This article is part of the Arthritis Archives.
Editor note: On 09/30/2004, Merck the maker of Vioxx, issued a worldwide recall, halting sales of the drug. On 04/07/2005, Following scrutiny of the class of arthritis drugs known as NSAIDs and COX-2 inhibitors, the FDA announced planned regulatory actions. See: Questions & Answers: FDA Actions On COX-2 Inhibitors & NSAIDs Fallout from the Vioxx recall will continue for years to come.
Dateline: February 9, 2001
Label Changes Requested
Both Pharmacia and Merck (the makers of Celebrex and Vioxx, respectively) requested that the Food and Drug Administration (FDA) review study results which they say show that warnings on their labels should be removed. The warning at issue is indicative of a risk of ulcers comparable to that of older, traditional NSAIDs.
COX-2 Inhibitors
Since their debut, the popular arthritis drugs, Celebrex and Vioxx, both have made claims about being safer and more gentle on the stomach than older NSAIDs. The reason for the claim - NSAIDs target an enzyme known as cyclooxygenase or COX. There are two forms of COX. COX-1 is involved in protecting the lining of the stomach. COX-2 is involved in the pain and inflammation pathway. Older NSAIDs inhibit both COX-1 and COX-2, while only COX-2 is inhibited by Celebrex and Vioxx.
Blockbuster sales resulted from the theory that Celebrex and Vioxx were safer and gentler. In 2000, the two arthritis drugs accounted for about $5 billion in sales. Since the sales are so significant, Pharmacia and Merck are both vying for the greater share of the market.
On February 7/8, 2001, the FDA Arthritis Advisory Committee met in Gaithersburg, MD., to review the study results and to assess if either Celebrex or Vioxx should have warnings on their label reduced or any changes made to the prescribing information. The FDA Arthritis Advisory Committee makes recommendations to the FDA.
Celebrex
After analyzing results from Pharmacia's CLASS study, the committee concluded that a "clinically meaningful" safety advantage of Celebrex over older NSAIDs had not been established. Though the CLASS trial did demonstrate an overall reduction in gastrointestinal complications, the trend did not hold up among patients who also took low dose aspirin. Among the group of patients who also took low dose aspirin, Pharmacia did not demonstrate a superior safety record over ibuprofen or pooled NSAID data. The CLASS study also did not demonstrate a superior safety record over NSAIDs among patients with ulcer complications. Based on this information, the Arthritis Advisory Committee advised that further studies be done to assess the risk of COX-2 drugs and NSAIDs when taken with aspirin. The committee did not recommend any label changes for Celebrex.
The CLASS trial involved 8,000 patients, mostly female, average 60 years of age, with rheumatoid arthritis or osteoarthritis. The trial compared 800 mg. Celebrex (4 times the recommended daily dose for osteoarthritis, and twice the recommended daily dose for rheumatoid arthritis) to normal doses of ibuprofen and diclofenac.
Vioxx
After formulating conclusions about Celebrex based on the CLASS trial, the Arthritis Advisory Committee turned its attention to Merck's Vioxx. The committee analyzed the VIGOR (Vioxx Gastrointestinal Outcomes Research) study. In this case, the committee recognized that Vioxx appeared to cause fewer ulcers than the older NSAID, naproxen. The committee felt that Vioxx's label should reflect the result of this one study but still retain the more broad warning that Vioxx still can cause ulcers. The committee also advised that a warning should exist based on the fact that Vioxx had twice the risk of heart attacks and cardiovascular side effects as naproxen users.
The VIGOR trial involved 8,000 patients and evaluated the gastrointestinal profile of Vioxx 50 mg. (twice the highest dose approved for osteoarthritis) to the older NSAID, naproxen.
Label Changes Unlikely
The FDA is not bound to follow the recommendations of the Arthritis Advisory Committee but usually does. It is unlikely that the FDA will allow either Celebrex or Vioxx to make overall claims of safety superiority over older NSAIDs but they may allow claims of advantage over individual NSAIDs. It is felt that Celebrex may be allowed to claim better safety than ibuprofen, and Vioxx may be permitted to claim better safety than naproxen. On the flip side, however, both Celebrex and Vioxx may be required to keep a warning that they lack the cardioprotection of some older NSAIDs.
As Pharmacia and Merck attempted to have labels changed and warnings removed for the purpose of gaining the upper-hand in the pharmaceutical industry, it appears neither will gain the momentum they had hoped for -- this time.
Sources: Scientists Advise On New Drug Vioxx, 2/8/01, Associated Press; FDA Warned About Arthritis Drug, 2/8/01, Intelihealth; US Panel Urges Label Changes For Merck's Vioxx, 2/8/01, Reuters
First published: 2/09/2001
