Brodalumab

1 INDICATIONS AND USAGE SILIQ ® (brodalumab) is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. SILIQ is a human interleukin-17 receptor A (IL-17RA) antagonist indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. ( 1 )

12.1 Mechanism of Action Brodalumab is a human monoclonal IgG2 antibody that selectively binds to human IL-17RA and inhibits its interactions with cytokines IL-17A, IL-17F, IL-17C, IL-17A/F heterodimer, and IL-25. IL-17RA is a protein expressed on the cell surface and is a required component of receptor complexes utilized by multiple IL-17 family cytokines. Blocking IL-17RA inhibits IL-17 cytokine-induced responses including the release of pro-inflammatory cytokines and chemokines.

2 DOSAGE AND ADMINISTRATION Administer 210 mg of SILIQ by subcutaneous injection at Weeks 0, 1, and 2 followed by 210 mg every 2 weeks. ( 2.2 ) 2.1 Tuberculosis Assessment Prior to Initiation of SILIQ Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SILIQ [see Warnings and Precautions ( 5.4 )]. 2.2 Dosage The recommended SILIQ dose is 210 mg administered by subcutaneous injection at Weeks 0, 1, and 2 followed by 210 mg every 2 weeks. If an adequate response has not been achieved after 12 to 16 weeks of treatment with SILIQ, consider discontinuing therapy. Continued treatment beyond 16 weeks in patients who have not achieved an adequate response is not likely to result in greater success. 2.3 Important Administration Instructions Administer SILIQ subcutaneously. Each prefilled syringe is for single dose only. Instruct patients to review the Medication Guide before use [see Medication Guide] . SILIQ is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject SILIQ when deemed appropriate by a healthcare professional and after proper training in subcutaneous injection technique using the prefilled syringe. Advise patients who are self-administering to inject the full dose and to read the Instructions for Use before administration [see Instructions for Use] . Do not inject SILIQ into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis. 2.4 Preparation of SILIQ Prefilled Syringe • Allow SILIQ prefilled syringe to reach room temperature (approximately 30 minutes) before injecting. Do not warm in any other way. Do not remove the gray needle cap on the prefilled syringe while allowing it to reach room temperature. • Visually inspect SILIQ for particles and discoloration prior to administration. SILIQ is a clear to slightly opalescent, colorless to slightly yellow solution. Do not use SILIQ if it is cloudy or discolored or if foreign matter is present. • Instruct patients to use the prefilled syringe and to inject the full amount (1.5 mL), which provides 210 mg of SILIQ, according to the directions provided in the Instructions for Use [see Instructions for Use].

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 t

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 tr

4 CONTRAINDICATIONS SILIQ is contraindicated in patients with: • Crohn’s disease because SILIQ may cause worsening of disease [see Warnings and Precautions ( 5.7 )] . • Clinically significant hypersensitivity to brodalumab or to any of the excipients in SILIQ or component of the container. Hypersensitivity reactions, including anaphylaxis, have been reported with postmarket use of SILIQ [see Warnings and Precautions ( 5.3 )] . • Crohn’s disease ( 4 ) • Clinically significant hypersensitivity to brodalumab or to any of the excipients in SILIQ or component of the container ( 4 )