Sylvant Drug Information

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. 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.

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 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.

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. 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. 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.

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. 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. 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.