Celebrex

[celecoxib]

One area in the rectum and up to four areas in the colon were identified at baseline for specific follow-up, and polyps were counted at baseline and following six months of treatment. The mean reduction in the number of colorectal polyps was 28% for CELEBREX 400 mg BID, 12% for CELEBREX 100 mg BID and 5% for placebo. The reduction in polyps observed with CELEBREX 400 mg BID was statistically superior to placebo at the six-month timepoint (p=0.003). (See Figure 1.)

Figure 1 Figure 1
Percent Change from Baseline inPercent Change from Baseline in
Number of Colorectal PolypsNumber of Colorectal Polyps
(FAP Patients)(FAP Patients)

-50-50
-45-45
-40-40
-35-35
-30-30
-25-25
-20-20
-15-15
-10-10
-5-5
00
-50-50
-45-45
-40-40
-35-35
-30-30
-25-25
-20-20
-15-15
-10-10
-5-5

Placebo
-4.5%
100 mg BID
-11.9%
400 mg BID*
-28.0%

Text Continues Below

---

N=15 N=32 N=30

Percent Change from BaselinePercent Change from Baseline

* p=0.003 versus placebo

Special Studies

Endoscopic Studies:

Scheduled upper GI endoscopic evaluations were performed in over 4,500 arthritis patients who were enrolled in five controlled randomized 12-24 week trials using active comparators, two of which also included placebo controls. There was no consistent relationship between the incidence of gastroduodenal ulcers and the dose of CELEBREX over the range studied.

Table 2 summarizes the incidence of endoscopic ulcers in two 12-week studies that enrolled patients in whom baseline endoscopies revealed no ulcers.

Table 2
Incidence of Gastroduodenal Ulcers from Endoscopic Studies in OA and RA Patients
3 Month Studies

Study 1 (n = 1108) Study 2 (n= 1049)

Placebo 2.3% (5/217) 2.0% (4/200)
Celebrex 50 mg BID 3.4% (8/233) ---
Celebrex 100 mg BID 3.1% (7/227) 4.0% (9/223)
Celebrex 200 mg BID 5.9% (13/221) 2.7% (6/219)
Celebrex 400 mg BID --- 4.1% (8/ 197)
Naproxen 500 mg BID 16.2% (34/210)* 17.6% (37/210)*

*p 0.05 vs all other treatments

Table 3 summarizes data from two 12-week studies that enrolled patients in whom baseline endoscopies revealed no ulcers. Patients underwent interval endoscopies every 4 weeks to give information on ulcer risk over time.

Table 3
Incidence of Gastroduodenal Ulcers from 3-Month Serial Endoscopy Studies in OA and RA Patients
Week 4 Week 8 Week 12 Final
Study 3 (n=523)
Celebrex 4.0% 2.2% 1.5% 7.5%
200 mg BID (10/252)* (5/227)* (3/196)* (20/266)*
----------------------------------------------------------------------------------------
Naproxen 19.0% 14.2% 9.9% 34.6%
500 mg BID (47/247) (26/182) (14/141) (89/257)
_______________________________________________________

Study 4 (n=1062)
Celebrex 3.9% 2.4% 1.8% 7.0%
200 mg BID (13/337) † (7/296) † (5/274) † (25/356) †
----------------------------------------------------------------------------------------
Diclofenac 5.1% 3.3% 2.9% 9.7%
75 mg BID (18/350) (10/306) (8/278) (36/372)
----------------------------------------------------------------------------------------
Ibuprofen 13.0% 6.2% 9.6% 23.3%
800 mg TID (42/323) (15/241) (21/219) (78/334)
_______________________________________________________
*p 0.05 Celebrexvs. naproxen based on interval and cumulative analyses
† p0.05 Celebrex vs. ibuprofen based on interval and cumulative analyses

One randomized and double-blind 6-month study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The incidence of endoscopic ulcers in patients taking CELEBREX 200 mg BID was 4% vs 15% for patients taking diclofenac SR 75 mg BID (p<0.001).

In 4 of the 5 endoscopic studies, approximately 11% of patients (440/4,000) were taking aspirin (325 mg/day). In the CELEBREX groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in non-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin.

The correlation between findings of endoscopic studies, and the relative incidence of clinically significant serious upper GI events has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving CELEBREX in controlled and open-labeled trials, albeit infrequently (see Use with Aspirin and WARNINGS - Gastrointestinal (GI) Effects).

Use with Aspirin:

The Celecoxib Long-Term Arthritis Safety Study (CLASS) was a prospective long-term safety outcome study conducted postmarketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received CELEBREX 400 mg BID (4-fold and 2-fold the recommended OA and RA doses, respectively, and the approved dose for FAP), ibuprofen 800 mg TID or diclofenac 75 mg BID (common therapeutic doses).

Median exposures for CELEBREX (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The Kaplan-Meier cumulative rates at 9 months are provided for all analyses. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction). Patients were allowed to take concomitant low-dose ( 325 mg/day) aspirin (ASA) for cardiovascular prophylaxis (ASA subgroups: CELEBREX, n = 882; diclofenac, n = 445; ibuprofen, n = 412).

Differences in the incidence of complicated ulcers between CELEBREX and the combined group of ibuprofen and diclofenac were not statistically significant. Those patients on CELEBREX and concomitant low-dose ASA experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (see WARNINGS - Gastrointestinal (GI) Effects). The results for CELEBREX are displayed in Table 4. For complicated and symptomatic ulcer rates, see WARNINGS - Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation.

Table 4
Effects of Co-Administration of Low-Dose Aspirin on Complicated Ulcer Rates with
CELEBREX 400 mg BID (Kaplan-Meier Rates at 9 months [%])
Non-Aspirin Users Aspirin Users
n=3105 n=882
Complicated Ulcers 0.32 1.12
Platelets:

In clinical trials, CELEBREX at single doses up to 800 mg and multiple doses of 600 mg BID for up to 7 days duration (higher than recommended therapeutic doses) had no effect on platelet aggregation and bleeding time. Comparators (naproxen 500 mg BID, ibuprofen 800 mg TID, diclofenac 75 mg BID) significantly reduced platelet aggregation and prolonged bleeding time.

Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis.

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