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)]

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 1summarizes 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
* Subjects receiving 210 mg of SILIQ at Weeks 0, 1, and 2, followed by treatment every 2 weeks during the 12-week period † Trials 2 and 3 included the active comparator, ustekinumab
Adverse Reactions	Placebo (N=879) n (%)	SILIQ 210 mg every 2 weeks* (N=1,496) n (%)	Ustekinumab (N=613)† 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)] .