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TRANSFORMAR COMO VOCÊ USA INFORMAÇÕES SOBRE DROGAS
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NOTE: The FDA has designated siltuximab as an orphan drug for Castleman disease.
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]
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]
11 mg/kg IV.
11 mg/kg IV.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
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]
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 indicationSiltuximab 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]
For storage information, see the specific product information within the How Supplied section.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Reconstitution:
Dilution:
Intravenous Infusion:
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]
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. Neonates and infants born to pregnant persons 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]
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: 12/17/2024, 02:01:00 AMSiltuximab 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]
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]
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 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]
Age (range, 18 to 85 years) did not affect siltuximab exposure in a population pharmacokinetic analysis (n = 378).[57062]
Gender did not affect siltuximab exposure in a population pharmacokinetic analysis (females, n = 175; males, n = 203).[57062]
Weight correlated with siltuximab clearance in a population pharmacokinetic analysis (n = 378); therefore, weight-based dosing is appropriate.[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]
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]
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