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.

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 first of these studies was the APC (Prevention of Sporadic Colorectal Adenomas with Celecoxib) study, which compared Celebrex 400 mg twice daily (N=671) and Celebrex 200 mg twice daily (N=685) to placebo (N=679). Preliminary safety information from this trial demonstrated a dose-related increase in serious cardiovascular events (mainly myocardial infarction [MI]) at Celebrex doses of 200 mg and 400 mg twice daily compared to placebo). The cumulative rates of serious cardiovascular thrombotic events began to differ between the Celebrex treatment groups and placebo after approximately one year of treatment. There were 2.8 to 3.1 years of follow-up in the APC trial except those patients who died earlier. The relative risk (RR) for the composite endpoint of cardiovascular death, MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for the higher dose and 2.5 (95% CI 1.0 – 6.4) for the lower dose of Celebrex compared to placebo. The absolute risk for the composite endpoint was 3.0% for the higher dose of Celebrex, 2.2% for the lower dose of Celebrex, and 0.9% for placebo.

The second long-term study, PreSAP (Prevention of Colorectal Sporadic Adenomatous Polyps) compared Celebrex 400 mg once daily to placebo. Preliminary safety information from this trial demonstrated no increased cardiovascular risk for the composite endpoint of cardiovascular death, MI or stroke. The reason for the differing results for CV events in the APC and PreSAP trials is not known.

Clinical trials of other COX-2 selective and nonselective 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.

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.

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 Special Studies - CLASS).

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.

Serious clinically significant upper GI bleeding has been observed in patients receiving Celebrex in controlled and open-labeled trials (see Special Studies - CLASS and WARNINGS – Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding and Perforation ).

Animal Toxicology

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