Sylvant Drug Information

is indicated for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. SYLVANT is an interleukin-6 (IL-6) antagonist indicated for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. Limitations of Use SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.

Limitations of Use SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.

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 Best Supportive Care n=53 Placebo+BSC n=26 All Grades Grades 3-4 All Grades Grades 3-4 Skin disorders Rash (rash, rash generalized, rash maculo-papular, 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%) Anaphylactic reaction 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

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.

Cytochrome P450 Substrates Cytochrome P450s in the liver are down regulated by

infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in patients treated with SYLVANT may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment with SYLVANT. Upon initiation or discontinuation of SYLVANT, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of SYLVANT on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when SYLVANT is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).

Pregnancy Risk-Summary In an animal reproduction study, intravenous administration of a human antibody to IL-6 to pregnant monkeys from the onset of organogenesis through delivery caused functional impairment in pregnant animals and in the offspring. Siltuximab and the human antibody to IL-6 crossed the placenta in monkeys ( see Data ). The limited available information on SYLVANT use during pregnancy is not sufficient to inform a drug-associated risk of major birth defects or miscarriage. Infants born to pregnant women treated with SYLVANT may be at increased risk of infection (see Clinical Considerations ). Advise pregnant women of the potential risk to a fetus.

The estimated background risk for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Infants born to pregnant women treated with SYLVANT may be at increased risk of infection. Consider the risks and benefits of administering live or live-attenuated vaccines to infants exposed to SYLVANT in utero . Data Animal Data In an embryo-fetal development study in cynomolgus monkeys, pregnant animals received intravenous doses of siltuximab of 9.2 or 46 mg/kg/week during gestation days (GD) 20 to 118, which includes the period of organogenesis.

Fetuses were evaluated on GD 140, approximately 25 days prior to the natural birth. Exposures at the low and high dose after the 25 th administration were approximately 3 and 7 times, respectively, the human exposure based on AUC in patients with MCD at the recommended dose of 11 mg/kg every three weeks. No maternal or fetal structural abnormalities were observed.

However, siltuximab crossed the placenta at both doses and when measured on GD 140, fetal serum concentrations of siltuximab were similar to maternal concentrations. In a combined embryofetal and pre- and post-natal development study in cynomolgus monkeys, pregnant animals received intravenous doses of 10 or 50 mg/kg/week of a human antibody to IL-6 from GD 20 to natural delivery (GD 167). The offspring were evaluated up to 7 months after birth for developmental effects. No maternal or infant structural abnormalities were observed; however, globulin levels were decreased in pregnant animals (GD 34 through lactation day 30) and in the offspring (lactation days 30-120) at both doses.

Pediatric Use The safety and efficacy of SYLVANT have not been established in pediatric patients.

Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT . Hypersensitivity reactions, including anaphylactic reaction, hypersensitivity, and drug hypersensitivity have been reported in patients treated with siltuximab. Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT.