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misery after withdrawing its painkiller Vioxx from the market. Two of Pfizer's arthritis drugs, which belong to the same class as Vioxx, are now under regulatory and investor scrutiny. Here's a list of key events and dates.

Sept. 30

: Merck pulls Vioxx from the market because a test showed that the drug caused a significant increase in cardiovascular risk among people who took the drug for more than 18 months.

Oct. 1

: Pfizer says three large long-term Celebrex studies involving more than 6,000 patients "have not shown any significant safety issues and are expected to continue to completion." Pfizer adds that "the data we've accumulated over time demonstrate that Celebrex does not increase the risk of serious cardiovascular events in patients with arthritis and pain, even at higher-than-recommended doses." Celebrex reached the U.S. market in 1998, a year before Vioxx was available.

Oct. 7

: An editorial published in an online version of

The New England Journal of Medicine

raises questions about

COX-2 inhibitors in general. Dr. Garret A. FitzGerald, a medical researcher at the University of Pennsylvania, says the FDA should examine all COX-2 drugs. "We must remember that the absence of evidence is not the evidence of absence," FitzGerald says. He doesn't advocate banning all COX-2 drugs for all patients. These drugs "remain a rational choice for patients at a low cardiovascular risk who have had serious gastrointestinal events, especially while taking traditional" pain relievers. He says it would "seem prudent" to avoid prescribing COX-2 drugs for patients "who have cardiovascular disease or who are at risk for it."

Oct. 15

: Pfizer says it is working with regulatory agencies "around the world" to update the label of its COX-2 drug Bextra. Pfizer would later reveal that this update is a black box warning -- the toughest warning required by the FDA -- for a rare but potentially fatal skin rash called Stevens-Johnson syndrome. A warning about this side effect had been on the Bextra label since 2002, a year after Bextra reached the U.S. market. This side effect exists with other medications, including other COX-2 drugs, but it occurs more often with Bextra.

Oct. 15

: Pfizer says a review of Bextra clinical trial data covering nearly 8,000 patients shows that there is "no increased risk" of heart attack or stroke for patients taking the drug for six to 52 weeks as a treatment for osteoarthritis or rheumatoid arthritis.

However, Pfizer also reviewed results of two studies involving patients who received Bextra after undergoing heart bypass surgery. In one study, patients who received Bextra plus another COX-2 drug unavailable in the U.S. showed a statistically significant high cardiovascular risk. In the other study, patients receiving Bextra alone had a higher risk; but Pfizer later says these results are not statistically significant. Pfizer says a third study of patients undergoing general surgery found no significant risk of cardiovascular problems among those receiving Bextra and the other COX-2 drug. Bextra is not approved in the U.S for any postsurgical care.

Oct. 15

: Pfizer says it will conduct additional studies "to confirm the long-term cardiovascular safety profile" of Bextra in patients who require chronic treatment for arthritis.

Oct. 18

: Pfizer says it will conduct a new test of Celebrex to assess its effect on osteoarthritis patients at high risk for heart disease. The study is part of a larger cardiovascular testing program with Celebrex that started in 2002. The new trial is expected to start early in 2005. The test will take two years. Pfizer says some previous small tests "suggest that Celebrex's anti-inflammatory properties, as well as additional unique Celebrex-specific characteristics, may improve vascular function in patients with established coronary artery disease."

Nov. 10:

: A report in

The New York Times

quotes Dr. Garrett FitzGerald as saying people taking Bextra have more than twice the risk of heart attacks and strokes compared with people who took placebos. He bases his comments on pooling data from 5,930 patients participating in 12 clinical trials. FitzGerald says Bextra "is a time bomb waiting to go off." Pfizer says the article "draws unsubstantiated conclusions about the cardiovascular safety" of Bextra and "has not been ... subject to independent scientific review. "

Nov. 30

: Meeting with analysts, a Pfizer executive says the results of the Bextra tests involving heart bypass surgery patients will be added to a revised label. The label is changed on Dec. 3; the FDA doesn't issue an announcement until Dec. 9. "Bextra is not approved for use in the treatment of postoperative pain of any type," the agency says. "However, the FDA believes that these new findings should be made available to health care professionals and patients."

Nov. 30

: Pfizer says it will submit to the FDA by year-end an application for Dynastat. This is the intravenous COX-2 drug tested with Bextra during the heart bypass surgery and general surgery clinical trials. Although not available in the U.S., Dynastat is sold in 45 countries.

Dec. 17

: Pfizer says that one of two clinical trials examining Celebrex as a possible treatment for certain colon polyps demonstrated an increased cardiovascular risk over a placebo. However, the other trial revealed no greater cardiovascular risk than a placebo. "The cardiovascular findings in one of the studies are unexpected and are not consistent with the reported findings in the second study," Pfizer says. Most patients in both tests took higher doses than the average amount recommended for people with arthritis and pain.

Pfizer says it is studying the results and communicating with U.S. and foreign regulators as well as physicians and patients. Pfizer says it has no plans to withdraw Celebrex. The FDA says it is reviewing the data. Pfizer later says it will

suspend direct-to-consumer advertising for Celebrex until the FDA responds.