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Zinbryta

Generic Name: Daclizumab
Class: Immunomodulatory Agents

Warning(s)

WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE HEPATITIS and OTHER IMMUNE-MEDIATED DISORDERS

See full prescribing information for complete boxed warning.

  • Daclizumab can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. Obtain transaminase and bilirubin levels before initiation of daclizumab. Monitor and evaluate transaminase and bilirubin levels monthly and up to 6 months after the last dose.1

  • Daclizumab is contraindicated in patients with pre-existing hepatic disease or hepatic impairment.1

  • Immune-mediated disorders including skin reactions, lymphadenopathy, non-infectious colitis, and other immune-mediated disorders can occur with daclizumab.1

  • These conditions may require treatment with systemic corticosteroids or immunosuppressive medication.1

  • Daclizumab is available only through a restricted distribution program called the Zinbryta REMS Program.1

REMS:

FDA approved a REMS for daclizumab to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of daclizumab and consists of the following: communication plan, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Daclizumab, an interleukin-2 (IL-2) receptor blocking antibody, is an immunomodulatory agent.

Uses for Zinbryta

Daclizumab has the following uses:

Daclizumab is an interleukin-2 receptor blocking antibody indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of daclizumab should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.1

Zinbryta Dosage and Administration

General

Daclizumab is available in the following dosage form(s) and strength(s):

Injection: 150 mg/mL solution in a single-dose prefilled syringe.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Recommended dosage: 150 milligrams once monthly.1

  • For subcutaneous use only.1

  • Train patients in the proper technique for self-administration.1

  • Conduct laboratory tests at baseline and at periodic intervals to monitor for early signs of potentially serious adverse reactions. 1

Cautions for Zinbryta

Contraindications

  • Pre-existing hepatic disease or hepatic impairment, including ALT or AST at least 2 times the ULN.1

  • History of autoimmune hepatitis or other autoimmune condition involving the liver.1

  • History of hypersensitivity to daclizumab or any other component of the formulation.1

Warnings/Precautions

Hepatic Injury

Daclizumab can cause life-threatening severe liver injury, including liver failure and autoimmune hepatitis. In controlled studies, serious drug-related hepatic injury occurred in 0.7% of daclizumab-treated patients compared with 0.4% of interferon beta-1a-treated patients (Study 1) and in 1.0% of daclizumab-treated patients compared with no injury in placebo patients (Study 2). Across all clinical studies (controlled and open-label), serious drug-related hepatic injury occurred in 1% of daclizumab-treated patients, with monthly monitoring of transaminases and total bilirubin. The incidence of discontinuation due to drug related hepatic injury was 5% in daclizumab-treated patients and 4% in interferon beta-1a-treated patients.1

Autoimmune Hepatitis

Across all clinical studies (controlled and open-label), 0.3% of daclizumab-treated patients developed autoimmune hepatitis. One fatal case of autoimmune hepatitis occurred in a patient re-initiating daclizumab after a planned 6 month treatment interruption period. This patient subsequently received two doses of daclizumab in the presence of persisting alanine aminotransferase levels (ALT) more than 5 times the upper limit of normal (ULN).1

Transaminase and Total Bilirubin Elevations

The incidence of increases in hepatic transaminases was greater in patients taking daclizumab than in those taking interferon beta-1a or placebo. The incidence of ALT or AST elevations above 5 times the ULN was 6% in daclizumab-treated patients compared with 3% in interferon beta-1a-treated patients (Study 1) and 4% in daclizumab-treated patients compared with 1% in patients on placebo (Study 2). Less than 1% of daclizumab-treated patients had ALT or AST greater than 20 times the ULN. Elevations of hepatic transaminases of at least 3 times the ULN combined with elevated bilirubin at least 2 times the ULN and alkaline phosphatase less than 2 times the ULN occurred in 0.7% of daclizumab-treated patients compared with 0.1% of interferon beta-1a-treated patients. In clinical trials, serum transaminase elevations occurred during treatment and up to 4 months after the last dose of daclizumab.1

Monitoring

Prior to starting treatment with daclizumab, obtain serum transaminases (ALT and AST) and total bilirubin levels. 1

Test transaminase levels and total bilirubin monthly and assess before the next dose of daclizumab. Follow transaminase levels and total bilirubin monthly for 6 months after the last dose of daclizumab.1

Treatment modifications are recommended based on serum transaminase and total bilirubin values. 1

If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with daclizumab, as appropriate.1

Patients with prolonged elevations of serum transaminases should be evaluated for other possible causes, such as infection, and a specialist should evaluate the patient. Discontinue daclizumab if autoimmune hepatitis is suspected. Treatment of autoimmune hepatitis with systemic corticosteroids and other immunosuppressant drugs may be required. Some patients may need long-term immunosuppression.1

Risk of Hepatic Injury with Concomitant Use of Other Hepatotoxic Drugs

Caution should be used when using hepatotoxic drugs, including non-prescription products, concomitantly with daclizumab. Also, carefully consider the need for the use of herbal products or dietary supplements that can cause hepatotoxicity. 1

Immune-Mediated Disorders

Treatment with daclizumab increases the risk of immune-mediated disorders, including autoimmune disorders such as autoimmune hepatitis. Across all clinical studies (controlled and open-label), immune-mediated disorders occurred in 28% of patients on daclizumab, the most common of which were skin reactions and lymphadenopathy. In the active-control study (Study 1), immune-mediated disorders were observed in 32% of daclizumab-treated patients compared with 12% for interferon beta-1a-treated patients. In Study 1, serious immune-mediated disorders were observed in 4% of patients treated with daclizumab compared with less than 1% for interferon beta-1a-treated patients. In the placebo-control study (Study 2), immune-mediated disorders were observed in 13% of daclizumab-treated patients compared with 7% of placebo-treated patients. In Study 2, serious immune-mediated disorders were observed in 0.5% of daclizumab-treated patients and in 0.5% of placebo-treated patients. In some cases, patients had concurrent or sequentially occurring disorders while taking daclizumab.1

Some patients required invasive procedures for diagnosis (e.g., colonoscopy, liver biopsy, kidney biopsy, lung biopsy), hospitalization for fluid replacement or blood transfusion, or prolonged treatment with systemic corticosteroids or immunosuppressant drugs. Some of these events did not resolve after stopping daclizumab during study follow-up.1

Patients receiving daclizumab should be carefully monitored for emergent immune-mediated disorders and For suspected immune-mediated disorders, ensure adequate evaluation to confirm etiology or to exclude other causes. If a patient develops a serious immune-mediated disorder, consider stopping daclizumab and refer the patient to an appropriate specialist for further evaluation and treatment.1

Skin Reactions

Daclizumab causes skin reactions. In clinical trials, skin reactions occurred in 37% of daclizumab-treated patients compared with 19% of interferon beta-1a-treated patients (Study 1) and in 18% of daclizumab-treated patients compared with 13% of patients on placebo (Study 2). Skin reactions occurred at any time during treatment with daclizumab. Rashes occurred in 11% of daclizumab-treated patients compared to 4% of interferon beta-1a-treated patients, and in 7% of daclizumab-treated patients compared to 3% of patients on placebo. Dermatitis occurred more frequently in daclizumab-treated patients compared to interferon beta-1a-treated patients or to patients on placebo, and eczema was observed more frequently in daclizumab-treated patients compared to interferon beta-1a-treated patients. Psoriatic conditions occurred in 2% of daclizumab-treated patients compared with 0.3% of interferon beta-1a-treated patients. Photosensitivity also occurred.1

Serious skin reactions occurred in 2% of patients treated with daclizumab compared with 0.1% of patients on interferon beta-1a (Study 1) and in 1% of patients treated with daclizumab compared with none treated with placebo (Study 2). One death resulted from infectious complications following a serious cutaneous reaction. In patients with a history of skin conditions, including eczema or psoriasis, use of daclizumab may exacerbate those conditions. Treatment of skin reactions included treatment with topical or systemic steroids or immunosuppressant drugs, including tacrolimus. In clinical trials, discontinuation because of skin reactions was 4% in daclizumab-treated patients. Rashes took a mean of 3 months to resolve, some were unresolved at the time of the last evaluation.1

If a patient develops a serious diffuse or inflammatory rash, it is recommended that a dermatologist evaluate the patient before the next dose of daclizumab. Discontinuation of daclizumab may be appropriate.1

Lymphadenopathy

Daclizumab increases the incidence of lymphadenopathy. In controlled studies, lymphadenopathy or lymphadenitis occurred in 6% of daclizumab-treated patients compared with 1% of interferon beta-1a-treated patients (Study 1) and in 2% of daclizumab-treated patients compared with 1% of placebo-treated patients (Study 2). Onset of lymphadenopathy or lymphadenitis occurred throughout the treatment period. Serious events related to lymphadenopathy or lymphadenitis included infections, benign salivary neoplasm, skin reactions, thrombocytopenia, and interstitial lung changes. The majority of cases resolved with or without continued treatment with daclizumab and took a mean of 3 months to resolve. Lymphadenopathy resulted in discontinuation in 0.6% of daclizumab-treated patients.1

Some patients with lymphadenopathy underwent diagnostic biopsy. In the event that lymph node biopsy is considered, full diagnostic evaluation should be conducted by a specialist. 1

Non-Infectious Colitis

An increased incidence of serious colitis (less than 1%) was reported in patients treated with daclizumab compared with none for patients treated with interferon beta-1a or placebo in clinical trials. Consider referring patients who develop symptoms of colitis (e.g., abdominal pain, fever, prolonged diarrhea) to a specialist.1

Other Immune-Mediated Disorders

A wide variety of other immune-mediated disorders, some serious, have occurred infrequently with the use of daclizumab. These include single organ or systemic multi-organ inflammatory reactions. Many events occurred in only one patient, and the relationship to daclizumab is unknown. Some required treatment with systemic corticosteroids. Some required several months for resolution after the last dose of daclizumab.1

For suspected immune-mediated disorders, ensure adequate evaluation to confirm etiology or to exclude other causes. If a patient develops a serious immune-mediated disorder, consider stopping daclizumab and refer the patient to an appropriate specialist for further evaluation and treatment.1

REMS Program

Daclizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Zinbryta REMS Program, because of the risks of hepatic injury including autoimmune hepatitis, and other immune-mediated disorders. 1

Notable requirements of the REMS Program include the following: 1

  • Prescribers must be certified with the program by enrolling and completing training. 1

  • Patients must enroll in the program and comply with ongoing monitoring requirements. 1

  • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive daclizumab.1

Further information, including a list of qualified pharmacies/distributors, is available at 1-800-456-2255. 1

Acute Hypersensitivity

Daclizumab can cause anaphylaxis, angioedema, and urticaria after the first dose or at any time during treatment. Discontinue and do not re-start daclizumab if anaphylaxis or other allergic reactions occur.1

Infections

Daclizumab increases the risk for infections. In controlled trials, infections occurred in 65% of daclizumab-treated patients compared with 57% of interferon beta-1a-treated patients (Study 1) and in 50% of daclizumab-treated patients compared with 44% of patients taking placebo (Study 2). Serious infections occurred in 4% of daclizumab-treated patients compared with 2% of interferon beta-1a-treated patients (Study 1) and in 3% of daclizumab-treated patients compared with none on placebo (Study 2).1

The most common types of infections observed were upper respiratory tract infections, urinary tract infections and viral infections. 1

In clinical trials, cases of tuberculosis occurred in countries where tuberculosis is endemic. Evaluate high-risk patients for tuberculosis infection prior to initiating treatment with daclizumab. For patients testing positive for tuberculosis, treat by standard medical practice prior to therapy with daclizumab. 1

Avoid initiating daclizumab in patients with severe active infection until the infection is fully controlled. If serious infection develops, consider withholding treatment with daclizumab until the infection resolves.1

Vaccinations

The safety of immunization with live viral vaccines during treatment with daclizumab has not been studied. Vaccination with live vaccines is not recommended during treatment and up to 4 months after discontinuation of daclizumab. 1

Depression and Suicide

Depression-related events occurred more frequently in patients receiving daclizumab than in patients receiving interferon beta-1a or placebo. In controlled trials, depression-related events occurred in 10% of daclizumab-treated patients compared with 8% of interferon beta-1a-treated patients (Study 1) and in 7% of daclizumab-treated patients compared with 2% of patients taking placebo (Study 2). In Study 1, serious events related to depression, including suicidal ideation or suicide attempt, occurred in 0.4% of daclizumab-treated patients and in 0.7% of interferon beta-1a-treated patients. None occurred in Study 2 (placebo-controlled).1

Administer daclizumab with caution to patients with previous or current depressive disorders. Advise patients and/or caregivers to immediately report any symptoms of new or worsening depression and/or suicidal ideation to their healthcare provider.1

If a patient develops severe depression and/or suicidal ideation, consider discontinuation of daclizumab.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risk associated with use of daclizumab in pregnant women.1

Administration of daclizumab to monkeys during gestation resulted in embryofetal death and reduced fetal growth at maternal exposures greater than 30 times that expected clinically. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. 1

In monkeys administered daclizumab (0, 10, 50, or 200 mg/kg) weekly by subcutaneous injection during organogenesis (gestation days 20 through 50), there was a decrease in fetal body weight and crown-rump length, and an increase in embryofetal death at the highest dose tested. Plasma exposure (AUC) at the no-effect dose of 50 mg/kg was approximately 30 times that in humans at the recommended human dose (RHD) of 150 mg.1 In monkeys administered daclizumab (50 mg/kg) weekly by subcutaneous injection from gestation day 50 to birth, there were no effects on pre- or postnatal development for up to 6 months after birth. Plasma exposure (AUC) at the administered dose was 55 times that in humans at the RHD.1

Lactation

There are no data on the presence of daclizumab in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Daclizumab was excreted in the milk of daclizumab-treated monkeys.1

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for daclizumab and any potential adverse effects on the breastfed child from daclizumab or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness of daclizumab in patients less than 17 years old have not been established. Use of daclizumab is not recommended in pediatric patients due to the risks of hepatic injury and immune-mediated disorders.1

Geriatric Use

Clinical studies of daclizumab did not include a sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients.1

Hepatic Impairment

Clinical trials did not include patients with ALT or AST more than two times the ULN. Patients with signs and symptoms of hepatic impairment may be at increased risk for hepatotoxicity from daclizumab.1

Common Adverse Effects

The most common adverse reactions (incidence ≥5% and ≥2% higher incidence than comparator) reported for daclizumab were nasopharyngitis, upper respiratory tract infection, rash, influenza, dermatitis, oropharyngeal pain, bronchitis, eczema and lymphadenopathy compared with interferon beta-1a; and upper respiratory tract infection, depression, rash, pharyngitis, and increased alanine aminotransferase (ALT) compared with placebo.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Hepatotoxic Drugs: Evaluate potential for increased risk of hepatotoxicity with concomitant use.1

Actions

Mechanism of Action

The precise mechanism by which daclizumab exerts therapeutic effects in multiple sclerosis is unknown but is presumed to involve modulation of IL-2 mediated activation of lymphocytes through binding to CD25, a subunit of the high-affinity IL-2 receptor. 1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Hepatic Injury

Inform the patient of the risk of severe hepatic injury associated with daclizumab. Advise patients of the symptoms of hepatic dysfunction, and instruct patients to report such symptoms to their health care provider immediately.1

Discuss with the patient the importance of measuring hepatic laboratory values and having them evaluated by the health care provider monthly while taking daclizumab and for up to 6 months after the last dose of daclizumab.1

Discuss with the patient the risk of concomitant use of other hepatotoxic medications, over the counter medications, herbal products, or dietary supplements. 1

Inform the patient that they will be given a daclizumab patient wallet card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation.1

Advise the patient to show the daclizumab patient wallet card to other treating health care providers.1

Immune-Mediated Disorders

Advise patients that daclizumab can cause their immune system to attack healthy cells in their body and that this can affect any organ system.1

Skin Reactions

Advise patients that daclizumab can cause dermatologic reactions that can range from mild rashes to serious reactions that could require treatment with other medications or result in hospitalization. Instruct patients to seek immediate medical attention if dermatologic reactions occur. 1

Lymphadenopathy

Inform patients that daclizumab may cause lymphadenopathy that can range from mild events that can resolve on their own to serious lymphadenopathy that may require invasive procedures for diagnosis. Inform patients of the symptoms and instruct patients to contact their health care provider if they develop lymphadenopathy.1

Non-Infectious Colitis

Inform patients that daclizumab may cause gastrointestinal reactions that may be serious and could require treatment. Advise patients of the symptoms of colitis and instruct patients to promptly contact their healthcare provider if they experience these symptoms.1

REMS Program

Daclizumab is available only through a restricted program called the Zinbryta REMS Program. Inform the patient of the following notable requirements: patients must enroll in the program and comply with ongoing monitoring requirements. 1

Daclizumab is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.1

Allergic Reactions and Anaphylaxis

Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur.1

Risk of Infections

Inform patients that they may be more likely to get infections when taking daclizumab, and that they should contact their health care provider if they develop symptoms of infection. 1

Depression and Suicide

Advise patients of the symptoms of depression and suicidal ideation as they have occurred with the use of daclizumab and instruct patients to report symptoms of depression or thoughts of suicide to their health care provider immediately. 1

Instructions for Self-Injection Technique and Procedures

Provide appropriate instruction for methods of self-injection, including careful review of the daclizumab Instructions for Use. Instruct the patient in the use of aseptic technique when administering daclizumab.1

Inform the patient that a health care provider should show them or their caregiver how to inject daclizumab before administering the first dose. Tell the patient not to re-use needles or syringes, and instruct the patient on safe disposal procedures. Inform the patient to dispose of used needles and syringes in a puncture-resistant container.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Daclizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Solution

150 mg /1 mL

Zinbryta

Abbvie

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: September 08, 2016
Last reviewed: September 08, 2016
Date modified: October 12, 2016

References

1. Abbvie . Zinbryta (Daclizumab) SUBCUTANEOUS prescribing information. 2016 May.

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