Siltuximab

1 INDICATIONS AND USAGE SYLVANT 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. ( 1 ) 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.

2 DOSAGE AND ADMINISTRATION For intravenous infusion only. Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks. ( 2 ) 2.1 Recommended Dosage Administer SYLVANT 11 mg/kg over 1 hour as an intravenous infusion every 3 weeks until treatment failure. Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in Table 1 are not met, consider delaying treatment with SYLVANT. Do not reduce dose. Table 1: Treatment Criteria Laboratory parameter Requirements before first SYLVANT administration Retreatment criteria Absolute Neutrophil Count ≥1.0 × 10 9 /L ≥1.0 × 10 9 /L Platelet count ≥75 × 10 9 /L ≥50 × 10 9 /L Hemoglobin SYLVANT may increase hemoglobin levels in MCD patients <17 g/dL <17 g/dL Do not administer SYLVANT to patients with severe infections until the infection resolves. Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment. 2.2 Instructions for Preparation and Administration Use aseptic technique for reconstitution and preparation of dosing solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit 1. Calculate the dose (mg), total volume (mL) of reconstituted SYLVANT solution required and the number of vials needed. A 21-gauge 1½ inch needle is recommended for preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of polyvinyl chloride (PVC), or polyolefin (PO), or polypropylene (PP), or polyethylene (PE). Alternatively PE bottles may be used. 2. Allow the vial(s) of SYLVANT to come to room temperature over approximately 30 minutes. SYLVANT should remain at room temperature for the duration of the preparation. 3. Aseptically reconstitute each SYLVANT vial as instructed in Table 2. Table 2: Reconstitution Instructions Strength Amount of Sterile Water for Injection, USP required for reconstitution Post-reconstitution concentration 100 mg vial 5.2 mL 20 mg/mL 400 mg vial 20 mL 20 mg/mL Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes. Once reconstituted, and prior to further dilution, inspect the vials for particulates and discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. The reconstituted product should be kept for no more than two hours prior to addition into the infusion bag. 4. Dilute the reconstituted SYLVANT solution dose to 250 mL with sterile Dextrose 5% in Water by withdrawing a volume equal to the total calculated volume of reconstituted SYLVANT from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted SYLVANT solution to the Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution. 5. Administer the diluted SYLVANT solution in 5% Dextrose in Water 250 mL by intravenous infusion over a period of 1 hour using administration sets lined with PVC, or polyurethane (PU), or PE, containing a 0.2-micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 hours of the dilution of the reconstituted solution to the infusion bag. 6. Do not infuse SYLVANT concomitantly in the same intravenous line with other agents. 7. SYLVANT does not contain preservatives. Do not store any unused portion of the reconstituted product or of the infusion solution. Waste material should be disposed of in accordance with local requirements.

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) ] The most common adverse reactions (>10% of patients) were rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia. To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc., at 1-888-575-8344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 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.

12.3 Pharmacokinetics The pharmacokinetics of siltuximab were evaluated in patients with multicentric Castleman's disease and hematological and non-hematological malignancies. The serum siltuximab pharmacokinetics are adequately described by a linear two-compartment intravenous model with first-order elimination. Distribution Following SYLVANT administration (11 mg/kg, once every 3 weeks as 1-hour intravenous infusion) in patients with multicentric Castleman's disease, the maximum serum siltuximab concentration (C max ) occurred close to the end of infusion. At steady state, the serum mean C max value for siltuximab is 332 mcg/mL (42% CV), and the serum mean predose trough value is 84 mcg/mL (78% CV). With the once every 3 week dosing regimen, siltuximab steady state is achieved by the sixth infusion, and siltuximab accumulates approximately 1.7-fold relative to a single dose. Following multiple dosing, siltuximab showed approximately dose proportional pharmacokinetics over the dose range of 2.8 to 11 mg/kg. Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L (20% CV). Elimination Based on the population pharmacokinetic analysis, the clearance of siltuximab in patients is 0.23 L/day (51% CV). Based on population pharmacokinetic analysis (n=378), body weight was identified as the only statistically significant covariate for siltuximab clearance. Therefore, the body weight based dosing is appropriate. The mean terminal half-life (t 1/2 ) for siltuximab in patients after the first intravenous infusion of 11 mg/kg is 20.6 days (range: 14.2 to 29.7 days). Specific Populations Age and Gender Based on population pharmacokinetic analysis, age [range: 18 to 85 years (n=378)] and gender [female (n=175), male (n=203)] do not affect exposure of siltuximab. Renal Impairment A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 377 patients enrolled in clinical trials, including 176 with normal renal function (CLCr ≥ 90 mL/min), 122 with mild renal impairment (CLCr 60 to <90 mL/min), 75 with moderate renal impairment (CLCr 30 to <60 mL/min), and 3 with severe renal impairment (CLCr 15 to 29 mL/min). The apparent clearance of siltuximab was similar in patients with pre-existing mild, moderate and severe renal impairment (CLCr 15 to <90 mL/min) compared to patients with normal renal function. The potential effect of end stage renal disease on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient. Hepatic Impairment A population pharmacokinetic analysis (based on pre-existing hepatic function) was carried out with data from 377 patients enrolled in clinical trials, including 302 with normal hepatic function, 72 with mild hepatic impairment (Child-Pugh A), and 3 with moderate hepatic impairment (Child-Pugh B). The apparent clearance of siltuximab was similar in patients with pre-existing mild and moderate hepatic impairment (Child-Pugh Class A and B) compared to patients with normal hepatic function. The potential effect of severe hepatic impairment on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are not available.