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WASHINGTON -(Dow Jones)- The U.S. Food and Drug Administration added a boxed warning to the anti-clotting medication Plavix, alerting doctors that the product doesn't work as well in some patients.

A boxed warning is the FDA's toughest warning and appears prominently at the top of a drug's label. Plavix is marketed by Bristol-Myers Squibb Co. (BMY) and Sanofi Aventis SA (SNY, SAN.FR). The drug is used by patients with cardiovascular disease to reduce the risk of heart attacks and strokes.

The FDA, in a posting on its Web site Friday, said some patients have a difference in a liver enzyme known as CYP2C19, which helps to convert Plavix to an active form that the human body can use. The agency said there are tests that can identify genetic differences in CYP2C19 function, which would allow doctors to determine whether a patient can fully metabolize Plavix.

For patients who are considered "poor metabolizers," the FDA said doctors should consider other anti-platelet medications or alternative doses of Plavix. According to the FDA, an estimated 2% to 14% of the population are poor metabolizers.

"In these patients, Plavix has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death," the FDA said.

One alternative for some patients is Effient, an anti-clotting drug from Eli Lilly & Co. (LLY) and Daiichi Sankyo Co. (4568.TO) that was approved last year for patients who undergo angioplasty, a common procedure to unblock a clogged artery. That drug, however, carries its own boxed warning discussing bleeding risks. It isn't recommended for patients who are expected to undergo open-heart surgery.

Agency officials said the decision as to whether patients should be tested before they start using Plavix should be left up to doctors and their patients. While Plavix is approved for long-term use, the product is often used in an emergency setting for patients receiving stents to open blocked heart vessels and for some types of strokes, making testing unfeasible.

Christopher Cannon, of Harvard Medical School and an associate physician in the cardiovascular division at Brigham and Women's Hospital in Boston, said he expected "mass confusion" among doctors about how to handle the FDA's recommendations, noting the lack of rapid tests that could be used in an emergency setting. He also said that higher dosages of Plavix that might be used in "poor metabolizers" haven't been tested.

At least one company, Quest Diagnostics Inc. (DGX), recently started offering a CYP2C19 test. The Scripps Health system in San Diego is using it for patients who are electing to undergo coronary-stent procedures. Quest said some private insurance companies do pay for it.

FDA officials said CYP2C19 tests typically cost less than $500. Roche Holdings AG (RHHBY, ROG.VX) also makes a gene-chip that can test for CYP2C19 although none of the tests are FDA-approved to test patients for Plavix effectiveness.

Bristol-Myers and Sanofi said patients who are considered poor metabolizers represent approximately 2% of whites, 4% of blacks and 14% of Chinese. The percentage of poor metabolizers is estimated to be approximately 3% of the total population.

Laura Hortas, a spokeswoman for Bristol-Myers Squibb, said "the revisions to the prescribing information for Plavix reflect the companies' ongoing research in collaboration with the FDA, which better defines the patient population that may be affected by a genetic variation in CYP2C19 and alternate treatment strategies."

Plavix is the second-best selling drug globally with $8.6 billion in sales in 2008, according to IMS Health.

(Ron Winslow in New York contributed to this article.)

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