Siltuximab

Indications

Siltuximab is used for: Indicated for multicentric Castleman disease in patients who are negative for HIV and human herpesvirus-8

Adult Dose

Intravenous Multicentric Castleman’s disease 11 mg/kg IV q3weeks; infuse over 1 hr Continue until treatment failure Hepatic impairment Mild-to-moderate (Child-Pugh A and B): No initial dosage adjustment required Severe (Child-Pugh C): No information

Child Dose

Renal Dose

Renal impairment CrCl >15 mL/min: No initial dosage adjustment required End-stage renal disease: No information

Administration

IV Preparation Use aseptic technique Calculate the dose and total volume of reconstituted solution required and the number of vials needed Allow the vial(s) to come to room temperature over ~30 minutes Siltuximab should remain at room temperature for the duration of the preparation Reconstitute vials with sterile water for injection; 100-mg vial with 5.2 mL and 400-mg vial with 20 mL Reconstituted concentration is 20 mg/mL Gently swirl vials to aid dissolution of lyophilized powder; do NOT shake or swirl vigorously Do not withdraw contents until all solids are completely dissolved (should dissolve in <60 minutes) Within 2 hr of reconstitution, further dilute in D5W (PVC with DEHP, or polyolefin) Withdraw volume from 250-mL bag of D5W that is equal to total calculated volume of reconstituted siltuximab, then slowly add calculated volume of reconstituted siltuximab; gently invert to mix solution IV Administration Administer in a setting that has resuscitation equipment, medication, and personnel trained to provide resuscitation Administer IV over 1 hr using administration sets lined with PVC with DEHP or polyurethane containing a 0.2 micron inline polyethersulfone filter Complete infusion within 4 hr of dilution of the reconstituted solution to the infusion bag Do not infuse concomitantly in the same IV line with other agents

Contra Indications

Concomitant use with live viral vaccines.

Precautions

Patient with risk for gastrointestinal perforation (e.g. diverticulitis, ulcers), concurrent active severe infection. Pregnancy and lactation. Not indicated for use for HIV and human herpesvirus-8 (HHV-8) positive patients. Lactation Unknown if distributed in human breast milk; because many drugs and immunoglobulins are excreted in human milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother

Pregnancy-Lactation

Pregnancy There are no adequate or well-controlled studies in pregnant women; In animal reproduction studies, administration of a human antibody to IL-6 to pregnant cynomolgus monkeys caused decreases in globulin levels in pregnant animals and in the offspring; the drug crossed the placenta in monkeys; infants born to pregnant women receiving therapy, may be at increased risk of infection, and caution is advised in administration of live vaccines to these infants; therapy should be used during pregnancy only if potential benefit justifies potential risk to fetus; advise patients of childbearing potential to avoid pregnancy; women of childbearing potential should use contraception during and for 3 months after treatment Monoclonal antibodies are transported across placenta as pregnancy progresses, with largest amount transferred during third trimester; infants born to pregnant women treated, may be at increased risk of infection; consider risks and benefits of administering live or live-attenuated vaccines to infants exposed to drug in utero Lactation There are no data on the presence of siltuximab in human milk, the effects on the breastfed child, or the effects on milk production; low levels of human antibody to IL-6 was present in milk of lactating cynomolgus monkeys; when a drug is present in animal milk, it is likely that the drug will be present in human milk; because of potential for serious adverse reactions in breastfed child including gastrointestinal perforations, advise patients that breastfeeding is not recommended during treatment with drug, and for 3 months after last dose

Interactions

May decrease serum concentration of CYP3A4 substrate (e.g. warfarin, ciclosporin). May enhance adverse effects of live vaccines. May diminish therapeutic effects of inactivated and live vaccines. May decrease therapeutic effect of oral contraceptives, atorvastatin.

Adverse Effects

Side effects of Siltuximab : >10% Pruritus (28%) Rash (28%) Edema (16-26%) Upper respiratory tract infection (26%) Increased weight (19%) Abdominal pain/distension (12%) Hyperuricemia (11%) 1-10% Thrombocytopenia (9%) Lower respiratory tract infection (8%) Constipation (8%) Oropharyngeal pain (8%) Renal impairment (8%) Headache (8%) Hypertriglyceridemia (8%) Hypotension (4-6%) Hypercholesterolemia (4%) Skin hyperpigmentation (4%) Eczema (4%) Psoriasis (4%) Dry skin (4%) Decreased appetite (4%) Dehydration (4%)

Mechanism of Action

Siltuximab is a chimeric murine/human monoclonal antibody that selectively binds cytokine interleukin-6 (IL-6) and prevents its binding to soluble and membrane-bound receptors. This leads to inhibition of immunoglobulin secretion and hepatic acute phase protein synthesis, thereby lowering IL-6 and C-reactive protein levels.