Bextra Withdrawn from Market
DERMAdoctor weighs in on skin risks of popular pain relievers

Citing no clear advantages and significant risks including a potentially fatal skin reaction, the federal food and Drug Administration called for the withdrawal of the painkiller valdecoxib (Bextra) from the market in early April 2005.

The FDA also called for new warnings on popular over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDS) that cite, among other things, the agents' potential to cause skin reactions.

Bextra belongs to a small class of drugs called cyclooxygenase-2 (COX-2) inhibitors. These drugs were originally created to confer gastrointestinal (GI) protection over older painkillers, which can cause ulcers and bleeding in some people. The theory is that the enzyme Cox-1, which is inhibited by traditional non-selective NSAIDS such as Advil and Alleve, also produces prostaglandins that help maintain the smooth protective layering of the stomach that prevents ulcers and other stomach irritation. But by blocking only the COX-2 enzyme, selective COX-2 blockers could reduce pain while sparing the stomach. By 2000 (just one year after the first COX-2 blocker was approved), more patients were receiving COX-2 inhibitors than standard NSAIDs.

However, soon studies began to suggest that COX-2 blockers might increase risk of heart attack and stroke. In fact, Vioxx (rofecoxib) manufacturer, Merck & Co.. pulled Vioxx from market in September 2004 when a long-term study showed it did increase such risk. Other studies of the remaining two drugs in this class celebrex (celecoxib) and Bextra (valdecoxib) soon followed suit as did a study suggesting that the traditional NSAID naproxen also upped risk of heart attack and stroke.

But the FDA only pulled Bextra, why?

In addition to increased risk of heart attack and stroke, Bextra also increases risk of a serious and potentially life-threatening skin reaction called Stevens-Johnson Syndrome (SJS). SJS can cause skin peeling rashes, and inflammation or blistering of the mucous membrane. The mucous membrane lines all body passages that communicate with the air such as the respiratory and alimentary tracts. It also contains cells and associated glands that secrete mucus. In SJS, blisters typically occur in the mouth, eyes and vagina. Moreover, patients who continue to take the drug despite the rash can develop toxic epidermal necrolysis (TEN) which resembles severe burn injuries all over the body. TEN can be fatal in up to one-third of cases.

These skin reactions are most likely to occur in the first 2 weeks of treatment, but can occur any time during therapy. Also, Bextra contains sulfa, and patients with a history of allergic reactions to sulfa may be at a greater risk of skin reactions.

As of November 2004, the FDA had received reports of a total of 87 cases in the United States of severe skin reactions in association with Bextra (including SJS and TEN). Twenty of the 87 cases involved patients with a known allergy to sulfa. Of these 87 cases, 36 hospitalizations were reported, including 4 deaths.

Other Cox-2 selective inhibitors and traditional NSAIDs such as naproxen and ibuprofen also have a risk for these rare, serious skin reactions, but the reported rate of these serious side effects appears to be greater for Bextra than for other COX-2 agents.

That's why the FDA will ask the manufacturers of all non-prescription products containing ibuprofen, naproxen and ketoprofen to revise their labeling to include a warning about potential skin reactions.

In some people, bruising may occur because NSAIDs affect cells involved in blood clotting. More rarely they can cause an inflammation of blood vessels (vasculitis), often showing palpable non-blanching purple-red spots on the skin.

Another reaction is called pseudoporphyria. This causes blisters, erosions, and scars on the skin in areas of sun exposure, often involving the face and backs of the hands. This reaction can continue for a number of months after stopping the medication, and is worse in sunny climates. This side effect is most common with naproxen (Naprosyn, Aleve, and others), ibuprofen (Motrin, Advil], diflunisal (Dolobid), ketoprofen (Orudis), nabumetone (Relafen) and oxaprozin (Daypro).

DERMAdoctor's Rx

Firstly, don't panic. Theses drugs are not any less safe today then they were yesterday. Follow dosing instructions on the label and remember that these agents are for short-term use only. If you do develop a skin reaction, call your doctor. As these reactions may be more pronounced with sun exposure, always use a broad-spectrum sunscreen with an SPF of at least 15 on all exposed skin, including the lips, even on cloudy days and reapply sunscreen frequently.

In addition, the FDA encourages anyone aware of a serious adverse reaction to make a MedWatch report by visiting www.fda.gov/medwatch and clicking on "How to Report" or calling 1-800-FDA-1088

To find out more about all NSAIDs from FDA, visit www.fda.gov/cder or call the agency's drug information hotline at 888-INFO-FDA (888-463-6332)

Denise Mann
DERMAdoctor Staff Writer

(Any topic discussed in this article is not intended as medical advice. If you have a medical concern, please check with your doctor.)

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