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Plavix Response Reduced for Patients With CYP2C19 Gene Difference
  FDA Adds Warning to Plavix
Wall St Jnl March 13 2010 By JENNIFER CORBETT DOOREN
WASHINGTON-The 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. and Sanofi Aventis SA. 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. and Daiichi Sankyo Co. 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., 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 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.

Sanofi, Bristol-Myers Strengthen Warning on Plavix
March 12 (Bloomberg) -- Sanofi-Aventis SA and Bristol-Myers Squibb Co. upgraded a warning for the blood thinner Plavix, saying that a genetic variant in some people keeps their bodies from unleashing the full power of the drug.
Plavix, the world's second-biggest selling medicine, will carry the U.S. Food and Drug Administration's strictest caution, known as a black box, to warn that certain patients are "poor metabolizers," according to a notice posted today on the FDA's Web site.
Plavix is prescribed to millions of Americans after surgery to prevent heart attacks and strokes. Global sales rose 17 percent last year to $9.5 billion, second only to Pfizer Inc.'s cholesterol pill Lipitor. Four months ago, the FDA ordered Paris-based Sanofi and New York-based Bristol-Myers to notify doctors and patients that Plavix's anti-clotting benefits are cut almost in half when taken with the heartburn medicine Prilosec.
"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 the genetic variant "and alternate treatment strategies," Laura Hortas, a Bristol-Myers spokeswoman, said today in an interview.
Today's warning also tells doctors that genetic tests are available to identify which patients are unlikely to metabolize the drug effectively. Doctors, when treating those patients, should consider using other anti-clotting medications or changing the Plavix dose, FDA officials said.
Heart Attack, Stroke
Plavix is less likely to prevent heart attack, stroke and cardiovascular death in patients who are poor metabolizers, Mary Ross Southworth, deputy director for safety at the FDA's Division of Cardiovascular and Renal Products, said on a conference call with reporters. About 2 percent of Caucasians, 4 percent of blacks and 14 percent of Chinese fall into that category, she said.
There is "some evidence" that prescribing a higher Plavix dose to such patients can inhibit platelets, which cause blood to clot, said Robert Temple, deputy director for clinical science at the FDA's Center for Drug Evaluation and Research.
"What there hasn't been is a clear test of whether you can take people who are poor metabolizers, double their dose and do just as well," he said. "There is more uncertainty than we wish we had about exactly what to do."
Ticlid, Effient
Two other FDA-approved drugs, ticlopidine and Effient, are prescribed as platelet inhibitors. Ticlopidine, which includes Roche Holding AG's Ticlid and generics, "has some fairly high frequency of some unpleasant hematologic problems, so it has lost popularity considerably," Temple said.
Effient, developed by Daiichi Sankyo Co. and Eli Lilly & Co. and approved by the FDA in July, carries a black-box warning to doctors about an increased risk of potentially fatal bleeding. Still, "some people will consider using" Effient because it isn't linked to the same problems with metabolism that Plavix has, Temple said.
Tests are widely available to determine which patients are slow metabolizers of Plavix, Southworth said. A single test typically costs less than $500, said Courtney Harper, director of the FDA's Division of Chemistry and Toxicology Devices.
Medco's Plans
Medco Health Solutions Inc., the largest pharmacy benefits manager by revenue, plans to offer genetics testing to Plavix users in its personalized medicine program after April 1, said Robert Epstein, the company's chief medical officer. More than 200 client plans representing 8 million people currently participate in the Franklin Lakes, New Jersey, company's program, which offers genetic testing for patients who take either the blood thinner warfarin or the breast cancer drug tamoxifen, Epstein said today in an e-mailed statement.
Medco was among those to raise red flags about the ability of Plavix to be metabolized by everyone based on one's genetic makeup. The company is comparing the effectiveness of Plavix against Eli Lilly & Co.'s branded drug Effient in a study expected to be completed in 2011. It will focus on whether the 70 to 75 percent of Plavix users considered "extensive metabolizers" will have comparable outcomes to those who take the branded drug.

Sanofi-aventis and Bristol-Myers Squibb Announce Important Updates to PLAVIX U.S. Prescribing Information
BRIDGEWATER, N.J. & PRINCETON, N.J.--(BUSINESS WIRE)--Sanofi-aventis U.S. and Bristol-Myers Squibb Company (NYSE: BMY) today announced revisions to the U.S. prescribing information for PLAVIX (clopidogrel bisulfate), which include a boxed warning. The boxed warning concerns the diminished effectiveness of PLAVIX in patients who have a genetic variation leading to reduced formation of the active metabolite. These patients, who are designated as poor metabolizers, represent, according to the prescribing information, approximately 2% of whites, 4% of blacks, and 14% of Chinese. The percentage of poor metabolizers is estimated to be approximately 3% of the population, based on published studies.
Patients should continue taking PLAVIX unless told to do otherwise by their healthcare professional. They should talk with their healthcare professional if they have any concerns about PLAVIX.
Today, the U.S. Food and Drug Administration (FDA) issued a press release on this update, which is included below:
FDA Announces New Boxed Warning on Plavix
The U.S. Food and Drug Administration today added a boxed warning to the anti-blood clotting drug Plavix (clopidogrel), alerting patients and health care professionals that the drug can be less effective in people who cannot metabolize the drug to convert it to its active form.
Plavix reduces the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease by making platelets less likely to form blood clots. Plavix does not have its anti-platelet effects until it is metabolized into its active form by the liver enzyme, CYP2C19.
People who have reduced functioning of their CYP2C19 liver enzyme cannot effectively convert Plavix to its active form. As a result, Plavix may be less effective in altering platelet activity in those people. These "poor metabolizers" may not receive the full benefit of Plavix treatment and may remain at risk for heart attack, stroke, and cardiovascular death.
"We want to highlight this warning to make sure health care professionals use the best information possible to treat their patients," said Mary Ross Southworth, Pharm.D., a clinical analyst in the Division of Cardiovascular and Renal Products in the FDA's Center for Drug Evaluation and Research.
In May 2009, the FDA added this warning to the drug's label. After reviewing more data, the agency felt it was important to highlight this risk in a boxed warning.
It is estimated that 2 percent to 14 percent of the U.S. population are poor metabolizers. The FDA recommends that health care professionals consider alternative dosing of Plavix for these patients, or consider using other anti-platelet medications. Tests are available to assess CYP2C19 genotype to determine if a patient is a poor metabolizer.
Patients should not stop taking Plavix unless told to do so by their health care professional. They should talk with their health care professional if they have any concerns about Plavix.
Plavix is made under a Bristol-Myers Squibb - Sanofi Pharmaceuticals partnership. These 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.
The effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)]. Plavix at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with Plavix at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see Clinical Pharmacology (12.5)]. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3)].
Plavix is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
Plavix is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product.
Avoid concomitant use of Plavix and drugs that inhibit CYP2C19 activity. Co-administration of Plavix with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of Plavix if given concomitantly or if given 12 hours apart [see Drug Interactions (7.1)].
Thienopyridines, including Plavix, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue Plavix 5 days prior to surgery.
Avoid lapses in therapy, and if Plavix must be temporarily discontinued, restart as soon as possible. Premature discontinuation of Plavix may increase the risk of cardiovascular events.
In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding.
TTP, sometimes fatal, has been reported following use of Plavix, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange).
Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction.
Coadministering warfarin with Plavix increases the risk of bleeding.
Coadministration of Plavix and NSAIDs increases the risk of gastrointestinal bleeding.
Nursing mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother.
Acute Coronary Syndrome (ACS)
For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization, Plavix has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
For patients with ST-elevation myocardial infarction (STEMI), Plavix has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown.
The optimal duration of Plavix therapy in ACS is unknown.
Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, Plavix has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
Please see full prescribing information, including BOXED WARNING for the United States by visiting
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