FDA label f32389f3-b45f-44a7-a008-d0e1910cca0a

WARNING Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe ZENAPAX ® (daclizumab). The physician responsible for ZENAPAX administration should have complete information requisite for the follow-up of the patient. ZENAPAX should only be administered by healthcare personnel trained in the administration of the drug who have available adequate laboratory and supportive medical resources.

WARNINGS (see Boxed WARNING) 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 cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving ZENAPAX 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 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 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. 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, 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 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.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Rates observed in clinical studies may not reflect those observed in clinical practice. Adverse reaction information obtained in clinical trials does, however, provide a basis for identifying adverse events that appear to be related to drug use and for approximating the rate of occurrence. The safety of ZENAPAX was determined in four clinical studies of renal allograft rejection, three of which were randomized controlled clinical trials, in 629 patients receiving renal allografts of whom 336 received ZENAPAX and 293 received placebo. All patients received concomitant cyclosporine and corticosteroids. In these clinical trials, ZENAPAX did not appear to alter the pattern, frequency or severity of known major toxicities associated with the use of immunosuppressive drugs. The use of ZENAPAX was associated with a higher incidence of mortality when compared to placebo in a large (n=434) randomized controlled study of patients receiving cardiac transplants (see WARNINGS and Incidence of Infectious Episodes ). Adverse events were reported by 95% of the patients in the placebo-treated group and 96% of the patients in the group treated with ZENAPAX. The proportion of patients prematurely withdrawn from the combined studies because of adverse events was 8.5% in the placebo-treated group and 8.6% in the group treated with ZENAPAX. ZENAPAX did not increase the number of serious adverse events observed compared with placebo. The most frequently reported adverse events were gastrointestinal disorders, which were reported with equal frequency in ZENAPAX- (67%) and placebo-treated (68%) patient groups. The incidence and types of adverse events were similar in both placebo-treated patients and patients treated with ZENAPAX. The following adverse events occurred in ≥5% of patients treated with ZENAPAX. These events included: Gastrointestinal System: constipation, nausea, diarrhea, vomiting, abdominal pain, pyrosis, dyspepsia, abdominal distention, epigastric pain not food-related; Metabolic and Nutritional: edema extremities, edema; Central and Peripheral Nervous System: tremor, headache, dizziness; Urinary System: oliguria, dysuria, renal tubular necrosis; Body as a Whole - General: posttraumatic pain, chest pain, fever, pain, fatigue; Autonomic Nervous System: hypertension, hypotension, aggravated hypertension; Respiratory System: dyspnea, pulmonary edema, coughing; Skin and Appendages: impaired wound healing without infection, acne; Psychiatric: insomnia; Musculoskeletal System: musculoskeletal pain, back pain; Heart Rate and Rhythm: tachycardia; Vascular Extracardiac: thrombosis; Platelet, Bleeding and Clotting Disorders: bleeding; Hemic and Lymphatic: lymphocele. The following adverse events occurred in <5% and ≥2% of patients treated with ZENAPAX. These included: Gastrointestinal System: flatulence, gastritis, hemorrhoids; Metabolic and Nutritional: fluid overload, diabetes mellitus, dehydration; Urinary System: renal damage, hydronephrosis, urinary tract bleeding, urinary tract disorder, renal insufficiency; Body as a Whole - General: shivering, generalized weakness; Central and Peripheral Nervous System: urinary retention, leg cramps, prickly sensation; Respiratory System: atelectasis, congestion, pharyngitis, rhinitis, hypoxia, rales, abnormal breath sounds, pleural effusion; Skin and Appendages: pruritus, hirsutism, rash, night sweats, increased sweating; Psychiatric: depression, anxiety; Musculoskeletal System: arthralgia, myalgia; Vision: vision blurred; Application Site: application site reaction. Incidence of Malignancies One and 3 years posttransplant, the incidence of malignancies was 2.7% and 7.8%, respectively, in the placebo group compared with 1.5% and 6.4%, respectively, in the ZENAPAX group. Addition of ZENAPAX did not increase the number of posttransplant lymphomas up to 3 years posttransplant. Lymphomas occurred at a frequency of ≤1.5% in both placebo-treated and ZENAPAX-treated groups. Hyperglycemia No differences in abnormal hematologic or chemical laboratory test results were seen between groups treated with placebo or ZENAPAX with the exception of fasting blood glucose. Fasting blood glucose was measured in a small number of patients treated with placebo or ZENAPAX. A total of 16% (10 of 64 patients) of placebo-treated and 32% (28 of 88 patients) of patients treated with ZENAPAX had high fasting blood glucose values. Most of these high values occurred either on the first day posttransplant when patients received high doses of corticosteroids or in patients with diabetes. Incidence of Infectious Episodes The overall incidence of infectious episodes, including viral infections, fungal infections, bacteremia and septicemia, and pneumonia, was not higher in patients treated with ZENAPAX than in placebo-treated patients in trials of renal transplantation. In a large randomized study of ZENAPAX used for the prevention of allograft rejection in patients receiving cardiac allografts, more patients receiving ZENAPAX experienced severe or fatal infections after 12 months of therapy when compared to those receiving placebo (10% vs 7%, respectively). The risks of infection or death may be increased in patients receiving concomitant anti-lymphocyte antibody therapy (see WARNINGS ). The types of infections reported in trials of renal transplantation were similar in both the ZENAPAX-treated and the placebo-treated groups. Cytomegalovirus infection was reported in 16% of the patients in the placebo group and 13% of the patients in the ZENAPAX group. One exception was cellulitis and wound infections, which occurred in 4.1% of placebo-treated patients and 8.4% of patients treated with ZENAPAX. At 1 year posttransplant, 7 placebo patients and 1 patient treated with ZENAPAX had died of an infection. At 3 years posttransplant, 8 placebo patients and 4 patients treated with ZENAPAX had died of infection. Immunogenicity Low titers of anti-idiotype antibodies to daclizumab were detected in the adult patients treated with ZENAPAX with an overall incidence of 14%. The incidence of anti-daclizumab antibodies observed in the pediatric patients was 34%. No antibodies that affected efficacy, safety, serum daclizumab levels or any other clinically relevant parameter examined were detected. The data reflect the percentage of patients whose test results were considered positive for antibodies to daclizumab in an ELISA assay and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to daclizumab with the incidence of antibodies to other products may be misleading. Post-Marketing Experience The following adverse reactions have been identified and reported during post-approval use of ZENAPAX (daclizumab). Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure. Severe acute hypersensitivity reactions including anaphylaxis characterized by 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, as well as cytokine release syndrome, have been reported during post-marketing experience with ZENAPAX. The relationship between these reactions and the development of antibodies to ZENAPAX is unknown.