Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Sylvant: 100 mg (1 ea); 400 mg (1 ea) [contains mouse (murine) and/or hamster protein, polysorbate 80]
Pharmacology
Mechanism of Action
Chimeric monoclonal antibody which binds with high affinity and specificity to IL-6; prevents IL-6 from binding to both soluble and membrane-bound IL-6 receptors. Overproduction of IL-6 may lead to systemic manifestations in multicentric Castleman disease (MCD) patients by inducing C-reactive protein (CRP) synthesis (Kurzrock 2013). Lowering serum IL-6 levels may improve systemic symptoms of Castleman disease.
Pharmacokinetics/Pharmacodynamics
Distribution
4.5 L
Onset of Action
Response is usually evident after 3 to 4 doses; lymphadenopathy resolves at a median of 5 months (van Rhee 2018)
Half-Life Elimination
~21 days (range: 14.2 to 29.7 days)
Use: Labeled Indications
Castleman disease: Treatment of multicentric Castleman disease (MCD) in patients who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative
Limitations of use: Siltuximab has not been studied in patients with MCD who are HIV positive or HHV-8 positive because in a nonclinical study, siltuximab did not bind to virally produced IL-6
Contraindications
Severe hypersensitivity to siltuximab or any component of the formulation
Dosage and Administration
Dosing: Adult
Note: Consider delaying first dose if ANC <1000/mm3, platelets <75,000/mm3, and hemoglobin ≥17 g/dL; subsequent doses may be delayed if ANC <1000/mm3, platelets <50,000/mm3, and hemoglobin ≥17 g/dL. Do not reduce dose.
Castleman disease, multicentric (in patients who are HIV negative and HHV-8 negative): IV: 11 mg/kg once every 3 weeks until treatment failure (van Rhee 2014; manufacturer's labeling). For initial disease control, adjunctive corticosteroids may be also administered for 4 to 8 weeks, followed by a corticosteroid taper; patients who are more symptomatic may require higher initial doses of adjunctive corticosteroids and a more gradual taper (van Rhee 2018).
Severe disease in critically ill patients (off-label dosing): IV: 11 mg/kg once weekly for one month, followed by 11 mg/kg once every 3 weeks until treatment failure. For initial disease control, also administer adjunctive high-dose corticosteroids, followed by a slow corticosteroid taper (van Rhee 2018).
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Hematologic toxicity: ANC <1000/mm3, platelets <50,000/mm3, and hemoglobin ≥17 g/dL: Consider delaying treatment until ANC ≥1000/mm3, platelets ≥50,000/mm3, and hemoglobin <17 g/dL
Anaphylaxis, cytokine release syndromes, and/or severe infusion-related or allergic reactions: Discontinue permanently.
Infection, severe: Withhold treatment until infection resolves.
Reconstitution
Allow intact vials to come to room temperature (~30 minutes) and remain at room temperature for the duration of preparation. Reconstitute with 5.2 mL (100 mg vial) or 20 mL (400 mg vial) SWFI to a final concentration of 20 mg/mL; gently swirl to fully dissolve powder (usually takes <60 minutes). Do not shake or swirl vigorously. Must further dilute within 2 hours to 250 mL with D5W (infusion bag must be made of polyvinyl chloride [PVC], polyolefin [PO], polypropylene [PP], or polyethylene [PE], or PE bottles may be used. After all solids are completely dissolved, remove a volume equal to the total calculated dose volume of reconstituted siltuximab from the bag of D5W; slowly add the appropriate volume of reconstituted siltuximab solution to the infusion bag and gently invert to mix. Complete infusion within 4 hours of dilution of the reconstituted solution to the infusion bag.
Administration
IV: Administer IV over 1 hour using administration sets lined with polyvinyl chloride (PVC), polyurethane (PU), or polyethylene (PE), which contain a 0.2 micron inline polyethersulfone (PES) filter. Do not infuse in the same line with other medications. Complete infusion within 4 hours of dilution of the reconstituted solution to the infusion container.
Storage
Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Keep in original carton to protect from light. Reconstituted solution should be further diluted in D5W for infusion within 2 hours; complete infusion within 4 hours of dilution of the reconstituted solution to the infusion container. Discard any unused portion of the reconstituted solution or solution diluted for infusion.
Drug Interactions
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
CYP3A4 Substrates (High risk with Inducers): Siltuximab may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification
Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination
Adverse Reactions
>10%:
Cardiovascular: Edema (≤26%)
Dermatologic: Pruritus (28%), skin rash (28%)
Endocrine & metabolic: Weight gain (19%), hyperuricemia (11%)
Local: Localized edema (≤26%)
Respiratory: Upper respiratory tract infection (26%)
1% to 10%:
Cardiovascular: Hypotension (4%)
Central nervous system: Headache (8%)
Dermatologic: Eczema (4%), psoriasis (4%), skin hyperpigmentation (4%), xeroderma (4%)
Endocrine & metabolic: Hypertriglyceridemia (8%), hypercholesterolemia (4%)
Gastrointestinal: Constipation (8%)
Hematologic & oncologic: Thrombocytopenia (9%)
Hypersensitivity: Hypersensitivity reaction (≤6.3%)
Immunologic: Antibody development (2%, non-neutralizing)
Renal: Renal insufficiency (8%)
Respiratory: Lower respiratory tract infection (8%), oropharyngeal pain (8%)
Miscellaneous: Infusion related reaction (≤6.3%)
Frequency not defined:
Cardiovascular: Hypertension
Central nervous system: Dizziness
Gastrointestinal: Abdominal pain, diarrhea, gastroesophageal reflux disease, nausea, oral mucosa ulcer, vomiting
Genitourinary: Urinary tract infection
Hematologic & oncologic: Neutropenia
Respiratory: Nasopharyngitis
<1%: Anaphylaxis
Warnings/Precautions
Concerns related to adverse effects:
- Gastrointestinal perforation: Gastrointestinal perforation has been observed in clinical trials. Use with caution in patients at risk for perforation; promptly evaluate concerning symptoms.
- Hemoglobin levels: Siltuximab administration may result in elevated hemoglobin levels in patients with multicentric Castleman disease; monitor blood counts prior to each dose for the first 12 months and every 3 dosing cycles thereafter, or as clinically necessary. May require therapy interruption.
- Infection: Siltuximab may mask signs and symptoms of infection, including signs of acute inflammation (eg, fever, C-reactive protein elevation). Do not administer to patients with severe infections (until infection resolves); monitor closely for infections and initiate appropriate anti-infective therapy if needed. If infection develops, withhold therapy until resolved.
- Infusion-related/hypersensitivity reactions: Hypersensitivity, anaphylactic reaction, and drug hypersensitivity have been observed with siltuximab. Discontinue infusion immediately (and permanently) if signs of anaphylaxis occur; do not reinitiate therapy. Discontinue in patients with severe infusion reaction, severe allergic reactions, or cytokine release syndromes. If a mild to moderate infusion reaction develops, temporarily discontinue the infusion; if the reaction resolves, may reinitiate at a lower infusion rate. Consider premedication with acetaminophen, antihistamines, and corticosteroids. If infusion-related reactions recur despite appropriate premedication and infusion rate reduction, discontinue therapy. Administer in a setting equipped to provide resuscitation equipment; medications for the treatment of hypersensitivity reactions (eg, bronchodilators, epinephrine, antihistamines, and corticosteroids) should be readily available.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Dosage form specific issues:
- Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
- Vaccinations: Do not administer live vaccines to patients receiving siltuximab; IL-6 inhibition may interfere with immune response to vaccination.
Monitoring Parameters
Monitor complete blood count with differential prior to each dose for the first 12 months and every 3 dosing cycles thereafter, or as clinically necessary; monitor for anaphylaxis and signs/symptoms of infusion-related, allergic, or cytokine release reactions; monitor for infection and signs/symptoms of gastrointestinal perforation.
Pregnancy
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events were not observed in animal reproduction studies. However, decreased globulin levels were detected in the pregnant animals and their offspring. Infants born to pregnant females treated with siltuximab may be at increased risk for infection. Use during pregnancy only if the potential benefit outweighs the possible risk to the fetus. Females of reproductive potential should use effective contraception during treatment and for 3 months following the last dose of siltuximab.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience constipation, headache, joint pain, pharyngitis, common cold symptoms, or weight gain. Have patient report immediately to prescriber signs of infection, signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), dizziness, passing out, severe abdominal pain, severe nausea, vomiting, back pain, chest pain, abnormal heartbeat, flushing, edema, bruising, or bleeding (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
