FDA Continues to Investigate Bleeding Risk for Xigris

Rochelle Nataloni

February 04, 2009

February 4, 2009 — The US Food and Drug Administration (FDA) announced today in an early communication that it is continuing to evaluate the incidence of serious bleeding events and death in patients who received drotrecogin alfa activated (Xigris, Eli Lilly and Co), a recombinant human activated protein C indicated for the treatment of severe sepsis.

The FDA is not recommending that clinicians stop prescribing this medication. "Prescribers should refer to the product label for the specific contraindications, warnings, and precautions and carefully weigh the increased risk of bleeding against the benefits of Xigris," according to the FDA.

The early communication indicates that the FDA is considering but has not reached a conclusion about whether any regulatory action is warranted.

The FDA is working with the manufacturer to further evaluate the incidence of serious bleeding events and mortality in patients treated with this drug and will relay its findings along with any recommendations when its review is complete, which may take several months.

A recently published retrospective study, which prompted the investigation, reports an increased risk for serious bleeding events and death in patients with sepsis. Baseline bleeding risk factors in patients who received drotrecogin alfa activated were also reported (Gentry et al. Crit Care Med. 2009;37[1]:19-25.), according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program.

Serious bleeding events occurred in 7 (35%) of 20 patients who had a risk factor for bleeding compared with 2 (3.8%) of 53 patients without bleeding risk factors. Of the patients with baseline bleeding risk factors, more died (13 [65%] of 20 patients) vs patients without any bleeding risk factors (13 (24.5%) of 53 patients). Study limitations include its retrospective design and its small patient population.

In an accompanying editorial, the authors suggest a possible strategy of not administering drotrecogin alfa activated to any patients with sepsis and risk factors for bleeding, which would "effectively [change] a warning in the product labeling to a contraindication. Under FDA regulations, contraindications in the prescribing information describe situations where the risks are known (that is, are not theoretical) and where the risks of use clearly outweigh any possible benefit," according to the FDA.

The prescribing information for drotrecogin alfa activated already describes an increased risk of bleeding, and the risk factors defined by this study are the same as those described in the drug's package insert, the FDA points out.

The "contraindications" section of the drug's prescribing information says that Xigris should not be used "in the following clinical situations where bleeding could lead to significant morbidity or death":

  • Active internal bleeding

  • Recent (within 3 months) hemorrhagic stroke

  • Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma

  • Trauma with an increased risk of life-threatening bleeding

  • Presence of an epidural catheter

  • Intracranial neoplasm or mass lesion or evidence of cerebral herniation

Adverse events related to drotrecogin alfa activated should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at https://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.


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