Osteoarthritis
CELEBREX has demonstrated significant reduction in joint pain compared to
placebo. CELEBREX was evaluated for treatment of the signs and the symptoms
of OA of the knee and hip in placebo- and active-controlled clinical trials
of up to 12 weeks duration. In patients with OA, treatment with CELEBREX
100 mg twice daily or 200 mg once daily resulted in improvement in WOMAC
(Western Ontario and McMaster Universities) osteoarthritis index, a composite
of pain, stiffness, and functional measures in OA. In three 12-week studies
of pain accompanying OA flare, CELEBREX doses of 100 mg twice daily and
200 mg twice daily provided significant reduction of pain within 24-48 hours
of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice
daily the effectiveness of CELEBREX was shown to be similar to that of naproxen
500 mg twice daily. Doses of 200 mg twice daily provided no additional benefit
above that seen with 100 mg twice daily. A total daily dose of 200 mg has
been shown to be equally effective whether administered as 100 mg twice
daily or 200 mg once daily.
Rheumatoid Arthritis
CELEBREX has demonstrated significant reduction in joint tenderness/pain
and joint swelling compared to placebo. CELEBREX was evaluated for treatment
of the signs and symptoms of RA in placebo- and active-controlled clinical
trials of up to 24 weeks in duration. CELEBREX was shown to be superior
to placebo in these studies, using the ACR20 Responder Index, a composite
of clinical, laboratory, and functional measures in RA. CELEBREX doses of
100 mg twice daily and 200 mg twice daily were similar in effectiveness
and both were comparable to naproxen 500 mg twice daily.
Although CELEBREX 100 mg twice daily and 200 mg twice daily provided
similar overall effectiveness, some patients derived additional benefit
from the 200 mg twice daily dose. Doses of 400 mg twice daily provided no
additional benefit above that seen with 100-200 mg twice daily.
Juvenile Rheumatoid Arthritis
In a 12-week, randomized, double-blind active-controlled, parallel-group,
multicenter, non-inferiority study, patients from 2 years to 17 years of
age with pauciarticular, polyarticular course JRA or systemic onset JRA
(with currently inactive systemic features), received one of the following
treatments: celecoxib 3 mg/kg (to a maximum of 150 mg) twice daily; celecoxib
6 mg/kg (to a maximum of 300 mg) twice daily; or naproxen 7.5 mg/kg (to
a maximum of 500 mg) twice daily. The response rates were based upon the
JRA Definition of Improvement greater than or equal to 30% (JRA DOI 30)
criterion, which is a composite of clinical, laboratory, and functional
measures of JRA. The JRA DOI 30 response rates at week 12 were 69%, 80%
and 67% in the celecoxib 3 mg/kg BID, celecoxib 6 mg/kg BID, and naproxen
7.5 mg/kg BID treatment groups, respectively.
The efficacy and safety of CELEBREX for JRA have not been studied beyond
six months. The long-term cardiovascular toxicity in children exposed to
CELEBREX has not been evaluated and it is unknown if the long-term risk
may be similar to that seen in adults exposed to CELEBREX or other COX-2
selective and non-selective NSAIDS (see Boxed Warning, Warnings and Precautions).
Ankylosing Spondylitis
CELEBREX was evaluated in AS patients in two placebo- and active-controlled
clinical trials of 6 and 12 weeks duration. CELEBREX at doses of 100 mg
twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically
superior to placebo in these studies for all three co-primary efficacy measures
assessing global pain intensity (Visual Analogue Scale), global disease
activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing
Spondylitis Functional Index). In the 12-week study, there was no difference
in the extent of improvement between the 200 mg and 400 mg CELEBREX doses
in a comparison of mean change from baseline, but there was a greater percentage
of patients who responded to CELEBREX 400 mg, 53%, than to CELEBREX 200
mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria
(ASAS 20). The ASAS 20 defines a responder as improvement from baseline
of at least 20% and an absolute improvement of at least 10 mm, on a 0 to
100 mm scale, in at least three of the four following domains: patient global
pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The
responder analysis also demonstrated no change in the responder rates beyond
6 weeks.
Analgesia, including Primary Dysmenorrhea
In acute analgesic models of post-oral surgery pain, post-orthopedic surgical
pain, and primary dysmenorrhea, CELEBREX relieved pain that was rated by
patients as moderate to severe. Single doses [see Dosage and Administration]
of CELEBREX provided pain relief within 60 minutes.
Familial Adenomatous Polyposis
CELEBREX was evaluated to reduce the number of adenomatous colorectal polyps.
A randomized, double-blind, placebo-controlled study was conducted in patients
with FAP. The study population included 58 patients with a prior subtotal
or total colectomy and 25 patients with an intact colon. Thirteen patients
had the attenuated FAP phenotype.
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 twice daily, 12% for CELEBREX
100 mg twice daily and 5% for placebo. The reduction in polyps observed
with CELEBREX 400 mg twice daily was statistically superior to placebo at
the six-month timepoint (p=0.003). (See Figure 1.)
Figure 1
Percent Change from Baseline in
Number of Colorectal Polyps
(FAP Patients)
Special Studies
Adenomatous Polyp Prevention Studies:
Cardiovascular safety was evaluated in two randomized, double-blind, placebo-controlled,
three year studies involving patients with Sporadic Adenomatous Polyps treated
with CELEBREX: the APC trial (Adenoma Prevention with Celecoxib) and the
PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC
trial, there was a dose-related increase in the composite endpoint (adjudicated)
of cardiovascular death, myocardial infarction, or stroke with celecoxib
compared to placebo over 3 years of treatment. The PreSAP trial did not
demonstrate a statistically significant increased risk for the same composite
endpoint (adjudicated):
- In the APC trial, the hazard ratios compared to placebo for a composite
endpoint (adjudicated) of cardiovascular death, myocardial infarction,
or stroke were 3.4 (95% CI 1.4 - 8.5) with celecoxib 400 mg twice daily
and 2.8 (95% CI 1.1 - 7.2) with celecoxib 200 mg twice daily. Cumulative
rates for this composite endpoint over 3 years were 3.0% (20/671 subjects)
and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects)
with placebo treatment. The increases in both celecoxib dose groups
versus placebo-treated patients were mainly due to an increased incidence
of myocardial infarction.
- In the PreSAP trial, the hazard ratio for this same composite endpoint
(adjudicated) was 1.2 (95% CI 0.6 - 2.4) with celecoxib 400 mg once
daily compared to placebo. Cumulative rates for this composite endpoint
over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects),
respectively.
Clinical trials of other COX-2 selective and non-selective NSAIDs of up
to three-years duration have shown an increased risk of serious cardiovascular
thrombotic events, myocardial infarction, and stroke, which can be fatal.
As a result, all NSAIDs are considered potentially associated with this
risk.
Celecoxib Long-Term Arthritis Safety Study (CLASS):
This was a prospective long-term safety outcome study conducted post-marketing
in approximately 5,800 OA patients and 2,200 RA patients. Patients received
CELEBREX 400 mg twice daily (4-fold and 2-fold the recommended OA and RA
doses, respectively, and the approved dose for FAP), ibuprofen 800 mg three
times daily or diclofenac 75 mg twice daily (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 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.
Patients on CELEBREX and concomitant low-dose ASA (N=882) experienced
4-fold higher rates of complicated ulcers compared to those not on ASA (N=3105).
The Kaplan-Meier rate for complicated ulcers at 9 months was 1.12% versus
0.32% for those on low-dose ASA and those not on ASA, respectively (see
Warnings and Precautions).
The estimated cumulative rates at 9 months of complicated and symptomatic
ulcers for patients treated with CELEBREX 400 mg twice daily are described
in Table 4. Table 4 also displays results for patients less than or greater
than 65 years of age. The difference in rates between CELEBREX alone and
CELEBREX with ASA groups may be due to the higher risk for GI events in
ASA users.
Table 4
Complicated and Symptomatic Ulcer Rates in Patients
Taking CELEBREX 400 mg Twice Daily (Kaplan-Meier
Rates at 9 months [%]) Based on Risk Factors
In a small number of patients with a history of ulcer disease, the complicated
and symptomatic ulcer rates in patients taking CELEBREX alone or CELEBREX
with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48 weeks.
These results are to be expected in patients with a prior history of ulcer
disease (see Warnings and Precautions and Adverse Reactions).
Cardiovascular safety outcomes were also evaluated in the CLASS trial.
Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular
thromboembolic adverse events (including MI, pulmonary embolism, deep venous
thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular
accidents) demonstrated no differences between the CELEBREX, diclofenac,
or ibuprofen treatment groups. The cumulative rates in all patients at nine
months for CELEBREX, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%,
respectively. The cumulative rates in non-ASA users at nine months in each
of the three treatment groups were less than 1%. The cumulative rates for
myocardial infarction in non-ASA users at nine months in each of the three
treatment groups were less than 0.2%. There was no placebo group in the
CLASS trial, which limits the ability to determine whether the three drugs
tested had no increased risk of CV events or if they all increased the risk
to a similar degree.
Endoscopic Studies: The correlation between findings of
short-term endoscopic studies with CELEBREX and the relative incidence of
clinically significant serious upper GI events with long-term use has not
been established. Serious clinically significant upper GI bleeding has been
observed in patients receiving CELEBREX in controlled and open-labeled trials
(see Warnings and Precautions and Clinical Studies).
A randomized, double-blind 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 twice daily was
4% vs. 15% for patients taking diclofenac SR 75 mg twice daily. However,
CELEBREX was not statistically different than diclofenac for clinically
relevant GI outcomes in the CLASS trial (see Clinical Studies).
The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled
studies in 2157 OA and RA patients in whom baseline endoscopies revealed
no ulcers. There was no dose relationship for the incidence of gastroduodenal
ulcers and the dose of CELEBREX (50 mg to 400 mg twice daily). The incidence
for naproxen 500 mg twice daily was 16.2 and 17.6% in the two studies, for
placebo was 2.0 and 2.3%, and for all doses of CELEBREX the incidence ranged
between 2.7%-5.9%. There have been no large, clinical outcome studies to
compare clinically relevant GI outcomes with CELEBREX and naproxen.
In the endoscopic studies, approximately 11% of patients 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.