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  • CLASSES

    Antineoplastic Monoclonal Antibodies Targeting Interleukin 6 (IL-6)

    DEA CLASS

    Rx, OTC

    DESCRIPTION

    Interleukin-6 antagonist
    Used in multicentric Castleman disease
    Severe infusion-related reactions including anaphylaxis may occur; administer in a setting that has resuscitation equipment and medication

    COMMON BRAND NAMES

    Sylvant

    HOW SUPPLIED

    Siltuximab/Sylvant Intravenous Inj Pwd F/Sol: 100mg, 400mg

    DOSAGE & INDICATIONS

    For the treatment multicentric Castleman disease (MCD) in patients who are human immunodeficiency virus (HIV)-negative and human herpesvirus-8 (HHV-8)-negative.
    NOTE: The FDA has designated siltuximab as an orphan drug for Castleman disease.
    Intravenous dosage
    Adults

    11 mg/kg IV over 1 hour every 3 weeks until treatment failure. Prior to starting siltuximab therapy, verify that the absolute neutrophil count is 1 x 109 cells/L or greater, the platelet count is 75 x 109 cells/L or greater, and the hemoglobin concentration is less than 17 grams/dL. Interrupt the siltuximab infusion for mild or moderate infusion-related reactions. The response (complete response (CR) plus partial response (PR)) rate with improvement or stabilization of disease-related symptoms for at least 18 weeks (primary endpoint) was significantly higher in patients who received siltuximab (n = 53; median duration of therapy, 19 cycles) compared with placebo (n = 26) (34% vs. 0%; p = 0.0012) for the treatment of multicentric Castleman disease in a multinational, randomized, double-blind trial; the median duration of response was 383 days (range, 232 to 676 days). In this study, 55% of patients in the siltuximab arm had received prior systemic therapy. During the study, all patients received best supportive care specified by institutional guidelines. The response rates (evaluated by independent review using modified Cheson criteria) were 39% (CR, n = 2; PR, n = 18) and 4% (PR, n = 1) in the siltuximab and placebo arms, respectively (p = 0.0022); the time to response was 155 days (range, 44 to 742 days) in patients who received siltuximab. The durable symptomatic response rates (based on a disease-related overall symptom score evaluated by investigators) were 57% (n = 30) and 19% (n = 5) in the siltuximab and placebo arms, respectively (p = 0.0018); the time to response was 170 days (range, 67 to 274 days) in patients who received siltuximab. Of note, no patients with the hyaline vascular disease subtype achieved a durable tumor and symptomatic response evaluated by independent review. At a median follow-up of 422 days (range, 55 to 1,051 days), the median time to treatment failure was not reached in the siltuximab arm and was 134 days in the placebo arm (p = 0.0084). The 1-year overall survival rate was 100% and 92% in the siltuximab and placebo arms, respectively.

    INVESTIGATIONAL USE: For adjunctive use in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection†, the virus that causes coronavirus disease 2019 (COVID-19)†.
    Intravenous dosage
    Adults

    Efficacy has not been established. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend against the use of siltuximab outside clinical trials. A single dose of 11 mg/kg via intravenous infusion over 1 hour is being evaluated. In one study, a second dose could be administered at the physician's discretion; a total of 5 patients received a second dose [dosing interval: 2 days (n = 3/5), 3 days (n = 2/5)].

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    11 mg/kg IV.

    Geriatric

    11 mg/kg IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Siltuximab use has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C).

    Renal Impairment

    No dosage adjustment is necessary in patients with renal impairment (creatinine clearance of 15 to 90 mL/min). Siltuximab use has not been evaluated sufficiently in patients with end-stage renal disease.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution:
    Allow the lyophilized vial(s) to come to room temperature over approximately 30 minutes; vials should remain at room temperature for the duration of the preparation.
    A 21-gauge, 1 and 1/2 inch needle is recommended for preparation.
    Add 5.2 mL of Sterile Water for Injection to the 100-mg vial and 20 mL of Sterile Water for Injection to the 400-mg vial for a final vial concentration of 20 mg/mL.
    Gently swirl the reconstituted vial; do NOT shake or swirl vigorously.
    Allow the lyophilized powder to completely dissolve; powder should dissolve in less than 60 minutes.
    Storage following reconstitution: further dilute the vial contents within 2 hours of reconstitution.
    Dilution:
    Withdraw the appropriate volume (mL) from the siltuximab 20 mg/mL vials for the calculated dose; discard any unused portion left in the vial.
    Dilute the calculated dose in 5% Dextrose Injection to a total infusion bag volume of 250 mL; this may be achieved by withdrawing a volume equal to the calculated volume of siltuximab from a 250-mL bag of 5% Dextrose Injection.
    Gently invert the bag to mix the solution after slowing adding the calculated volume to the 5% Dextrose Injection solution.
    Infusion bags must be made of polyvinyl chloride (PVC), polyolefin, polypropylene, or polyethylene (PE); PE bottles may also be used.
    Storage after dilution: use within 4 hours after dilution.
    Intravenous Infusion:
    Administer over 1 hour using an administration set lined with PVC, polyurethane, or PE containing a 0.2 micron inline polyethersulfone (PES) filter.
    Do not infuse concomitantly in the same IV line with other agents.
    Do not store any unused portion of the infusion solution.

    STORAGE

    Sylvant:
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Infusion-related reactions

    Siltuximab use is contraindicated in patients who have had a severe hypersensitivity reaction to siltuximab or any components of the product. If anaphylaxis, severe allergic reactions, or cytokine release syndrome occur during therapy, immediately stop the siltuximab infusion and do not resume therapy. Only give siltuximab therapy in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation. Infusion-related reactions have been reported. Symptoms include back pain, chest pain/discomfort, nausea, vomiting, flushing, erythema, and palpitations. Interrupt the siltuximab infusion for mild or moderate infusion-related reactions; therapy may be resumed at a slower infusion rate if the reaction resolves. The use of antihistamines, acetaminophen, and corticosteroids may be considered to help prevent or lessen infusion-related reactions. If the patient does not tolerate the siltuximab infusion despite the use of prophylactic medications, discontinue therapy.

    Infection

    Siltuximab may mask signs and symptoms of infection (e.g., suppress fever and/or C-reactive protein (CRP) levels) or lower resistance to infection due to its immunosuppressive effects. Do not administer siltuximab to patients with severe infections until the infection resolves. Monitor patients closely for signs or symptoms of infection during therapy. If an infection develops during therapy, start anti-infective therapy and hold siltuximab until the infection resolves.

    Diverticulitis, GI perforation, peptic ulcer disease

    GI perforation has been reported with siltuximab therapy. Use siltuximab with caution in patients who may be at increased risk for GI perforation such as patients with diverticulitis or peptic ulcer disease. Promptly evaluate patients who have symptoms suggestive of GI perforation.

    Neutropenia, thrombocytopenia

    Hematologic adverse events (e.g., neutropenia and thrombocytopenia) have been reported with siltuximab therapy. Monitor complete blood counts prior to each dose for the first 12 months of therapy and then every 3 dosing cycles thereafter. Prior to starting siltuximab, ensure that the absolute neutrophil count (ANC) is 1 x 109 cells/L or greater, the platelet count is 75 x 109 cells/L or greater, and the hemoglobin concentration is less than 17 grams/dL. Ensure that the ANC is 1 x 109 cells/L or greater, the platelet count is 50 x 109 cells/L or greater, and the hemoglobin concentration is less than 17 grams/dL prior to giving subsequent siltuximab doses.

    Infants, neonates, vaccination

    Avoid vaccination with live vaccines in patients receiving siltuximab as IL-6 inhibition may interfere with the normal immune response to new antigens. Infants and neonates born to pregnant women who were treated with siltuximab may have an increased risk of infection; administer live vaccines to these patients with caution.

    Pregnancy

    Based on findings in animal reproduction studies, siltuximab may cause fetal harm when administered during human pregnancy. There are no available data on siltuximab use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Females of reproductive potential should avoid pregnancy during siltuximab therapy. Advise pregnant women of the potential fetal risk. Monoclonal antibodies appear to cross via the placenta. In cynomolgus monkey reproduction studies, siltuximab administration during organogenesis resulted in fetal serum concentrations that were similar to maternal concentrations at exposures above those occurring at the maximum recommended human dose of 11 mg/kg given every 3 weeks.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during siltuximab treatment. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 3 months after treatment with siltuximab.

    Breast-feeding

    Because of the potential for serious adverse reactions in the breast-fed child, including gastrointestinal perforation, breast-feeding is not recommended during situximab treatment and for 3 months after the last dose. There are no data on the presence of situximab in human milk, the effects on the breast-fed child, or the effects on milk production.[57062]

    ADVERSE REACTIONS

    Severe

    edema / Delayed / 8.0-8.0
    nephrotoxicity / Delayed / 8.0-8.0
    infection / Delayed / 2.0-4.0
    thrombocytopenia / Delayed / 4.0-4.0
    rash / Early / 2.0-2.0
    maculopapular rash / Early / 0-2.0
    hyperuricemia / Delayed / 2.0-2.0
    weight gain / Delayed / 2.0-2.0
    hypotension / Rapid / 2.0-2.0
    infusion-related reactions / Rapid / 0.8-0.8
    anaphylactoid reactions / Rapid / 0.1-0.1
    GI perforation / Delayed / Incidence not known
    cytokine release syndrome / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 8.0-8.0
    hypertriglyceridemia / Delayed / 8.0-8.0
    psoriasis / Delayed / 4.0-4.0
    hypercholesterolemia / Delayed / 4.0-4.0
    antibody formation / Delayed / 0.9-0.9
    neutropenia / Delayed / 10.0
    oral ulceration / Delayed / 10.0
    hypertension / Early / 10.0
    chest pain (unspecified) / Early / Incidence not known
    erythema / Early / Incidence not known
    palpitations / Early / Incidence not known

    Mild

    pruritus / Rapid / 28.0-28.0
    headache / Early / 8.0-8.0
    skin hyperpigmentation / Delayed / 4.0-4.0
    xerosis / Delayed / 4.0-4.0
    pharyngitis / Delayed / 10.0
    nausea / Early / 10.0
    gastroesophageal reflux / Delayed / 10.0
    abdominal pain / Early / 10.0
    diarrhea / Early / 10.0
    vomiting / Early / 10.0
    dizziness / Early / 10.0
    flushing / Rapid / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Alfentanil: (Moderate) Monitor for evidence of reduced effect if alfentanil coadministration with siltuximab is necessary; alfentanil dosage adjustment may be needed. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as alfentanil, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Alfentanil is a CYP3A4 substrate and a narrow therapeutic index drug.
    Amlodipine; Atorvastatin: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as atorvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Apixaban: (Moderate) Monitor for a decrease in efficacy of apixaban if used with siltuximab. Until more data are available, consider using an anticoagulant without dependence on CYP450 enzymes for metabolism (e.g., heparins, edoxaban). The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. It is expected that the activity of CYP450 enzymes could increase to normal concentrations during treatment with an IL-6 antagonist such as siltuximab; these effects on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes [including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4]. Apixaban is a substrate for CYP3A4.
    Atorvastatin: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as atorvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Atorvastatin; Ezetimibe: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as atorvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor for decreased efficacy of ergotamine if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ergotamine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Ergotamine is a CYP3A4 substrate and narrow therapeutic index drug.
    Canakinumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as siltuximab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Carbamazepine: (Moderate) Monitor carbamazepine concentrations and watch for decreased efficacy of carbamazepine if coadministration with siltuximab is necessary; adjust carbamazepine dosage as necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as carbamazepine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Carbamazepine is a substrate of both CYP1A2 and CYP3A4 and a narrow therapeutic index drug.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cisapride: (Moderate) Monitor for decreased efficacy of cisapride if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cisapride, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Cisapride is a CYP3A4 substrate and a narrow therapeutic index drug.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cyclosporine: (Moderate) Monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cyclosporine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Cyclosporine is a CYP3A4 substrate and a narrow therapeutic index drug.
    Desogestrel; Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Dextromethorphan; Quinidine: (Moderate) Monitor quinidine levels and adjust the dose of quinidine as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as quinidine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Quinidine is a CYP3A4 substrate and narrow therapeutic index drug.
    Dienogest; Estradiol valerate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Dihydroergotamine: (Moderate) Monitor for decreased efficacy of dihydroergotamine if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as dihydroergotamine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Dihydroergotamine is a CYP3A4 substrate and narrow therapeutic index drug.
    Drospirenone: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Drospirenone; Estetrol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Drospirenone; Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Drospirenone; Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Ergotamine: (Moderate) Monitor for decreased efficacy of ergotamine if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ergotamine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Ergotamine is a CYP3A4 substrate and narrow therapeutic index drug.
    Ergotamine; Caffeine: (Moderate) Monitor for decreased efficacy of ergotamine if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ergotamine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Ergotamine is a CYP3A4 substrate and narrow therapeutic index drug.
    Estradiol; Levonorgestrel: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Estradiol; Norethindrone: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Estradiol; Norgestimate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Ethinyl Estradiol; Norgestrel: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Ethosuximide: (Moderate) Monitor for reduced efficacy of ethosuximide, monitor drug concentrations, and adjust the dose of ethosuximide as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ethosuximide, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Ethosuximide is a CYP3A4 substrate and narrow therapeutic index drug.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Everolimus: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with siltuximab. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as everolimus, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Everolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Ezetimibe; Simvastatin: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as simvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Fentanyl: (Moderate) Monitor for evidence of reduced pain control or opioid withdrawal if fentanyl coadministration with siltuximab is necessary; fentanyl dosage adjustment may be needed. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fentanyl, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fentanyl is a CYP3A4 substrate and narrow therapeutic index drug.
    Fosphenytoin: (Moderate) Monitor fosphenytoin concentrations and watch for decreased efficacy of fosphenytoin if coadministration with siltuximab is necessary; adjust fosphenytoin dosage as necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fosphenytoin, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fosphenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
    Leuprolide; Norethindrone: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Levonorgestrel: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Live Vaccines: (Contraindicated) Do not administer live vaccines to siltuximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving siltuximab. Before initiation of siltuximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Siltuximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Lovastatin: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as lovastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Lovastatin; Niacin: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as lovastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Mestranol; Norethindrone: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor sirolimus levels and adjust the dose of sirolimus as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as sirolimus, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Sirolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Niacin; Simvastatin: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as simvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Norethindrone: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Norethindrone; Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Norgestimate; Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Norgestrel: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Oral Contraceptives: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Phenytoin: (Moderate) Monitor phenytoin concentrations and watch for decreased efficacy of phenytoin if coadministration with siltuximab is necessary; adjust phenytoin dosage as necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as phenytoin, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Phenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
    Pimozide: (Moderate) Monitor for an altered patient response to pimozide if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as pimozide, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Pimozide a substrate of both CYP2D6 and CYP3A4 and narrow therapeutic index drug.
    Quinidine: (Moderate) Monitor quinidine levels and adjust the dose of quinidine as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as quinidine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Quinidine is a CYP3A4 substrate and narrow therapeutic index drug.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Rivaroxaban: (Moderate) Monitor for a decrease in efficacy of rivaroxaban if used with siltuximab. Until more data are available, consider using an anticoagulant without dependence on CYP450 enzymes for metabolism (e.g., heparins, edoxaban). The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. It is expected that the activity of CYP450 enzymes could increase to normal concentrations during treatment with an IL-6 antagonist such as siltuximab; these effects on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes [including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4]. Rivaroxaban is a substrate for CYP3A4/5.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Caution is warranted when siltuximab is used in patients taking CYP3A4 substrates, such as oral contraceptives, in which a decreased effect would be undesirable. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Simvastatin: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as simvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Simvastatin; Sitagliptin: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as simvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
    Sirolimus: (Moderate) Monitor sirolimus levels and adjust the dose of sirolimus as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as sirolimus, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Sirolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Tacrolimus: (Moderate) Monitor tacrolimus levels and adjust the dose of tacrolimus as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tacrolimus, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tacrolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Theophylline, Aminophylline: (Moderate) Monitor drug concentrations and watch for decreased efficacy of aminophylline or theophylline if coadministration with siltuximab is necessary; a dosage increase of these methylxanthines may be necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Aminophylline and Theophylline are CYP1A2 substrates and narrow therapeutic index drugs.
    Thioridazine: (Moderate) Monitor for an altered patient response to thioridazine if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as thioridazine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Thioridazine is a CYP2D6 substrate and narrow therapeutic index drug.
    Tizanidine: (Moderate) Monitor for reduced efficacy of tizanidine if coadministered with siltuximab. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tizanidine, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tizanidine is a CYP1A2 substrate and narrow therapeutic index drug.
    Warfarin: (Moderate) Monitor the INR if siltuximab is coadministered with warfarin due to the potential for decreased warfarin efficacy; adjust the dose of warfarin as necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as warfarin, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab.

    PREGNANCY AND LACTATION

    Pregnancy

    Based on findings in animal reproduction studies, siltuximab may cause fetal harm when administered during human pregnancy. There are no available data on siltuximab use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Females of reproductive potential should avoid pregnancy during siltuximab therapy. Advise pregnant women of the potential fetal risk. Monoclonal antibodies appear to cross via the placenta. In cynomolgus monkey reproduction studies, siltuximab administration during organogenesis resulted in fetal serum concentrations that were similar to maternal concentrations at exposures above those occurring at the maximum recommended human dose of 11 mg/kg given every 3 weeks.

    Because of the potential for serious adverse reactions in the breast-fed child, including gastrointestinal perforation, breast-feeding is not recommended during situximab treatment and for 3 months after the last dose. There are no data on the presence of situximab in human milk, the effects on the breast-fed child, or the effects on milk production.[57062]

    MECHANISM OF ACTION

    Siltuximab is a human-mouse chimeric monoclonal antibody that binds human interleukein-6 (IL-6) and prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors. IL-6 is a proinflammatory cytokine and overproduction of IL-6 has been linked to systemic manifestations in patients with multicentric Castleman disease (MCD).

    PHARMACOKINETICS

    Siltuximab is administered intravenously (IV). The pharmacokinetic profile is a linear two-compartment intravenous model with first-order elimination. Based on population pharmacokinetic analyses, the volume of distribution in a male patient weighing 70 kg was 4.5 L (coefficient of variance (CV), 20%), the clearance was 0.23 L/day (CV, 51%), and the terminal half-life after the first IV infusion was 20.6 days (range, 14.2 to 29.7 days).
     
    Affected cytochrome P450 isoenzymes: CYP3A4
    Siltuximab has not been evaluated in in vitro or in vivo drug interaction studies. However, inhibition of IL-6 signaling may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates. If siltuximab is administered with a CYP450 substrate with a narrow therapeutic index (e.g., warfarin, cyclosporine, theophylline), therapeutic drug monitoring is recommended and a dose adjustment of the CYP450 substrate may be necessary. Use siltuximab with caution in patients who are receiving a CYP3A4 substrate in which a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).

    Intravenous Route

    In patients with multicentric Castleman disease, the steady-state mean Cmax value was 332 micrograms (mcg)/mL (coefficient of variance (CV), 42%) and the mean Cmin value was 84 mcg/mL (CV, 78%) following siltuximab 11 mg/kg IV over 1 hour once every 3 weeks. Steady state levels are achieved by the sixth infusion following siltuximab IV once every 3 week dosing; it accumulates about 1.7-fold compared to a single dose. Siltuximab demonstrates approximately dose proportional pharmacokinetics over the dose range of 2.8 to 11 mg/kg.