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FDA Updates Warfarin Labeling with PGx-Guided Dosing Ranges


Originally published on Feb. 2.

By Turna Ray

WASHINGTON, DC — The US Food and Drug Administration has updated the labeling for the anticoagulant warfarin with pharmacogenomically guided dosing ranges.

The agency initially updated the drug's label in 2007 to reflect the influence of the CYP2C9 and VKORC1 genes in metabolizing the drug. Although the agency recommended doctors consider lower initiation doses for patients with variations in these genes, at the time, the FDA held off on making specific dosing recommendations until ongoing outcomes studies were completed [see PGx Reporter 09-05-2007].

Then on Jan. 22, the FDA updated the "Dosage and Administration" section of the label, following a supplemental new drug application submitted by Bristol-Myers Squibb on July 24, 2009, for Coumadin, the branded version of warfarin. Since Coumadin was approved initially in 1954, several generic versions of the drug are available.

The drug's label now states: "The patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose." The label then instructs healthcare providers to refer to a table containing stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 variants. "Consider these ranges in choosing the initial dose," the label recommends.

The agency provided a range of PGx-guided doses in order to provide flexibility to doctors in their treatment of hypertension and other cardiovascular conditions that require anticoagulation therapy, Lawrence Lesko, director of the Office of Clinical Pharmacology and Biopharmaceutics in FDA's Center for Drug Evaluation and Research, said at a pharmacogenomics conference here this week.

The FDA derived the dosing ranges from multiple published studies. One of these studies, conducted by the The International Warfarin Pharmacogenetics Consortium and published in the New England Journal of Medicine in February 2009, compared a dosing algorithm based only on clinical factors to an algorithm that factored in genetic variation and clinical factors. The researchers evaluated the clinical value of each algorithm in more than 1,000 patients by calculating the percentage of patients whose predicted dose of warfarin fell within 20 percent of their actual stable therapeutic dose.

"The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach," the researchers concluded in the study. "The greatest benefits were observed in the 46.2 percent of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation."

The newly updated warfarin label also notes that the dosing ranges in the table account for clinical factors, such as age, race, body weight, sex, concomitant medications, and comorbidities, along with genotype.

While the dosing ranges in the label are based on VKORC1 –1639 G-A (rs9923231), "other co-inherited VKORC1 variants may also be important determinants of warfarin dose," FDA informs in the label. Additionally, patients with CYP2C9 *1/*3, *2/*2, *2/*3 and *3/*3 variants may require as much as two to four weeks to achieve maximum INR effect for a given dosage regimen, according to the label.

"It's safe to say that this label has actionable information in it," Lesko said at the meeting.

Since FDA's initial labeling update, some diagnostics manufacturers have complained that the agency recommendations were not actionable for doctors. Specifically, industry representatives criticized that without more specific guidance from the agency on PGx doses and stronger language requiring PGx-guided warfarin administration in certain circumstances, doctors will be resistant to adopting genetic testing into their practices.

To this, Lesko noted that the FDA has purposefully held off on explicitly requiring genetic testing in any of its drug labeling updates. Such a specific directive requiring genetic testing in labeling "doesn't allow flexibility," he explained.

For instance, in updating the labeling for the HIV drug Abacavir, the chemotherapeutic 6-mercaptopurine, and the anticonvulsant carbamazepine, the agency only "recommends" physicians conduct genetic testing.

In the labeling for the anti-platelet drug Plavix and 6-mercaptopurine, the FDA only informs physicians and patients that genetic testing is available.

Despite FDA's updates to the wafarin label, payors have been resistant to cover genetic testing to dose warfarin in the absence of more definitive clinical utility data from randomized, controlled trials.

In May, the Centers for Medicare & Medicaid Services decided not to cover PGx-guided warfarin dosing for its Medicare beneficiaries. Instead, CMS proposed a more "appropriate" alternative, employing a "coverage with evidence development" strategy in which it would pay for PGx-based warfarin dosing only for Medicare beneficiaries who are part of a prospectively designed RCT showing pharmacogenomics-guided dosing strategies improve health outcomes over standard dosing methods [see PGx Reporter 05-06-2009].

With the latest labeling update including dosing ranges for warfarin, FDA is hoping doctors will be more comfortable with PGx testing. "Doctors tell us all the time, don't tell us about VKORC1, just tell us what the right dose is for patients," Janet Woodcock, director of FDA's CDER, told participants at the meeting, emphasizing the need to educate physicians in pharmacogenomics.