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(see Boxed WARNING)
The use of ZENAPAX (daclizumab) 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 (daclizumab) for the prevention of allograft rejection in 434 cardiac transplant recipients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving ZENAPAX (daclizumab) compared to those receiving placebo (7% vs 5%, respectively at 6 months; 10% vs 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 anti-lymphocyte antibody therapy may also be a factor in some of the fatal infections.
ZENAPAX (daclizumab) should be administered under qualified medical supervision. Patients should be informed of the potential benefits of therapy and the risks associated with administration of immunosuppressive therapy.
While the incidence of lymphoproliferative disorders and opportunistic infections in the limited clinical trial experience was no higher in patients treated with ZENAPAX (daclizumab) compared with placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing lymphoproliferative disorders and opportunistic infections and should be monitored accordingly.
Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to ZENAPAX (daclizumab) and following re-exposure. These reactions may include hypotension, bronchospasm, 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 (daclizumab) should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. Patients previously administered ZENAPAX (daclizumab) 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.
It is not known whether ZENAPAX (daclizumab) use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during ZENAPAX (daclizumab) -induced immunosuppression.
Re-administration of ZENAPAX (daclizumab) after an initial course of therapy has not been studied in humans. The potential risks of such re-administration, specifically those associated with immunosuppression and/or the occurrence of anaphylaxis/anaphylactoid reactions, are not known.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Long-term studies to evaluate the carcinogenic potential of ZENAPAX (daclizumab) have not been performed. ZENAPAX (daclizumab) was not genotoxic in the Ames or the V79 chromosomal aberration assays, with or without metabolic activation. The effect of ZENAPAX (daclizumab) on fertility is not known, because animal reproduction studies have not been conducted with ZENAPAX (see WARNINGS and ADVERSE REACTIONS).
Pregnancy Category C: A preclinical developmental toxicity study with ZENAPAX (daclizumab) has shown an increased risk of early prenatal loss in cynomolgus monkeys compared to placebo. However, the clinical experience of ZENAPAX (daclizumab) exposed pregnancies is still limited. In general, IgG molecules are known to cross the placental barrier. ZENAPAX (daclizumab) should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should use effective contraception before beginning ZENAPAX (daclizumab) therapy, during therapy, and for 4 months after completion of ZENAPAX (daclizumab) therapy.
It is not known whether ZENAPAX (daclizumab) is excreted in human milk. However, in preclinical developmental toxicity studies with ZENAPAX (daclizumab) , four out of seven lactating cynomolgus monkeys given a 5-10 fold multiple (10mg/kg) of the normal human dose were found to secrete very low levels of ZENAPAX (daclizumab) (0.17 – 0.28% of maternal serum levels) in breast milk. Because many drugs are excreted in human milk, including human antibodies, and because of the potential for adverse reactions, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of ZENAPAX (daclizumab) have been established in pediatric patients from 11 months to 17 years of age. Use of ZENAPAX (daclizumab) in this age group is supported by evidence from adequate and well-controlled studies of ZENAPAX (daclizumab) in adults with additional pediatric pharmacokinetic data (see CLINICAL PHARMACOLOGY). Data from the pediatric pharmacokinetic study were also analyzed for efficacy, immunogenicity and safety. In an open-label study, 60 pediatric renal transplant recipients [median age of 10 years] received standard immunosuppressive agents in addition to a regimen of ZENAPAX (daclizumab) administered at a dose of 1.0 mg/kg at intervals of 14 days for a total of 5 doses, starting immediately before transplantation. In this study, the combined incidence of biopsy-proven and clinically presumptive acute rejection at 1 year posttransplant was 17% (10/60). Patient and graft survival at 1 year posttransplant were 100% and 96.7%, respectively. The incidence of anti-daclizumab antibodies (34%) observed in the first 3 months posttransplant was higher than the incidence previously observed in adult patients (14%) (see ADVERSE REACTIONS: Immunogenicity).
The safety profile of ZENAPAX (daclizumab) in pediatric transplant patients was shown to be comparable with that in adult transplant patients with the exception of the following adverse events, which occurred more frequently in pediatric patients ( > 15% difference in incidence): diarrhea, post-operative pain, fever, vomiting, aggravated hypertension, pruritus, and infections of the upper respiratory tract and urinary tract.
It is not known whether the immune response to vaccines, infection, and other antigenic stimuli administered or encountered during ZENAPAX (daclizumab) therapy is impaired or whether such response will remain impaired after ZENAPAX therapy.
Clinical studies of ZENAPAX (daclizumab) did not include sufficient numbers of subjects age 65 and older to determine whether they respond differently from younger subjects. Caution must be used in giving immunosuppressive drugs to elderly patients.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 10/28/2008
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