It is not known whether ZENAPAX use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during ZENAPAX-induced immunosuppression.
Re-administration of ZENAPAX 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.
The following medications have been administered with ZENAPAX in clinical trials in renal allograft patients with no incremental increase in adverse reactions: cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. Very limited experience exists in these patients with the use of ZENAPAX concomitantly with tacrolimus, muromonab-CD3, antithymocyte globulin, and anti-lymphocyte globulin.
In renal allograft recipients (n=50) treated with ZENAPAX and mycophenolate mofetil, no pharmacokinetic interaction between ZENAPAX and mycophenolic acid, the active metabolite of mycophenolate mofetil, was observed.
However, in a large clinical study in cardiac transplant recipients (n=434), the use of ZENAPAX as part of an immunosuppression regimen including cyclosporine, mycophenolate mofetil, and corticosteroids was associated with an increase in mortality, particularly in patients receiving concomitant anti-lymphocyte antibody therapy and in patients who developed severe infections (see WARNINGS and ADVERSE REACTIONS: Incidence of Infectious Episodes).
CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY
Long-term studies to evaluate the carcinogenic potential of ZENAPAX have not been performed. ZENAPAX was not genotoxic in the Ames or the V79 chromosomal aberration assays, with or without metabolic activation. The effect of ZENAPAX on fertility is not known, because animal reproduction studies have not been conducted with ZENAPAX (see WARNINGS and ADVERSE REACTIONS).
Pregnancy Category C: Animal reproduction studies have not been conducted with ZENAPAX. Therefore, it is not known whether ZENAPAX can cause fetal harm when administered to pregnant women or can affect reproductive capacity. In general, IgG molecules are known to cross the placental barrier. ZENAPAX 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 therapy, during therapy, and for 4 months after completion of ZENAPAX therapy.
It is not known whether ZENAPAX is excreted in human 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 have been established in pediatric patients from 11 months to 17 years of age. Use of ZENAPAX in this age group is supported by evidence from adequate and well-controlled studies of ZENAPAX 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 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 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 therapy is impaired or whether such response will remain impaired after ZENAPAX therapy.
Also see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.
Clinical studies of ZENAPAX 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.