Archived - Notice to Hospitals - Increased mortality and risk of serious adverse events when prophylactic heparin is abruptly discontinued in patients to be started on Xigris [drotrecogin alfa (activated)] for severe sepsis

Starting date:

December 21, 2006

Posting date:

December 22, 2006

Type of communication:

Notice to Hospitals

Subcategory:

Biologic/vaccine

Source of recall:

Health Canada

Audience:

Healthcare Professionals

Identification number:

RA-170001505

This is duplicated text of a letter from Eli Lilly Canada Inc.

Contact the company for a copy of any references, attachments or enclosures.

Notice about Health Canada advisories

Notice to Hospitals - Health Canada Endorsed Important Safety Information on Xigris [drotrecogin alfa (activated)]

December 21, 2006

To: Hospital Chief of Medical Staff

Please distribute to relevant Departments of Intensive Care, Surgery, Emergency Medicine, Pharmacy, Anaesthesia, Internal Medicine, Nursing and/or other Departments as required, and other involved professional staff and post this Notice in your institution.

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 Xigris^® [drotrecogin alfa (activated)] therapy for severe sepsis.

Eli Lilly Canada Inc., following discussions with Health Canada, would like to inform you of 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 1,935 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=0.029). 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=0.026) or any bleeding event (10.8% vs 8.1%, p=0.049), compared to placebo, but did not have an increased risk of serious haemorrhagic events (2.3% vs 2.5%, p=0.720), including central nervous system bleeding (0.3% vs 0.3%, p=0.983).

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.

Sincerely,

original signed by

Loren D. Grossman, MD, FRCPC, FACP

Vice President, Research and Development

Eli Lilly Canada Inc.

Xigris^® is a registered trademark of Eli Lilly and Company, used under license.