Archived - For Health Professionals - Association of a Rapamune (sirolimus) containing immunosuppressant regimen with a high rate of acute rejection in de novo renal transplant patients

Starting date:

August 18, 2006

Posting date:

August 24, 2006

Type of communication:

Dear Healthcare Professional Letter

Subcategory:

Drugs

Source of recall:

Health Canada

Audience:

Healthcare Professionals

Identification number:

RA-170001450

This is duplicated text of a letter from Wyeth Pharmaceuticals.

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

Notice about Health Canada advisories

Health Canada Endorsed Important Safety Information on Rapamune (sirolimus)

August 18, 2006

Dear Health Care Professional,

Subject: Association of a Rapamune^® (sirolimus) containing immunosuppressant regimen with a high rate of acute rejection in de novo renal transplant patients

Wyeth Pharmaceuticals, Division of Wyeth Canada, after discussions with Health Canada, wish to advise you about important safety and efficacy information regarding a finding of an increased risk of rejection in de novo renal transplant patients receiving Rapamune, mycophenolate mofetil, and corticosteroid, used in combination with interleukin-2 receptor antibody induction, in an investigational setting. In this setting, the term "de novo" refers to the use of this regimen from the time of transplantation.

• Based on information from recent clinical trials, the use of Rapamune, mycophenolate mofetil (MMF), and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not recommended in the de novo organ transplant setting.
• Rapamune is authorized solely for the prevention of renal transplant rejection. It is recommended that Rapamune be used initially in combination with cyclosporine and steroids.
• The safety and efficacy of Rapamune as immunosuppressant therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended.

Wyeth has terminated an investigational clinical trial because review of interim results revealed a higher than expected rate of acute rejection and did not support a renal function benefit in renal transplant patients receiving IL2R Ab (basiliximab) + Rapamune (RAPA) + mycophenolate mofetil (MMF) + corticosteroids (ST) relative to the control group. This terminated study was designed to compare renal function at 12 months in de novo renal transplant recipients receiving a RAPA + MMF + ST regimen versus a cyclosporine + MMF + ST regimen from the time of transplantation. All subjects received a course of basiliximab. The reported rates of biopsy-confirmed acute rejection were 17.5% and 2.5%, respectively (P=0.002). The reported death rates were 2.9% and 0.6%, respectively (P=0.11).

One arm of another ongoing study, in which de novo renal transplant patients received an IL2R Ab (daclizumab - 2 doses) + RAPA + MMF + ST, was terminated when 12 month interim data also showed an increase in acute rejection rate and a numerically higher death rate.

Rapamune is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal transplants. It is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids. In patients at low to moderate immunologic risk, cyclosporine should be withdrawn 2 to 4 months after transplantation and the Rapamune dose should be increased to reach recommended blood concentrations. The safety and efficacy of cyclosporine withdrawal in high-risk patients have not been adequately studied and it is therefore not recommended. This includes patients with Banff 93 grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, or with serum creatinine > 400 µmol/L (4.5 mg/dL), black patients, re-transplants, multi-organ transplants, and patients with high panel of reactive antibodies.

Refer to the current Canadian Product Monograph for Rapamune for full prescribing information.

Ongoing clinical trials continue to investigate the efficacy and safety of Rapamune based immunosuppressant regimens in patients who were initially treated with cyclosporine or tacrolimus.

Adverse drug reactions (ADRs) that occur within the context of a clinical trial that are both serious and unexpected are subject to expedited reporting to Health Canada. A completed ADR Expedited Reporting Form should be attached to the front of the report and reports should be submitted, by fax to the:

• Therapeutic Products Directorate for Pharmaceuticals: 613-941-2121
• Biologics and Genetic Therapies Directorate for Biologics and Radiopharmaceuticals: 613-957-0364

For more information on clinical trials and ADR reporting within the context of a clinical trial please refer to the following guidance document: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/clini/ctdcta_ctddec-eng.php. ADRs that occur outside the parameters of a clinical trial should be reported to Health Canada as described below.

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-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of serious or unexpected adverse reactions in patients receiving Rapamune should be reported to Wyeth Canada or Health Canada at the following addresses:

Wyeth Canada

Medical Information & Pharmacovigilance

50 Minthorn Boulevard

Markham, Ontario L3T 7Y2

Tel: 1-800-461-8844

Fax: (905) 470-4385

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

Please share this information with your colleagues involved in the care of organ transplant patients. Wyeth Canada is committed to supporting Rapamune and clinical research in renal transplantation and will be working with Health Canada to update the Product Monograph. Please contact Wyeth Canada Medical Information at 1-800-461-8844 with any questions or concerns, or to request a copy of the current Product Monograph.

Sincerely,

original signed by

Dr. Neil Maresky, M.B., B.Ch.

Vice-President

Scientific Affairs