Siltuximab
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From MedlinePlus, U.S. National Library of Medicine
Interleukin-6 Antagonist
Dosing in kidney impairment
Patients with Renal Impairment Based on a population pharmacokinetic analysis using data from clinical trials in patients, no significant difference in siltuximab clearance was observed in patients with pre-existing renal impairment (creatinine clearance (CLCr) ≥ 15 mL/min) compared to patients with baseline normal renal function (CLCr ≥ 90 mL/min).
No initial dosage adjustment is necessary for patients with CLCr ≥ 15 mL/min. The potential effect of end stage renal disease on siltuximab pharmacokinetics cannot be determined [see Clinical Pharmacology ].
Dosing in liver impairment
Patients with Hepatic Impairment Based on a population pharmacokinetic analysis using data from clinical trials in patients, no significant difference in siltuximab clearance was observed in patients with pre-existing mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) compared to patients with baseline normal hepatic function.
No initial dosage adjustment is necessary for patients with mild to moderate hepatic impairment. Patients with baseline severe hepatic impairment (Child-Pugh Class C) were not included in clinical trials [see Clinical Pharmacology ].
Preparation and administration
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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. [See table below.] <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.
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. [See table below.] 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.
| 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 |
Drug interactions
Check siltuximab against a medication listLabel text (3 paragraphs)
7 DRUG INTERACTIONS
7.1 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).
Contraindications
Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT [see Warnings and Precautions (5.3) ] . 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. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
ELikelihood score E: Unlikely cause of clinically apparent liver injury.
Siltuximab is a chimeric human-mouse monoclonal antibody to interleukin-6 which is used in the therapy of Castleman disease. Siltuximab commonly causes mild serum aminotransferase elevations which are usually short lived and asymptomatic, but it has not been linked to instances of clinically apparent liver injury with jaundice.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 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 [see Warnings and Precautions (5.2) ] . 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…
Breastfeeding (LactMed)
No information is available on the clinical use of siltuximab during breastfeeding. Because siltuximab is a large protein molecule with a molecular weight of about 145,000 Da, the amount in milk is likely to be very low. It is also likely to be partially destroyed in the infant's gastrointestinal tract and absorption by the infant is probably minimal. Until more data become available, siltuximab should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. The manufacturer recommends that breastfeeding be discontinued during siltuximab therapy and for 3 months after the last dose.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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