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FDA Issues Boxed Warning for CYP2C19-Linked Poor Metabolism of Plavix

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By Turna Ray

This article was originally posted on March 12.

A new boxed pharmacogenomics warning from the US Food and Drug Administration for the anti-platelet drug Plavix leaves doctors to make some difficult risk/benefit determinations about whether to genetically test their patients ahead of Plavix administration, or put them on another drug and risk different toxicities.

The boxed warning on the new Plavix label, issued by FDA this week, alerts doctors and patients that the CYP2C19 enzyme converts Plavix into its active form in order for the body to metabolize the drug. As such, patients with diminished CYP2C19 function, or poor metabolizers of the drug, are at greater risk of cardiovascular adverse events after an acute coronary syndrome or percutaneous coronary intervention than normal metabolizers of Plavix, the boxed warning notes.

The FDA then goes on to inform physicians that there are available tests "to identify a patient's CYP2C19 genotype [that] can be used as an aid in determining therapeutic strategy," though it does not specify any particular tests. Additionally, the agency recommends physicians to "consider alternative treatment … strategies in patients identified as CYP2C19 poor metabolizers."

"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, a clinical analyst in the Division of Cardiovascular and Renal Products in the FDA's Center for Drug Evaluation and Research, in a statement.

However, in the real world, depending on the urgency of their patients' medical condition, doctors can't always wait for genetic test results, which could take anywhere between several hours or a few weeks to come back from the laboratory. Ultimately, the FDA has left it up to the doctors to determine if they should genetically test patients before Plavix administration, or if they should see how patients react on a particular dose of Plavix and decide whether to switch to another drug depending on the outcome.

"In the acute setting, we have to realize that CYP2C19 functional status is not going to be available for the prescribers, so [they] will have to think of that ahead of time and maybe make choices about what kind of therapies they use in a certain patient, maybe one that doesn't have this kind of problem," Ross Southworth said during a call held this week to announce the new boxed warning.

"Later on in therapy, maybe after the patient has been on Plavix for a period of time, I think the prescriber has to look at the patient, see what dose they are on, see what they are taking Plavix for, and do an assessment of the risk and benefits that are available … and make a decision about testing or changing therapy at that point," Ross Southworth added.

According to cardiologist Eric Topol, if doctors are uncertain whether their patients' genotype is affecting Plavix metabolism, they can test the platelet function.

"The drug doesn't work unless you can metabolize it ─ it's an inactive drug," he recently told Pharmacogenomics Reporter. "So, if you're unsure about the effect of the genotype, you can then check the platelet function and see whether or not the platelets are being suppressed, which is the desirable endpoint.

"So, there's an intermediate way to make sure that Plavix is truly working beyond just the genes, and that's a big plus," said Topol, who, as the chief academic officer of Scripps Health, is administering CYP2C19 testing to patients before they receive Plavix at Scripps Green Hospital through a collaboration with Quest Diagnostics [see PGx Reporter 10-28-2009].

Alternative Treatments

Plavix is administered in patients with cardiovascular disease to reduce their risk of heart attack, unstable angina, stroke, and cardiovascular death. Alternative medications to Plavix include Roche Pharmaceuticals' Ticlid and Eli Lilly's Effient, but the latter may introduce new risk/benefit considerations for patients.

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In a 13,608-patient trial comparing Effient to Plavix, fewer patients on the Effient arm experienced non-fatal heart attacks than in the Plavix arm. However, patients on Effient with a history of stroke were more likely to have another stroke in the study. Additionally, the study found that while Effient showed greater efficacy than Plavix, those on the newer drug displayed a higher risk of fatal bleeding. The pharmacy-benefit manager Medco is currently conducting a study comparing treatment outcomes of "extensive metabolizers" on Plavix with patients taking Effient [see PGx Reporter 10-21-2009].

The new boxed warning comes after Sanofi-Aventis, which co-markets Plavix with Bristol-Myers Squibb, completed a study comparing how well patients with reduced CYP2C19 function and patients without this reduced enzyme function responded to Plavix. The post-marketing study was conducted by Sanofi-Aventis at the request of the FDA.

The crossover study Sanofi-Aventis submitted looked at 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups ─ ultrarapid, extensive, intermediate, and poor metabolizers ─ and evaluated their pharmacokinetic and anti-platelet responses using 300 mg Plavix followed by 75 mg doses per day and 600 mg followed by 150 mg per day, for five days each. "Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups," the label notes.

In the study, when poor metabolizers received the 600 mg/150 mg regimen, active metabolite exposure and anti-platelet response were greater than with the 300 mg/75 mg regimen. Still, "an appropriate dose regimen for this patient population has not been established in clinical outcome trials," the FDA warned doctors.

Even with this new information, it seems the FDA issued the boxed warning with imperfect data, as is often the case. "The data are not perfectly clear about [whether] all [poor metabolizers] have a very poor outcome. The data are somewhat mixed and the study designs are mostly not intended to answer that question," Robert Temple, director of the Office of Medical Policy at FDA's CDER, said during the call to discuss the labeling update.

This is the third CYP2C19-related labeling update to Plavix. In May 2009, the FDA initially updated the Plavix's label to inform healthcare providers of studies indicating that poor CYP2C19 metabolizers have limited response to Plavix. At the time, the agency also said it was awaiting results from ongoing studies before making pharmacogenetically-guided dosing recommendations for Plavix [see PGx Reporter 06-17-2009].

Six months later, the agency added more information to Plavix's label warning healthcare providers and patients against concomitant use of the drug and other CYP2C19-inhibiting agents. Even then, the FDA acknowledged that there are many unanswered questions about the link between Plavix response and CYP2C19 metabolism pending results from ongoing studies [see PGx Reporter 11-18-2009].

Testing Available

Since the new boxed warning highlights the availability of CYP2C19 testing, agency officials noted during the call that Roche's AmpliChip CYP450 test has been validated to gauge CYP2C19 alleles but it hasn't been approved by the agency specifically as a companion test for Plavix response.

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The FDA approved AmpliChip in 2005. The test's label states its intended use is "to identify a patient's CYP2D6 and CYP2C19 genotype from genomic DNA" and that information about these genotypes "may be used as an aid to clinicians in determining therapeutic strategy and treatment dose for therapeutics that are metabolized by the CYP2D6 and CYP2C19 product."

The AmpliChip label, however, does not list Plavix among several "clinically relevant" drugs that are known substrates of CYP2D6 and CYP2C19 enzymes. Test results can be available within eight hours according to the company's website.

FDA officials have indicated that for a diagnostic to be specifically named in a drug's label as a companion test, it must be cleared by the agency. During the call discussing the update to Plavix's label, FDA officials said Roche had not submitted an application to update the intended use of its test for this specific indication.

A spokesperson for Roche told Pharmacogenomics Reporter that "it’s too soon to say whether [the company] would pursue an indication specific for any one drug with the Roche AmpliChip CYP450 Test."

There are laboratory developed tests available for CYP2C19 genotyping. Quest's LDT, which is being used at Scripps Green Hospital in San Diego, gauges *1, *2, *3, *4, *5 alleles [see PGx Reporter 10-28-2009]. Test results are available in four to five days.

"We encourage healthcare providers to contact their local laboratory directors to determine [whether] the test that is offered … is accurate enough," Ross Southworth said. "We recommend that the test be at least 98 percent accurate in making genotype calls for CYP2C19."

Most available tests cost less than $500, said Courtney Harper, associate director for toxicology at FDA's Division of Chemistry and Toxicology Devices.

It is estimated that between 2 percent to 14 percent of the US population are poor metabolizers of Plavix. According to Ross Southworth, approximately 2 percent of Caucasians, 4 percent of blacks, and 14 percent of Chinese patients fall in the poor metabolizer category.

According to the FDA, patients harboring the CYP2C19*1 allele can fully metabolize Plavix. Those with the CYP2C19*2 and *3 alleles have no functional metabolism of the drug. "These two alleles account for most of the reduced-function alleles in patients of Caucasian (85%) and Asian (99%) descent classified as poor metabolizers," the FDA told healthcare providers and patients.

Meanwhile, CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associated with absent or reduced metabolism of Plavix, but are less frequent than the CYP2C19*2 and *3 alleles. "A patient with two loss-of-function alleles (as defined above) will have poor metabolizer status," the FDA noted.

Plavix is not the first drug to have a boxed warning informing doctors and patients of genetic information liked to drug response. The mood stabilizing drug carbamazepine and the HIV treatment abacavir have similar boxed warnings that include genetic testing information.

However, Plavix, which had global sales of $9 billion in 2008, is the first blockbuster drug to have a boxed PGx warning added to its label.


Additional reporting for this story was provided by Bernadette Toner.

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