Celebrex, Bextra Face FDA Scrutiny This Week

The fate of a highly controversial class of painkillers is likely to be decided at a federal inquiry scheduled to open later this week.

In three days of hearings set to begin Wednesday, the FDA and a panel of outside experts will investigate the safety of arthritis drugs called Cox-2 inhibitors (search). This group includes Vioxx (search), Celebrex (search), and Bextra (search).

FDA documents show that the hearings will focus on evidence that the drugs increase the risk of heart attacks and stroke, a finding that pushed Vioxx’s manufacturer to pull it from the market in September 2004. This has also led many experts to call for a broad re-evaluation of the other Cox-2 inhibitors.

One consumer watchdog group has called for a ban on the two other available Cox-2 drugs because they have also been linked to an increased risk of heart problems. Others urge a less drastic approach, noting that the drugs are useful to elderly patients and others with arthritis pain because they may cause fewer of the side effects seen with older painkillers like ibuprofen (search).

“Everything is on the table as far as I’m concerned. But something is obviously going to need to be done,” says one member of the FDA advisory panel who spoke on condition of anonymity.

The evidence is scheduled for review before a joint panel of members from the agency’s arthritis and drug safety advisory committees. Experts will review a number of trials suggesting that, like Vioxx, other drugs in its class can increase the risk of dangerous heart problems by up to three or four times.

Celebrex's Safety

Data on Celebrex are mixed.

The National Institutes of Health suddenly halted one Celebrex trial in December 2004 when researchers noticed that patients taking 400 mg of the drug per day had a 3.4 times higher risk of a heart attack or stroke compared with patients who took a placebo. But they were taking twice the normal dose of 200 mg a day.

The study led Celebrex’s manufacturer, Pfizer Inc., to halt all advertising promoting the drug.

Another NIH-backed trial showed no increased heart risk in 8,000 patients who took Celebrex. But the study was still halted because officials said it showed that the widely available drug Aleve, also called naproxen, raised the risk of heart problems in patients.

The decision of officials to halt the study remains controversial amid criticism that evidence of Aleve’s adverse effects was weak.

In response to the Aleve results, John H. Klippel, MD, president of the Arthritis Foundation, told WebMD in December, "We are talking about a drug that has been around for 30 years and used by millions of people, and we are not aware that this issue has been raised elsewhere. So we don't believe this should have any immediate impact on the clinical use of this drug."

Also in December, the FDA issued strengthened warnings alerting doctors to a study showing that Bextra, also made by Pfizer, increases the risk of heart attack and stroke in patients who have had heart bypass surgery. Pfizer is a WebMD sponsor.

“If they were doing the right thing, they would take both of them off the market,” says Sidney Wolfe, MD, director of Public Citizen’s Health Research Group. The group has petitioned the FDA to ban both Celebrex and Bextra.

Eric Topol, MD, a cardiologist and leading Cox-2 researcher, warns that the highly charged atmosphere surrounding Vioxx and other drugs could lead to “hyper-responsiveness” by the FDA concerning related medications, especially Bextra. In December, the FDA issued a warning to not use Bextra in patients having heart bypass surgery.

But at a minimum, the FDA should consider similarly strict warnings alerting doctors and patients to the possible heart risks of Celebrex, Topol tells WebMD.

“Celebrex can’t go on as it has been,” says Topol, a provost at the Cleveland Clinic Lerner School of Medicine.

But others stress that despite increased safety concerns, Cox-2 drugs still have an important role in treating arthritis patients. Many doctors still value Celebrex and Bextra because of their ability to avoid stomach and intestinal bleeding sometimes seen with older anti-inflammatory drugs.

Cox-2 drugs also remain important for elderly arthritis patients on blood-thinning medications, such as Coumadin, who cannot take the older drugs because they can interfere with blood clotting, says William Shiel, MD, a practicing rheumatologist from Mission Viejo, Calif.

“I don’t want to lose them. I qualify that by saying I want to have this whole [safety] issue clarified,” says Shiel, who is also editor of medicinenet.com, which is owned by WebMD.

The hearings are also likely to focus attention on whether Cox-2 drugs are inappropriately prescribed to many of the millions of patients who take them, Shiel says. A national study released on Jan. 24 concluded that patients who could have taken older and less expensive arthritis drugs still accounted for 64% of the growth in Cox-2 prescriptions between 1999 and 2002.

Scrutiny on the FDA

Cox-2 safety concerns have also brought scrutiny on the FDA itself. Shortly after Merck & Company pulled Vioxx from the market in September 2004, FDA safety reviewer David Graham, MD, appeared on Capitol Hill complaining to lawmakers that his repeated warnings about the drug’s safety were stifled by higher-ups in the agency.

Graham cited five other drugs, including Bextra, as suffering from significant safety concerns and warned that the FDA was unable to protect Americans' safety.

The Institute of Medicine has launched an inquiry into how well the agency monitors the safety of drugs already on the market. Several lawmakers have backed calls to reform the agency by establishing an independent drug safety office.

FDA officials say that this week’s hearings are likely to go beyond Cox-2 drugs to broader issues of how the agency polices the safety of drugs already on the market, FDA officials say. The FDA has also faced questions over how it handled growing evidence that last year led to stricter warnings on an increased risk of suicidal behavior in children who take antidepressants.

In an interview in late January, acting FDA Commissioner Lester M. Crawford said the agency would also look to experts for cues on how to approach improving safety reviews in general.

President Bush on Monday nominated Crawford to become the FDA’s permanent commissioner, the White House announced. The post has been vacant for more than a year.

By Todd Zwillich, with reporting by Salynn Boyles, reviewed by Michael W. Smith, MD, .

SOURCES: FDA advisory panel member. Sidney Wolfe, MD, director, Public Citizen’s Health Research Group. Eric Topol, MD, professor of medicine, Cleveland Clinic Lerner College of Medicine. Archives of Internal Medicine, Jan. 24, 2005. William Shiel, MD, editor, medicinenet.com, A WebMD company. Lester M. Crawford, acting commissioner, FDA. News release, White House.