Drug information of Siltuximab

Siltuximab

Drug group:

Siltuximab is used to treat Multicentric Castleman's Disease (MCD). MCD is a rare condition in which the body produces too much of a certain type of white blood cell. MCD can increase your risk of certain cancers by changing the way your immune system works.

Mechanism of effect

Siltuximab is a chimeric (human-mouse) monoclonal immunoglobulin G1-kappa antibody produced in a Chinese hamster ovary (CHO) cell line by recombinant DNA technology. Siltuximab prevents the binding of IL-6 to soluble and membrane-bound IL-6 receptors by forming high affinity complexes with human interleukin-6 (IL-6). Its use is indicated for the treatment of adult patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. MCD is a rare blood disorder caused by dysregulated IL-6 production, proliferation of lymphocytes, and subsequent enlargement of the lymph nodes. It is administered as a 1 hour intravenous infusion every 3 weeks.

Pharmacodynamic

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

AbsorptionNot AvailableVolume of distribution
Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L.
Protein bindingNot AvailableMetabolism
As siltuximab is an antibody, the expected consequence of metabolism is proteolytic degradation to small peptides and individual amino acids, and receptor-mediated clearance.
Route of eliminationNot AvailableHalf-life
The mean terminal half life after the first intravenous infusion of 11 mg/kg is 20.6 days.
Clearance
Body weight was identified as the only statistically significant covariate of siltuximab clearance, therefore body weight based dosing is appropriate. Based on population pharmacokinetic analysis, the clearance of situximab in patients is 0.23 L/day.

Drug 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

Dosage

11 mg/kg IV over 1 hour every 3 weeks until treatment failure
Treatment Criteria:
-Requirements before the first dose is given: The absolute neutrophil count (ANC) must be 1 x 10(9) or greater AND the platelet count must be 75 x 10(9) or greater AND hemoglobin must be less than 17 g/dL.
-Retreatment criteria: The absolute neutrophil count (ANC) must be 1 x 10(9) or greater AND the platelet count must be 50 x 10(9) or greater AND hemoglobin must be less than 17 g/dL.

Drug contraindications

Severe hypersensitivity to siltuximab or any component of the formulation

Side effects

  • Black, tarry stools
  • bleeding gums
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • bloody urine
  • blurred vision
  • body aches or pain
  • chills
  • confusion
  • cough
  • decreased frequency or amount of urine
  • difficulty with breathing
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • ear congestion
  • fever
  • full or bloated feeling
  • headache
  • increased thirst
  • loss of appetite
  • loss of voice
  • lower back or side pain
  • nasal congestion
  • nausea
  • pinpoint red spots on the skin
  • pressure in the stomach
  • rapid weight gain
  • runny nose
  • sneezing
  • sore throat
  • stomach pain
  • sweating
  • swelling of the abdominal or stomach area
  • tingling of the hands or feet
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • vomiting

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. Risk D: Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Risk C: Monitor therapy
CYP3A4 Substrates (High risk with Inducers): Siltuximab may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Risk D: 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). Risk D: Consider therapy modification
Inebilizumab: May enhance the immunosuppressive effect of Immunosuppressants. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Risk D: Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Risk C: Monitor therapy
Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. Risk C: Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. Risk D: Consider therapy modification
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Risk C: 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. Risk D: Consider therapy modification
Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Risk C: 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. Risk D: Consider therapy modification
Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Risk X: Avoid combination

Alerts

• 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.

Points of recommendation

Comments:
-This drug was not studied in patients with MCD who are HIV positive or HHV-8 positive because it did not bind to virally produced IL-6 in a nonclinical study.
-Perform hematology laboratory tests prior to each dose for the first 12 months and every 3 dosing cycles thereafter.
-Do not initiate therapy in patients with severe infections until the infection resolves.
-Discontinue therapy in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.

Pregnancy level

Siltuximab is a humanized monoclonal antibody; monoclonal antibodies are expected to cross the placenta, generally increasing as pregnancy progresses. Infants born to pregnant females treated with siltuximab may be at increased risk for infection.

Breast feeding warning

It is not known if siltuximab is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 3 months following the last dose of siltuximab.

Drug forms

Sylvant

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