Brodalumab

5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur. If a serious hypersensitivity reaction occurs, immediately discontinue SILIQ and initiate appropriate therapy. ( 5.3 ) • Infections: Serious infections have occurred. Consider the risks and benefits prior to initiating SILIQ in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue SILIQ until the infection resolves. ( 5.4 ) • Tuberculosis (TB): Evaluate patients for TB infection prior to initiating treatment with SILIQ. ( 5.5 ) • Eczematous Eruptions: The onset of eczematous eruptions was variable, ranging from days to months after the first dose of SILIQ. Some cases of severe eczematous eruptions resulted in hospitalization. Treatment may need to be discontinued to resolve the eczematous eruption. Some patients with limited psoriasis treatment options were successfully treated for eczema while continuing SILIQ. ( 5.6 ) • Crohn’s Disease: Crohn’s disease occurred during clinical trials. Discontinue SILIQ if patient develops Crohn’s disease while taking SILIQ. ( 5.7 ) • Immunizations: Avoid using live vaccines concurrently with SILIQ. ( 5.8 ) 5.1 Suicidal Ideation and Behavior Suicidal ideation and behavior, including four completed suicides, occurred in subjects treated with SILIQ in the psoriasis clinical trials. There were no completed suicides in the 12-week placebo-controlled portion of the trials. SILIQ users with a history of suicidality or depression had an increased incidence of suicidal ideation and behavior as compared to users without such a history [see Adverse Reactions ( 6.1 )] . A causal association between treatment with SILIQ and increased risk of suicidal ideation and behavior has not been established. Prescribers should weigh the potential risks and benefits before using SILIQ in patients with a history of depression or suicidality. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate. Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation and behavior, new onset or worsening depression, anxiety, or other mood changes. Prescribers should also re-evaluate the risks and benefits of continuing treatment with SILIQ if such events occur. Because of the observed suicidal ideation and behavior in subjects treated with SILIQ, if an adequate response to SILIQ has not been achieved within 12 to 16 weeks, consider discontinuing therapy. SILIQ is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.2 )]. 5.2 SILIQ REMS Program SILIQ is available only through a restricted program under a REMS called the SILIQ REMS Program because of the observed suicidal ideation and behavior in subjects treated with SILIQ [see Warnings and Precautions ( 5.1 )]. Notable requirements of the SILIQ REMS Program include the following: • Prescribers must be certified with the program. • Patients must sign a Patient Enrollment Form. • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive SILIQ. • Distributors must be authorized to distribute SILIQ and must only distribute to certified prescribers and pharmacies. Further information, including a list of qualified pharmacies, is available at www.SILIQREMS.com or by calling the SILIQ REMS Program Call Center at 855-511-6135. 5.3 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported with postmarket use of SILIQ. Some cases required hospitalization. If a serious hypersensitivity reaction occurs, immediately discontinue SILIQ and initiate appropriate therapy. 5.4 Infections SILIQ may increase the risk of infections. In clinical trials, subjects treated with SILIQ had a higher rate of serious infections than subjects treated with placebo (0.5% versus 0.2%) and higher rates of fungal infections (2.4% versus 0.9%). One case of cryptococcal meningitis occurred in a subject treated with SILIQ during the 12-week randomized treatment period and led to discontinuation of therapy [see Adverse Reactions ( 6.1 )]. During the course of clinical trials for plaque psoriasis, the exposure-adjusted rates for infections and serious infections were similar in the subjects treated with SILIQ and those treated with ustekinumab. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing SILIQ. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy for the infection, monitor the patient closely and discontinue SILIQ therapy until the infection resolves. 5.5 Risk for Latent Tuberculosis Reactivation Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SILIQ. Do not administer SILIQ to patients with active TB infection. Initiate treatment for latent TB prior to administering SILIQ. Consider anti-TB therapy prior to initiation of SILIQ in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving SILIQ for signs and symptoms of active TB during and after treatment. 5.6 Eczematous Eruptions Postmarketing cases of severe eczematous eruptions, including atopic dermatitis-like eruptions, were reported in patients receiving SILIQ. The onset of eczematous eruptions was variable, ranging from days to months after the first dose of SILIQ. Some cases of severe eczematous eruptions resulted in hospitalization. Treatment may need to be discontinued to resolve the eczematous eruption. Some patients with limited psoriasis treatment options were successfully treated for eczema while continuing SILIQ. 5.7 Crohn’s Disease In psoriasis trials, which excluded subjects with active Crohn’s disease, Crohn’s disease occurred in one subject during treatment with SILIQ and led to discontinuation of therapy. In other trials, exacerbation of Crohn’s disease was observed with SILIQ use. SILIQ is contraindicated in patients with Crohn’s disease. Discontinue SILIQ if the patient develops Crohn’s disease while taking SILIQ. 5.8 Immunizations Avoid use of live vaccines in patients treated with SILIQ. No data are available on the ability of live or inactive vaccines to elicit an immune response in patients being treated with SILIQ.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of labeling: • Suicidal Ideation and Behavior [see Warnings and Precautions ( 5.1 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] • Infections [see Warnings and Precautions ( 5.4 )] • Crohn’s Disease [see Contraindications ( 4 ), Warnings and Precautions ( 5.7 )] Most common adverse reactions (incidence ≥1%) were arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, injection site reactions, influenza, neutropenia, and tinea infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The overall safety population included 4,558 subjects (3,066 SILIQ, 613 ustekinumab, 879 placebo) in controlled clinical trials and open-label extension studies. The majority of subjects were male (69%), white (91%), and aged 40-64 years old (58%). One third of subjects reported previous biologic use prior to enrollment. Across the clinical development program, 4,464 subjects received at least one dose of SILIQ; 3,755 subjects were exposed to SILIQ for at least 1 year. Weeks 0 to 12: Data from one multicenter, randomized, placebo-controlled trial (Trial 1), two multicenter, randomized, placebo- and active-controlled trials (Trials 2 and 3), and one dose-finding trial (Trial 4) in plaque psoriasis were pooled to evaluate the safety of SILIQ (210 mg weekly at Weeks 0, 1, and 2, followed by treatments every 2 weeks [Q2W]) compared to placebo for up to 12 weeks after treatment initiation. During the 12-week, randomized treatment period, about 1% of the subjects in the treatment groups (SILIQ, ustekinumab, and placebo) discontinued treatment because of adverse events. Adverse events leading to discontinuation of SILIQ included neutropenia, arthralgia, and urticaria. The proportion of subjects who developed serious adverse events was similar among the SILIQ, ustekinumab, and placebo groups. Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the SILIQ 210 mg Q2W group than in the placebo group during the 12-week randomized treatment period of the pooled trials. Table 1: Adverse Reactions Occurring in ≥ 1% of Subjects in the SILIQ Group and More Frequently than in the Placebo Group in Plaque Psoriasis Trials through Week 12 Adverse Reactions Placebo (N=879) n (%) SILIQ 210 mg every 2 weeks Subjects receiving 210 mg of SILIQ at Weeks 0, 1, and 2, followed by treatment every 2 weeks during the 12-week period. (N=1,496) n (%) Ustekinumab (N=613) Trials 2 and 3 included the active comparator, ustekinumab. n (%) Arthralgia 29 (3.3) 71 (4.7) 15 (2.4) Headache 31 (3.5) 64 (4.3) 23 (3.8) Fatigue 10 (1.1) 39 (2.6) 16 (2.6) Diarrhea 10 (1.1) 33 (2.2) 5 (0.8) Oropharyngeal pain 10 (1.1) 31 (2.1) 8 (1.3) Nausea 10 (1.1) 28 (1.9) 6 (1.0) Myalgia 3 (0.3) 26 (1.7) 4 (0.7) Injection site reactions (pain, erythema, bruising, hemorrhage, pruritus) 11 (1.3) 23 (1.5) 12 (2.0) Influenza 4 (0.5) 19 (1.3) 7 (1.1) Neutropenia 4 (0.5) 15 (1.0) 5 (0.8) Tinea infections (tinea pedis, versicolor, cruris) 2 (0.2) 15 (1.0) 3 (0.5) Adverse reactions that occurred in less than 1% of subjects in the SILIQ group through Week 12 were conjunctivitis and candida infections (including oral [0.2%], genital [0.1%], and esophageal [0.1%] versus none in the placebo group). Week 0 to End of Trial: Through Week 52, exposure-adjusted rates of serious adverse events were similar between subjects treated with SILIQ and those treated with ustekinumab. Through the end of the trial, the exposure-adjusted rates of treatment-emergent serious adverse events were similar to those seen in the 52-week period in the subjects treated with SILIQ. Specific Adverse Reactions: Suicidal Ideation and Behavior During the 12-week randomized treatment period in the pooled trials, one subject in the SILIQ group attempted suicide and none in the placebo or ustekinumab groups. From initiation through Week 52 of the trials, suicidal ideation or behavior occurred in 7 of 4,019 subjects (0.2 per 100 subject-years) treated with SILIQ and in 2 of 613 subjects (0.4 per 100 subject-years) treated with ustekinumab. During the course of the clinical trials for plaque psoriasis, suicidal ideation or behavior occurred in 34 of 4,464 subjects treated with SILIQ (0.37 per 100 subject-years). Eight of the 10 subjects who attempted or completed suicide had a history of depression and/or suicidal ideation or behavior [see Warnings and Precautions ( 5.1 , 5.2 )]. Infections During the 12-week randomized treatment period, infections occurred in 25.4% of the SILIQ group compared to 23.4% of the placebo group. The majority of infections consisted of nasopharyngitis, upper respiratory tract infection, pharyngitis, urinary tract infections, bronchitis, and influenza, and did not necessitate treatment discontinuation. The SILIQ group had a higher rate of fungal infections compared to the placebo group (1.8% vs 0.9%). The fungal infections were primarily non-serious skin and mucosal candida infections [see Warnings and Precautions ( 5.4 )]. Neutropenia During the 12-week randomized treatment period, neutropenia occurred in 0.7% of subjects in the SILIQ group. Most adverse reactions of neutropenia were transient. In subjects with normal absolute neutrophil count (ANC) at baseline, a reduction in ANC occurred in 6.8% of subjects in the SILIQ group, compared to 3.3% in the ustekinumab group, and 3.6% in the placebo group. Neutropenia ≥ Grade 3 (< 1,000/mm 3 ) occurred in 0.5% of subjects in the SILIQ group compared to 0.2% of subjects in the ustekinumab group and none in the placebo group. From Week 0 to end of trial, the exposure-adjusted rate of treatment-emergent neutropenia was 0.4 per 100 subject-years (0.1 per 100 subject-years were ≥ Grade 3). No serious infections were associated with cases of neutropenia. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity with SILIQ. Approximately 3% of subjects treated with SILIQ developed antibodies to brodalumab through the 52-week treatment period. Of the subjects who developed antibodies to brodalumab, none had antibodies that were classified as neutralizing. However, the assay to test for neutralizing antibodies had limitations detecting neutralizing antibodies in the presence of brodalumab; therefore, the incidence of neutralizing antibody development could be underestimated. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing 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 SILIQ with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SILIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Hypersensitivity reactions, anaphylaxis, including anaphylactic shock, pruritus, rashes, eczema, urticaria, and dermatitis [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] . Skin and Subcutaneous Tissue Disorders : Eczematous eruptions (atopic dermatitis-like eruptions) [see Warnings and Precautions ( 5.6 )] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no human data on SILIQ use in pregnant women to inform a drug-associated risk. Human IgG antibodies are known to cross the placental barrier; therefore, SILIQ may be transmitted from the mother to the developing fetus. In a combined embryofetal development and pre- and postnatal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of brodalumab during organogenesis through parturition at doses up to 26 times the maximum recommended human dose (MRHD) [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data A combined embryofetal development and pre- and postnatal development study was conducted in cynomolgus monkeys administered brodalumab. No brodalumab-related effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in infants from pregnant monkeys administered weekly subcutaneous doses of brodalumab up to 26 times the MRHD from the beginning of organogenesis to parturition (on a mg/kg basis of 90 mg/kg/week). 8.2 Lactation Risk Summary There are no data on the presence of brodalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Brodalumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SILIQ and any potential adverse effects on the breastfed infant from SILIQ or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of SILIQ have not been evaluated in pediatric patients. 8.5 Geriatric Use Of the 3,066 plaque psoriasis subjects initially randomized to SILIQ in clinical trials, 192 (6%) were ≥ 65 years old and no subjects were ≥ 75 years old. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 years and older was not sufficient to determine whether they responded differently from younger subjects [see Clinical Pharmacology ( 12.3 )].