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 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) 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 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 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.