Association of Xigris (drotrecogin alfa activated) with mortality in patients with single organ dysfunction and recent surgery.

Date: 2005-02-03

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NOTICE TO HOSPITALS
Health Canada Endorsed Important Safety Information on Xigris

January 31, 2005

To: Hospital Chief of Medical Staff

Please distribute to the relevant Departments of Surgery, Medicine, Intensive Care, Anaesthesiology, Pharmacy, and other involved professional staff and post this NOTICE in your institution.

Subject: Association of Xigris (drotrecogin alfa activated) with Mortality in Patients with Single Organ Dysfunction and Recent Surgery

Eli Lilly Canada Inc., following discussions with Health Canada, would like to inform you of important safety information regarding Xigris^® [drotrecogin alfa (activated)], recombinant human activated Protein C, rhAPC]. Xigris is indicated for the treatment of adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (e.g. as determined by APACHE II score or multiple organ dysfunctions). This new information applies only to patients with single organ dysfunction and recent surgery. These patients may not be at high risk of death and therefore may not be indicated for Xigris.

The Product Monograph will be revised to include information under Warnings and Precautions to address the recent observations and analyses of the ADDRESS and PROWESS studies:

In the randomized, placebo-controlled PROWESS (PROtein C Worldwide Evaluation in Severe Sepsis) trial, analysis showed that among the small number of patients with single organ dysfunction and surgery (within 30 days of study treatment), those treated with Xigris, had numerically, but not statistically significant, higher 28-day and in-hospital mortality rates than those treated with placebo (see Table 1).

In the randomized, placebo-controlled ADDRESS [ADministration of DRotrecogin alfa (activated) in Early stage Severe Sepsis] trial preliminary post-hoc analyses showed that for the surgical subpopulation of the single organ dysfunction subgroup, the 28-day mortality rate was higher in the Xigris treatment arm compared to placebo, which was statistically significant (based on unadjusted p-values). For this same subpopulation of patients, those treated with Xigris had a numerically but not statistically significant, higher in-hospital mortality rate than placebo treated patients (see Table 1).

Table 1: 28-Day All-Cause Mortality and In-Hospital Mortality for Surgical Patients With Single Organ Dysfunction in PROWESS and ADDRESS

	28-Day Mortality		In-Hospital Mortality
	Xigris	Placebo	Xigris	Placebo
PROWESS	10/49	8/49	14/48	8/47
	p=0.60 t		p=0.16 t
ADDRESS	67/323	44/313	76/325	62/314
	p=0.03 t		p=0.26 t

^t Chi-square test without adjustment for multiple comparisons.

This warning stems from exploratory, post hoc analyses of the ADDRESS clinical trial database and subsequent reanalysis of the PROWESS (Phase 3 registration) clinical trial database.

While a definitive explanation is not available, this observation underscores the importance of accurate severe sepsis diagnosis and assessment of risk of death when considering patients for Xigris.

Eli Lilly and Company is committed to further analysis in an effort to better understand this observation.

This Notice to Hospitals is posted on both the Eli Lilly Canada website at  http://www.lilly.ca and the Health Canada website at: http://www.hc-sc.gc.ca/
dhp-mps/medeff/advisories-avis/prof/index-eng.php.

The identification, characterization and management of marketed health product-related adverse reactions are dependent on the active participation of healthcare professionals in adverse reaction reporting programmes. You can assist us with monitoring the safety of Xigris by reporting adverse events to Eli Lilly Canada Inc. or Health Canada at the following addresses:

Lilly is committed to providing you with the most up-to-date and accurate information regarding its products. Inquiries from healthcare professionals should be directed to Eli Lilly Canada Customer Response Centre at 1-888-545-5972 between 8 a.m. and 6 p.m. EST.

Sincerely,

Original signed by

Loren D. Grossman, MD, FRCPC, FACP
Vice President, Research and Development
Eli Lilly Canada Inc.

^® Registered trademark owned by Eli Lilly and Company; used under license.