FDA label 44238333-9880-413b-9a9e-1f2b09e0fd6a

WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE HEPATITIS and OTHER IMMUNE-MEDIATED DISORDERS Hepatic Injury Including Autoimmune Hepatitis ZINBRYTA can cause severe liver injury, including autoimmune hepatitis and liver failure. Fatal cases have occurred. Liver injury, including autoimmune hepatitis and acute liver failure, can occur at any time during treatment with ZINBRYTA, with cases reported up to 5 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, a variety of immune-mediated disorders including skin reactions, lymphadenopathy, and immune-mediated colitis, and other serious conditions can occur in patients treated with ZINBRYTA. Overall, serious immune-mediated disorders 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 autoimmune hepatitis and liver failure. Fatal cases have occurred. 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, immune-mediated 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 ).

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Risk of anaphylaxis and angioedema. Discontinue and do not re-start ZINBRYTA if anaphylaxis or other allergic reactions occur ( 5.4 ) Infections: Increased risk of infections. If serious infection develops, consider withholding ZINBRYTA until infection resolves ( 5.5 ) Depression and Suicide: Advise patients to immediately report symptoms of depression and/or suicidal ideation to their health care provider. Consider discontinuation if severe depression and/or suicidal ideation occur ( 5.6 ) 5.1 Hepatic Injury ZINBRYTA can cause severe liver injury, including autoimmune hepatitis and liver failure. Fatal cases have occurred. 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 1.7% 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. Across all clinical studies (controlled and open-label), 0.3% of ZINBRYTA-treated patients were diagnosed with autoimmune hepatitis. One fatal case of autoimmune hepatitis with acute liver failure 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). Another case of acute liver failure occurred in a patient receiving ZINBRYTA in the postmarketing setting after 4 doses of ZINBRYTA, resulting in transplant and death. This patient had normal serum transaminase and total bilirubin levels 6 days prior to the last administration of ZINBRYTA. The patient was also receiving concomitant treatment with another drug known to be associated with hepatic injury [see Drug Interactions ( 7.1 )] . 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 Early identification of elevated liver enzymes may decrease the risk of a serious outcome. Prior to starting treatment with ZINBRYTA, obtain serum transaminases (ALT and AST) and total bilirubin levels [see Contraindications ( 4 )] . 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 ( 2.4 )] . Liver failure can occur at any time during treatment with ZINBRYTA even with monthly liver enzyme monitoring indicating normal values prior to each dose. Liver injury has been reported up to 5 months after the last dose of ZINBRYTA. Some cases of liver injury may be associated with fever, skin rash, or other immune-mediated disorders. Monitor patients for signs and symptoms of hepatic injury. 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 ( 2.4 ) ] . 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 ( 7.1 )] . 5.2 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 ( 6.1 )]. 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. In addition to serious cases of dermatitis, eczema, psoriasis and drug eruptions, cases of erythema multiforme, erythema nodosum, exfoliative rash, and oral ulcers occurred in ZINBRYTA clinical trials. Treatment of skin reactions included treatment with topical or systemic corticosteroids 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 ( 5.5 )] . 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. Autoimmune Hemolytic Anemia Across all clinical studies (controlled and open-label), autoimmune hemolytic anemia occurred in <1% of patients treated with ZINBRYTA. Autoimmune hemolytic anemia resolved with discontinuation of ZINBRYTA, corticosteroid or other immunosuppressant treatment, and blood transfusions in most cases. If a patient develops signs or symptoms of autoimmune hemolytic anemia (e.g., pallor, fatigue, dark urine, jaundice, shortness of breath), consider discontinuing ZINBRYTA and referring to an appropriate specialist for further evaluation and treatment. Immune-mediated 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. Cases have included reports of colitis, ulcerative colitis, Crohn's disease, microscopic colitis, inflammatory bowel disease, proctitis, and proctocolitis. Consider discontinuing ZINBRYTA and referring patients who develop symptoms of colitis (e.g., abdominal pain, fever, prolonged diarrhea, bloody stools) to a specialist. Other immune-mediated disorders A wide variety of other immune-mediated disorders, some serious, have occurred with the use of ZINBRYTA. These include single organ or systemic multi-organ inflammatory reactions [see Adverse Reactions ( 6.1 )] . Some required treatment with systemic corticosteroids or other immunosuppressants. Some required several months for resolution after the last dose of ZINBRYTA, and some had not resolved even several months after discontinuation of ZINBRYTA, at the time of last reported follow-up. 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. 5.3 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 ( 5.1 , 5.2 )] . 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 Warnings and Precautions ( 5.1 , 5.2 )] . 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. 5.4 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 ( 4 )]. 5.5 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. Cytomegalovirus (CMV) infections (hepatitis and pneumonia) occurred in ZINBRYTA-treated patients in clinical trials. 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 ( 2.3 )] . 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 ( 2.3 )] . 5.6 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.

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) Adverse Reaction ZINBRYTA 150 mg SQ Every 4 Weeks N=919 % AVONEX 30 mcg IM Once Weekly N=922 % 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 Nasopharyngitis 25 21 Upper respiratory tract infection 1 17 14 Rash 2 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) Adverse Reaction ZINBRYTA 150 mg SQ Every 4 Weeks N=208 % Placebo N=204 % 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 Upper respiratory tract infection 9 7 Depression 1 7 2 Rash 2 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 from AVONEX or placebo in controlled trials included abnormal liver function test, colitis, decreased lymphocyte count, diarrhea, dry skin, erythema, folliculitis, increased hepatic enzyme, laryngitis, lymphadenopathy, pneumonia, pruritus, psoriasis, respiratory tract infection, skin exfoliation, toxic skin eruption, vasculitis 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 In addition to immune-mediated hepatitis, skin reactions, colitis, lymphadenopathy, and autoimmune hemolytic anemia, types of immune-mediated or autoimmune conditions that were observed in 2 or more ZINBRYTA-treated patients in controlled and open-label trials include immune cytopenias (agranulocytosis, thrombocytopenia, and pancytopenia), type I diabetes, celiac disease, immune-mediated thyroiditis, interstitial lung disease, lupus-like syndrome, pancreatitis, glomerulonephritis, rheumatoid arthritis, sarcoidosis, seronegative arthritis, sialadenitis, vasculitis, vitiligo, and multiorgan hypersensitivity [ see Warnings and Precautions ( 5.2 )] . 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.

<table ID="t2" width="100%"> <caption>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) </caption> <col width="46.249%" align="left"/> <col width="26.309%" align="left"/> <col width="27.442%" align="left"/> <thead> <tr> <th align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content> </th> <th align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">ZINBRYTA</content> <content styleCode="bold">150 mg SQ</content> <content styleCode="bold">Every 4 Weeks</content> <content styleCode="bold">N=919</content> <content styleCode="bold">%</content> </th> <th align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">AVONEX</content> <content styleCode="bold">30 mcg IM</content> <content styleCode="bold">Once Weekly</content> <content styleCode="bold">N=922</content> <content styleCode="bold">%</content> </th> </tr> </thead> <tfoot> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ¹ includes upper respiratory tract infection and viral upper respiratory tract infection </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ² includes erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash, pruritic rash, rash, and vesicular rash </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ³ includes allergic dermatitis, atopic dermatitis, bullous dermatitis, dermatitis, exfoliative dermatitis, and seborrheic dermatitis </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ⁴ includes dyshidrotic eczema, eczema, and nummular eczema </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Nasopharyngitis </td> <td align="center" valign="top" styleCode="Botrule Rrule">25 </td> <td align="center" valign="top" styleCode="Botrule Rrule">21 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Upper respiratory tract infection ¹ </td> <td align="center" valign="top" styleCode="Botrule Rrule">17 </td> <td align="center" valign="top" styleCode="Botrule Rrule">14 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Rash² </td> <td align="center" valign="top" styleCode="Botrule Rrule">11 </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Influenza </td> <td align="center" valign="top" styleCode="Botrule Rrule">9 </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dermatitis ³ </td> <td align="center" valign="top" styleCode="Botrule Rrule">9 </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Oropharyngeal pain </td> <td align="center" valign="top" styleCode="Botrule Rrule">8 </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Bronchitis </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Eczema ⁴ </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Lymphadenopathy </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Tonsillitis </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Acne </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </td> </tr> </tbody> </table>

<table ID="t3" width="100%"> <caption>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) </caption> <col width="46.249%" align="left"/> <col width="26.876%" align="left"/> <col width="26.876%" align="left"/> <thead> <tr> <th align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content> </th> <th align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">ZINBRYTA</content> <content styleCode="bold">150 mg SQ</content> <content styleCode="bold">Every 4 Weeks</content> <content styleCode="bold">N=208</content> <content styleCode="bold">%</content> </th> <th align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Placebo</content> <content styleCode="bold">N=204</content> <content styleCode="bold">%</content> </th> </tr> </thead> <tfoot> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ¹ includes depressed mood and depression </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ² includes erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash, pruritic rash, rash, and vesicular rash </paragraph> </td> </tr> <tr> <td colspan="3" align="left" valign="top"> <paragraph styleCode="footnote"> ³ includes allergic dermatitis, atopic dermatitis, bullous dermatitis, dermatitis, exfoliative dermatitis, and seborrheic dermatitis </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Upper respiratory tract infection </td> <td align="center" valign="top" styleCode="Botrule Rrule">9 </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Depression¹ </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Rash² </td> <td align="center" valign="top" styleCode="Botrule Rrule">7 </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Pharyngitis </td> <td align="center" valign="top" styleCode="Botrule Rrule">6 </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased ALT </td> <td align="center" valign="top" styleCode="Botrule Rrule">5 </td> <td align="center" valign="top" styleCode="Botrule Rrule">2 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Rhinitis </td> <td align="center" valign="top" styleCode="Botrule Rrule">4 </td> <td align="center" valign="top" styleCode="Botrule Rrule">1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Anemia </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Pyrexia </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased AST </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dermatitis ³ </td> <td align="center" valign="top" styleCode="Botrule Rrule">3 </td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1 </td> </tr> </tbody> </table>