December 20, 2004

On December 17, 2004, an ongoing clinical trial investigating a new use of the Cox-2 inhibitor Celebrex (celecoxib) to prevent colon polyps, which was being conducted by the National Cancer Institute (NCI) and Pfizer, Inc., was discontinued because of an increased risk of cardiovascular (CV) events in patients taking Celebrex versus those taking a placebo.

In September, patients taking Merck's Vioxx were dismayed and disappointed when it was pulled from the market due after a study in patients at risk of developing recurrent colon polyps was discontinued early because of an increased risk of serious cardiovascular events, including heart attacks and strokes, among study patients taking Vioxx compared to patients receiving placebo.

Does the data on Celebrex mean it, too will be pulled from the market? It's too soon to tell. The situation with Celebrex is different than the situation with Vioxx. In the Celebrex study, the subjects were taking larger doses than are currently used. Patients in the clinical trial taking 400 mg. of Celebrex twice daily had a 3.4 times greater risk of cardiovascular events compared to placebo. For patients in the trial taking 200 mg. of Celebrex twice daily, the risk was 2.5 times greater. The average duration of treatment in the trial was 33 months. A similar ongoing study comparing Celebrex 400 mg once a day versus placebo, in patients followed for a similar period of time, has not shown increased risk. On the surface, it would seem that doses over 400 mg per day may well be problematic, but the second trial contradicts the data from the first trial regarding doses of 400 mg. per day. Analysis of the interim data revealed:

• placebo - 6 cardiovascular events
• celecoxib 200 mg twice a day - 15 cardiovascular events (2.5 fold increase over placebo)
• celecoxib 400 mg twice a day - 20 cardiovascular events (3.4 fold increase over placebo)

Until the issue of the safety of Celebrex is resolved, the FDA recommends that physicians with patients taking celecoxib, or who are considering prescribing the drug, consider the following:

• Information about the cardiovascular risk of celecoxib is evolving and patients should be informed accordingly.
• Alternatives to celecoxib should be considered, based on individual patient needs and risk factors.
• If alternatives to celecoxib are not acceptable, the lowest effective dose of the drug should be used.
• The currently approved dosing regimens are:
  • For osteoarthritis: 200 mg once a day or 100 mg twice per day
  • For rheumatoid arthritis: 100 to 200 mg twice per day
  • For pain: 400 mg to start, then 200 mg twice a day, if needed
  • For colon polyps: 400 mg twice a day with food

• The FDA is aware of no long term safety studies of older, COX-2 nonselective inhibitor NSAIDs that address cardiovascular risk.

According to Pfizer spokeswoman Mariann Caprino, Pfizer is suspending television, radio, newspaper, magazine, and other advertising to consumers until the safety issue is resolved. In an interview on "This Week," on ABC Television, Pfizer's chief executive, Henry A. McKinnell, Jr., said the company has no plans to pull Celebrex from the market, adding that, for many patients, Celebrex works better than other pain medications. He commented, "We're leaving Celebrex on the market because it is an appropriate option for many, many patients."³

It's Pfizer's position that Celebrex has not been shown to be dangerous when taken at the standard dose for arthritis. Cardiovascular risk has been shown only in the one study, and occurred only when patients took Celebrex at two to four times the usual dose for long periods of time.

Adding to the confusion, another study, which was testing whether Celebrex or Naproxen would be effective in reducing the risk of Alzheimer's disease was suspended on December 20 when researchers noted an increase in heart attack and stroke in patients taking naproxen (brand name Aleve). National Institutes of Health officials reported that patients taking naproxen had a 50% greater incidence of heart attack or stroke than the patients taking placebo. According to Dr. Sandra Kweder of the FDA, the NIH study is the first indicating that naproxen increases risk of heart attack or stroke.⁴

This is an obviously confusing and distressing situation for patients taking Celebrex. If you're taking Celebrex, it's advisable to discuss the risks and benefits with your doctor to decide whether to continue it while the investigation into its safety continues.

For more information:

• FDA Statement on the Halting of a Clinical Trial of the Cox-2 Inhibitor Celebrex

• FDA Alert for Practitioners on Celebrex (celecoxib)

¹ Food and Drug Administration. "FDA Statement on the Halting of a Clinical Trial of the Cox-2 Inhibitor Celebrex." December 17, 2004.

² Food and Drug Administration. "FDA Alert for Practitioners on Celebrex (celecoxib)." December 17, 2004.

³ Berenson, Alex. "Pfizer to Halt Its Advertising of Celebrex to Consumers." The New York Times. December 19, 2004.

⁴ Recer, Paul, AP Science Writer. "NIH stops study of Celebrex, naproxen." seattlepi.com. December 20, 2004.