The National Cancer Institute halted a three-year international study using Celebrex because long-term use of the painkiller at high doses more than tripled risk of heart problems, the drug’s manufacturer said yesterday.
But a second study using lower doses of Celebrex did not similarly increase cardiovascular risks when compared with dummy pills, said its maker, Pfizer Inc.
The company said it would not remove Celebrex from the market as rival Merck & Co. did when a similar study found that high doses of its painkiller Vioxx increased heart attack and stroke risk. While Pfizer termed heart problems associated with 400 mg and 800 mg doses of Celebrex the most commonly used new-generation painkiller a new and unexpected finding, critics have long predicted that all of the family of painkillers called Cox-2 inhibitors carry that risk and offer scant benefits to patients in pain.
The loss of Vioxx in the fall left Pfizerâ€™s arthritis drugs Celebrex and Bextra as the only remaining Cox-2 inhibitors n the market.
The Food and Drug Administration yesterday advised people taking Celebrex to talk to their doctors. The agency told physicians to consider alternative painkillers and to use the lowest effective dose of Celebrex for patients who choose not to switch.
Because heart risks have already been linked to Bextra and Vioxx, some doctors and consumer advocates criticized the FDA for not immediately removing Celebrex and Bextra from the market or, at minimum, limiting their use. Since the FDAâ€™s approval of Celebrex in 1998 to treat osteoarthritis and rheumatoid arthritis, the drug has become Americaâ€™s top-selling Cox-2 drug. American doctors wrote 19.8 million prescriptions for Celebrex in the first 10 months of 2004, according to IMS Health, a Fairfield, Conn., pharmaceutical information company.
Lester Crawford, acting FDA commissioner, told reporters the agency within days will launch regulatory action that could include requiring black box warnings on the drug label, the agencyâ€™s most strident safety warning. The agency may also impose limits on Pfizerâ€™s ability to advertise Celebrex directly to consumers. Pfizer stepped up print and television ads after the Vioxx recall, attempting to woo consumers seeking pain relief without mentioning Vioxx by name.
Despite acknowledging â€˜â€˜great concernsâ€™â€™ about all of the new-generation painkillers, Crawford stopped short of saying the FDA action would pull Celebrex from the market. â€˜â€˜Weâ€™re leaving open all regulatory options as we move forward, but we do not have a decision yet on the fate of the product,â€™â€™ he said.
Merck officials learned of increased risks of heart attacks and stroke from long-term use of Vioxx on Sept. 24. However, the company waited three days to tell the FDA there was a problem and delayed a public announcement until Sept. 30.
Those problems with Vioxx led the National Cancer Institute to reanalyze the safety of a study it was conducting to determine if Celebrex prevents tumors that lead to colon cancer. An initial review found no cause for concern. But to ensure the cancer specialists werenâ€™t missing something, an independent panel of heart specialists looked at the data.
â€˜â€˜Had we not done this level this of analysis I think we still might be missing the signal,â€™â€™ said Monica Bertagnolli, a surgical oncologist at Brigham and Womenâ€™s Hospital who was the trialâ€™s principal investigator.
A Brigham staffer looked at each time a patient in the study was hospitalized for heart problems and categorized them.
Bertagnolli got the news before dinner on Thursday night: The study should stop because the risk of serious cardiovascular events more than doubled for patients taking both higher and lower oses of Celebrex.
Within minutes of getting word of the heightened heart risk, Pfizer, Bertagnolli, and the National Cancer Institute pulled together an action plan of who would call whom. Pfizer alerted the FDA late Thursday night, Crawford said. The company issued a news release at 9:30 a.m. yesterday as the stock market opened, causing the companyâ€™s stock to slide. It ended down 11.2 percent, to $25.75.
Dr. Elias Zerhouni, director of the National Institutes of Health, said four dozen ongoing government-funded studies involving Cox-2 inhibitors, including Celebrex, will now undergo the same close scrutiny.
Garret A. FitzGerald, a University of Pennsylvania cardiologist who five years ago pointed to heart attack and stroke risks with Cox-2 inhibitors, said finding risk with Celebrex ends â€˜â€˜the conversationâ€™â€™ about whether that class of painkillers is suspect.
â€˜â€˜What we need to do now is instruct patients who are at high cardiovascular risk to avoid members of this class while remembering these drugs remain useful in the treatment of pain and inflammation for people at a low cardiovascular risk,â€™â€™ FitzGerald said.
Public Citizen, a consumer advocacy group based in Washington, D.C., is calling for the FDA to ban Celebrex and Bextra.
â€™â€™You have a medicine like Vioxx, like Bextra, like Celebrex that is studied carefully in a few thousand patientsâ€™â€™ before FDA approval, said Wayne Ray, professor of preventive medicine at Vanderbilt University in Nashville. After approval, the drugs are used by millions with few post-market safety studies, he said. â€˜â€˜Thatâ€™s an invitation to disaster and the disasters seem to be occurring, unfortunately,â€™â€™ Ray said.
Senator Chuck Grassley, chairman of the Senate Finance Committee and an advocate of creating an independent office of drug safety, renewed his criticism of the FDA yesterday.
â€˜â€˜Right now, we have a situation where the public is left wondering when the next shoe might drop when it comes to drug safety,â€™â€™ Grassley said in a statement.
John Jenkins, director of the agencyâ€™s office of new drugs, said, â€˜â€˜I donâ€™t see this as a failure of the systemâ€™â€™ because FDA safety reviews mirror the way other regulators around the world do them.