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Highlights of Prescribing Information HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------------CONTRAINDICATIONS----------------------------- These highlights do not include all the information needed to use Severe hypersensitivity reaction to siltuximab or any of the excipients SYLVANT® safely and effectively. See full prescribing information in SYLVANT. (4) for SYLVANT. -----------------------WARNINGS AND PRECAUTIONS----------------------- • Concurrent Active Severe Infections: Do not administer SYLVANT to patients SYLVANT (siltuximab) for injection, for intravenous use with severe infections, monitor for infections, institute prompt treatment, and Initial U.S. Approval: 2014 interrupt SYLVANT until resolution of infection. (2, 5.1) • Vaccinations: Do not administer live vaccines because IL-6 inhibition may --------------------------INDICATIONS AND USAGE-------------------------- interfere with the normal immune response to new antigens. (5.2) SYLVANT is an interleukin-6 (IL-6) antagonist indicated for the treatment of • Infusion Related Reactions: Administer SYLVANT in a setting that provides patients with multicentric Castleman’s disease (MCD) who are human resuscitation equipment, medication, and personnel trained to provide immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) resuscitation. (5.3, 6.1) negative. (1) • Gastrointestinal (GI) perforation: Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation. (5.4) Limitations of Use SYLVANT was not studied in patients with MCD who are HIV positive or ----------------------------ADVERSE REACTIONS---------------------------- HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a The most common adverse reactions (>10% of patients) were nonclinical study. rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia. -----------------------DOSAGE AND ADMINISTRATION----------------------- For intravenous infusion only. To report SUSPECTED ADVERSE REACTIONS, contact EUSA Pharma (UK) Ltd, Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion at 1-888-255-9029 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. every 3 weeks. (2) ----------------------USE IN SPECIFIC POPULATIONS------------------------ -----------------------DOSAGE FORMS AND STRENGTHS---------------------- Pregnancy: May cause fetal harm (8.1) For injection • 100 mg of lyophilized powder in a single-dose vial. (3) See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient • 400 mg of lyophilized powder in a single-dose vial. (3) labeling. Revised: 12/2019 FULL PRESCRIBING INFORMATION: CONTENTS* 8.3 Females and Males of Reproduction Potential 8.4 Pediatric Use 1 INDICATIONS AND USAGE 8.5 Geriatric Use 2 DOSAGE AND ADMINISTRATION 8.6 Patients with Renal Impairment 2.1 Recommended Dosage 8.7 Patients with Hepatic Impairment 2.2 Instructions for Preparation and Administration 11 DESCRIPTION 3 DOSAGE FORMS AND STRENGTHS 12 CLINICAL PHARMACOLOGY 4 CONTRAINDICATIONS 12.1 Mechanism of Action 5 WARNINGS AND PRECAUTIONS 12.2 Pharmacodynamics 5.1 Concurrent Active Severe Infections 12.3 Pharmacokinetics 5.2 Vaccinations 13 NONCLINICAL TOXICOLOGY 5.3 Infusion Related Reactions and Hypersensitivity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.4 Gastrointestinal Perforation 14 CLINICAL STUDIES 6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 6.1 Clinical Trials Experience 16.1 How Supplied 7 DRUG INTERACTIONS 16.2 Storage and Stability 7.1 Cytochrome P450 Substrates 17 PATIENT COUNSELING INFORMATION 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy *Sections or subsections omitted from the full prescribing information are 8.2 Lactation not listed. FULL PRESCRIBING INFORMATION Table 2: Reconstitution Instructions 1 INDICATIONS AND USAGE SYLVANT is indicated for the treatment of patients with multicentric Castleman’s Amount of Sterile Water Post-reconstitution disease (MCD) who are human immunodeficiency virus (HIV) negative and human Strength for Injection, USP required concentration herpesvirus-8 (HHV-8) negative. for reconstitution 100 mg vial 5.2 mL 20 mg/mL Limitations of Use SYLVANT was not studied in patients with MCD who are HIV positive or 400 mg vial 20 mL 20 mg/mL HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study. 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 2 DOSAGE AND ADMINISTRATION all of the solids have been completely dissolved. The lyophilized powder should 2.1 Recommended Dosage dissolve in less than 60 minutes. Administer SYLVANT 11 mg/kg over 1 hour as an intravenous infusion every 3 weeks until treatment failure. 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 Perform hematology laboratory tests prior to each dose of SYLVANT therapy if visibly opaque. The reconstituted product should be kept for no more than two for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria hours prior to addition into the infusion bag. outlined in Table 1 are not met, consider delaying treatment with SYLVANT. Do not reduce dose. 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 Table 1: Treatment Criteria reconstituted SYLVANT from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted SYLVANT solution to the Laboratory Requirements before first Retreatment Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution. parameter SYLVANT administration criteria 5. Administer the diluted SYLVANT solution in 5% Dextrose in Water 250 mL by Absolute Neutrophil intravenous infusion over a period of 1 hour using administration sets lined with ≥1.0 x 109/L ≥1.0 x 109/L Count PVC, or polyurethane (PU), or PE, containing a 0.2-micron inline polyethersulfone Platelet count ≥75 x 109/L ≥50 x 109/L (PES) filter. The infusion should be completed within 4 hours of the dilution of the Hemoglobina <17 g/dL <17 g/dL reconstituted solution to the infusion bag. a SYLVANT may increase hemoglobin levels in MCD patients 6. Do not infuse SYLVANT concomitantly in the same intravenous line with other agents. Do not administer SYLVANT to patients with severe infections until the infection resolves. 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 Discontinue SYLVANT in patients with severe infusion related reactions, disposed of in accordance with local requirements. anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment. 3 DOSAGE FORMS AND STRENGTHS SYLVANT (siltuximab) for injection is available as: 2.2 Instructions for Preparation and Administration • 100 mg of lyophilized powder in a single-dose vial for intravenous infusion. Use aseptic technique for reconstitution and preparation of dosing solution. • 400 mg of lyophilized powder in a single-dose vial for intravenous infusion. Parenteral drug products should be inspected visually for particulate 4 CONTRAINDICATIONS matter and discoloration prior to administration, whenever solution Severe hypersensitivity reaction to siltuximab or any of the excipients in and container permit SYLVANT [see Warnings and Precautions (5.3)]. Hypersensitivity reactions, including anaphylactic reaction, hypersensitivity, and drug hypersensitivity 1. Calculate the dose (mg), total volume (mL) of reconstituted SYLVANT have been reported in patients treated with siltuximab. solution required and the number of vials needed. A 21-gauge 1½ inch needle is recommended for preparation. Infusion bags (250 mL) must 5 WARNINGS AND PRECAUTIONS contain Dextrose 5% in Water and must be made of polyvinyl chloride (PVC), 5.1 Concurrent Active Severe Infections or polyolefin (PO), or polypropylene (PP), or polyethylene (PE). Alternatively PE Do not administer SYLVANT to patients with severe infections until the infection bottles may be used. resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive 2. Allow the vial(s) of SYLVANT to come to room temperature over approximately protein (CRP). Monitor patients receiving SYLVANT closely for infections. Institute 30 minutes. SYLVANT should remain at room temperature for the duration of prompt anti-infective therapy and do not administer further SYLVANT until the the preparation. infection resolves. 3. Aseptically reconstitute each SYLVANT vial as instructed in Table 2. 5.2 Vaccinations To control for disparate exposure between arms, Table 3 reports the per patient Do not administer live vaccines to patients or infants born to patients receiving incidence of adverse reactions that occurred during the first 8 infusions. Adverse SYLVANT because IL-6 inhibition may interfere with the normal immune response reactions that occurred >3% in the SYLVANT arm are presented. to new antigens [see Use in Specific Populations (8.1)]. The most common adverse reactions (> 10% compared to placebo) during 5.3 Infusion Related Reactions and Hypersensitivity treatment with SYLVANT in the MCD clinical trial were rash, pruritus, upper SYLVANT may cause infusion related reactions and anaphylaxis.
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