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siltuximab
Siltuximab is a chimeric monoclonal antibody to IL-6 that prevents binding of IL-6 to both soluble and membrane-bound IL-6 receptors, inhibiting formation of a signalling complex with gp130 on the cell surface. IL-6 is a pro-inflammatory cytokine produced by many cell types, including malignant cells.
Limited extravascular tissue distribution
Antibodies are degraded into small peptides and amino acids via catabolism.
No formal studies have been conducted.
| Half-life | 16 days (following single-dose) |
The treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpes virus-8 (HHV-8)-negative.
Emetogenic Potential:
Extravasation Potential: None
Adverse effects reported were mainly from a pooled analysis of the randomized, phase 2 study and the phase 1 study comparing siltuximab to placebo, where the incidence was higher than placebo.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Hypertension (13%) | E | |||
| Hypotension (4%) | E | ||||
| Dermatological | Rash (23%) | E | |||
| Skin hyperpigmentation (6%) | E | ||||
| Gastrointestinal | Abdominal pain (16%) | E | |||
| Constipation (12%) | E | ||||
| Diarrhea (26%) | E | ||||
| Gastroesophageal reflux disease (5%) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (4%) | E | ||||
| Nausea, vomiting (18%) | E | ||||
| General | Edema - limbs (26%) | E | |||
| Fever (11%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (13%) (including atypical infection; may be severe) | E | |||
| Other (1.2%) (polycythemia) | E | ||||
| Hepatobiliary | ↑ LFTs (10%) | E | |||
| Hypersensitivity | Hypersensitivity (1.5%) (severe) | I E | |||
| Infection | Infection (38%) (including atypical) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (13%) (decreased K, Ca, Mg, Na) | E | |||
| ↑ Cholesterol (9%) | E | ||||
| Hyperuricemia (15%) | E | ||||
| ↑ Triglycerides (13%) | E | ||||
| Musculoskeletal | Musculoskeletal pain (12%) | E | |||
| Nervous System | Dizziness (9%) | E | |||
| Headache (13%) | E | ||||
| Peripheral neuropathy (22%) | E | ||||
| Syncope (4%) | E | ||||
| Ophthalmic | Blurred vision (6%) | E | |||
| Renal | Creatinine increased (12%) | E | |||
| Vascular | Hot flashes (17%) (night sweats) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for siltuximab include infection, diarrhea, edema - limbs, rash, peripheral neuropathy, nausea, vomiting, hot flashes, abdominal pain, hyperuricemia and ↑ triglycerides.
Serious infections have been reported with siltuximab, including pneumonia and sepsis. The drug may mask signs and symptoms of acute inflammation, including fever and elevated C-reactive protein. Patients should be monitored closely and infections should be treated promptly.
Infusion-related reactions were reported in 7.5% of patients in the clinical study. Mild to moderate reactions may improve by slowing or stopping the infusion temporarily. Consider pre-medication with antihistamines, acetaminophen and corticosteroids prior to the next infusion.
GI perforation was reported in other clinical trials, but not in MCD trials. Use with caution in patients at risk.
Hypertriglyceridemia and hypercholesterolemia have been reported. Patients who develop these should be managed according to clinical guidelines.
Refer to protocol by which patient is being treated. Patients should be tested to confirm they are not HIV or HHV-8 positive before starting treatment. Infections, including localized ones should be treated prior to starting siltuximab.
Do not initiate treatment until ANC ≥ 1.0 x 109/L, platelets ≥ 75 x 109/L and hemoglobin is < 170 g/L.
Dose reduction is not recommended. Doses may be delayed for toxicity for up to 3 weeks (van Rhee 2014).
| Toxicity | Action |
| ANC < 1 x 109/L or platelets < 50 x 109/L | Hold* until recovery |
| Severe infection or non-hematologic toxicity | Hold* until recovery |
| Mild to moderate infusion-related reaction | Slow or hold infusion until recovery and treat. Consider pre-medication** prior to the next infusion. |
| Severe infusion-related reaction, anaphylaxis or cytokine-release syndrome | Discontinue and manage appropriately. |
*Do not retreat until ANC ≥ 1 x 109/L, platelets ≥ 50 x 109/L, non-hematologic toxicity ≤ grade 2 or baseline
**Antihistamine, acetaminophen and corticosteroids
No formal studies have been conducted. Mild to moderate hepatic impairment had no significant effect on siltuximab pharmacokinetics.
No formal studies have been conducted. Mild to moderate renal impairment had no significant effect on siltuximab pharmacokinetics.
No major age-related changes in pharmacokinetics or safety were observed in clinical studies, but these did not include sufficient numbers of patients aged 65 and older to determine the effect of age on efficacy.
No clinical effect on drug clearance was observed in population pharmacokinetic analyses.
No clinical effect on drug clearance was observed in population pharmacokinetic analyses.
Safety and efficacy have not been established in pediatric patients.
- Reconstitute with sterile water for injection as directed in the product monograph
- Gently swirl to mix; DO NOT shake or stir vigorously
- Do not use if visibly opaque particles are present and/or solution is discoloured
- Dilute reconstituted solution with D5W to the desired concentration
- Administer diluted solution over 1 hour using administration sets lined with PVC, PU or PE containing a 0.2-micron inline PES filter
- Diluted solution should be administered within 6 hours of preparation
- Siltuximab should be refrigerated between 2 to 8oC
- DO NOT freeze and protect from light
- Patients who have a hypersensitivity to this drug or any of its components
Other Warnings/Precautions:
- Live, attenuated vaccines should not be given concurrently or within 4 weeks of starting treatment.
- Clinical studies excluded patients with significant infections, including patients positive for hepatitis B surface antigen. Cases of reactivated hepatitis B have been reported when siltuximab was given with chemotherapy in multiple myeloma patients.
- Use with caution in patients who may be at risk of GI perforation.
Other Drug Properties:
- Carcinogenicity: Unknown
Pregnancy and Lactation:
- Embryotoxicity: Unknown
- Fetotoxicity: Unknown
- Teratogenicity: Unlikely
Siltuximab is not recommended for use in pregnancy unless the benefit clearly outweighs the risk. Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose.
As siltuximab can cross the placenta, exposed infants may be at increasd risk of infection; caution is advised in the administration of live vaccines.
- Excretion into breast milk: Probable
Breastfeeding is not recommended.
- Fertility effects: Unlikely
No formal drug interaction studies have been conducted. Binding of siltuximab to IL-6 may increase the metabolism of CYP450 subtrates.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↓ concentration and/or efficacy | ↑ metabolism of substrates | Caution with drugs with narrow therapeutic index; monitor closely |
| CYP 2C9 substrates (e.g. warfarin, meloxicam, fluvastatin) | ↓ concentration and/or efficacy | ↑ metabolism of substrates | Caution with drugs with narrow therapeutic index; monitor closely |
| Oral contraceptives | ↓ concentration and/or efficacy | ↑ metabolism | Caution; consider alternative method of contraception |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC | Baseline and before each dose for the first 12 months and every 3 cycles thereafter |
Liver and renal function tests | Baseline and as clinically indicated |
Blood pressure | Baseline and as clinically indicated |
Cholesterol and triglycerides | Baseline and periodic |
Clinical toxicity assessment for infection, bleeding, infusion-related reactions, GI effects | At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Hepatitis B serology | Especially in patients at risk of reactivation |
Siltuximab product monograph. Janssen Inc. January 6, 2016.
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 Aug;15(9):966-74.
October 2017 added public funding information
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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