Data from FDA - Curated by Toby Galbraith - Last updated 05 September 2017

Indication(s)

1 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. ZINBRYTA 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 ZINBRYTA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. (1)

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Advisory information

contraindications
4 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 (2.3) and Warnings and Precautions (5.1)]. A history of autoimmune hepatitis or other autoimmune condition involving the liver [see Warnings and Precautions (5.1)]. 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 (5.4)]. Pre-existing hepatic disease or hepatic impairment, including ALT or AST at least 2 times the ULN (4) History of autoimmune hepatitis or other autoimmune condition involving the liver (4) History of hypersensitivity to daclizumab or any other component of the formulation (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Hepatic Injury [see Warnings and Precautions (5.1)] Immune-Mediated Disorders [see Warnings and Precautions (5.2)] Acute Hypersensitivity [see Warnings and Precautions (5.4)] Infections [see Warnings and Precautions (5.5)] Depression and Suicide [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (incidence ≥5% and ≥2% higher incidence than comparator) reported for ZINBRYTA 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 (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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) 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 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 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) 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 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 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 (5.2)]. 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. 6.2 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 ( 12.3 )]. 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended dosage: 150 milligrams once monthly (2.1) For subcutaneous use only (2.1) Train patients in the proper technique for self-administration (2.2) Conduct laboratory tests at baseline and at periodic intervals to monitor for early signs of potentially serious adverse reactions (2.3, 2.4). 2.1 Dosing Information The recommended dosage of ZINBRYTA is 150 milligrams injected subcutaneously once monthly [see Dosage and Administration (2.3, 2.4)]. 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. 2.2 Important Administration Instructions ZINBRYTA is for subcutaneous use only. Train patients in the proper technique for self-administering subcutaneous injections using the prefilled autoinjector or 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 (16.2)]. 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 autoinjector or syringe one time and then place in a sharps disposal container for disposal according to community guidelines [see How Supplied/Storage and Handling (16.3)]. 2.3 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 (4) and Warnings and Precautions (5.1)]. Assessment for Tuberculosis and Other Infections Evaluate patients at high risk for tuberculosis infection prior to initiating treatment with ZINBRYTA [see Warnings and Precautions (5.5)]. 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 (5.5)]. Prior to initiation of ZINBRYTA, screen patients for Hepatitis B and C. ZINBRYTA is contraindicated in patients with pre-existing hepatic disease [see Contraindications (4)]. 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 (5.5)]. 2.4 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 (5.1)]. Table 1: ZINBRYTA Treatment Modification for Liver Test Abnormalities Elevated Transaminases and/or Total Bilirubin [see Warnings and Precautions (5.1)] 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
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 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. 8.2 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. 8.4 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 (5.1, 5.2)]. 8.5 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. 8.6 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 (2.3, 2.4), Contraindications (4), and Warnings and Precautions (5.1)].

Interactions

7 DRUG INTERACTIONS Hepatotoxic Drugs: Evaluate potential for increased risk of hepatotoxicity with concomitant use (7.1) 7.1 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 (5.1)].

More information

Category Value
Authorisation number BLA761029
Agency product number CUJ2MVI71Y
Orphan designation No
Product NDC 0074-0033,0074-0034
Date Last Revised 31-05-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1925211
Storage and handling 16.2 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.
Marketing authorisation holder Abbvie
Warnings WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE HEPATITIS AND OTHER IMMUNE-MEDIATED DISORDERS Hepatic Injury Including Autoimmune Hepatitis ZINBRYTA can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. In clinical trials, 1 patient died due to autoimmune hepatitis. Liver injury, including autoimmune hepatitis, can occur at any time during treatment with ZINBRYTA, with cases reported up to 4 months after the last dose of ZINBRYTA. ZINBRYTA is contraindicated in patients with pre-existing hepatic disease or hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.1)] . Prior to starting ZINBRYTA, obtain serum transaminases (ALT and AST) and bilirubin levels [see Dosage and Administration (2.3)] . 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. In case of elevation in transaminases or total bilirubin, treatment interruption or discontinuation may be required [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. Other Immune-Mediated Disorders In addition to autoimmune hepatitis, immune-mediated disorders such as skin reactions, lymphadenopathy, and non-infectious colitis can occur in patients treated with ZINBRYTA. Overall, serious immune-mediated conditions were observed in 5% of patients treated with ZINBRYTA [see Warnings and Precautions (5.2)]. If a patient develops a serious immune-mediated disorder, consider stopping ZINBRYTA and refer the patient to a specialist to ensure comprehensive diagnostic evaluation and appropriate treatment. Some patients required systemic corticosteroids or other immunosuppressant treatment for autoimmune hepatitis or other immune-mediated disorders and continued this treatment after the last dose of ZINBRYTA [see Warnings and Precautions (5.1, 5.2)]. Because of the risks of hepatic injury, including autoimmune hepatitis, and other immune-mediated disorders, ZINBRYTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZINBRYTA REMS Program [see Warnings and Precautions (5.3)]. WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE HEPATITIS and OTHER IMMUNE-MEDIATED DISORDERS See full prescribing information for complete boxed warning. Hepatic Injury Including Autoimmune Hepatitis ZINBRYTA can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. Obtain transaminase and bilirubin levels before initiation of ZINBRYTA. Monitor and evaluate transaminase and bilirubin levels monthly and up to 6 months after the last dose (2.3, 2.4, 5.1). ZINBRYTA is contraindicated in patients with pre-existing hepatic disease or hepatic impairment (4, 5.1). Other Immune-Mediated Disorders Immune-mediated disorders including skin reactions, lymphadenopathy, non-infectious colitis, and other immune-mediated disorders can occur with ZINBRYTA (5.2). These conditions may require treatment with systemic corticosteroids or immunosuppressive medication (5.1, 5.2). ZINBRYTA is available only through a restricted distribution program called the ZINBRYTA REMS Program (5.3).