Sylvant
(Siltuximab)Dosage & Administration
For intravenous infusion only.
Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks. (
For intravenous infusion only.
Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks.
Administer SYLVANT 11 mg/kg over 1 hour as an intravenous infusion every 3 weeks until treatment failure.
Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in Table 1 are not met, consider delaying treatment with SYLVANT. Do not reduce dose.
| Laboratory parameter | Requirements before first SYLVANT administration | Retreatment criteria |
|---|---|---|
| Absolute Neutrophil Count | ≥1.0 × 109/L | ≥1.0 × 109/L |
| Platelet count | ≥75 × 109/L | ≥50 × 109/L |
| HemoglobinSYLVANT may increase hemoglobin levels in MCD patients | <17 g/dL | <17 g/dL |
Do not administer SYLVANT to patients with severe infections until the infection resolves.
Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.
Use aseptic technique for reconstitution and preparation of dosing solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit
1. Calculate the dose (mg), total volume (mL) of reconstituted SYLVANT solution required and the number of vials needed. A 21-gauge 1½ inch needle is recommended for preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of polyvinyl chloride (PVC), or polyolefin (PO), or polypropylene (PP), or polyethylene (PE). Alternatively PE bottles may be used.
2. Allow the vial(s) of SYLVANT to come to room temperature over approximately 30 minutes. SYLVANT should remain at room temperature for the duration of the preparation.
3. Aseptically reconstitute each SYLVANT vial as instructed in Table 2.
| Strength | Amount of Sterile Water for Injection, USP required for reconstitution | Post-reconstitution concentration |
|---|---|---|
| 100 mg vial | 5.2 mL | 20 mg/mL |
| 400 mg vial | 20 mL | 20 mg/mL |
Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes.
Once reconstituted, and prior to further dilution, inspect the vials for particulates and discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. The reconstituted product should be kept for no more than two hours prior to addition into the infusion bag.
4. Dilute the reconstituted SYLVANT solution dose to 250 mL with sterile Dextrose 5% in Water by withdrawing a volume equal to the total calculated volume of reconstituted SYLVANT from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted SYLVANT solution to the Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution.
5. Administer the diluted SYLVANT solution in 5% Dextrose in Water 250 mL by intravenous infusion over a period of 1 hour using administration sets lined with PVC, or polyurethane (PU), or PE, containing a 0.2-micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 hours of the dilution of the reconstituted solution to the infusion bag.
6. Do not infuse SYLVANT concomitantly in the same intravenous line with other agents.
7. SYLVANT does not contain preservatives. Do not store any unused portion of the reconstituted product or of the infusion solution. Waste material should be disposed of in accordance with local requirements.
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Sylvant Prescribing Information
SYLVANT is indicated for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
For intravenous infusion only.
Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks. (
For intravenous infusion only.
Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks.
Administer SYLVANT 11 mg/kg over 1 hour as an intravenous infusion every 3 weeks until treatment failure.
Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in Table 1 are not met, consider delaying treatment with SYLVANT. Do not reduce dose.
| Laboratory parameter | Requirements before first SYLVANT administration | Retreatment criteria |
|---|---|---|
| Absolute Neutrophil Count | ≥1.0 × 109/L | ≥1.0 × 109/L |
| Platelet count | ≥75 × 109/L | ≥50 × 109/L |
| HemoglobinSYLVANT may increase hemoglobin levels in MCD patients | <17 g/dL | <17 g/dL |
Do not administer SYLVANT to patients with severe infections until the infection resolves.
Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.
Use aseptic technique for reconstitution and preparation of dosing solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit
1. Calculate the dose (mg), total volume (mL) of reconstituted SYLVANT solution required and the number of vials needed. A 21-gauge 1½ inch needle is recommended for preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of polyvinyl chloride (PVC), or polyolefin (PO), or polypropylene (PP), or polyethylene (PE). Alternatively PE bottles may be used.
2. Allow the vial(s) of SYLVANT to come to room temperature over approximately 30 minutes. SYLVANT should remain at room temperature for the duration of the preparation.
3. Aseptically reconstitute each SYLVANT vial as instructed in Table 2.
| Strength | Amount of Sterile Water for Injection, USP required for reconstitution | Post-reconstitution concentration |
|---|---|---|
| 100 mg vial | 5.2 mL | 20 mg/mL |
| 400 mg vial | 20 mL | 20 mg/mL |
Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes.
Once reconstituted, and prior to further dilution, inspect the vials for particulates and discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. The reconstituted product should be kept for no more than two hours prior to addition into the infusion bag.
4. Dilute the reconstituted SYLVANT solution dose to 250 mL with sterile Dextrose 5% in Water by withdrawing a volume equal to the total calculated volume of reconstituted SYLVANT from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted SYLVANT solution to the Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution.
5. Administer the diluted SYLVANT solution in 5% Dextrose in Water 250 mL by intravenous infusion over a period of 1 hour using administration sets lined with PVC, or polyurethane (PU), or PE, containing a 0.2-micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 hours of the dilution of the reconstituted solution to the infusion bag.
6. Do not infuse SYLVANT concomitantly in the same intravenous line with other agents.
7. SYLVANT does not contain preservatives. Do not store any unused portion of the reconstituted product or of the infusion solution. Waste material should be disposed of in accordance with local requirements.
SYLVANT (siltuximab) for injection is available as:
- 100 mg of lyophilized powder in a single-dose vial for intravenous infusion.
- 400 mg of lyophilized powder in a single-dose vial for intravenous infusion.
Pregnancy: May cause fetal harm (
In an animal reproduction study, intravenous administration of a human antibody to IL-6 to pregnant monkeys from the onset of organogenesis through delivery caused functional impairment in pregnant animals and in the offspring. Siltuximab and the human antibody to IL-6 crossed the placenta in monkeys (
The estimated background risk for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Monoclonal antibodies are transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Infants born to pregnant women treated with SYLVANT may be at increased risk of infection. Consider the risks and benefits of administering live or live-attenuated vaccines to infants exposed to SYLVANT in utero
In an embryo-fetal development study in cynomolgus monkeys, pregnant animals received intravenous doses of siltuximab of 9.2 or 46 mg/kg/week during gestation days (GD) 20 to 118, which includes the period of organogenesis. Fetuses were evaluated on GD 140, approximately 25 days prior to the natural birth. Exposures at the low and high dose after the 25thadministration were approximately 3 and 7 times, respectively, the human exposure based on AUC in patients with MCD at the recommended dose of 11 mg/kg every three weeks. No maternal or fetal structural abnormalities were observed. However, siltuximab crossed the placenta at both doses and when measured on GD 140, fetal serum concentrations of siltuximab were similar to maternal concentrations. In a combined embryofetal and pre- and post-natal development study in cynomolgus monkeys, pregnant animals received intravenous doses of 10 or 50 mg/kg/week of a human antibody to IL-6 from GD 20 to natural delivery (GD 167). The offspring were evaluated up to 7 months after birth for developmental effects. No maternal or infant structural abnormalities were observed; however, globulin levels were decreased in pregnant animals (GD 34 through lactation day 30) and in the offspring (lactation days 30-120) at both doses.
Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT
SYLVANT may cause infusion related reactions and anaphylaxis. Approximately 945 patients have been treated with SYLVANT in clinical trials. Of these, one patient experienced an anaphylactic reaction. Data from 254 patients treated with SYLVANT monotherapy forms the basis of the safety evaluation of infusion related reactions. Infusion related reactions were reported in 5.1% of these patients. Two (0.8%) were Grade 3 or higher, and 1 (0.4%) was serious; none were fatal. Symptoms of infusion reactions consisted of back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations.
In long-term treatment of MCD patients with siltuximab at the recommended dosage of 11 mg/kg every 3 weeks, infusion related reactions or hypersensitivity reactions occurred at a frequency of 6.3% (1.3% for severe reactions).
Stop the infusion of SYLVANT if the patient develops signs of anaphylaxis. Discontinue further therapy with SYLVANT.
Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the SYLVANT infusion may be restarted at a lower infusion rate. Consider medication with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions
Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
- Concurrent Active Severe Infections: Do not administer SYLVANT to patients with severe infections, monitor for infections, institute prompt treatment, and interrupt SYLVANT until resolution of infection. (,
2 DOSAGE AND ADMINISTRATIONFor intravenous infusion only.
Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks.
2.1 Recommended DosageAdminister SYLVANT 11 mg/kg over 1 hour as an intravenous infusion every 3 weeks until treatment failure.
Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in Table 1 are not met, consider delaying treatment with SYLVANT. Do not reduce dose.
Table 1: Treatment Criteria Laboratory parameter Requirements before first SYLVANT administration Retreatment criteria Absolute Neutrophil Count ≥1.0 × 109/L ≥1.0 × 109/L Platelet count ≥75 × 109/L ≥50 × 109/L HemoglobinSYLVANT may increase hemoglobin levels in MCD patients <17 g/dL <17 g/dL Do not administer SYLVANT to patients with severe infections until the infection resolves.
Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.
2.2 Instructions for Preparation and AdministrationUse aseptic technique for reconstitution and preparation of dosing solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit
1. Calculate the dose (mg), total volume (mL) of reconstituted SYLVANT solution required and the number of vials needed. A 21-gauge 1½ inch needle is recommended for preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of polyvinyl chloride (PVC), or polyolefin (PO), or polypropylene (PP), or polyethylene (PE). Alternatively PE bottles may be used.
2. Allow the vial(s) of SYLVANT to come to room temperature over approximately 30 minutes. SYLVANT should remain at room temperature for the duration of the preparation.
3. Aseptically reconstitute each SYLVANT vial as instructed in Table 2.
Table 2: Reconstitution Instructions Strength Amount of Sterile Water for Injection, USP required for reconstitution Post-reconstitution concentration 100 mg vial 5.2 mL 20 mg/mL 400 mg vial 20 mL 20 mg/mL Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes.
Once reconstituted, and prior to further dilution, inspect the vials for particulates and discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. The reconstituted product should be kept for no more than two hours prior to addition into the infusion bag.
4. Dilute the reconstituted SYLVANT solution dose to 250 mL with sterile Dextrose 5% in Water by withdrawing a volume equal to the total calculated volume of reconstituted SYLVANT from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted SYLVANT solution to the Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution.
5. Administer the diluted SYLVANT solution in 5% Dextrose in Water 250 mL by intravenous infusion over a period of 1 hour using administration sets lined with PVC, or polyurethane (PU), or PE, containing a 0.2-micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 hours of the dilution of the reconstituted solution to the infusion bag.
6. Do not infuse SYLVANT concomitantly in the same intravenous line with other agents.
7. SYLVANT does not contain preservatives. Do not store any unused portion of the reconstituted product or of the infusion solution. Waste material should be disposed of in accordance with local requirements.
)5.1 Concurrent Active Severe InfectionsDo not administer SYLVANT to patients with severe infections until the infection resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive protein (CRP). Monitor patients receiving SYLVANT closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT until the infection resolves.
- Vaccinations: Do not administer live vaccines because IL-6 inhibition may interfere with the normal immune response to new antigens. ()
5.2 VaccinationsDo not administer live vaccines to patients or infants born to patients receiving SYLVANT because IL-6 inhibition may interfere with the normal immune response to new antigens
[see Use in Specific Populations (8.1)]. - Infusion Related Reactions: Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation. (,
5.3 Infusion Related Reactions and HypersensitivitySYLVANT may cause infusion related reactions and anaphylaxis. Approximately 945 patients have been treated with SYLVANT in clinical trials. Of these, one patient experienced an anaphylactic reaction. Data from 254 patients treated with SYLVANT monotherapy forms the basis of the safety evaluation of infusion related reactions. Infusion related reactions were reported in 5.1% of these patients. Two (0.8%) were Grade 3 or higher, and 1 (0.4%) was serious; none were fatal. Symptoms of infusion reactions consisted of back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations.
In long-term treatment of MCD patients with siltuximab at the recommended dosage of 11 mg/kg every 3 weeks, infusion related reactions or hypersensitivity reactions occurred at a frequency of 6.3% (1.3% for severe reactions).
Stop the infusion of SYLVANT if the patient develops signs of anaphylaxis. Discontinue further therapy with SYLVANT.
Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the SYLVANT infusion may be restarted at a lower infusion rate. Consider medication with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions
[see Adverse Reactions (6)].Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
)6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Study 1, in MCD, was an international, multicenter, randomized Phase 2 study of every 3 week infusions comparing SYLVANT and best supportive care (BSC) to placebo and BSC. There were 53 patients randomized to the SYLVANT arm at a dosage of 11 mg/kg and 26 patients randomized to the placebo arm. Of the 26 placebo-treated patients, 13 patients subsequently crossed-over to receive SYLVANT. The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The patients randomized to SYLVANT received a median of 19 infusions (range 1 to 50) compared to patients randomized to placebo who received a median of 8 infusions (range 2 to 32). To control for disparate exposure between arms, Table 3 reports the per patient incidence of adverse reactions that occurred during the first 8 infusions. Adverse reactions that occurred >3% in the SYLVANT arm are presented.
The most common adverse reactions (> 10% compared to placebo) during treatment with SYLVANT in the MCD clinical trial were rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia.
Table 3: Per Patient Incidence of Common Adverse Reactions in Study 1 During Initial 8 Infusions Body System/Adverse Reactions SYLVANT+BSCBest Supportive Care
n=53Placebo+BSC
n=26All Grades Grades 3-4 All Grades Grades 3-4 Skin disorders Rash (rash, rash generalized, rash maculo-papular, rash popular and rash pruritic) 15 (28%) 1 (2%) 3 (12%) 0 Pruritus 15 (28%) 0 2 (8%) 0 Skin hyperpigmentation 2 (4%) 0 0 0 Eczema 2 (4%) 0 0 0 Psoriasis 2 (4%) 0 0 0 Dry skin 2 (4%) 0 0 0 Infections Lower respiratory tract 4 (8%) 2 (4%) 1 (4%) 1 (4%) Upper respiratory tract 14 (26%) 1 (2%) 4 (15%) 1 (4%) Blood and lymphatic system disorders Thrombocytopenia 5 (9%) 2 (4%) 1 (4%) 1 (4%) General disorders Edema (general and localized) 14 (26%) 4 (8%) 7 (27%) 0 Gastrointestinal disorders Constipation 4 (8%) 0 1 (4%) 0 Metabolism Hypertriglyceridemia 4 (8%) 0 0 0 Hypercholesterolemia 2 (4%) 0 0 0 Hyperuricemia 6 (11%) 1 (2%) 0 0 Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 4 (8%) 0 1 (4%) 0 Renal and urinary disorders Renal impairment 4 (8%) 0 0 0 Nervous system disorders Headache 4 (8%) 0 1 (4%) 0 Investigations Weight increased 10 (19%) 1 (2%) 0 0 Vascular disorders Hypotension 2 (4%) 1 (2%)Anaphylactic reaction 0 0 Study CNTO328MCD2002 (referred to as Study 2) (NCT01400503) was an open label, long term extension study of patients with MCD treated on prior trials. The median duration of siltuximab treatment was 5.52 years (range: 0.8 to 10.8 years); more than 50% of patients received siltuximab treatment for ≥5 years. The rate of serious or Grade ≥3 adverse events did not increase over time as a function of cumulative exposure.
Other important adverse reactions reported in MCD clinical studies, all of which were very common, were:
Infections and infestations: nasopharyngitis, urinary tract infection
Blood and lymphatic system disorders: neutropenia
Nervous system disorders: dizziness
Vascular disorders: hypertension
Gastrointestinal disorders: nausea, abdominal pain, vomiting, diarrhea, gastroesophageal reflux disease, mouth ulceration
- Gastrointestinal (GI) perforation: Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation. ()
5.4 Gastrointestinal PerforationGastrointestinal (GI) perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation.