Zenapax

ZENAPAX (daclizumab) is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplants. It is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids.

The efficacy of ZENAPAX (daclizumab) for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

Because it may cause serious side effects, daclizumab should only be prescribed by a doctor experienced in immunosuppressive therapy and the management of organ transplant patients. Discuss the risks and benefits of using this medication with your doctor.

Before using daclizumab, tell your doctor if you

• have used daclizumab in the past;
• have had a previous allergic reaction to daclizumab;
• have any active or chronic viral, bacterial, or fungal infection; or
• have a suppressed immune system or take medications that may suppress the immune system (e.g., medicines to prevent rejection of a transplanted organ, some cancer medicines, others).

You may not be able to use daclizumab, or you may require a dosage adjustment or special monitoring if you have any of the conditions listed above.

Daclizumab is in the FDA pregnancy category C. This means that it is not known whether daclizumab will be harmful to an unborn baby. Do not use this medication without first talking to your doctor if you are pregnant or could become pregnant during treatment. For women who could become pregnant, contraception is recommended before starting, during, and for four months following treatment with daclizumab to ensure protection from pregnancy.

It is not known whether daclizumab passes into breast milk. Do not use daclizumab without first talking to your doctor if you are breast-feeding a baby.

• Kidney Failure

Get emergency medical help if you have signs of an allergic reaction: hives, rash, fever; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• any type of infection--sudden weakness or ill feeling, fever, chills, sore throat, cold or flu symptoms, pain or burning when you urinate; or
• symptoms of depression--sadness, crying spells, drowsiness, trouble concentrating, anger, aggression, feeling hopeless or irritable, or having thoughts about suicide or hurting yourself.

Your treatment may be delayed if you have certain side effects.

Common side effects may include:

• cold symptoms (stuffy nose, sinus pain, sore throat);
• flu symptoms (fever, body aches, sore throat, swollen glands);
• cough, chest tightness;
• mouth pain;
• depressed mood;
• rash or itching;
• dry flaky skin; or
• abnormal liver function tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Zenapax is contraindicated in patients with known hypersensitivity to daclizumab or to any components of this product.

General

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.

Drug Interactions

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

Pregnancy Category C: A preclinical developmental toxicity study with Zenapax has shown an increased risk of early prenatal loss in cynomolgus monkeys compared to placebo. However, the clinical experience of Zenapax exposed pregnancies is still limited. 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.

Nursing Mothers

It is not known whether Zenapax is excreted in human milk. However, in preclinical developmental toxicity studies with Zenapax, 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 (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.

Pediatric Use

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.

Geriatric Use

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.

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.

There have not been any reports of overdoses with Zenapax. A maximum tolerated dose has not been determined in patients. A dose of 1.5 mg/kg has been administered to bone marrow transplant recipients without any associated adverse events.

NDC 0004-0501-09

Zenapax®
(daclizumab)

Sterile
Concentrate for
Injection

25 mg/5 mL
(5 mg/mL)

Rx only
1 Vial
(5 mL Size)

Roche

Applies to daclizumab: subcutaneous solution

Along with its needed effects, daclizumab (the active ingredient contained in Zenapax) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking daclizumab:

• Bladder pain
• blistering, crusting, irritation, itching, or reddening of the skin
• bloody or cloudy urine
• body aches or pain
• cough or hoarseness
• cracked, dry, or scaly skin
• difficult, burning, or painful urination
• difficulty with breathing
• discouragement
• ear congestion
• feeling sad or empty
• fever or chills
• frequent urge to urinate
• headache
• irritability
• lack of appetite
• loss of interest or pleasure
• loss of voice
• lower back or side pain
• nasal congestion
• painful or difficult urination
• rash
• runny nose
• sneezing
• sore throat
• swelling
• swollen, painful, or tender lymph glands in the neck, armpit, or groin
• trouble concentrating
• trouble sleeping
• unusual tiredness or weakness

• Dark urine
• general feeling of tiredness or weakness
• light-colored stools
• persistent loss of appetite
• right upper quadrant tenderness
• stomach pain, continuing
• vomiting
• yellow eyes or skin

• Thoughts or attempts at killing oneself
• watery or bloody diarrhea

• Dizziness
• fast heartbeat
• hives or welts
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• tightness in the chest

Some side effects of daclizumab may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blemishes on the skin
• pimples
• seizures