When celecoxib (CELEBREX) and rofecoxib (VIOXX) were approved about two years ago, we were quite skeptical about claims that they were much, if any, safer in the gastrointestinal (GI) tract than the 20 older nonsteroidal anti-inflammatory drugs (NSAIDs) then on the market, such as ibuprofen (MOTRIN) and naproxen (NAPROSYN) to name only two. However, we were sure from the Food and Drug Administration’s (FDA) reviews of the new drugs that neither was more effective than the other NSAIDs in...
When celecoxib (CELEBREX) and rofecoxib (VIOXX) were approved about two years ago, we were quite skeptical about claims that they were much, if any, safer in the gastrointestinal (GI) tract than the 20 older nonsteroidal anti-inflammatory drugs (NSAIDs) then on the market, such as ibuprofen (MOTRIN) and naproxen (NAPROSYN) to name only two. However, we were sure from the Food and Drug Administration’s (FDA) reviews of the new drugs that neither was more effective than the other NSAIDs in controlling the symptoms of arthritis or for pain relief. In fact, celecoxib failed to gain FDA approval for the treatment of acute pain and we recommended that you should wait at least five years before taking either drug.
The media, writing from drug company press packages, uncritically proclaimed these drugs as “super aspirins” in hundreds of articles published before either drug was cleared for sale by the government. The pitch was that they would selectively inhibit the enzyme cyclooxygenase-2, hence the shorthand name COX-2, and thereby relieve the symptoms of osteo- and rheumatoid arthritis, without causing the perforations, ulcers, and bleeding that are such serious adverse effects of the NSAIDs. This turns out to have been a nice theory that has not been validated.
At the time of approval, neither Pharmacia, the manufacturer of celecoxib, nor Merck, the producer of rofecoxib, had done the comparative long-term, higher-dose randomized trials in which the newer COX-2 inhibitor drug would be compared to the least dangerous of these older drugs such as ibuprofen (MOTRIN) to find out if there is a statistically significantly lower amount of serious GI complications with the COX-2 inhibitor drug. In addition, we were worried, as we are about any new drug that does not have an important advantage over existing drugs, about hidden dangers. This is especially true for the COX-2 inhibitors since they affect so many different parts of the body.
The two companies submitted studies to the FDA that they hoped would persuade the agency to allow the labels of their drugs to state that they were safer, as far as GI toxicity is concerned, than the older NSAIDs. The requests for labeling changes were discussed at a meeting of the FDA’s Arthritis Drugs Advisory Committee on February 7 and 8, 2001. Our testimony before this committee can be found on our web site .
Pharmacia played more by the rules than Merck did, and conducted randomized studies in which celecoxib was compared with either ibuprofen or diclofenac, the two NSAIDs with the least GI toxicity. The study known as the Celecoxib Long-term Arthritis Safety Study or CLASS (companies come up with catchy acronyms for studies for promotional purposes). CLASS failed to show a significantly lower amount of these serious GI adverse effects for celecoxib, compared to the other drugs. CLASS was published in the
Cheating somewhat, Merck decided that rofecoxib would probably appear to have a more favorable GI safety profile if it were compared to an NSAID more dangerous than ibuprofen or diclofenac, and chose naproxen (NAPROSYN) as the comparison drug for its study. Not to be outdone in the PR department, Merck came up with the name VIGOR for their trial, Vioxx Gastrointestinal Outcomes Research that was published in the
Although the VIGOR study did find a statistically significantly lower amount of serious GI complications with rofecoxib compared to naproxen, there were several other problems, beyond the inappropriate choice of comparison drug, that make the findings not really applicable to the general population of people using rofecoxib. First, the study was limited to people who had rheumatoid arthritis, a disease for which rofecoxib is not even approved. Second, almost 60 percent of the people in the study were simultaneously using steroids such as prednisone (DELTASONE) as adjunctive treatment for the rheumatoid arthritis. Since steroids themselves can cause ulcers, this distorts the findings.
The FDA’s Office of Postmarketing Drug Risk Assessment, responsible for the agency’s safety monitoring functions, concluded that 36 deaths seen in the CLASS study in patients taking celecoxib and 37 in the VIGOR study in patients on rofecoxib from GI bleeding, obstruction, perforation or stenosis show that current labeling for the NSAID family of drugs that include these two drugs “reflect[s] the risk of fatal gastrointestinal bleeding, obstruction, perforation or stenosis.” We agree.
All NSAIDs including celecoxib and rofecoxib should continue to carry the following warning in their professional product labeling or “package insert:”
Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation: Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia [upset stomach], are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1 percent of patients treated for 3-6 months, and in about 2-4 percent of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
In a study published in the
In Merck’s VIGOR study comparing rofecoxib to naproxen, there was a highly statistically significant five-fold increase in heart attacks in the overall rofecoxib group (0.5 percent) compared to the naproxen group (0.1 percent). This amounted to 20 heart attacks with rofecoxib (out of 4,047 patients) compared with 4 with naproxen (out of 4,029 patients). This increased number of heart attacks was also accompanied by an increase in other thrombotic (blood clotting) adverse effects such as strokes and blood clots in the legs as well as problems with hypertension in the rofecoxib group compared with the naproxen group.
Although the CLASS study did not find a significantly elevated number of heart attacks in those using celecoxib compared with those using the older NSAIDs (ibuprofen or diclofenac), there was also cause for concern about heart toxicity with celecoxib. An expert from the FDA’s Division of Cardio-Renal Drug Products, Dr. Douglas Throckmorton, found that “the incidence of adverse events related to cardiac ischemia (decreased blood flow to the heart) was higher in the celecoxib [Celebrex] group...and was most pronounced in the group of patients not taking ASA (aspirin)” as a cardiovascular protective drug. In these patients the rate of heart attack was also highest in the celecoxib group (0.2 percent) compared with users of the other two drugs (0.1 percent). For all patients, on and off aspirin, there was a higher incidence of atrial fibrillation, a type of heart rhythm disturbance, in the celecoxib group compared to those taking ibuprofen or diclofenac. Again this was more pronounced in the group not taking aspirin. Dr. Throckmorton concluded by stating that “...the data do not exclude a less apparent pro-thrombotic [blood clot forming] effect of celecoxib, reflected in the relative rates of cardiac adverse events related to ischemia.”
We strongly urge the retention of the NSAID-class warning label for these drugs, possibly adding that there is no evidence of statistically significant reduction in serious GI toxicity for celecoxib. This should take the form of a box warning (for all NSAIDs) that should be placed at the beginning of the label.
A second box warning about cardiovascular toxicity needs to be added. It should warn of the lack of platelet aggregation inhibition of the drugs which protects those at risk from an increased occurrence of heart attacks. In addition, the evidence which is rapidly accumulating about the heart damage caused by these drugs must be mentioned in this cardiovascular box warning.
Once again, a seemingly magic bullet appears to have self-destructed as research reveals the larger context in which it operates—the risks as well as the benefits. The benefits of COX-2 inhibitors, as far as reducing GI toxicity goes, appear to have been grossly exaggerated and oversold. Years after the research on these benefits was done, a rapid accumulation of evidence on risks is occurring. For an important enzyme which is close to ubiquitous in the body, it is less than surprising that blocking its activity in one part (the GI tract) must be balanced against the apparently harmful effects of blocking its critical functions in other parts of the body (such as the heart).
The phenomenal success of celecoxib and rofecoxib in the marketplace is evidence of the power of advertising and an indictment of the prescribing practices of far too many doctors. The total number of prescriptions dispensed in the
Now that the results of the CLASS and VIGOR studies are available let’s see what happens to an elderly person who has osteoarthritis and no insurance covering prescription drugs when the doctor writes a prescription for celecoxib or rofecoxib or another NSAID. Celecoxib in the 200-milligram strength for 30 capsules, enough for a month, at a nearby CVS Pharmacy is $89.59. This is the maximum recommended dose for celecoxib in osteoarthritis. If the prescription was written for generic ibuprofen at its maximum recommended dose enough tablets for a month would cost $18.59 at the same pharmacy. From the CLASS study we know that celecoxib is no safer than ibuprofen on the GI tract and may be less safe on the heart, and from the FDA review of celecoxib we know it is no more effective than other NSAIDs for osteoarthritis. A similar result is obtained for rofecoxib.
Our elderly patient pays $71 a month more, ($852 a year more) for a drug that is no more effective for osteoarthritis, no safer on the GI tract, and perhaps less safe on the heart than ibuprofen. This is what happens when big drug companies are allowed into our medicine cabinets and push us to choose the drugs we use by advertising that is sometimes false and misleading.
Since celecoxib was approved, the FDA has issued five Notices of Violation and one Warning Letter to Pharmacia about the false and misleading advertising regarding the safety and effectiveness of celecoxib. The Warning Letter was issued
Merck has received two Notices of Violation letters from the agency about the false and misleading advertising of rofecoxib.
What You Can Do
In light of the above discussion, we continue to recommend the five-year patient-protective rule for these drugs, as we do for all other new products that are not true breakthroughs: Do Not Use until five years after release. In the case of these two drugs, the clock still has about three years to run