Zinbryta: Indications, Dosage, Precautions, Adverse Effects
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Zinbryta - Product Information

Manufacture: AbbVie
Country: United States
Condition: Multiple Sclerosis
Class: Interleukin inhibitors
Form: Liquid solution, Subcutaneous (SC)
Ingredients: Daclizumab, Sodium succinate, Anhydrous, Succinic acid, Sodium chloride, Polysorbate 80, Water for injection

Indications and Usage

ZINBRYTA is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of ZINBRYTA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Dosage and Administration

Dosing Information

The recommended dosage of ZINBRYTA is 150 milligrams injected subcutaneously once monthly [see Dosage and Administration (Assessment Prior to Initiating ZINBRYTA, Laboratory Testing and Monitoring to Assess Safety after Initiating ZINBRYTA)].

Instruct patients to inject a missed dose as soon as possible but no more than two weeks late. After two weeks, skip the missed dose and take the next dose on schedule. Administer only one dose at a time.

Important Administration Instructions

ZINBRYTA is for subcutaneous use only.

Train patients in the proper technique for self-administering subcutaneous injections using the prefilled syringe.

Thirty minutes prior to injection, remove ZINBRYTA from the refrigerator to allow the drug to warm to room temperature. Do not use external heat sources such as hot water to warm ZINBRYTA. Do not place ZINBRYTA back into the refrigerator after allowing it to warm to room temperature [see How Supplied/Storage and Handling (Storage and Handling)].

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ZINBRYTA is a colorless to slightly yellow, clear to slightly opalescent solution. Do not use ZINBRYTA if it is cloudy or there are visible particles.

Sites for injection include the thigh, abdomen, and back of the upper arm.

Use each prefilled syringe one time and then place in a sharps disposal container for disposal according to community guidelines [see How Supplied/Storage and Handling (Instructions for Disposal)].

Assessment Prior to Initiating ZINBRYTA

Hepatic Assessment

Prior to initiating ZINBRYTA, obtain and evaluate the following:

Serum transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) and total bilirubin levels. Initiation of ZINBRYTA is contraindicated in patients with pre-existing hepatic disease or hepatic impairment including ALT or AST at least 2 times the ULN [see Contraindications and Warnings and Precautions (Hepatic Injury)].

Assessment for Tuberculosis and Other Infections

Evaluate patients at high risk for tuberculosis infection prior to initiating treatment with ZINBRYTA [see Warnings and Precautions (Infections)]. For patients testing positive for tuberculosis, treat tuberculosis by standard medical practice prior to therapy with ZINBRYTA.

Avoid initiating ZINBRYTA in patients with tuberculosis or other severe active infection [see Warnings and Precautions (Infections)].

Prior to initiation of ZINBRYTA, screen patients for Hepatitis B and C. ZINBRYTA is contraindicated in patients with pre-existing hepatic disease [see Contraindications].

Vaccinations

Because vaccination with live vaccines is not recommended during treatment and up to 4 months after discontinuation of treatment, consider any necessary immunization with live vaccines prior to treatment with ZINBRYTA [see Warnings and Precautions (Infections)].

Laboratory Testing and Monitoring to Assess Safety after Initiating ZINBRYTA

Conduct the following laboratory tests at periodic intervals to monitor for early signs of potentially serious adverse effects:

Liver Tests

Test transaminase levels and total bilirubin monthly and assess before the next dose of ZINBRYTA. Follow transaminase levels and total bilirubin monthly for 6 months after the last dose of ZINBRYTA. As shown in Table 1, interruption or discontinuation of ZINBRYTA therapy is recommended for management of certain liver test abnormalities [see Warnings and Precautions (Hepatic Injury)].

Table 1: ZINBRYTA Treatment Modification for Liver Test Abnormalities
Elevated Transaminases and/or Total Bilirubin [see Warnings and Precautions (Hepatic Injury)]
Lab Value(s) Recommendations
ALT or AST greater than 5 times ULN
OR

Total bilirubin greater than 2 times ULN
OR

ALT or AST greater than or equal to 3 but less than 5 times ULN and total bilirubin greater than 1.5 but less than 2 times ULN
- Interrupt ZINBRYTA therapy and investigate for other etiologies of abnormal lab value(s).

- If no other etiologies are identified, then discontinue ZINBRYTA.

- If other etiologies are identified, re-assess the overall risk-benefit profile of ZINBRYTA in the patient and consider whether to resume ZINBRYTA when both AST or ALT are less than 2 times ULN and total bilirubin is less than or equal to ULN.

In clinical trials, permanent discontinuation of therapy was required if the patient had liver test abnormalities resulting in suspension of study treatment for at least 8 consecutive weeks.

ULN = upper limit of normal

Dosage Forms and Strengths

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

ZINBRYTA is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution.

Contraindications

ZINBRYTA is contraindicated in patients with:

  • Pre-existing hepatic disease or hepatic impairment, including ALT or AST at least 2 times the ULN, because ZINBRYTA could exacerbate existing liver dysfunction [see Dosage and Administration(Assessment Prior to Initiating ZINBRYTA) and Warnings and Precautions (Hepatic Injury)].
  • A history of autoimmune hepatitis or other autoimmune condition involving the liver [see Warningsand Precautions (Hepatic Injury)].
  • A history of hypersensitivity to daclizumab or any other components of the formulation. Use in such patients may result in anaphylaxis or life-threatening multi-organ hypersensitivity [see Warnings and Precautions (Acute Hypersensitivity)].
  • Warnings and Precautions

    Hepatic Injury

    ZINBRYTA 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 ZINBRYTA-treated patients compared with 0.4% of AVONEX-treated patients (Study 1) and in 1.0% of ZINBRYTA-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 ZINBRYTA-treated patients, with monthly monitoring of transaminases and total bilirubin. The incidence of discontinuation due to drug related hepatic injury was 5% in ZINBRYTA-treated patients and 4% in AVONEX-treated patients.

    Autoimmune Hepatitis

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

    Transaminase and Total Bilirubin Elevations

    The incidence of increases in hepatic transaminases was greater in patients taking ZINBRYTA than in those taking AVONEX or placebo. The incidence of ALT or AST elevations above 5 times the ULN was 6% in ZINBRYTA-treated patients compared with 3% in AVONEX-treated patients (Study 1) and 4% in ZINBRYTA-treated patients compared with 1% in patients on placebo (Study 2). Less than 1% of ZINBRYTA-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 ZINBRYTA-treated patients compared with 0.1% of AVONEX- treated patients. In clinical trials, serum transaminase elevations occurred during treatment and up to 4 months after the last dose of ZINBRYTA.

    Monitoring

    Prior to starting treatment with ZINBRYTA, obtain serum transaminases (ALT and AST) and total bilirubin levels [see Contraindications].

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

    Treatment modifications are recommended based on serum transaminase and total bilirubin values [see Dosage and Administration (Laboratory Testing and Monitoring to Assess Safety after Initiating ZINBRYTA)].

    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 ZINBRYTA, as appropriate.

    Patients with prolonged elevations of serum transaminases should be evaluated for other possible causes, such as infection, and a specialist should evaluate the patient [see Dosage and Administration(Laboratory Testing and Monitoring to Assess Safety after Initiating ZINBRYTA)]. Discontinue ZINBRYTA 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.

    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 ZINBRYTA. Also, carefully consider the need for the use of herbal products or dietary supplements that can cause hepatotoxicity [see Drug Interactions (Hepatotoxic Drugs)].

    Immune-Mediated Disorders

    Treatment with ZINBRYTA 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 ZINBRYTA, 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 ZINBRYTA-treated patients compared with 12% for AVONEX-treated patients. In Study 1, serious immune -mediated disorders were observed in 4% of patients treated with ZINBRYTA compared with less than 1% for AVONEX- treated patients. In the placebo- control study (Study 2), immune-mediated disorders were observed in 13% of ZINBRYTA-treated patients compared with 7% of placebo-treated patients. In Study 2, serious immune-mediated disorders were observed in 0.5% of ZINBRYTA-treated patients and in 0.5% of placebo -treated patients. In some cases, patients had concurrent or sequential occurring disorders while taking ZINBRYTA.

    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 ZINBRYTA during study follow-up.

    Prescribers should be vigilant regarding emergent immune -mediated disorders. 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 ZINBRYTA and refer the patient to an appropriate specialist for further evaluation and treatment.

    Skin Reactions

    ZINBRYTA causes skin reactions. In clinical trials, skin reactions occurred in 37% of ZINBRYTA-treated patients compared with 19% of AVONEX -treated patients (Study 1) and in 18% of ZINBRYTA-treated patients compared with 13% of patients on placebo (Study 2). Skin reactions occurred at any time during treatment with ZINBRYTA. Rashes occurred in 11% of ZINBRYTA-treated patients compared to 4% of AVONEX-treated patients, and in 7% of ZINBRYTA-treated patients compared to 3% of patients on placebo. Dermatitis occurred more frequently in ZINBRYTA-treated patients compared to AVONEX-treated patients or to patients on placebo, and eczema was observed more frequently in ZINBRYTA-treated patients compared to AVONEX-treated patients [see Adverse Reactions (Clinical Trials Experience)]. Psoriatic conditions occurred in 2% of ZINBRYTA-treated patients compared with 0.3% of AVONEX-treated patients. Photosensitivity also occurred.

    Serious skin reactions occurred in 2% of patients treated with ZINBRYTA compared with 0.1% of patients on AVONEX (Study 1) and in 1% of patients treated with ZINBRYTA 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 ZINBRYTA 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 ZINBRYTA-treated patients. Rashes took a mean of 3 months to resolve, some were unresolved at the time of the last evaluation.

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

    Lymphadenopathy

    ZINBRYTA increases the incidence of lymphadenopathy. In controlled studies, lymphadenopathy or lymphadenitis occurred in 6% of ZINBRYTA-treated patients compared with 1% of AVONEX-treated patients (Study 1) and in 2% of ZINBRYTA-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 [see Warnings and Precautions(Infections)]. The majority of cases resolved with or without continued treatment with ZINBRYTA and took a mean of 3 months to resolve. Lymphadenopathy resulted in discontinuation in 0.6 % of ZINBRYTA-treated patients.

    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.

    Non-Infectious Colitis

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

    Other immune-mediated disorders

    A wide variety of other immune-mediated disorders, some serious, have occurred infrequently with the use of ZINBRYTA. These include single organ or systemic multi-organ inflammatory reactions. Many events occurred in only one patient, and the relationship to ZINBRYTA is unknown [see Adverse Reactions (Clinical Trials Experience)]. Some required treatment with systemic corticosteroids. Some required several months for resolution after the last dose of ZINBRYTA.

    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 ZINBRYTA and refer the patient to an appropriate specialist for further evaluation and treatment.

    Zinbryta REMS Program

    ZINBRYTA 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 [see Warnings and Precautions(Hepatic Injury, Immune-Mediated Disorders)].

    Notable requirements of the ZINBRYTA REMS Program include the following:

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

    Patients must enroll in the program and comply with ongoing monitoring requirements [see Warningsand Precautions (Hepatic Injury, Immune-Mediated Disorders)].

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

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

    Acute Hypersensitivity

    ZINBRYTA can cause anaphylaxis, angioedema, and urticaria after the first dose or at any time during treatment. Discontinue and do not re-start ZINBRYTA if anaphylaxis or other allergic reactions occur [see Contraindications].

    Infections

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

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

    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 ZINBRYTA. For patients testing positive for tuberculosis, treat by standard medical practice prior to therapy with ZINBRYTA [see Dosage and Administration (Assessment Prior to Initiating ZINBRYTA)].

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

    Vaccinations

    The safety of immunization with live viral vaccines during treatment with ZINBRYTA has not been studied. Vaccination with live vaccines is not recommended during treatment and up to 4 months after discontinuation of ZINBRYTA [see Dosage and Administration (Assessment Prior to Initiating ZINBRYTA)].

    Depression and Suicide

    Depression-related events occurred more frequently in patients receiving ZINBRYTA than in patients receiving AVONEX or placebo. In controlled trials, depression-related events occurred in 10% of ZINBRYTA-treated patients compared with 8% of AVONEX-treated patients (Study 1) and in 7% of ZINBRYTA-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 ZINBRYTA-treated patients and in 0.7% of AVONEX-treated patients. None occurred in Study 2 (placebo-controlled).

    Administer ZINBRYTA 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.

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

    Adverse Reactions

    The following serious adverse reactions are described elsewhere in labeling:

    • Hepatic Injury [see Warnings and Precautions (Hepatic Injury)]
    • Immune-Mediated Disorders [see Warnings and Precautions (Immune-Mediated Disorders)]
    • Acute Hypersensitivity [see Warnings and Precautions (Acute Hypersensitivity)]
    • Infections [see Warnings and Precautions (Infections)]
    • Depression and Suicide [see Warnings and Precautions (Depression and Suicide)]

    Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of ZINBRYTA cannot be directly compared with rates in clinical trials of other drugs and may not reflect the rates observed in practice.

    In all controlled and uncontrolled trials performed in patients with relapsing multiple sclerosis, 2236 patients received ZINBRYTA for a total of 5214 person-years. Of these patients, 1576 received ZINBRYTA for at least 1 year, 1259 for at least 2 years, and 888 for at least 3 years. In the controlled studies, approximately 67% were female, 92% were Caucasian, and the mean age was 36 years at study entry.

    In the active-controlled study (Study 1), 919 patients received ZINBRYTA (150 mg SQ, every 4 weeks) and 922 patients received AVONEX (interferon beta-1a 30 mcg IM, weekly) for a minimum of 2 years and up to 3 years, with 1952 person-years of exposure to ZINBRYTA; the median length of treatment was approximately 27 months. The adverse reactions from Study 1 are presented in Table 2.

    In the placebo-controlled study (Study 2), 417 patients received ZINBRYTA with 423 person- years of exposure, of which 208 received 150 mg, and 204 received placebo every 4 weeks for up to 1 year; the median length of treatment was approximately 11 months. The adverse reactions from Study 2 are presented in Table 3.

    The most common adverse reactions (incidence at least 5% and at least 2% higher incidence than comparator) that occurred in ZINBRYTA-treated patients were nasopharyngitis, upper respiratory tract infection, rash, influenza, dermatitis, oropharyngeal pain, bronchitis, eczema, and lymphadenopathy compared with AVONEX; and upper respiratory tract infection, depression, rash, pharyngitis, and increased alanine aminotransferase (ALT) compared with placebo.

    The most common adverse reactions leading to discontinuation in up to 5% of patients treated with

    ZINBRYTA were hepatic events including elevations of serum transaminases and cutaneous events.

    Patients were excluded from the clinical studies for abnormal laboratory values including hemoglobin, complete blood count with differential, serum transaminases, or serum creatinine. Patients were excluded if they had a history of seizure disorder or of having a seizure within 6 months of beginning the study, or suicidal ideation or severe depression within 3 months of beginning the study. During Study 1, concomitant use of ZINBRYTA with the hepatotoxic drugs valproic acid, carbamazepine, lamotrigine, phenytoin, isoniazid, and propylthiouracil was not permitted except in patients already receiving the drugs at the time of study entry.

    In clinical studies, serum chemistry was evaluated at baseline and monthly. Hematology was evaluated at baseline, monthly for 6 months, and then every 3 months. Thyroid function was measured at baseline and every 6 months.

    Table 2: Adverse Reactions in Adults with RMS with an Incidence at Least 2% More for ZINBRYTA 150 mg SQ Every 4 Weeks than AVONEX 30 mcg IM Once Weekly (Study 1)
    Adverse Reaction ZINBRYTA
    150 mg SQ
    Every 4 Weeks
    N=919
    %
    AVONEX
    30 mcg IM
    Once Weekly
    N=922
    %
    Nasopharyngitis 25 21
    Upper respiratory tract infection 1 17 14
    Rash2 11 4
    Influenza 9 6
    Dermatitis 3 9 2
    Oropharyngeal pain 8 4
    Bronchitis 7 5
    Eczema 4 5 2
    Lymphadenopathy 5 <1
    Tonsillitis 4 2
    Acne 3 <1

    1 includes upper respiratory tract infection and viral upper respiratory tract infection

    2 includes erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash, pruritic rash, rash, and vesicular rash

    3 includes allergic dermatitis, atopic dermatitis, bullous dermatitis, dermatitis, exfoliative dermatitis, and seborrheic dermatitis

    4 includes dyshidrotic eczema, eczema, and nummular eczema

    Table 3: Adverse Reactions in Adults with RMS with an Incidence at Least 2% More for ZINBRYTA 150 mg SQ Every 4 Weeks than Placebo (Study 2)
    Adverse Reaction ZINBRYTA
    150 mg SQ
    Every 4 Weeks
    N=208
    %
    Placebo


    N=204
    %
    Upper respiratory tract infection 9 7
    Depression1 7 2
    Rash2 7 3
    Pharyngitis 6 4
    Increased ALT 5 2
    Rhinitis 4 1
    Anemia 3 <1
    Pyrexia 3 <1
    Increased AST 3 <1
    Dermatitis 3 3 <1

    1 includes depressed mood and depression

    2 includes erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash, pruritic rash, rash, and vesicular rash

    3 includes allergic dermatitis, atopic dermatitis, bullous dermatitis, dermatitis, exfoliative dermatitis, and seborrheic dermatitis

    Other clinically relevant adverse reactions observed at <2% difference included abnormal liver function test, decreased lymphocyte count, diarrhea, dry skin, erythema, folliculitis, increased hepatic enzyme, laryngitis, lymphadenitis, pneumonia, pruritus, psoriasis, respiratory tract infection, skin exfoliation, toxic skin eruption, and viral infection.

    Seizures

    In Study 1, seizures occurred in 1% of ZINBRYTA -treated patients, compared with 0.3% of AVONEX-treated patients. In Study 2, no seizures occurred in either treatment group.

    Immune-mediated disorders

    Types of immune-mediated or autoimmune conditions that were observed in 2 or more ZINBRYTA-treated patients include type I diabetes, celiac disease, autoimmune thyroiditis, immune hemolytic anemia, thrombocytopenia, pancreatitis, glomerulonephritis, sarcoidosis, rheumatoid arthritis, thyroiditis, and sialadenitis [see Warnings and Precautions (Immune-Mediated Disorders)]. The relationship of these events to ZINBRYTA is unknown.

    Breast Cancer

    In controlled studies, 1 ZINBRYTA- treated woman developed breast cancer compared with none in the AVONEX-treated group. Across all controlled and open- label clinical studies, 8 of 1485 (0.5%) ZINBRYTA-treated women developed breast cancer, and 1 of 751 (0.1%) ZINBRYTA-treated men developed breast cancer. It is unclear whether this represents an incidence increase over background rate.

    Immunogenicity

    As with all therapeutic proteins, there is potential for immunogenicity. In Study 1, patients were tested for anti-drug (daclizumab) antibodies at Week 4 and approximately every 3 months thereafter. Anti-drug antibodies and neutralizing antibodies were observed in 19% (175/913) and 8% (71/913) of patients, respectively. Anti-drug antibody responses were transient in 12% (110/913) of patients and persistent in 7% (65/913) of patients. Anti-drug and neutralizing antibody responses predominantly occurred during the first year of treatment, and their frequency declined with continued ZINBRYTA treatment.

    In patients with neutralizing antibodies, daclizumab clearance was increased on average by 19% [see Clinical Pharmacology (Pharmacokinetics)]. There was no apparent correlation of anti-drug antibody or neutralizing antibody development to clinical response, adverse reactions, or pharmacodynamic profile of ZINBRYTA.

    The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, 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.

    Drug Interactions

    Hepatotoxic Drugs

    Caution should be used when using hepatotoxic drugs, including non-prescription products, concomitantly with ZINBRYTA. Carefully consider the need for the use of herbal products or dietary supplements that can cause hepatotoxicity [see Warnings and Precautions (Hepatic Injury)].

    Use in Specific Populations

    Pregnancy

    Risk Summary

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

    Administration of ZINBRYTA to monkeys during gestation resulted in embryofetal death and reduced fetal growth at maternal exposures greater than 30 times that expected clinically [see Data]. 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.

    Data

    Animal Data

    In monkeys administered ZINBRYTA (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.

    In monkeys administered ZINBRYTA (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.

    Lactation

    Risk Summary

    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 ZINBRYTA-treated monkeys.

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

    Pediatric Use

    Safety and effectiveness of ZINBRYTA in patients less than 17 years old have not been established. Use of ZINBRYTA is not recommended in pediatric patients due to the risks of hepatic injury and immune-mediated disorders [see Warnings and Precautions (Hepatic Injury, Immune-Mediated Disorders)].

    Geriatric Use

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

    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 ZINBRYTA [see Dosage and Administration (Assessment Prior to Initiating ZINBRYTA, Laboratory Testing and Monitoring to Assess Safety after Initiating ZINBRYTA), Contraindications, and Warnings and Precautions (Hepatic Injury)].

    How Supplied/Storage and Handling

    How Supplied

    ZINBRYTA injection is a sterile, colorless to slightly yellow, clear to slightly opalescent solution for subcutaneous injection supplied in a single-dose prefilled syringe. The rubber plunger stopper and rigid needle shield are not made with natural rubber latex. A 29 gauge, 0.5 inch staked needle is pre-affixed to the syringe. The ZINBRYTA prefilled syringe is available in a carton containing a single-dose prefilled syringe providing 1 mL of 150 mg/mL of daclizumab. The NDC is 0074-0033-01.

    Storage and Handling

    Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or expose to temperatures above 30°C (86°F). Discard if frozen.

    If refrigeration is unavailable, ZINBRYTA may be stored protected from light up to 30°C (86°F) for a period up to 30 days. Do not place ZINBRYTA back into the refrigerator after allowing it to warm to room temperature. Discard after 30 days without refrigeration.

    Instructions for Disposal

    Dispose in a sharps container or other hard plastic or metal sealable container. Always follow local regulations for disposal.

    Patient Counseling Information

    Advise the patient to read the FDA-approved patient labeling (Consumer Medicine Information and Instructions for Use).

    Hepatic Injury

    Inform the patient of the risk of severe hepatic injury associated with ZINBRYTA. Advise patients of the symptoms of hepatic dysfunction, and instruct patients to report such symptoms to their health care provider immediately [see Warnings and Precautions (Hepatic Injury)].

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

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

    Inform the patient that they will be given a ZINBRYTA 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.

    Advise the patient to show the ZINBRYTA Patient Wallet Card to other treating health care providers.

    Immune-Mediated Disorders

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

    Skin Reactions

    Advise patients that ZINBRYTA 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 [see Warnings and Precautions (Immune-Mediated Disorders)].

    Lymphadenopathy

    Inform patients that ZINBRYTA 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 [see Warnings and Precautions (Immune-Mediated Disorders)].

    Non-Infectious Colitis

    Inform patients that ZINBRYTA 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 [see Warnings and Precautions (Immune-Mediated Disorders)].

    Zinbryta REMS Program

    ZINBRYTA is available only through a restricted program called the ZINBRYTA REMS Program [see Warnings and Precautions (ZINBRYTA REMS Program)]. Inform the patient of the following notable requirements:

    • Patients must enroll in the program and comply with ongoing monitoring requirements [see Warnings and Precautions (Hepatic Injury, Immune-Mediated Disorders)].

    ZINBRYTA 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.

    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 [see Warnings and Precautions (Acute Hypersensitivity)].

    Risk of Infections

    Inform patients that they may be more likely to get infections when taking ZINBRYTA, and that they should contact their health care provider if they develop symptoms of infection [see Warnings and Precautions (Infections)].

    Depression and Suicide

    Advise patients of the symptoms of depression and suicidal ideation as they have occurred with the use of ZINBRYTA and instruct patients to report symptoms of depression or thoughts of suicide to their health care provider immediately [see Warnings and Precautions (Depression and Suicide)].

    Instructions for Self-Injection Technique and Procedures

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

    Inform the patient that a health care provider should show them or their caregiver how to inject ZINBRYTA 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.

    Manufactured By

    Biogen Inc.

    Cambridge, MA 02142

    U.S. License # 1697

    Distributed By

    AbbVie Inc.

    North Chicago, IL 60064

    ZINBRYTA is a trademark of Biogen.

    2016 Biogen