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U.S. Department of Health and Human Services

Safety

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Zenapax (daclizumab) Dear Healthcare Professional Letter Aug 2003

The following is the text of a letter from Roche Pharmaceuticals. Contact the company for a copy of any referenced enclosures.


Important Drug Warnings
And Other Changes to the Prescribing Information


Dear Healthcare Provider:

We are writing to inform you of important changes to the prescribing information for ZENAPAX (daclizumab). These changes include the addition of two new Warning statements, one describing the increased mortality seen in a cardiac transplant study and the other, updated information regarding hypersensitivity reactions. Other sections of the ZENAPAX labeling impacted by the addition of the information from the cardiac transplant study have also been revised.

Immediately following are the two new Warnings added to the ZENAPAX labeling and a listing of the other sections changed to reflect the information obtained from the cardiac transplant study.

WARNINGS
The use of ZENAPAX as part of an immunosuppressive regimen including cyclosporine, mycophenolate mofetil, and corticosteroids may be associated with an increase in mortality. In a randomized, double-blind, placebo-controlled trial of ZENAPAX for the prevention of allograft rejection in 434 cardiac transplant recipients receiving concomitant cyclosoporine, mycophenolate mofetil and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving ZENAPAX compared to those receiving placebo (7% v 5%, respectively at 6 months; 10% v 6%, respectively at 12 months). Some, but not all, of the increase in mortality appeared related to a higher incidence of severe infections. Concomitant use of antilymphocyte antibody therapy may also be a factor in some of the fatal infections.

Hypersensitivity
Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to ZENAPAX and following re-exposure. These reactions may include hypotension, bronchospasms, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions. If a severe hypersensitivity reaction occurs, therapy with ZENAPAX should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. Patients previously administered ZENAPAX should only be re-exposed to a subsequent course of therapy with caution. The potential risks of such re-administration, specifically those associated with immunosuppression, are not known.

The following other sections of the ZENAPAX labeling have been modified to include information regarding the cardiac transplant study:

CLINICAL STUDIES; PRECAUTIONS: Drug Interactions: ADVERSE REACTIONS: Incidence of Infectious Episodes and Post-Marketing Experience

In addition to the above-mentioned changes, other modifications made to the labeling for ZENAPAX include the addition of three-year safety and efficacy data for adults and one-year data for pediatrics. This information is summarized below.

Adults
Treatment with ZENAPAX plus an immunosuppressive regimen of cyclosporine and corticosteroids was associated with better patient survival at three years post-transplant compared to placebo. However, there was no difference in three-year survival in patients receiving ZENAPAX plus a triple-therapy regimen of cyclosporine, corticosteroids and azathioprine when compared to placebo. There was no difference in graft survival at three years between treatment groups in either study, and no difference in the incidence of delayed graft function between groups.

Up to three years post-transplant, the addition of Zenapax did not increase the number of post-transplant lymphomas. While the incidence of lymphoproliferative disorders and opportunistic infections was no higher in the limited clinical study experience, patients on immunosuppressive therapy are at increased risk of lymphoproliferative disorders and opportunistic infections.

Pediatrics
Data from an open-label pharmacokinetic study in 60 pediatric renal transplant patients 11 months to 17 years of age were also analyzed for efficacy, immunogenicity and safety. In this study, 1 mg/kg of ZENAPAX was added to a standard immunosuppressive regimen every 14 days for a total of five doses before undergoing transplant surgery. At one year post-transplant, the combined incidence of biopsy-proven and clinically presumptive acute rejection was 17% and patient and graft survival at 100% and 96%, respectively. The incidence of anti-daclizumab antibody formation in the 3 months following transplant was 34%.

Additionally, the following adverse reactions occurred more frequently in pediatric transplant patients than adult transplant patients: diarrhea, postoperative pain, fever, vomiting, aggravated hypertension, pruritis and infections of the upper respiratory and urinary tracts.

Healthcare professionals are encouraged to report any serious adverse events that occur with ZENAPAX to Roche Pharmaceuticals Service Center at 1-800-526-6367 or to the FDA’s MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), via the MedWatch website (www.fda.gov/medwatch), or by mail (using postage paid and the FDA-3500 form) to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787.

Enclosed is a copy of the complete Prescribing Information for ZENAPAX that incorporates all of the changes described in this letter. If you have any further questions regarding ZENAPAX, please feel free to call Roche Pharmaceuticals Service Center at the toll-free number listed above.

Sincerely,


Robert D. Gordon, M.D.
Medical Director - Transplantation