Subject: Association of increased mortality and risk of serious adverse events when prophylactic low-dose heparin is abruptly discontinued in patients to be started on XigrisŪ [drotrecogin alfa (activated)] therapy for severe sepsis.
OTTAWA, CANADA -- January 3, 2007 -- Eli Lilly Canada Inc., following discussions with Health Canada, would like to inform hospitals as to important safety information regarding the use of Xigris [drotrecogin alfa (activated)], recombinant human activated protein C, rhAPC with prophylactic low-dose heparin.
Xigris is indicated for reduction of mortality in 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, or multiple acute organ dysfunctions), when added to current best practice. Efficacy has not been established in adult patients with severe sepsis and lower risk of death. Xigris should not be used in this category of patients.
The XPRESS (Xigris and Prophylactic Heparin in Severe Sepsis) study, a randomized, double-blind, placebo-controlled trial investigated the concomitant use of prophylactic low-dose heparin with Xigris in adult patients with severe sepsis who were at high risk of death. Based on the findings of the XPRESS study, the Product Monograph has been updated to include the following information:
· The XPRESS trial demonstrated that in 1935 adult patients with severe sepsis treated with Xigris, discontinuation of baseline prophylactic low-dose heparin was associated with increased mortality and risk of serious adverse events, including cardiac, gastrointestinal, and venous thrombotic events.
· Unless considered medically necessary, if already started, prophylactic low-dose heparin should not be discontinued when Xigris is added to the treatment of patients with severe sepsis.
· The co-administration of prophylactic low-dose heparin and Xigris did not affect mortality compared to treatment with Xigris alone.
· The co-administration of prophylactic low-dose heparin and Xigris was associated with a statistically significant increase in nonserious adverse events and in bleeding events, during study Days 0 through 6, although there was no statistically significant increase in serious bleeding events.
The primary objective of the XPRESS study was to demonstrate in adult patients with severe sepsis who received Xigris that concomitant treatment with prophylactic low molecular weight or unfractionated heparin is equivalent to treatment with placebo, as determined by 28-day mortality. Among patients exposed to prophylactic heparin at baseline, however, lower mortality was seen in the patients who remained on heparin compared with the patients who were switched to placebo (26.9% vs 35.6%, P =.029).
During study days 0 through 6, patients treated with prophylactic heparin had a higher incidence of study-drug-related non-serious adverse events (10.0% vs 7.2%, P =.026) or any bleeding event (10.8% vs 8.1%, P =.049), compared to placebo, but did not have an increased risk of serious haemorrhagic events (2.3% vs 2.5%, P =.720), including central nervous system bleeding (0.3% vs 0.3%, P =.983).
Xigris should not be used in combination with heparin doses above those recommended for prophylaxis.
This product should be administered under the supervision of a qualified health professional who is experienced in the use of drugs used in the treatment and in the management of severe sepsis. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available.
This Notice to Hospitals is posted on both the Eli Lilly Canada website at www.lilly.ca and the Health Canada website.
Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-market adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any cases of death or other serious or unexpected adverse reactions in patients receiving Xigris should be reported to Eli Lilly Canada Inc. or Health Canada at the following addresses:
Customer Response Centre
Eli Lilly Canada Inc.
3650 Danforth Avenue
Toronto, Ontario M1N 2E8
Toll Free Number: 1-888-545-5972
Any suspected adverse reaction can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701C
OTTAWA, Ontario, K1A 0K9
Tel: (613) 957-0337 or Fax: (613) 957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free:
Tel: 866 234-2345
Fax: 866 678-6789
cadrmp@hc-sc.gc.ca
The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.
For other inquiries related to this communication, please contact Health Canada at:
Marketed Health Products Directorate (MHPD)
E-mail: mhpd_dpsc@hc-sc.gc.ca
Tel: (613) 954-6522
Fax: (613) 952-7738
Inquiries from healthcare professionals should be directed to the Eli Lilly Canada Customer Response Centre at 1-888-545-5972 between 8 a.m. and 6 p.m. EST.
XigrisŪ is a registered trademark of Eli Lilly and Company, used under license.
SOURCE: Eli Lilly Canada Inc.
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