The Food and Drug Administration Friday warned physicians to consider alternatives to the popular arthritis drug Celebrex because of new evidence that it doubles the chances of heart attacks and strokes.
A similar drug, Vioxx, was removed from the market for the same reason in October.
The federal agency also said it may soon take other actions, including requiring stronger warnings, or even blocking the drug from sale. The statements call into question the future of the widely used class of painkilling drug called COX-2 inhibitors.
The FDA warning came just hours after Celebrex manufacturer Pfizer Inc. issued a statement say-ing that a study of the drug’s efficacy as a cancer treatment found evidence of increased cardiovascular risk.
The study’s findings added to the growing concerns about the effectiveness of the FDA’s system for assessing the risks of new drugs and for monitoring dangerous side effects in medications it already has approved.
“Right now we have a situation where the public is left wondering when the next shoe might drop when it comes to drug safety,” said Sen. Charles Grassley, R-Iowa, who held hearings last month on the problems with Vioxx. “At this point, no one can say with confidence whether the worst drug safety problems are behind us or ahead of us.”
But Dr. John Jenkins, director of the FDA’s Office of New Drugs, said discovery of the problems with Celebrex is a sign that the system is working.
“I don’t see this as a failure of the system,” Jenkins said. “This is how drug development, drug approval and post-market monitoring is done, not only in the United States, but in all countries that have a regulatory system.”
Pfizer gave no indication that it would withdraw the drug.
Dr. Joseph Feczko, president of worldwide development for Pfizer
Dr. Joseph Feczko, president of worldwide development for Pfizer, said in a statement that doctors “should factor this new information” and weigh it against the risks of other painkilling drugs.
But patient groups voiced concern about the continued use of Celebrex and related drugs.
‘Doomed class of drugs’
The Arthritis Foundation issued a statement Friday urging caution in the use of any COX-2 inhibitor.
The consumer advocacy group Public Citizen said the findings should lead to the withdrawal of the drug.
“This is a doomed class of drugs,” said Dr. Sidney Wolfe, Public Citizen’s director of health research. “They will be taken off the market. It’s a matter of when, not whether.”
Celebrex and other COX-2 inhibitors were developed to be a stomach friendly alternative to old line anti-inflammatory medicines such as aspirin, ibuprofen and naproxen. Taken long term, the older medicines can cause stomach bleeding and gastric problems.
The new COX-2 inhibitors became tremendous money makers because they are used as maintenance drugs, taken on a daily basis by millions of people worldwide. They sell for as much as $3 a pill. The older medicines, by comparison, sell for pennies a pill in generic versions.
Just two COX-2 drugs, Celebrex and Bextra, were expected to account for $5 billion of Pfizer’s estimated 2005 sales of $55 billion, said Sena Lund a market analyst for Cathay Financial in New York.
Roughly 27 million patients have taken Celebrex, according to Pfizer.
But in September, a serious problem emerged with one of the COX-2 inhibitors. Merck & Co. pulled its Vioxx off the market after it was found to cause heart attacks in some patients.
Vioxx doubled the risk of heart attacks, although the actual number of cases was very small.
Some researchers suspected that COX-2 inhibitors might be reducing the body’s production of a protein that prevents blood platelets from clumping together, possibly leading to a stroke or heart attack.
Evidence of the risk in Celebrex surfaced in a Pfizer study, conducted by the National Cancer Institute, to see if high doses of the drug could prevent the formation of certain pre-cancerous colon polyps.
Dr. Ernest Hawk of the institute said the study, which has been going on for nearly three years, involved 2,000 patients, divided into three groups. Some were given a placebo. Others were given 400 or 800 milligrams of Celebrex a day.
The usual dose for arthritis patients ranges from 100 to 200 milligrams daily for those suffering from osteoarthritis to 200 to 400 milligrams daily for rheumatoid arthritis.
As concerns were being raised about Vioxx, the cancer institute brought in a special team of cardiac experts to evaluate its Celebrex data.
They found six cases of such adverse effects in the placebo group, 15 cases in the lower dose Celebrex group and 20 cases in the higher dose group. The risk of adverse effects was 2.5 times greater in the lower dose group and 3.4 times greater in the higher dose group, Hawk said.
The cancer institute halted the Celebrex study and the National Institutes of Health on Friday ordered a review of more than 40 studies involving COX-2 inhibitors.
Pfizer, however, said the cancer study was out of step with other evidence showing that Celebrex is safe.
There is a “large body of data that we and others have accumulated over time, in which an increased risk of serious cardiovascular events in arthritis patients, even at higher-than-recommended doses, had not been seen,” Feczko said.
Indeed, there was some confusion in the medical world over the study’s findings.
Researchers who have studied Vioxx said the FDA needs more information to reach a conclusion on Celebrex.
“I was caught by complete surprise,” said Dr. Gurkirpal Singh at Stanford Medical School. “Everything with Celebrex was pointing in the direction that it had a small cardio-protective effect.”
Singh said he would be “very cautious” about prescribing Celebrex to patients at this point, although he did not think there was enough information to pull the drug.
Another researcher, Dr. Bruce Psaty of the University of Washington, said this latest episode reinforces criticisms that the FDA’s drug review and approval process is flawed.
The FDA had planned to convene an advisory committee in February to discuss problems and strategies with COX-2 inhibitors
The FDA had planned to convene an advisory committee in February to discuss problems and strategies with COX-2 inhibitors. Now, the agency may have to act sooner.
On Friday, an influential House panel probing Vioxx added Celebrex to its investigation. The Energy and Commerce Committee sent a letter to Pfizer Chairman Dr. Hank McKinnell requesting extensive records on the drug’s development, approval, marketing and use by patients.
Pfizer’s disclosure Friday may also launch “a race to the courthouse,” said Jonathan Zasloff, a University of California, Los Angeles, law professor.
There are already attorney’s looking for Celebrex-takers who have had heart attacks in an effort to put together a class-action lawsuit against Pfizer.
Pfizer shares tumbled Friday, dropping $3.23, or 11 percent, to $25.75 on the New York Stock Exchange.
Bextra also drew criticism Friday with the release of a letter from three physicians at the Vanderbilt University School of Medicine warning doctors against prescribing the medicine “except in extraordinary circumstances.”
The letter, which will be published in the Dec. 23 edition of the New England Journal of Medicine, was released early due to Pfizer’s Celebrex announcement.
The doctors said that previous findings of an increase risk for heart bypass patients taking Bextra were serious enough to call into question the drug’s safety for other people.
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