Siltuximab

Registered South African indications:

• Treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpesvirus-8 (HHV-8)-negative

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

South African recommendations

Caution in the following patient groups

• Renal impairment
• Hepatic impairment
• Women of childbearing potential

Concurrent active serious infections

• Treat pre-existing infections (including localised ones) before starting siltuximab, as serious infections like pneumonia and sepsis have been observed in studies. Siltuximab may also mask signs and symptoms of acute inflammation (e.g. suppressing fever and C-reactive protein), requiring diligent monitoring to detect serious infections

Vaccinations

• Live, attenuated vaccines must not be given concurrently or within 4 weeks before initiating siltuximab, as the safety is unknown and the medicine's mechanism (IL-6 inhibition) may interfere with the normal immune response to the vaccine antigens

Lipid parameters

• Elevations in triglycerides and cholesterol have been observed; patients should be managed according to current clinical guidelines for hyperlipidaemia

Infusion-related reactions and hypersensitivity

• Mild to moderate infusion reactions may occur and can be managed by reinitiating the infusion at a lower rate after the reaction resolves, potentially with antihistamines, acetaminophen, and corticosteroids. Siltuximab must be discontinued if the patient does not tolerate the infusion after these interventions, or immediately if a severe hypersensitivity reaction (e.g. anaphylaxis) occurs. Personnel and medicine for treating anaphylaxis must be readily available

Malignancy

• Siltuximab may theoretically increase the risk of malignancy, though current limited data do not definitively suggest an increased risk

Gastrointestinal perforation

• Use siltuximab with caution in patients who are at increased risk for gastrointestinal (GI) perforation, as this has been reported in clinical trials. Patients who present with symptoms suggestive of GI perforation should be promptly evaluated

Effects on ability to drive and use machines

• No studies of the effects on the ability to drive and use machines have been performed. Siltuximab has no or negligible influence on the ability to drive and use machines

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpesvirus-8 (HHV-8)-negative

• IV: 11mg/kg, as an infusion over 1hr; Administer: Every 3 weeks until treatment failure; Haematology laboratory tests should be performed prior to each dose of siltuximab therapy for the first 12 months and every 3 dosing cycles thereafter; Consider delaying treatment if the treatment criteria outlined in the table below are not met, before admin. siltuximab; Dose reduction is not recommended

Treatment Criteria
Laboratory parameter	Requirements before first siltuximab administration	Retreatment criteria
Absolute Neutrophil Count	≥ 1.0 × 109/L	≥ 1.0 × 109/L
Platelet count	≥ 75 × 109 /L	≥ 50 × 109/L
Haemoglobina	< 170 g/L	< 170 g/L

^aSiltuximab may increase haemoglobin levels in MCD patients

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Siltuximab therapy should be withheld if the patient has a severe infection or any severe nonhaematological toxicity and can be restarted at the same dose after recovery

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If the patient develops a severe infusion related reaction, anaphylaxis, severe allergic reaction, or cytokine release syndrome related to siltuximab infusion, further administration of siltuximab should be discontinued. Discontinuing siltuximab should be considered if there are more than 2 dose delays due to toxicities related to the treatment during the first 48 weeks

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Method of administration
Intravenous infusion (IV) of siltuximab should be administered by qualified healthcare professionals
For instructions on reconstitution and dilution of the medicinal product before administration, see Additional Prescribing Points

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• There are no data from the use of siltuximab in pregnant women. Studies in animals with siltuximab have shown no adverse effect on pregnancy or on embryofetal development
• The safety of siltuximab in pregnancy has not been established and is therefore contraindicated in pregnancy
• It is not known whether siltuximab can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Doctors should also exercise caution when siltuximab is administered with CYP3A4 substrates where a decrease in effectiveness would be undesirable e.g. oral contraceptives (see Interactions)
• Siltuximab crosses the placenta, as was observed in studies in monkeys. Consequently, infants born to women treated with siltuximab may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants

Women of childbearing potential

• Women of childbearing potential must use effective contraception during and up to 3 months after treatment

Breastfeeding

South African recommendations

• Contraindicated
• The safety of siltuximab in lactation has not been established. Women should not breastfeed their babies while taking siltuximab
• It is not known whether siltuximab or its metabolites are excreted in human milk

Fertility

South African recommendations

• Effects of siltuximab on fertility have not been evaluated in humans. Available non-clinical data do not suggest an effect on fertility under siltuximab treatment

South African recommendations

• Caution; no information available
  No formal studies have been conducted to investigate the pharmacokinetics of siltuximab in patients with renal impairment

South African recommendations

• Caution; no information available
  No formal studies have been conducted to investigate the pharmacokinetics of siltuximab in patients with hepatic impairment
  Following treatment with siltuximab in clinical trials, transient or intermittent mild-to-moderate elevation of hepatic transaminases or other liver function tests such as bilirubin have been reported
  Siltuximab-treated patients with known hepatic impairment as well as patients with elevated transaminase or bilirubin levels should be monitored

South African recommendations

• No dose adjustment recommended
  No major age-related differences in pharmacokinetic (PK) or in safety profile were observed in clinical studies. No dose adjustment is required

Infections and Infestations

Very common

• Upper respiratory tract infection
• Urinary tract infection
• Nasopharyngitis

Blood and Lymphatic System Disorders

Very common

• Neutropenia
• Thrombocytopenia

Immune System Disorders

Common

• Anaphylactic reaction

Metabolism and Nutrition Disorders

Very common

• Hypertriglyceridaemia
• Hyperuricaemia

Common

• Hypercholesterolaemia

Nervous System Disorders

Very common

• Dizziness
• Headache

Respiratory, Thoracic and Mediastinal Disorders

Very common

• Oropharyngeal pain

Vascular Disorders

Very common

• Hypertension

Gastrointestinal Disorders

Very common

• Nausea
• Abdominal pain
• Vomiting
• Constipation
• Diarrhoea
• Gastroesophageal reflux disease
• Mouth ulceration

Skin and Subcutaneous Tissue Disorders

Very common

• Rash
• Pruritus
• Eczema

Musculoskeletal and Connective Tissue Disorders

Very common

• Arthralgia
• Pain in extremity

Renal and Urinary Disorders

Very common

• Renal impairment

General Disorders and Administration Site Conditions

Very common

• Localised oedema

Investigations

Very common

• Increased weight

• CYP450 substrates (with a narrow therapeutic index)
• Warfarin
• Ciclosporin
• Theophylline
• Oral contraceptives

• Haematology profile (absolute neutrophil count, platelet count, haemoglobin)
  - Prior to each dose of siltuximab therapy for the first 12 months and every 3 dosing cycles thereafter
• Hepatic function
• Lipid profile (triglycerides and cholesterol)

Additional Observations

• Infections
  - Monitor patients receiving treatment in order to detect serious infections (e.g., pneumonia, sepsis). Siltuximab may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP). Treatment should be withheld if the patient has a severe infection until the infection resolves
• Gastrointestinal perforation
  - Use with caution in patients who may be at increased risk. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation
• Infusion-related reactions and hypersensitivity
  - During IV infusion, patients should be monitored. For mild to moderate reactions, slowing or stopping the infusion and therapeutic administration of antihistamines, acetaminophen, and corticosteroids may be considered. For severe reactions, anaphylaxis, severe allergic reaction, or cytokine release syndrome, further administration must be discontinued. Appropriate personnel and medicine should be available to treat anaphylaxis

Special precautions for disposal of a used medicine or waste materials derived from such medicine and other handling of the product

For single use only. Use aseptic technique.

• Calculate the dose, total volume of reconstituted siltuximab solution required and the number of vials needed. The recommended needle for preparation is 21 - gauge 1 - ½ inch (38mm). Infusion bags (250ml) must contain Dextrose 5% and must be made of polyvinyl chloride (PVC), or polyolefin (PO), or polypropylene (PP) or polyethylene (PE). Alternatively, PE bottles may be used
• Allow vial(s) of siltuximab to come to room temperature over approximately 30 minutes. Siltuximab should remain at room temperature for the duration of the preparation. For 100mg and 400mg vials: Each vial should/must be reconstituted as instructed in the table below

Reconstitution Instructions

Strength	Amount of Sterile Water for Injection, required for reconstitution	Post-reconstitution concentration
100mg vial	5.2ml	20mg/ml
400mg vial	20.0ml	20mg/ml

• Gently swirl (do not shake or vortex or swirl vigorously) the reconstituted vials to aid the dissolution of the lyophilised powder. Do not remove contents until all of the solids have been completely dissolved. The lyophilised powder should dissolve in less than 60 minutes. Inspect the vials for particulate matter and discolouration prior to dose preparation
• Do not use if visibly opaque or foreign particles and/or solution discolouration are present. Dilute the total volume of the reconstituted siltuximab solution dose to 250ml with sterile Dextrose 5%, by withdrawing a volume equal to the volume of reconstituted siltuximab from the Dextrose 5%, 250ml bag. Slowly add the total volume of reconstituted siltuximab solution to the 250ml infusion bag. Gently mix
• The reconstituted siltuximab should be kept for no more than two hours prior to addition into the IV bag. The infusion should be completed within 6 hours of the addition of the reconstituted solution to the infusion bag. Administer the diluted solution 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. Siltuximab does not contain preservatives; therefore, do not store any unused portion of the infusion solution for reuse
• No physical biochemical compatibility studies have been conducted to evaluate the co-administration of siltuximab with other agents. Do not infuse siltuximab concomitantly in the same intravenous line with other agents
• Any unused product or waste material should be disposed of in accordance with local requirements

Siltuximab is a chimeric (human murine) monoclonal antibody against human Interleukin-6 (IL 6) produced in a Chinese Hamster Ovary (CHO) cell line. Siltuximab forms stable complexes with soluble bioactive forms of human interleukin 6 (IL-6), thereby preventing the binding of human IL-6 to both soluble and membrane-bound IL-6 receptors (IL-6R), thus inhibiting several processes mediated by IL-6. This includes inhibition of immunoglobulin secretion, hepatic acute phase protein synthesis, and haematopoietic precursor cell proliferation and differentiation. Overproduction of IL-6, in chronic inflammatory diseases and malignancies, has been linked to anaemia and cachexia and has been hypothesised to play a central role in driving plasma cell proliferation and systemic manifestations in patients with Crohn’s disease (CD).