6 ADVERSE REACTIONS

The following clinically significant adverse reactions are also discussed in other sections of the labeling:

Concurrent active severe infections [see Warnings and Precautions (5.1)]
Infusion-related reactions and hypersensitivity [see Warnings and Precautions (5.3)]
Gastrointestinal perforation [see Warnings and Precautions (5.4)]

6.1 Clinical Trials 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 clinical practice.

Study 1, in MCD, was an international, multicenter, randomized Phase 2 study of every 3 week infusions comparing SYLVANT and best supportive care (BSC) to placebo and BSC. There were 53 patients randomized to the SYLVANT arm at a dosage of 11 mg/kg and 26 patients randomized to the placebo arm. Of the 26 placebo-treated patients, 13 patients subsequently crossed-over to receive SYLVANT. The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The patients randomized to SYLVANT received a median of 19 infusions (range 1 to 50) compared to patients randomized to placebo who received a median of 8 infusions (range 2 to 32). To control for disparate exposure between arms, Table 3 reports the per patient incidence of adverse reactions that occurred during the first 8 infusions. Adverse reactions that occurred >3% in the SYLVANT arm are presented.

The most common adverse reactions (> 10% compared to placebo) during treatment with SYLVANT in the MCD clinical trial were rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia.

Table 3: Per Patient Incidence of Common Adverse Reactions in Study 1 During Initial 8 Infusions
Body System/Adverse Reactions	SYLVANT+BSC * n=53		Placebo+BSC n=26
	All Grades	Grades 3-4	All Grades	Grades 3-4
* Best Supportive Care † Anaphylactic reaction
Skin disorders
Rash (rash, rash generalized, rash maculopapular, rash popular and rash pruritic)	15 (28%)	1 (2%)	3 (12%)	0
Pruritus	15 (28%)	0	2 (8%)	0
Skin hyperpigmentation	2 (4%)	0	0	0
Eczema	2 (4%)	0	0	0
Psoriasis	2 (4%)	0	0	0
Dry skin	2 (4%)	0	0	0
Infections
Lower respiratory tract	4 (8%)	2 (4%)	1 (4%)	1 (4%)
Upper respiratory tract	14 (26%)	1 (2%)	4 (15%)	1 (4%)
Blood and lymphatic system disorders
Thrombocytopenia	5 (9%)	2 (4%)	1 (4%)	1 (4%)
General disorders
Edema (general and localized)	14 (26%)	4 (8%)	7 (27%)	0
Gastrointestinal disorders
Constipation	4 (8%)	0	1 (4%)	0
Metabolism
Hypertriglyceridemia	4 (8%)	0	0	0
Hypercholesterolemia	2 (4%)	0	0	0
Hyperuricemia	6 (11%)	1 (2%)	0	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	4 (8%)	0	1 (4%)	0
Renal and urinary disorders
Renal impairment	4 (8%)	0	0	0
Nervous system disorders
Headache	4 (8%)	0	1 (4%)	0
Investigations
Weight increased	10 (19%)	1 (2%)	0	0
Vascular disorders
Hypotension	2 (4%)	1 (2%) †	0	0

Study CNTO328MCD2002 (referred to as Study 2) (NCT01400503) was an open label, long term extension study of patients with MCD treated on prior trials. The median duration of siltuximab treatment was 5.52 years (range: 0.8 to 10.8 years); more than 50% of patients received siltuximab treatment for ≥5 years. The rate of serious or Grade ≥3 adverse events did not increase over time as a function of cumulative exposure.

Other important adverse reactions reported in MCD clinical studies, all of which were very common, were:

Infections and infestations: nasopharyngitis, urinary tract infection

Blood and lymphatic system disorders: neutropenia

Nervous system disorders: dizziness

Vascular disorders: hypertension

Gastrointestinal disorders: nausea, abdominal pain, vomiting, diarrhea, gastroesophageal reflux disease, mouth ulceration

6.2 Immunogenicity

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to SYLVANT with the incidence of antibodies to other products may be misleading. The clinical significance of anti-siltuximab antibodies following treatment with SYLVANT is not known.

The immunogenicity of siltuximab has been evaluated using antigen-bridging enzyme immunoassay (EIA) and electrochemiluminescence-based immunoassay (ECLIA) methods. A total of 432 patients across the clinical studies were evaluated at multiple time points for anti-therapeutic antibody (ATA) responses to siltuximab after treatment with SYLVANT. Following SYLVANT dosing, 0/243 (0%) patients tested positive for anti-siltuximab antibodies by EIA and 4/189 (2%) patients tested positive by ECLIA. Further immunogenicity analyses were conducted for all positive samples from the 4 patients with detectable anti-siltuximab antibodies. None of these patients had neutralizing antibodies.