Celebrex Label Update Has CV Profile Similar To NSAIDs, No New GI Safety

The updated labeling for Pharmacia/Pfizer's COX-2 inhibitor Celebrex draws an unequivocal distinction between it and Merck's COX-2 Vioxx .

FDA's June 7 approval of a labeling supplement based on the CLASS study should give Celebrex a cardiovascular safety edge in its head-to-head marketing battle with Merck's Vioxx - but will leave the product at a disadvantage in terms of gastrointestinal safety.

"Based on Kaplan-Meir cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events, there were no differences between the Celebrex, diclofenac or ibuprofen treatment groups" in the CLASS study, Celebrex (celecoxib) labeling states.

"The rates in all patients at nine months for Celebrex, diclofenac and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively," labeling states. The CV thromboembolic event rates for non-aspirin "users in each of the three treatment groups were less than 1%. The rates for myocardial infarction in each of the three non-ASA treatment groups were less than 0.2%."

Updated labeling also bolds a statement in the precautions section that says Celebrex does not provide cardiovascular prophylaxis: "Because of its lack of platelet effects, Celebrex is not a substitute for aspirin for cardiovascular prophylaxis."

FDA recently updated Vioxx (rofecoxib) labeling to include new information on an apparent increased risk of cardiovascular thrombotic events in the VIGOR trial (¹ (Also see "Vioxx Label Balances CV Risk With GI Safety: Can Merck Reverse Damage?" - Pink Sheet, 15 Apr, 2002.), p. 20).

However, the Vioxx VIGOR labeling change included a clear declaration of a GI safety advantage over other NSAIDS, while Celebrex' CLASS update does not.

The Celecoxib Long-term Arthritis Safety Study "did not show a safety advantage in upper gastrointestinal events for Celebrex compared to either ibuprofen or diclofenac," a June 7 FDA "Talk Paper" states.

"Inclusion of patients on low-dose aspirin [up to 325 mg/day] in the study was valuable for safety assessment of Celebrex in this important population of arthritis sufferers. However, the use of aspirin (a drug known to cause stomach ulcers and bleeding) may have obscured the ability to accurately compare the GI safety of Celebrex to other nonsteroidal anti-inflammatory drugs," FDA said.

Therefore, "the agency concluded that the drug labeling for Celebrex should continue to include the standard warning for doctors and their patients about risks associated with all NSAIDS, including risks of GI ulceration, bleeding and perforation."

CLASS data show that .78% of Celebrex-treated patients versus 2.19% of Celebrex and aspirin-treated patients experienced "complicated and symptomatic ulcers," labeling notes.

FDA's Arthritis Advisory Committee concluded in February 2001 that Celebrex did not show a safety advantage in the CLASS study, FDA noted. However, after reviewing the VIGOR study the next day, members of the committee said that the agency should not treat Celebrex and Vioxx differently in terms of GI safety (² (Also see "Celebrex, Vioxx GI Safety Differences May Be Indistinguishable - FDA Cmte." - Pink Sheet, 12 Feb, 2001.), p. 6).

The updated Vioxx label includes a statement that the VIGOR results show that patients treated with rofecoxib 50 mg once-daily have a "significantly" lower risk of GI toxicity than those treated with naproxen 500 mg twice-daily.

The updated Celebrex label includes new information about the risk of serious GI and renal effects in the elderly.

"As with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous postmarketing reports of fatal GI events and acute renal failure in the elderly than in younger patients," the precautions section of labeling states.

FDA noted that the CLASS study used patients treated with Celebrex 400 mg twice-daily, which is "twice the highest approved dose for Celebrex to treat" rheumatoid arthritis. Patients used the standard dose for ibuprofen or diclofenac.

"Doses up to 2,400 mg/day for up to 10 days in 12 patients did not result in serious toxicity," the overdosage section of Celebrex labeling adds.