Xigris May Increase Mortality in Lower-Risk Sepsis Patients

Yael Waknine


March 18, 2005

March 18, 2005 -- The U.S. Food and Drug Administration (FDA) and Eli Lilly and Co. have warned healthcare professionals via letter against use of activated drotrecogin alfa (Xigris) injection in patients with single-organ dysfunction who have undergone recent surgery, according to an alert sent yesterday from MedWatch, the FDA's safety information and adverse event reporting program. Use of drotrecogin in this population may be linked to an increased risk of mortality.

The FDA notes that recent postsurgical patients with single-organ dysfunction may not be at high risk of death (regardless of Acute Physiology And Chronic Health Evaluation [APACHE] II score), and therefore may not meet criteria for treatment with drotrecogin, which is used to treat severe sepsis in high-risk adults.

The warning was based on analyses of data from two clinical trial databases showing that drotrecogin alfa therapy was associated with an increased risk of mortality in this population. Although the data are not conclusive, the FDA recommends that the potential risk be taken under advisement prior to therapy initiation.

Reanalysis of the randomized Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial showed that mortality from all causes was increased in patients with single-organ dysfunction and recent surgery treated with drotrecogin alfa compared with placebo at 28 days (10/49 vs 8/49 deaths) and over the course of inpatient stay (14/48 vs 8/47 deaths).

Preliminary analysis of subset data from a second randomized clinical trial (Administration of Drotrecogin Alfa in Early Severe Sepsis [ADDRESS]) showed that drotrecogin alfa therapy was linked to increased mortality compared with placebo in septic patients at lower risk of death (APACHE II score < 25 or sepsis-induced single-organ failure at any score; 28-day mortality: 67/323 vs 44/313 deaths; in-hospital mortality: 76/325 vs 62/314 deaths).

In the letter, the FDA emphasizes the importance of accurate diagnosis for severe sepsis and careful consideration of the risks and benefits of drotrecogin alfa therapy prior to its initiation in patients with single-organ dysfunction and recent surgery.

Adverse events related to use of drotrecogin alfa should be reported to the Lilly Answer Center at 1-800-LILLYRx (1-800-545-5979). Alternatively, this information can be reported to the FDA's MedWatch program by phone 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.

Reviewed by Gary D. Vogin, MD


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