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Siltuximab

Pronunciation

(sil TUX i mab)

Index Terms

  • CNTO 328

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]

Brand Names: U.S.

  • Sylvant

Pharmacologic Category

  • Antineoplastic Agent, Monoclonal Antibody
  • Interleukin-6 Receptor Antagonist

Pharmacology

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, 2010). Lowering serum IL-6 levels may improve systemic symptoms of Castleman disease.

Distribution

4.5 L

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: 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

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 over 1 hour every 3 weeks until treatment failure

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥15 mL/minute: No initial dosage adjustment is necessary.

CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

End-stage renal disease (ESRD): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild to moderate impairment (Child Pugh class A or B): No initial dosage adjustment is necessary.

Severe impairment (Child Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

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

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.

Compatibility

Stable in D5W

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); 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

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP3A4 Substrates: Siltuximab may decrease the serum concentration of CYP3A4 Substrates. 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

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

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. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (16%)

Central nervous system: Fatigue (21%; long-term exposure)

Dermatologic: Pruritus (28%), skin rash (28%)

Endocrine & metabolic: Weight gain (19%), hyperuricemia (11%)

Gastrointestinal: Diarrhea (32%; long-term exposure), abdominal pain (12%)

Neuromuscular & skeletal: Arthralgia (21%; long-term exposure), limb pain (21%; long-term exposure)

Respiratory: Upper respiratory tract infection (26%; long-term exposure: 63%)

1% to 10%:

Cardiovascular: Hypotension (4% to 6%; grades 3/4: 2% [anaphylactic reaction])

Central nervous system: Headache (8%)

Dermatologic: Eczema (4%), psoriasis (4%), skin hyperpigmentation (4%), xeroderma (4%)

Endocrine & metabolic: Hypertriglyceridemia (8%), dehydration (4%), hypercholesterolemia (4%)

Gastrointestinal: Constipation (8%), decreased appetite (4%)

Hematologic & oncologic: Thrombocytopenia (9%)

Renal: Renal insufficiency (8%)

Respiratory: Lower respiratory tract infection (8%), oropharyngeal pain (8%)

Miscellaneous: Infusion related reaction (5%)

<1% (Limited to important or life-threatening): 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: 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.

Other warnings/precautions:

• Appropriate use: Approved for use only in patients who are HIV negative and HHV-8 negative. Siltuximab was not studied in patients positive for these disease states due to the lack of drug binding to virally produced IL-6 in a nonclinical study.

• 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 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 women 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. Women of childbearing potential should use effective contraception during and for 3 months following treatment discontinuation.

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 headache, pharyngitis, or weight gain. Have patient report immediately to prescriber signs of infection, severe dizziness, passing out, severe abdominal pain, severe nausea, severe vomiting, severe diarrhea, severe constipation, edema, difficult urination, 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.

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