The commercial future of Pfizer's Bextra may be at stake during FDA's early 2005 advisory committee discussion of the COX-2 inhibitor class.

The advisory committee meeting is being convened to review the cardiovascular safety problems that led to the withdrawal of Merck's Vioxx , and to consider the implications for all other COX-2s.

However, the release of new data about Bextra's (valdecoxib) safety profile may make that a pressing issue for consideration.

One objective of the advisory committee review will be "to find ways of further evaluating whether there is a risk of oral valdecoxib," FDA Office of New Drugs Acting Director Sandra Kweder, MD, said during a Nov. 10 Drug & Device Dialogue audio conference sponsored by F-D-C Reports and Polidais LLC.

[Editor's note: An archived webcast of the Nov. 10 Drug & Device Dialogue is available from F-D-C Reports. For more information, visit our website, ¹ www.DrugDeviceDialogue.com , or call 1-800-332-2181.]

The audio conference was held the day after University of Pennsylvania researcher Garret FitzGerald, MD, presented a new analysis at the American Heart Association meeting in New Orleans that questions the cardiovascular safety of Bextra.

Kweder said that FDA has seen only the media reports about the trial, not the data.

Pfizer responded to those reports Nov. 10 by objecting to the "unsubstantiated conclusions" being drawn about Bextra's safety profile.

Pfizer, however, is taking steps to restrict use of the drug: the company expects to add a "black box" warning to labeling about skin reactions associated with the COX-2 inhibitor.

"Revised labeling for the product...will likely include the addition of a black box," Pfizer said in a Nov. 5 Securities & Exchange Commission filing. The new warning "will be issued upon completion of discussions with FDA and other regulatory agencies," the ² 10-Q filing states.

FDA appears to be working with Pfizer separately on the skin reaction issue and the cardiovascular safety review. "We have already been discussing the skin reaction issue with the company for some period of time," Kweder said. "This is a sulfonamide product and skin reactions are associated with many drugs of that type."

Pfizer describes the new warning in the context of a discussion of a "Dear Doctor" letter sent by the company Oct. 15. The letter warned of a risk of severe skin reactions emerging within the first two weeks of therapy with Bextra. It also included a discussion of an apparent increased risk in cardiovascular events seen in two studies in high-risk surgery patients (³ Also see "Pfizer Goes On Offense With Celebrex: TV Ads, Study Proposal Stress Safety" - Pink Sheet, 25 October, 2004., p. 12).

Bextra labeling currently includes a warning that "serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving Bextra."

"Fatalities due to Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported," labeling adds.

A black box warning would obviously complicate the positioning of Bextra but would not necessarily mean the product stops being commercially important to Pfizer if it can remain on the market.

Roche/Syntex' Toradol (ketorolac) added a boxed warning in the early 1990s after reports of safety problems prompted some European regulators to pull the drug. Once the new labeling was complete, the brand continued to be successful, particularly in the hospital setting.

Since Pfizer also markets the COX-2 inhibitor Celebrex (celecoxib), the positioning issue could be simplified. Pfizer maintains that Celebrex is free of cardiovascular safety issues - and may be cardioprotective.

Pfizer is developing an injectable pro-drug formulation of Bextra, parecoxib, although the first review of the NDA ended with a "not approvable" letter in 2001.

Adding to the sense of uncertainty surrounding Bextra, Pfizer disclosed in its 10-Q that the drug received a "not approvable" decision from FDA for the treatment of migraines in August - before the Vioxx withdrawal.

Pfizer maintains, and FDA has agreed, that all data collected so far indicate that Celebrex has no cardiovascular safety issues with long-term use.

Kweder expects FDA to be in a position to present new long-term, placebo-controlled data on Celebrex to the advisory committee.

"There is data accumulating on celecoxib, particularly from the placebo-controlled trials, and we expect that by the time the committee meets, we will have some additional data that might be able to be brought to that committee," she said.

"We'll have to work with those investigators and the company on what might be shared and what cannot be shared," she added.

FDA also expects the advisory committee review to include "scrutiny of new agents (some approved in Europe)."

"We will be going back where we have reviewed them in the past as part of INDs to look at whether there is anything in those applications," Kweder said.

That may mean some discussion of Merck's Vioxx follow-on Arcoxia (etoricoxib), which FDA deemed "approvable" Oct. 29. Arcoxia is marketed in 48 countries outside the U.S.

The committee could also discuss Novartis' Prexige (lumiracoxib) which was deemed "not approvable" in September 2003 (⁴ Also see "Novartis Prexige NDA Re-Submission Expected In 2006; TARGET Data “Clean”" - Pink Sheet, 14 June, 2004., p. 9).

Kweder noted that the advisory committee will likely also have to consider cardiovascular safety issues related to the broader NSAID class, at least to provide "context" for the COX-2 discussion.

"We have not yet determined the full agenda for that meeting," Kweder noted. "We're certainly limited by time."

"But, the overall profile of the NSAIDs is really part of the context of the COX-2s. I think we would be remiss if we didn't at least bring that up, although how much data we'll have to address it remains to be seen. Most of these are very old drugs," she said.

During the audio conference, Kweder provided an extensive description of Vioxx' regulatory history - which is likely to be reviewed publicly during an upcoming Senate Finance Committee hearing (see ⁵ Also see "Senate Vioxx Hearing Looks Like Tough Going For Merck, Pfizer" - Pink Sheet, 15 November, 2004. ).

COX-2 Advisory Committee May Decide Fate of Pfizer’s Bextra

More from Archive

More from Pink Sheet