JUNE 25, 1999

HealthNews from the publishers of the New England Journal of Medicine

The scenario has become increasingly familiar: A highly touted new drug finds huge initial success, only to come under scrutiny a short time later as reports trickle in of serious, or even fatal, complications. In a few cases, such problems lead to the drug's removal from the market, as with the diet drug Redux, which was found to cause heart-valve abnormalities. In other cases, the product remains available but carries additional warnings, as with the popular impotence medication Viagra.
In late April, a report in The Wall Street Journal raised similar fears about the new and highly celebrated arthritis pain reliever Celebrex (celecoxib). The first in a new class of drugs known as COX-2 inhibitors, Celebrex was approved by the FDA in December 1998 and since then U.S. physicians have written more than 2.5 million prescriptions for it. However, according to The Wall Street Journal, the FDA has received reports that 10 people have died while taking Celebrex and 11 more have been hospitalized for gastrointestinal (GI) bleeding since the drug was launched. Ironically, researchers developed COX-2 inhibitors to avoid just these types of complications. While the traditional nonsteroidal anti-inflammatory drugs (NSAIDs) used by millions of Americans for pain relief are widely known to cause GI bleeding or ulcers, scientists designed COX-2 inhibitors to sidestep the mechanism that harms the stomach lining.
The idea is based on the discovery several years ago that there are two forms of the enzyme cylcooxygenase (COX): COX-1 and COX-2. These enzymes are responsible for the formation of prostaglandins, chemicals that play a role in causing inflammation, among other tasks. COX-1 appears to produce prostaglandins that help to maintain normal functioning of the stomach lining, liver, kidneys and platelets (a component of blood). COX-2 works to rally prostaglandins at sites of injury or inflammation, contributing to the inflammatory process. Traditional NSAIDs, such as ibuprofen and naproxen, block both the COX-1 and COX-2 enzymes, quashing COX-2-induced inflammation but also squelching COX-1's protective effects. Researchers proposed that by developing a drug that inhibited COX-2 but spared COX-1, they could get the anti-inflammatory benefits of an NSAID without its harmful side effects.
Clinical studies prior to the drug's approval seem to support this theory. Studies in more than 13,000 people found that patients taking Celebrex had about the same percentage of stomach ulcers as people taking a dummy drug. By comparison, patients taking NSAIDs in these trials developed far more ulcers. In fact, they developed ulcers at about the same rate as NSAID users in the general population. More than 100,000 hospitalizations and more than 16,000 deaths occur every year due to NSAID-related complications.
So are these latest reports of GI complications and deaths linked to COX-2 inhibitors cause for alarm? Not likely, say experts familiar with the evidence. For one thing, although these patients were taking Celebrex, it's not clear that the GI problems or deaths were directly caused by the drug, says Jay Goldstein, M.D., a University of Illinois gastroenterologist who was involved in the clinical trials. Other medical conditions or medications the patients were taking may have been responsible for the adverse effects.
More important, experts say that the rate of complications seen so far with Celebrex is actually substantially lower than with other NSAIDs. According to the nation's largest database of information about arthritis medications at Stanford University, one would expect to see 821 bleeding ulcers and more than 120 deaths for every million patients using a traditional NSAID over the same time period.
"Ten deaths out of 2.5 million [prescriptions] is a minuscule percentage," agrees W. Hayes Wilson, M.D., chief of rheumatology at the Piedmont Medical Clinic in Atlanta and a spokesman for the Arthritis Foundation. Although even one death is one too many, "unfortunately there's no perfect medicine," he says. Dr. Wilson adds that even people who aren't taking NSAIDs can develop ulcers.
Still, some questions about this new class of drugs remain. Research in animals suggests that the COX-2 enzyme might actually help ulcer healing - and that suppressing it could lead to unanticipated, and harmful, consequences. However, it's too soon to say whether the results apply in people as well.
With yet another COX-2 inhibitor, Vioxx, recently receiving preliminary FDA clearance, the question of these drugs' safety is likely to resurface. For now, arthritis specialists say that Celebrex is a viable option for people who have not responded well to older NSAIDs, but the drug is not for everyone, or for all forms of arthritis. Those at greatest risk for complications include people over age 60, those with other chronic diseases, smokers, people with a prior history of ulcers, and those using other NSAIDs or cortisonelike drugs. People with allergies to sulfonamide drugs or aspirin also should not take Celebrex.
It's also important to remember that COX-2 inhibitors are no more effective at relieving pain or inflammation than other NSAIDs. Anyone taking a COX-2 inhibitor should work closely with a physician to understand the risk factors and to watch for potentially dangerous side effects. - The Editors

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