Siltuximab (Monograph)

Brand name: Sylvant
Drug class: Antineoplastic Agents
- Interleukin-6 Antagonists
VA class: AN900
Chemical name: Disulfide with human-mouse monoclonal CNTO 328 κ-chain anti-(human interleukin 6) (human-mouse monoclonal CNTO 328 heavy chain) immunoglobulin G1 dimer
Molecular formula: C₆₄₅₀H₉₉₃₂N₁₆₈₈O₂₀₁₆S₅₀
CAS number: 541502-14-1

Introduction

Antineoplastic agent; a recombinant chimeric (human-murine) monoclonal antibody and interleukin-6 (IL-6) antagonist.

Uses for Siltuximab

Multicentric Castleman's Disease (MCD)

Treatment of MCD in patients who are HIV-negative and human herpes virus type 8 (HHV-8)-negative (designated an orphan drug by FDA for this use).

MCD is a rare lymphoproliferative disorder associated with excessive release of IL-6 and other proinflammatory cytokines. Pathogenesis not fully understood, but excessive production and dysregulation of IL-6 appear to play a prominent role and lead to stimulation of the production of acute phase reactants in the liver.

Common systemic manifestations of MCD include fever, night sweats, anorexia, weight loss, weakness and fatigue, edema, effusions, pruritus, pain, and/or dyspnea. Laboratory abnormalities may include anemia, elevated concentrations of inflammatory markers (e.g., C-reactive protein [CRP]), hypergammaglobulinemia, and hypoalbuminemia.

Manufacturer states siltuximab not studied for use in HIV- and HHV-8-positive patients with MCD^{† [off-label]} because the drug did not bind to virally produced IL-6 in a nonclinical study. Some clinicians suggest that anti-IL6 therapy may help to decrease IL-6 activity and help control the disease. Very limited clinical experience treating HIV- and HHV-8-associated MCD with anti-IL-6 therapy; clinical trials needed to determine whether siltuximab is effective in this population. (See Actions.)

Siltuximab Dosage and Administration

General

• Administer in setting where resuscitation equipment, medications, and personnel trained in resuscitation are available. (See Infusion-related Reactions and Hypersensitivity under Cautions.)

• Obtain CBC prior to each dose of siltuximab for first 12 months of therapy and then every 3 cycles thereafter. Siltuximab may increase hemoglobin concentrations in patients with MCD. (See Hematologic Toxicity under Dosage and Administration.)

• Do not administer to patients with severe infections until the infection resolves. (See Concurrent Active Severe Infections under Cautions.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.

Administer through a 0.2-µm inline polyethersulfone filter. Use PVC- or polyurethane-lined administration sets.

Siltuximab powder for injection must be reconstituted and diluted prior to administration.

Do not administer any other drug simultaneously through the same IV line.

Discard any unused portion of the reconstituted or diluted solutions since vials of siltuximab for injection contain no preservatives and are intended for single use only.

Reconstitution

Remove appropriate number of vials of siltuximab lyophilized powder from the refrigerator; allow to stand at room temperature (15–25°C) for approximately 30 minutes prior to reconstitution.

Manufacturer recommends using a 21-gauge, 1.5-inch needle for preparation.

To reconstitute siltuximab lyophilized powder, add 5.2 mL of sterile water for injection to a vial containing 100 mg of the drug or add 20 mL to a vial containing 400 mg of the drug to provide a solution containing 20 mg/mL.

Gently swirl vial to aid dissolution; the lyophilized powder should dissolve in <1 hour. Do not shake or vigorously swirl reconstituted solution. Do not remove contents of the reconstituted vials until all solids have completely dissolved.

Do not store reconstituted solution at room temperature for >2 hours.

Dilution

Remove the volume of diluent equal to the total required volume of reconstituted siltuximab solution from a 250-mL bag of 5% dextrose injection. Then slowly add total required volume of reconstituted siltuximab solution to the diluent in a diethylhexyl phthalate (DEHP)-plasticized PVC or non-PVC (polyolefin) infusion bag. Mix the diluted solution by gentle inversion.

Complete infusion within 4 hours of the dilution of the reconstituted solution (including infusion time).

Rate of Administration

Administer by IV infusion over 60 minutes.

Dosage

Adults

MCD

IV

11 mg/kg every 3 weeks. Continue therapy until treatment failure.

Therapy Interruption for Toxicity

Hematologic Toxicity

Manufacturer recommends considering delaying administration of the first dose of siltuximab in patients with an ANC <1000/mm³, platelet count <75,000/mm³, and/or hemoglobin concentration ≥17 g/dL. Do not reduce dosage.

For subsequent doses, consider delaying therapy if ANC is <1000/mm³, platelet count is <50,000/mm³, and/or the hemoglobin concentration is ≥17 g/dL. Do not reduce dosage.

Infusion-related Reactions and Hypersensitivity

If mild to moderate infusion-related reactions occur, temporarily interrupt therapy. If reaction resolves, may resume therapy at a slower infusion rate. Consider treatment with antihistamines, acetaminophen, and/or corticosteroids. Discontinue siltuximab if patient is unable to tolerate the infusion following these interventions.

If severe infusion-related reactions or cytokine release syndromes occur, permanently discontinue therapy.

If anaphylaxis occurs, immediately and permanently discontinue therapy. (See Contraindications and also see Infusion-related Reactions and Hypersensitivity under Cautions.)

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No adjustment of initial dosage needed.

Severe hepatic impairment (Child-Pugh class C): Not studied; no specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)

Renal Impairment

Cl_cr ≥15 mL/minute: No initial dosage adjustment needed.

Cl_cr <15 mL/minute and end-stage renal disease: Limited data available; no specific dosage recommendations at this time. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)

Cautions for Siltuximab

Contraindications

• Severe hypersensitivity reaction to siltuximab or any ingredient in the formulation. (See Infusion-related Reactions and Hypersensitivity under Cautions.)

Warnings/Precautions

Concurrent Active Severe Infections

Siltuximab may mask signs and symptoms of acute inflammation (i.e., suppression of fever and acute phase reactants [e.g., CRP]).

Do not administer siltuximab in patients with severe infections until the infection resolves.

Closely monitor patients for possible infections. If an infection develops, promptly initiate anti-infective therapy and withhold siltuximab until the infection resolves.

Immunization

Inhibition of IL-6 may interfere with the normal immune response to new antigens. Do not administer live vaccines to patients receiving siltuximab. (See Advice to Patients.)

Infusion-related Reactions and Hypersensitivity

Anaphylactic reaction reported rarely. If signs of anaphylaxis or other severe allergic reactions occur, immediately and permanently discontinue siltuximab therapy. (See Contraindications under Cautions.)

Infusion-related reactions (including back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations) reported in 4.8% of patients receiving siltuximab monotherapy.

If mild or moderate infusion-related reactions occur, temporarily interrupt the siltuximab infusion; if reaction resolves, may resume infusion at a slower infusion rate. Consider treatment with antihistamines, acetaminophen, and corticosteroids. If unable to tolerate the infusion following these interventions, discontinue siltuximab.

If severe infusion reactions or cytokine release syndromes occur, permanently discontinue therapy. (See Infusion-Related Reactions and Hypersensitivity under Dosage and Administration.)

GI Perforation

GI perforation reported in siltuximab-treated patients in clinical trials; however, no cases were reported in MCD trials of the drug.

Use with caution in patients who may be at increased risk for GI perforation (e.g., those with diverticulitis or ulcers). Promptly evaluate patients if manifestations suggestive of GI perforation occur (e.g., stomach pain, nausea, change in bowel habits, fever).

Immunogenicity

Potential for immunogenicity. Development of anti-siltuximab antibodies reported in 1 of 411 patients (0.2%) receiving siltuximab in clinical studies. No evidence of altered toxicity of the drug observed in the patient who developed the antibodies.

Specific Populations

Pregnancy

Category C.

No adequate and well-controlled studies in pregnant women. Maternal and fetal toxicity was not observed when siltuximab was administered to pregnant animals; however, siltuximab crossed the placenta and fetal serum concentrations were similar to maternal concentrations. Administration of a human antibody to IL-6 to pregnant animals caused decreased globulin concentrations in pregnant animals and offspring.

Possible increased risk of infection in infants born to pregnant women treated with siltuximab; use live vaccines with caution in these infants.

Avoid pregnancy during therapy. Use during pregnancy only if potential benefit justifies the potential risk to the fetus. Use contraception during siltuximab treatment and for 3 months following discontinuance of the drug.

Lactation

Not known whether distributed into human milk or absorbed systemically after ingestion. Discontinue nursing or the drug.

Pediatric Use

MCD usually affects adults. Safety and efficacy of siltuximab not established in pediatric patients <18 years of age.

Geriatric Use

No overall differences in safety relative to younger patients, but increased sensitivity cannot be ruled out.

Insufficient experience in patients ≥65 years of age with MCD to determine whether they respond differently than younger adults. (See Absorption: Special Populations, under Pharmacokinetics.)

Hepatic Impairment

Clearance not substantially affected by mild or moderate hepatic impairment (Child-Pugh class A or B).

Not studied in patients with severe hepatic impairment (Child-Pugh class C). (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Clearance not substantially affected by mild, moderate, or severe renal impairment (Cl_cr 15–89 mL/minute).

Effect of end-stage renal disease on pharmacokinetics not known; clinical and pharmacokinetic data are very limited. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Rash (e.g., maculopapular, papular, generalized, pruritic), pruritus, upper respiratory tract infection, weight gain, localized edema, abdominal pain, thrombocytopenia, nasopharyngitis, hyperuricemia.

Drug Interactions

No formal drug interaction studies to date.

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increased metabolism of drugs metabolized by CYP isoenzymes. Because IL-6 may downregulate CYP isoenzymes, inhibition of IL-6 by siltuximab may restore CYP enzyme activity to higher levels. Effects on CYP enzyme activity may persist for several weeks after drug discontinuance.

Drugs metabolized by CYP isoenzymes that have a low therapeutic index: Monitor therapeutic effect and/or serum concentrations following initiation or discontinuance of siltuximab and adjust dosage, if necessary.

CYP3A4 substrates: Caution advised when a reduction in efficacy of the substrate would be undesirable.

Specific Drugs

Siltuximab Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are approximately dose proportional over the dosage range of 2.8–11 mg/kg every 3 weeks.

Steady-state concentrations achieved by the sixth infusion (within 18 weeks), resulting in systemic accumulation of approximately 1.7-fold.

Special Populations

Age (range: 18–85 years) and gender do not affect exposure of siltuximab.

Distribution

Extent

Crosses the placenta in animals.

Not known whether distributed into human milk.

Elimination

Half-life

Mean half-life following first IV infusion: 20.6 days.

Special Populations

Mild or moderate (Child-Pugh class A or B) hepatic impairment: Clearance similar to patients with normal hepatic function.

Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics not studied.

Mild, moderate, or severe (Cl_cr of 15–89 mL/minute) renal impairment: Clearance similar to patients with normal renal function.

Stability

Storage

Parenteral

Powder for Injection

2–8°C. Protect vials from light.

Following reconstitution, store vial at room temperature and use within 2 hours.

Following dilution, store infusion solution at room temperature; use within 4 hours (including infusion time).

Compatibility

Parenteral

Solution Compatibility

Actions

• Binds to human IL-6 and prevents its binding to both soluble and membrane-bound IL-6 receptors.

• IL-6 is involved in a variety of normal physiologic processes, including induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and cell proliferation and differentiation.

• Overproduction of IL-6 appears to play a critical role in the disease process of MCD, resulting in plasma cell proliferation and a variety of systemic manifestations. (See Multicentric Castleman's Disease [MCD] under Uses.)

• Cause of MCD in patients who are not infected with HIV and HHV-8 not fully elucidated; however, HHV-8 is a well established cause of hypercytokinemia in HIV-infected and in some HIV-negative patients with the disease.

• Siltuximab did not bind to virally produced IL-6 in a nonclinical study.

Advice to Patients

• Importance of advising patients about potential benefits and risks of siltuximab. Importance of patients reading the manufacturer's patient information prior to initiation of therapy and each time they receive an infusion of the drug.

• Risk of increased susceptibility to infection. Instruct patients to immediately contact their clinician if symptoms suggesting an infection occur to ensure rapid evaluation and appropriate treatment.

• Importance of advising patients that they should not receive live vaccines during siltuximab therapy. Importance of informing clinician of recent or scheduled vaccinations and of discussing recommended vaccinations with their clinician prior to beginning siltuximab therapy.

• Risk of infusion-related and allergic reactions. Importance of immediately reporting signs and symptoms of such reactions, including dizziness, lightheadedness, wheezing, swelling of the lips, rash, breathing difficulty, or chest pain or tightness.

• Importance of advising patients to report any new or worsening medical conditions to their clinician.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of advising women not to breast-feed during therapy. Necessity of advising women of childbearing potential to use effective contraception while receiving siltuximab and for 3 months after the drug is discontinued.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., infections, GI disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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