combined Anginal Disorders^c^**   | **10    | **3     | **2     |
|                                       | (       | (       | (       |
|                                       | 0.6%)** | 0.4%)** | 0.2%)** |
+---------------------------------------+---------+---------+---------+
| > Myocardial Infarction               | 6       | 2       | 2       |
|                                       | (0.3%)  | (0.2%)  | (0.2%)  |
+---------------------------------------+---------+---------+---------+
| > Thrombophlebitis Combined^d^        | 8       | 4 (0.5  | 0 (0%)  |
|                                       | (0.4%)  | %)      |         |
+---------------------------------------+---------+---------+---------+

1.  Data from electronic data submission, Appendix 2.9.4 and 2.9.3.

b\. Sum of atrial arrhythmia, atrial fibrillation, bradycardia and
tachycardia.

c\. Includes unstable angina, angina pectoris and coronary artery
disorder.

d\. Includes AEs reported under the following terms: phlebitis,
thrombophlebitis, thrombophlebitis arm, thrombophlebitis deep,
thrombophlebitis leg, thrombophlebitis leg deep, thrombophlebitis leg
superficial.

e\. These SAEs were not reported by investigators.

[Discussion/Conclusions (Section 12):]{.underline}

#### Safety

In contrast to efficacy, the CLASS trial was designed to assess safety
endpoints of celecoxib relative to the NSAIDs, diclofenac and ibuprofen.
In so doing, arguments were made that this trial was also testing the
COX-2 safety hypothesis; this hypothesis being (in general terms) that
if COX-2 is not present in any particular organ or cell, drugs targeting
COX-2 should not be a problem. Safety may be considered more from the
molecular understanding of receptor structure and function, and less so
from the prospective of a xenobiotic with its potentially unknown (and
non-mechanism based) safety hazards.

The central clinical trial feature in CLASS that tested this hypothesis
was the bona fide use of twice to four-fold the highest doses for two
FDA-approved labeled indications, RA and OA respectively. As noted by
the Sponsor, the multiples of dosing employed for celecoxib was to make
comparisons of safety in a "robust" fashion. A safety trial, with
"NSAIDs" at similar multiples of their respective labeled doses for OA
and RA has not yet been conducted despite the long history of usage of
these important and widely used drugs. Unfortunately, the fact that such
multiples of the NSAIDs selected for this trial were not included
ultimately confounds all discussions and/or conclusions of this CLASS
trial.

While some might comment that these multiples were not robust enough
(i.e. should be 10X), it appears clear that the dosing, sample size, and
selection of safety endpoints all contributed to the highly unique and
progressive character of the CLASS trial. Certainly, pushing the
envelope in terms of safety has the potential for improvements in safety
at both the patient and population levels. As noted, one of the unique
aspects of the CLASS trial was the selection of the primary UGI safety
endpoint. The gastrointestinal toxicity of NSAIDs, particularly to the
upper GI tract, has long been felt by many to be one of the most
important iatrogenic adverse events associated with modern drug
therapies.

# Cardiovascular events

*(More details of cardiovascular events are found in the review by
Douglas Throckmorton, M.D.)*

When considering the deaths and other serious adverse events that
occurred in this trial, they appear to be consistent in nature and
frequency with those that would be expected in a long-term trial in this
patient population. For example, most patients enrolled had several
concomitant illnesses or significant medical histories, and many were
elderly. As noted (Table 5) the median age was approximately 61 years,
with about 11% of patients in each group 75 years. Approximately 40% of
patients in each treatment group had a self-reported history of
cardiovascular disease and approximately 20% took ASA prophylactically.

While serious adverse events and deaths related to cardiovascular
disorders were not unexpected, was there evidence in the CLASS trial
that any treatment group had an excess of these types of events relative
to the other groups? For example, concerns have been raised about the
possibility that COX-2 selective agents may predispose to thromboembolic
events (i.e. myocardial infarction, deep venous thrombosis, pulmonary
emboli, cerebrovascular accidents, etc.) owing to their preferential
inhibition of endothelial prostacyclins relative to platelet
thromboxanes. Further, literature reports of trials (i.e. VIGOR) of
other COX-2 selective agents have also raised this possibility.

In the original NDA, myocardial infarction was noted to occur at a
higher rate in celecoxib-treated as compared to placebo-treated
patients. In the long-term trial (Trial 024) that was included in the
NDA submission, the predominate (\>90%) cause of death for patients
taking celecoxib at any dose was cardiovascular. The majority of these
deaths were felt to represent progression of previously known
cardiovascular disease. Examination of Kaplan-Meier survival curves for
both the controlled and long-term trials in the NDA did not support the
conclusion that there was a relationship between any given duration of
exposure to celecoxib and increased mortality. There were suggestions of
a dose-response relationship (Table 60, NDA 20-998; 100 mg BID
celecoxib, 0% crude mortality rate vs. 400 mg BID celecoxib, 0.64% crude
mortality rate) between cardiovascular mortality and celecoxib use that
could not be adequately addressed by the data. However, the
cardiovascular mortality rates with celecoxib were lower than those seen
with the active controls employed in the NDA, which confounded
interpretation of these data. Of note, there was no suggestion, in the
original NDA, of any rare or unusual cardiac toxicities.

In the CLASS trial, it is not possible to examine any dose-response
relationships, rather, only comparisons of drugs at the doses employed
and in the population studied. Given these caveats, there was no
apparent, consistent adverse effect of celecoxib in the reported
parameters of cardiovascular safety when compared to either diclofenac
or ibuprofen (Table 52). When these events were examined with or without
aspirin use, these relationships did not appear to change (Table 53) in
any significant way. However, as expected since they are at higher risk,
patients taking aspirin had a higher incidence of cardiac ischemic
events in all three treatment groups as compared to those not taking
aspirin. Of note, discontinuations for thrombotic cardiac events were
not significantly different in the treatment groups (Table T41.1, sNDA
and 2.1.d.1, Cardiorenal Consult).

When cardiac adverse events (Table 54) or serious cardiac adverse events
(Table 55) and the relationship of **aspirin use** are analyzed in more
detail, some differences appear to emerge. For example, examination of
selected cardiac adverse events (Table 54) reported during the trial
suggests that anginal disorders (especially the combined disorders) was
numerically higher in those patients receiving celecoxib, regardless of
aspirin use. In the patients not receiving aspirin, the rate of
myocardial infarction was also slightly higher in the celecoxib group
(0.2%) compared with the other two drugs (0.1%). Of note, for edema and
hypertension, there appears to be a trend toward more events in those
patients receiving ibuprofen regardless of aspirin use.

For serious cardiac adverse events (Table 55) in the non-aspirin users,
there appears to be a trend toward more events in those patients
receiving celecoxib for atrial events and anginal disorders, especially
when combined; this does not appear to be the case for aspirin users.
The importance of any of these differences are difficult to interpret
especially since the trial randomization was not stratified for aspirin
use, any comparisons of the aspirin or non-aspirin users has limited
power to detect only large differences between these groups. This
difficulty in interpretation is also evident in considering
cardiovascular mortality rates (Table 39 and comment). Overall though,
these findings would not seem to support a conclusion that celecoxib has
a large adverse effect on cardiovascular mortality compared to the
non-selective NSAIDs. If the incidence rates for adverse events
(including serious) is confirmed in trials designed to specifically
address these important issues, it may be that the degree of loss of
blood flow may be a factor in understanding these events, compared to
mortality.

# Renal events

*(More details of renal events are found in the review by Douglas
Throckmorton, M.D.)*

As noted in the original NDA, the overall findings with celecoxib were
that renal events were more like the comparator NSAIDs than the placebo
controls. For example, there was an association between celecoxib
administration and the development of clinically significant edema (i.e.
peripheral), sodium retention, worsened hypertension in susceptible
individuals, hypophosphatemia, hyperchloremia, and elevations of serum
creatinine and BUN with proteinuria as was noted in the comparator
NSAIDs. There were not clear signals, however, for serious renal events
such as bony fractures (suggesting significant acid-base changes), renal
stone formation, nephrotic syndrome, acute renal failure requiring
dialysis, papillary necrosis, or interstitial nephritis. However, there
were patients on celecoxib that were withdrawn from the long-term,
open-label trial (Trial 024) because of renal adverse events, including
acute renal failure. One outstanding issue was whether celecoxib altered
the acid-base balance since no measurements (e.g. serum bicarbonate,
arterial pH) were performed as part of the original NDA.

Regarding the issue of acid-base balance, serum HCO~3~ was measured in
the CLASS trial and adverse events possibly related to changes in
acid-base balance were collected. Between 1 and 2% of the subjects in
all three treatment groups had a measured HCO~3~ \<20 meq/dl during the
study after starting with a normal baseline \>25 mg/dl. The rate for
celecoxib, however, was less than that of the two comparator drugs. In
addition, there was no increase in reported clinical adverse events
related to changes in acid-base balance (such as bony fractures which
could indicate chronic acidosis with demineralization, Table T41.1,
sNDA) in the celecoxib group although such adverse events were quite
rare in the database for all three drugs. Overall, then, the rate of
clinically-relevant changes in acid-base balance was similar for
celecoxib, diclofenac and ibuprofen.

Regarding the comparative incidence of reported clinical renal adverse
events between the three treatment groups, there was no consistent
adverse effect of celecoxib in the reported parameters of renal safety
when compared with either diclofenac or ibuprofen. In particular, the
reported rates of uremia, nephrotic syndrome and severe hyperkalemia in
CLASS were all less than 1 per 1000 patient-years of exposure for all
three drugs. Celecoxib use was also not apparently associated with an
increase in hypertension or edema compared with diclofenac and ibuprofen
(Table 50).

When renal adverse events related to laboratory measurements were
examined, celecoxib did not appear to have a striking adverse effect
with regard to any renal parameter measured, compared with diclofenac or
ibuprofen (Tables 47, 50). The incidence of hyperkalemia, assessed as
clinical events and as changes in lab measurements, was consistently
more common in the celecoxib group than in either of the comparators,
although the difference did not achieve nominal statistical significance
for any measure (Table T 41.1 sNDA and 2.1.c.1 and 2.1.c.2, Cardiorenal
Consult).

Regarding changes in renal laboratory parameters, **when examined as
mean changes** from baseline, no clinically relevant differences between
the three treatment groups were seen at any time point for the changes
in mean BUN, serum creatinine, phosphate, bicarbonate and chloride. The
reported differences, some of which achieved nominal statistical
significance, were quite small and of no apparent clinical relevance
(Table T44.1, sNDA). Use or not of aspirin did not seem to influence
these particular results.

Of note, it does appear that patients who used **aspirin** in all three
treatment groups had a higher incidence of increases in BUN than
patients who did not use aspirin. Hyperkalemia as an AE was somewhat
higher in the celecoxib group, regardless of aspirin use (Table T 41.2
and T41.3, sNDA and 2.1.c.2, Cardiorenal Consult). For the renal SAEs
(Table T43, sNDA and 2.1.b.1, Cardiorenal Consult), too few (i.e. none
in any treatment group for hyper- or hypokalemia, acidosis, nephrotic
syndrome, edema, uremia-1 case for ibuprofen, or renal calculus-4 cases
for celecoxib, 2 for ibuprofen) were reported to analyze according to
the use of aspirin.

**Overall Safety of Celebrex**

The results presented in this sNDA with celecoxib at the
supratherapeutic doses studied, support the overall safety of celecoxib.
While adverse events for celecoxib during the entire study period were
statistically greater than those of the comparator drugs (Table 42),
this did not seem to translate into more withdrawals for celecoxib
versus ibuprofen or diclofenac (Table 3). Also, although serious adverse
events were numerically higher for celecoxib (Table 41), there were no
obvious trends to suggest any specific safety risks. Similarly, the
death rate and pattern (Tables 38 and 39) did not suggest any obvious
safety risks for celecoxib. Interestingly, no deaths in the celecoxib
group occurred for GI, hepatic, renal or dermatologic causes, but the
same was true for the comparators.

**Conclusions:**

As noted earlier, the CLASS trial was a robust testing of the safety of
Celebrex at doses 2-4 times those currently labeled for RA or OA,
respectively. The NSAID comparators, ibuprofen and diclofenac, were
given at their commonly prescribed (not maximum) doses. Therefore, any
conclusions regarding the relative safety or efficacy of Celebrex needs
to be viewed in this context. However, the following are some
conclusions from this CLASS trial:

1.  Celecoxib does not appear to be more effective for treating the
    signs and symptoms of OA or RA than the NSAID comparators.

2.  Celecoxib did not demonstrate statistical superiority to NSAIDs
    (pooled) or either comparator (diclofenac and ibuprofen) with
    regards to the primary safety endpoint of CSUGIEs at any point in
    the trial although there were trends (noted below) that favored
    celecoxib. When the subgroup of non-aspirin users was considered, or
    the definition of the UGI endpoints was expanded to include ulcer
    events not deemed to be CSUGIEs (i.e. GDUs), celecoxib did
    demonstrate superiority to pooled NSAIDs, and to ibuprofen (only),
    during this trial. This superiority was not a pre-specified efficacy
    endpoint and was not corrected statistically for multiplicity.
    Celecoxib did not demonstrate statistical superiority to diclofenac
    regardless of selection of study endpoint or aspirin use during any
    point in the trial.

3.  Aspirin use appears to influence event rates for gastrointestinal,
    renal and possibly cardiac outcomes. However, owing to the nature of
    this trial, particularly that use of aspirin would indicate a higher
    level of pre-existing cardiovascular disease and aspirin use was not
    stratified, it is unclear how aspirin impacts these outcomes among
    the treatment groups evaluated in this trial.

4.  Of note, a "paradoxical" effect was noted with regards to ASA use
    and the UGI endpoints of CSUGIE GDU. While co-use of ASA increased
    rates of these events in the celecoxib and diclofenac arms, the
    events decreased in the ibuprofen arm. The clinical significance, if
    any, of these results remains to be determined from the database.

5.  The CLASS trial contains no evidence for an adverse effect of
    celecoxib on acid-base balance relative to either diclofenac or
    ibuprofen. All groups rarely had changes in this renal parameter.

6.  The CLASS trial data do not support an apparent adverse effect of
    celecoxib on cardiovascular mortality or on serious adverse events
    related to thrombosis relative to either diclofenac or ibuprofen.
    The data do not exclude a less apparent effect, reflected in the
    relative rates of cardiac adverse events related to ischemia.

7.  The CLASS trial data do not support an apparent adverse effect of
    celecoxib on renal or cardiac adverse events relative to either
    diclofenac or ibuprofen. This includes adverse events reported by
    investigators (*e.g.*, hypertension, uremia) and those detected
    through routine laboratory or blood pressure measurements (*e.g.*,
    increased BUN/ serum creatinine or systolic blood pressure).

8.  Hyperkalemia, however measured, was consistently more frequent in
    patients taking celecoxib than for diclofenac or ibuprofen, but
    these differences were small and not reflected in an increase in
    serious adverse events related to hyperkalemia.

9.  The CLASS trial data do not support the conclusion that serious
    hepatic adverse events are more frequent in those patients taking
    celecoxib than diclofenac or ibuprofen. In fact, hepatic enzyme
    elevations and withdrawals for these elevations were significantly
    and consistently reduced compared to diclofenac.

10. The incidence of rash (generally mild or moderate, none were
    serious) was statistically significantly higher for celecoxib than
    for either diclofenac or ibuprofen. The incidence of pruritis was
    also statistically significantly higher for celecoxib than
    ibuprofen, but not diclofenac. The incidence of clinically
    significant rash with celecoxib was estimated to be 0.13%. The
    percentage of patients withdrawing for either rash or pruritis was
    generally higher in the celecoxib group.

11. There were no deaths from gastrointestinal, hepatic, renal or
    dermatologic causes in any treatment group during the time period of
    the CLASS trial.

12. No new safety issues were apparent regarding respiratory,
    endocrine/metabolic, CNS/PNS or infectious disease safety.

13. Celecoxib was generally safe and well tolerated at the
    supratherapeutic doses employed in this CLASS trial.

14. Overall safety, as defined by the endpoints of deaths, serious
    adverse events and withdrawals due to adverse events did not appear
    to be meaningfully or consistently different among the three
    treatment groups.