Siltuximab

SYLVANT is indicated for the treatment of adult patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.

This medicinal product should be administered by qualified healthcare professionals and under appropriate medical supervision. Posology The recommended dose is 11 mg/kg siltuximab given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure.

Treatment criteria Haematology laboratory tests should be performed prior to each dose of SYLVANT therapy for the first 12 months and every third dosing cycle thereafter. Before administering the infusion, the prescriber should consider delaying treatment, if the treatment criteria outlined in Table 1 are not met.

Dose reduction is not recommended. 6 mmol/L) a SYLVANT may increase haemoglobin levels in MCD patients The SYLVANT therapy should be withheld if the patient has a severe infection or any severe non-haematological toxicity and can be restarted at the same dose after recovery.

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

Special populations Elderly patients No major age-related differences in pharmacokinetics (PK) or in safety profile were observed in clinical studies. 2). 4). Paediatric population The safety and efficacy of siltuximab in children aged 17 years and younger have not been established.

No data are available. Method of administration Siltuximab must be administered as an intravenous infusion. 6.

Summary of the safety profile Infections (including upper respiratory tract infections), pruritus, rash, arthralgia, and diarrhoea were the most common adverse reactions , occurring in > 20% of siltuximab-treated patients in Castleman’s disease (CD) clinical studies.

The most serious adverse reaction associated with the use of siltuximab was anaphylactic reaction. Data from all patients treated with siltuximab monotherapy (n = 370) form the overall basis of the safety evaluation. 1). Tabulated list of adverse reactions Table 2 lists adverse reactions observed in MCD patients treated with siltuximab at the recommended dosage of 11 mg/kg every 3 weeks.

Within the system organ class, adverse reactions are listed under headings of frequency using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10000 and <1/1000); very rare (<1/10000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 8%) of patients treated with siltuximab monotherapy. 3% for severe reactions). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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AND CLINICAL USE ..................................................................................... 3 CONTRAINDICATIONS .......................................................................................................... 3 WARNINGS AND PRECAUTIONS .........................................................................................

3 ADVERSE REACTIONS ........................................................................................................... 7 DRUG INTERACTIONS .........................................................................................................

15 DOSAGE AND ADMINISTRATION ..................................................................................... 15 OVERDOSAGE .......................................................................................................................

17 ACTION AND CLINICAL PHARMACOLOGY ................................................................... 17 STORAGE AND STABILITY ................................................................................................. 19 SPECIAL HANDLING INSTRUCTIONS ..............................................................................

19 DOSAGE FORMS, COMPOSITION AND PACKAGING .................................................... 19 PART II: SCIENTIFIC INFORMATION .............................................................................. 21 PHARMACEUTICAL INFORMATION .................................................................................

21 CLINICAL TRIALS ................................................................................................................. 21 DETAILED PHARMACOLOGY ............................................................................................

24 TOXICOLOGY ........................................................................................................................ 27 REFERENCES .........................................................................................................................

31 PATIENT MEDICATION INFORMATION .......................................................................... 32 PrSYLVANT® siltuximab for injection Lyophilized powder for injection, for intravenous infusion 100 mg/vial and 400 mg/vial Interleukin-6 monoclonal antibody PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients Intravenous Sterile lyophilized powder for injection / 100 mg and 400 mg per vial None For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

INDICATIONS AND CLINICAL USE SYLVANT® (siltuximab) is indicated for: • 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.

Pediatrics:

The safety and efficacy of SYLVANT® have not been studied in pediatric patients. CONTRAINDICATIONS • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

2%], grade 3) has occurred during infusion with SYLVANT® in MCD studies. Appropriate personnel and medication should be available during infusion to treat anaphylaxis. g. anaphylaxis) (see WARNINGS AND PRECAUTIONS, Allergic and Infusion Reactions, and ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions).

Serious Infections Infections, including localized infections, should be treated prior to administration of SYLVANT®. Serious infections including pneumonia and sepsis were observed during clinical studies. SYLVANT® may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP).

Therefore, prescribers should diligently monitor patients receiving treatment in order to detect serious infections. Treat infections promptly, and do not administer further SYLVANT® until the infection resolves. Allergic and infusion reactions Anaphylaxis has occurred during infusion with SYLVANT® (see Anaphylaxis above).

5% of patients treated with SYLVANT® monotherapy vs. 0 % in the placebo group. During IV infusion of SYLVANT®, mild to moderate infusion reactions may improve following slowing of or stopping the infusion. 7% of patients in clinical trials required dose delay or interruption due to an infusion- related reaction.

The most common infusion related reactions reported in siltuximab-treated subjects (≥2 subjects) were pruritus, erythema, chest pain, and nausea. Upon resolution of the reaction, reinitiating the infusion at a lower infusion rate and therapeutic administration of antihistamines, acetaminophen, and corticosteroids may be considered.

8% were administered corticosteroids in association with an infusion-related reaction versus 0% in the placebo group. For patients who do not tolerate the infusion following these interventions, SYLVANT® should be discontinued. Carcinogenesis and Mutagenesis Immunomodulatory drugs may increase the risk of malignancy.

On the basis of limited experience with siltuximab the present data do not suggest any increased risk of malignancy. Cardiovascular Hypertension has been reported as an adverse event in siltuximab clinical trials in MCD patients […]

SYLVANT is indicated for the treatment of adult patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.

This medicinal product should be administered by qualified healthcare professionals and under appropriate medical supervision. Posology The recommended dose is 11 mg/kg siltuximab given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure.

Treatment criteria Haematology laboratory tests should be performed prior to each dose of SYLVANT therapy for the first 12 months and every third dosing cycle thereafter. Before administering the infusion, the prescriber should consider delaying treatment, if the treatment criteria outlined in Table 1 are not met.

Dose reduction is not recommended. 6 mmol/L) a SYLVANT may increase haemoglobin levels in MCD patients The SYLVANT therapy should be withheld if the patient has a severe infection or any severe non-haematological toxicity and can be restarted at the same dose after recovery.

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

Special populations Elderly patients No major age-related differences in pharmacokinetics (PK) or in safety profile were observed in clinical studies. 2). 4). Paediatric population The safety and efficacy of siltuximab in children aged 17 years and younger have not been established.

No data are available. Method of administration Siltuximab must be administered as an intravenous infusion. 6.

Summary of the safety profile Infections (including upper respiratory tract infections), pruritus, rash, arthralgia, and diarrhoea were the most common adverse reactions , occurring in > 20% of siltuximab-treated patients in Castleman’s disease (CD) clinical studies.

The most serious adverse reaction associated with the use of siltuximab was anaphylactic reaction. Data from all patients treated with siltuximab monotherapy (n = 370) form the overall basis of the safety evaluation. 1). 6 Tabulated list of adverse reactions Table 2 lists adverse reactions observed in MCD patients treated with siltuximab at the recommended dosage of 11 mg/kg every 3 weeks.

Within the system organ class, adverse reactions are listed under headings of frequency using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10000 and <1/1000); very rare (<1/10000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 8%) of patients treated with siltuximab monotherapy. 3% for severe reactions). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 7 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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