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Apr.09.2020

Siltuximab

Indications/Dosage

Labeled

  • multicentric Castleman disease

Off-Label

    † Off-label indication

    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.[57062] 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.[59439]

    Therapeutic Drug Monitoring

    Management of Treatment-Related Toxicity

    Hematologic Toxicity

    Verify that the absolute neutrophil count (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 g/dL prior to giving the next siltuximab dose. Delay therapy until the hematologic criteria are met; do not reduce the siltuximab dose.[57062]

    Maximum Dosage Limits

    • 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.

    Patients with Hepatic Impairment Dosing

    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).[57062]

    Patients with Renal Impairment Dosing

    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.[57062]

    † Off-label indication
    Revision Date: 04/09/2020, 12:17:25 PM

    References

    57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.59439 - van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 2014;15(9):966-974.

    How Supplied

    Siltuximab Lyophilisate for solution for injection

    Sylvant 100mg Powder for Injection (73090-0420) (EUSA Pharma (UK) Ltd) null

    Siltuximab Lyophilisate for solution for injection

    Sylvant 100mg Powder for Injection (57894-0420) (EUSA Pharma (US) LLC) null

    Siltuximab Lyophilisate for solution for injection

    Sylvant 100mg Powder for Injection (57894-0420) (Janssen Biotech, Inc.) (off market)

    Siltuximab Lyophilisate for solution for injection

    Sylvant 400mg Powder for Injection (73090-0421) (EUSA Pharma (UK) Ltd) null

    Siltuximab Lyophilisate for solution for injection

    Sylvant 400mg Powder for Injection (57894-0421) (EUSA Pharma (US) LLC) null

    Siltuximab Lyophilisate for solution for injection

    Sylvant 400mg Powder for Injection (57894-0421) (Janssen Biotech, Inc.) (off market)

    Description/Classification

    Description

    Siltuximab is an interleukin-6 antagonist indicated for the treatment of adult patients with multicentric Castleman disease who are human immunodeficiency virus-negative and human herpesvirus-8-negative. Monitor patients for signs and symptoms of an infection; do not start siltuximab in patients with a severe active infection. Severe infusion-related reactions may occur; therefore, administer siltuximab in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.[57062]

    Classifications

    • Antineoplastic and Immunomodulating Agents
      • Antineoplastics
        • Antineoplastic Monoclonal Antibodies
          • Immunomodulatory Monoclonal Antibodies
            • Antineoplastic Monoclonal Antibodies Targeting Interleukin 6 (IL-6)
    Revision Date: 04/21/2023, 04:24:15 PM

    References

    57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Route-Specific 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.[57062]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

    Siltuximab

    pH Range
    pH is approximately 5.2 (reconstituted).
    ReferencesSylvant (siltuximab) injection package insert. Horsham, PA. Janssen Biotech, Inc. 2019; Dec
      Revision Date: 01/06/2017, 04:23:50 PMCopyright 2004-2023 by Lawrence A. Trissel. All Rights Reserved.

      References

      57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.

      Adverse Reactions

      Mild

      • abdominal pain
      • back pain
      • diarrhea
      • dizziness
      • flushing
      • gastroesophageal reflux
      • headache
      • infection
      • maculopapular rash
      • nausea
      • pharyngitis
      • pruritus
      • rash
      • skin hyperpigmentation
      • vomiting
      • weight gain
      • xerosis

      Moderate

      • antibody formation
      • chest pain (unspecified)
      • constipation
      • edema
      • erythema
      • hypercholesterolemia
      • hypertension
      • hypertriglyceridemia
      • hyperuricemia
      • hypotension
      • infusion-related reactions
      • neutropenia
      • oral ulceration
      • palpitations
      • psoriasis
      • thrombocytopenia

      Severe

      • anaphylactoid reactions
      • cytokine release syndrome
      • edema
      • GI perforation
      • hyperuricemia
      • hypotension
      • infection
      • infusion-related reactions
      • maculopapular rash
      • nephrotoxicity
      • rash
      • thrombocytopenia
      • weight gain

      Dermatologic adverse events that were reported more often in patients with multicentric Castleman disease who received siltuximab plus best supportive care (BSC) (n = 53) compared with placebo plus BSC (n = 26) in a randomized, phase 2 study included rash (28% vs. 12%; grade 3 or 4, 2% vs. 0%), pruritus (28% vs. 8%), skin hyperpigmentation (4% vs. 0%), eczema (4% vs. 0%), psoriasis (4% vs. 0%), and xerosis (4% vs. 0%). Rash included generalized rash, maculopapular rash, and pruritic rash.[57062]

      Infection has been reported with siltuximab therapy. Monitor patients closely for signs or symptoms of infection during therapy. If an infection develops, start anti-infective therapy and hold siltuximab until the infection resolves. Lower respiratory tract infection (8% vs. 4%; grade 3 or 4, 4% vs. 4%) and upper respiratory tract infection (26% vs. 15%; grade 3 or 4, 2% vs. 4%) were reported more often in patients with multicentric Castleman disease (MCD) who received siltuximab plus best supportive care (BSC) (n = 53) compared with placebo plus BSC (n = 26) in a randomized, phase 2 study. Additionally, naso-pharyngitis and urinary tract infection have been reported commonly in patients with MCD who received siltuximab in clinical studies.[57062]

      Hematologic adverse events have been reported in patients who received siltuximab in clinical trials. Monitor complete blood counts prior to each dose for the first 12 months of therapy and then every 3 dosing cycles thereafter. After the first dose of therapy, 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 each siltuximab dose. Thrombocytopenia was reported in 9% of patients who received siltuximab plus best supportive care (BSC) (n = 53) compared with 4% of patients with multicentric Castleman disease (MCD) who received placebo plus BSC (n = 26) in a randomized, phase 2 study; grade 3 or 4 thrombocytopenia occurred in 4% of siltuximab-treated patients. Additionally, neutropenia has been reported commonly in patients with MCD who received siltuximab in clinical studies.[57062]

      Edema was reported in 26% of patients with multicentric Castleman disease who received siltuximab plus best supportive care (BSC) (n = 53) and 27% of patients who received placebo plus BSC (n = 26) in a randomized, phase 2 study; grade 3 or 4 edema occurred in 8% and 0% of patients, respectively.[57062]

      Gastrointestinal (GI) adverse events such as abdominal pain, diarrhea, gastroesophageal reflux disease, nausea, mouth/oral ulceration, and vomiting have been reported commonly in patients with multicentric Castleman disease (MCD) who received siltuximab in clinical studies. Additionally, GI perforation has been reported with siltuximab use. Promptly evaluate patients who have symptoms suggestive of GI perforation. Constipation (8% vs. 4%) and oropharyngeal pain (8% vs. 4%) were reported more often in patients with MCD who received siltuximab plus best supportive care (BSC) (n = 53) compared with placebo plus BSC (n = 26) in a randomized, phase 2 study.[57062]

      Metabolic adverse events that were reported more often in patients with multicentric Castleman disease who received siltuximab plus best supportive care (BSC) (n = 53) compared with placebo plus BSC (n = 26) in a randomized, phase 2 study included hypertriglyceridemia (8% vs. 0%), hypercholesterolemia (4% vs. 0%), hyperuricemia (11% vs. 0%; grade 3 or 4, 2% vs. 0%) and weight gain (19% vs. 0%; grade 3 or 4, 2% vs. 0%).[57062]

      Headache was reported in 8% of patients with multicentric Castleman disease (MCD) who received siltuximab plus best supportive care (BSC) (n = 53) compared with 4% of patients who received placebo plus BSC (n = 26) in a randomized, phase 2 study. Additionally, dizziness has been reported commonly in patients with MCD who received siltuximab in clinical studies.[57062]

      Hypotension was reported in 4% of patients with multicentric Castleman disease (MCD) who received siltuximab plus best supportive care (BSC) (n = 53) compared with 0% of patients who received placebo plus BSC (n = 26) in a randomized, phase 2 study; grade 3 or 4 hypotension occurred in 2% of siltuximab-treated patients. Additionally, hypertension has been reported commonly in patients with MCD who received siltuximab in clinical studies.[57062]

      Hypersensitivity reactions including anaphylactoid reactions have been reported with siltuximab therapy. One of 945 patients who received siltuximab in clinical studies experienced an anaphylactic reaction. If anaphylaxis, severe allergic reactions, or cytokine release syndrome occurs during therapy, immediately stop the siltuximab infusion and do not resume therapy.[57062]

      Infusion-related reactions were reported in 5.1% of patients who received single-agent siltuximab in clinical studies (n = 254); 0.8% of patients experienced grade 3 or 4 infusion-related reactions. Symptoms may include back pain, chest pain (unspecified) or discomfort, nausea, vomiting, flushing, erythema, and palpitations. Interrupt the siltuximab infusion for mild or moderate infusion-related reactions; therapy may be resumed at a lower 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. Infusion-related or hypersensitivity reactions were reported in 6.3% of patients treated with siltuximab in a long-term safety trial (n = 19); grade 3 or 4 reactions occurred in 1.3% of these patients.[57062

      Antibody formation has been reported in 0.9% of patients who received siltuximab in clinical trials (n = 432). None of 243 patients who were evaluated using the antigen-bridging enzyme immunoassay method experienced an anti-therapeutic antibody (ATA) response. However, 4 of 189 patients evaluated using the electrochemiluminescence-based immunoassay method tested positive for ATA; none of these patients had neutralizing antibodies.[57062]

      Nephrotoxicity, specifically renal impairment, was reported in 8% of patients with multicentric Castleman disease who received siltuximab plus best supportive care (BSC) (n = 53) compared with 0% of patients who received placebo plus BSC (n = 26) in a randomized, phase 2 study.[57062]

      Revision Date: 04/08/2020, 04:45:39 PM

      References

      57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • breast-feeding
      • contraception requirements
      • diverticulitis
      • GI perforation
      • infants
      • infection
      • infusion-related reactions
      • neonates
      • neutropenia
      • peptic ulcer disease
      • pregnancy
      • reproductive risk
      • thrombocytopenia
      • vaccination

      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.[57062]

      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.[57062]

      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.[57062]

      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.[57062]

      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.[57062]

      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.[57062]

      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.[57062]

      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]

      Revision Date: 12/01/2020, 12:30:26 PM

      References

      57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.

      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).[57062]

      Revision Date: 04/09/2020, 12:10:28 PM

      References

      57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.

      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).[57062]

      Route-Specific Pharmacokinetics

      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.[57062]

      Special Populations

      Hepatic Impairment

      Mild or moderate hepatic impairment did not significantly affect the apparent clearance of siltuximab in a population pharmacokinetic (PK) analysis (n = 377); the influence of severe hepatic impairment on the PK parameters of siltuximab has not been evaluated. In this analysis, 72 patients with mild pre-existing hepatic impairment (Child-Pugh class A) and 3 patients with moderate pre-existing hepatic impairment (Child-Pugh class B) were compared with 302 patients who had normal hepatic function.[57062]

      Renal Impairment

      Renal impairment did not significantly affect the apparent clearance of siltuximab in a population pharmacokinetic (PK) analysis (n = 377); the influence of end-stage renal disease (ESRD) on the PK parameters of siltuximab cannot be determined because only 1 patient had ESRD. In this analysis, 122 patients with mild pre-existing renal impairment (creatinine clearance (CrCl), 60 to 89 mL/min), 75 patients with moderate pre-existing renal impairment (CrCl, 30 to 59 mL/min), and 3 patients with severe pre-existing renal impairment (CrCl, 15 to 29 mL/min) were compared with 176 patients who had normal renal function (CrCl, 90 mL/min or greater).[57062]

      Geriatric

      Age (range, 18 to 85 years) did not affect siltuximab exposure in a population pharmacokinetic analysis (n = 378).[57062]

      Gender Differences

      Gender did not affect siltuximab exposure in a population pharmacokinetic analysis (females, n = 175; males, n = 203).[57062]

      Obesity

      Weight correlated with siltuximab clearance in a population pharmacokinetic analysis (n = 378); therefore, weight-based dosing is appropriate.[57062]

      Revision Date: 01/30/2017, 03:35:34 PM

      References

      57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.

      Pregnancy/Breast-feeding

      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.[57062]

      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]

      Revision Date: 04/08/2020, 02:07:51 PM

      References

      57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.

      Interactions

      Level 1 (Severe)

      • Live Vaccines

      Level 2 (Major)

      • Canakinumab
      • Clozapine

      Level 3 (Moderate)

      • Alfentanil
      • Amlodipine; Atorvastatin
      • Apixaban
      • Atorvastatin
      • Carbamazepine
      • Cholera Vaccine
      • Cisapride
      • Cyclosporine
      • Desogestrel; Ethinyl Estradiol
      • Dextromethorphan; Quinidine
      • Dienogest; Estradiol valerate
      • Drospirenone
      • Drospirenone; Estetrol
      • Drospirenone; Estradiol
      • Drospirenone; Ethinyl Estradiol
      • Drospirenone; Ethinyl Estradiol; Levomefolate
      • Elagolix; Estradiol; Norethindrone acetate
      • Estradiol; Levonorgestrel
      • Estradiol; Norethindrone
      • Estradiol; Norgestimate
      • Ethinyl Estradiol; Norelgestromin
      • Ethinyl Estradiol; Norethindrone Acetate
      • Ethinyl Estradiol; Norgestrel
      • Ethosuximide
      • Ethynodiol Diacetate; Ethinyl Estradiol
      • Etonogestrel; Ethinyl Estradiol
      • Everolimus
      • Ezetimibe; Simvastatin
      • Fentanyl
      • Fosphenytoin
      • Leuprolide; Norethindrone
      • Levonorgestrel
      • Levonorgestrel; Ethinyl Estradiol
      • Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate
      • Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate
      • Lovastatin
      • Norethindrone
      • Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate
      • Norethindrone; Ethinyl Estradiol
      • Norethindrone; Ethinyl Estradiol; Ferrous fumarate
      • Norgestimate; Ethinyl Estradiol
      • Norgestrel
      • Oral Contraceptives
      • Phenytoin
      • Pimozide
      • Quinidine
      • Relugolix; Estradiol; Norethindrone acetate
      • Rivaroxaban
      • SARS-CoV-2 (COVID-19) vaccines
      • Segesterone Acetate; Ethinyl Estradiol
      • Simvastatin
      • Tacrolimus
      • Theophylline, Aminophylline
      • Thioridazine
      • Tizanidine
      • Warfarin
      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. [57062] 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. [57062] 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. [52739] [57062] [65210] 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. [57062] 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. [41378] 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. [57062] 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. [60871] 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. [57062] 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. [28262] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] Levonorgestrel; 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. [57062] 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. [43236] [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [44854] [57062] [65210] 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. [65107] [66080] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [57062] 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. [28549] [57062]
      Revision Date: 09/20/2023, 01:32:00 AM

      References

      28262 - Clozaril (clozapine) tablets package insert. Rosemont, PA: HLS Therapeutics (USA), Inc.; 2023 May.28549 - Coumadin (warfarin tablets) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2017 Aug.41378 - Ilaris (canakinumab) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2023 Aug.43236 - National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011;60(2):1-64.44854 - Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2023 Feb.52739 - Eliquis (apixaban) package insert. Bristol-Myers Squibb Company; Princeton, NJ. 2021 Apr.57062 - Sylvant (siltuximab) injection package insert. Hertfordshire, U.K.: EUSA Pharma (UK), Ltd.; 2019 Dec.60871 - Vaxchora (Cholera Vaccine, live, oral) package insert. Redwood City, CA: Emergent Travel Health Inc.; 2022 Dec.65107 - Kroger A, Bahta L, Hunter P. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP).Available on the world wide web at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Revised April 27, 2022. Accessed on July 14, 2022.65210 - University of Liverpool. COVID-19 Drug Interactions. Retrived April 6, 2020. Available on the World Wide Web at https://www.covid19-druginteractions.org/.66080 - Food and Drug Administration (FDA). Fact Sheet for Healthcare Providers Administering Vaccine: Emergency Use Authorization (EUA) of Pfizer-BioNTech COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19) for 12 years and older. Purple cap and purple border. Retrieved November 22, 2022.

      Monitoring Parameters

      • CBC with differential

      US Drug Names

      • Sylvant
      ;