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
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