Sylvant

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SYLVANT 100 mg powder for concentrate for solution for infusion 
SYLVANT 400 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
SYLVANT 100 mg powder for concentrate for solution for infusion 
Each single-use vial contains 100 mg siltuximab powder for concentrate for solution for infusion. 
After reconstitution the solution contains 20 mg siltuximab per mL. 
 
SYLVANT 400 mg powder for concentrate for solution for infusion 
Each single-use vial contains 400 mg siltuximab powder for concentrate for solution for infusion. 
After reconstitution the solution contains 20 mg siltuximab per mL. 
 
Siltuximab is a chimeric (human-murine) immunoglobulin G1κ (IgG1κ) monoclonal antibody 
produced in a Chinese hamster ovary (CHO) cell line by recombinant DNA technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion (powder for concentrate). 
 
The product is a freeze-dried white powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
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. 



3 

 
Table 1: Treatment criteria 
Laboratory parameter Requirements before first 

SYLVANT administration 
Retreatment criteria 

Absolute neutrophil count ≥ 1.0 x 109/L ≥ 1.0 x 109/L 
Platelet count ≥ 75 x 109/L ≥ 50 x 109/L 
Haemoglobina < 170 g/L (10.6 mmol/L) < 170 g/L (10.6 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. No dose adjustment is required (see section 5.2). 
 
Renal and/or hepatic impairment 
No formal studies have been conducted to investigate the PK of siltuximab in patients with renal or 
hepatic impairment (see section 4.4). 
 
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. 
For instructions on reconstitution and dilution of the medicinal product before administration, see 
section 6.6. 
 
4.3 Contraindications 
 
Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Traceability  
In order to improve the traceability of biological medicinal products, the tradename and the batch 
number of the administered product should be clearly recorded. 
 
Concurrent active serious infections 
Infections, including localised infections, should be treated prior to administration of SYLVANT. 
Serious infections, including pneumonia and sepsis, were observed during clinical studies (see 
section 4.8). 
 
Hypoglobulinaemia was observed in 4 to 11.3% of patients in the clinical study. 
Decreases in total IgG, IgA, or IgM levels below normal were observed in the range of 4 to 11% 
patients in the MCD trial (Study 1). 
 



4 

All clinical studies with SYLVANT excluded patients with clinically significant infections, including 
those known to be hepatitis B surface antigen positive. Two cases of reactivated hepatitis B have been 
reported when SYLVANT was administered concomitantly with high dose dexamethasone, and 
bortezomib, melphalan and prednisone in multiple myeloma patients. 
 
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. 
 
Vaccinations 
Live, attentuated vaccines should not be given concurrently or within 4 weeks before initiating 
SYLVANT as clinical safety has not been established. 
 
Lipid parameters 
Elevations in triglycerides and cholesterol (lipid parameters) were observed in patients treated with 
SYLVANT (see section 4.8). Patients should be managed according to current clinical guidelines for 
management of hyperlipidaemia. 
 
Infusion related reactions and hypersensitivity 
During intravenous infusion of SYLVANT, mild to moderate infusion reactions may improve 
following slowing of or stopping the infusion. Upon resolution of the reaction, reinitiating the infusion 
at a lower infusion rate and therapeutic administration of antihistamines, acetaminophen, and 
corticosteroids may be considered. For patients who do not tolerate the infusion following these 
interventions, SYLVANT should be discontinued. During or following infusion, treatment should be 
discontinued in patients who have severe infusion related hypersensitivity reactions (e.g., 
anaphylaxis). The management of severe infusion reactions should be dictated by the signs and 
symptoms of the reaction. Appropriate personnel and medicinal product should be available to treat 
anaphylaxis if it occurs (see section 4.8). 
 
Malignancy 
Immunomodulatory medicinal products 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. 
 
Gastrointestinal perforation 
Gastrointestinal (GI) perforation has been reported in siltuximab 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 with or suggestive of GI perforation. 
 
Hepatic impairment 
Following treatment with SYLVANT  in clinical trials, transient or intermittent mild-to-moderate 
elevation of hepatic transaminase levels or other liver function tests such as bilirubin have been 
reported. SYLVANT-treated patients with known hepatic impairment as well as patients with elevated 
transaminase or bilirubin levels should be monitored. 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. 
 
In non-clinical studies, interleukin-6 (IL-6) is known to decrease the activity of cytochrome P450 
(CYP450). Binding bioactive IL-6 by siltuximab may result in increased metabolism of CYP450 
substrates, because CYP450 enzyme activity will normalise. Therefore, administering siltuximab with 
CYP450 substrates that have a narrow therapeutic index has the potential to change therapeutic effects 
and toxicity of these medicinal products due to alteration in the CYP450 pathways. Upon initation or 
discontinuation of siltuximab in patients being treated with concomitant medicinal products that are 
CYP450 substrates and have a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or 
concentration of medicinal product (e.g., cyclosporine or theophylline) is recommended. The dose of 



5 

the concomitant medicinal products should be adjusted as needed. The effect of siltuximab on 
CYP450 enzyme activity can persist for several weeks after stopping therapy. Prescribers should also 
exercise caution when siltuximab is co-administered with medicinal products that are CYP3A4 
substrates where a decrease in effectiveness would be undesirable (e.g., oral contraceptives). 
 
Paediatric population 
No interaction studies have been performed in this population. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
Women of childbearing potential must use effective contraception during and up to 3 months after 
treatment (see section 4.5). 
 
Pregnancy 
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 (see section 5.3). 
Siltuximab is not recommended during pregnancy and in women of childbearing potential not using 
contraception. 
 
Siltuximab should be given to a pregnant woman only if the benefit clearly outweighs the risk. 
 
As with other immunoglobulin G antibodies, siltuximab crosses the placenta as 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 (see 
section 4.4). 
 
Breast-feeding 
It is unknown whether siltuximab is excreted in human milk. 
A risk to the newborns/infants cannot be excluded. 
A decision must be made whether to discontinue breast-feeding or discontinue/abstain from siltuximab 
therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the 
woman. 
 
Fertility 
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 (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Siltuximab has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
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. 
Table 2 reflects the frequencies of identified adverse reactions in the 87 MCD patients (Study 1, 
Study 2 and Study 3) treated at the recommended dosage of 11 mg/kg every 3 weeks (details provided 
in section 5.1). 
 



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. 
 
Table 2: Adverse reactions in siltuximab treated patients in MCD clinical studiesa 
System organ class 
Frequency 

Adverse reaction 

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 
Gastointestinal 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 Weight increased 
a All patients with CD treated with siltuximab at recommended dose of 11 mg/kg every 3 weeks [including crossover 

patients (N = 87)] 
 
Infusion related reactions and hypersensitivity 
In clinical studies, siltuximab was associated with an infusion related reaction or hypersensitivity 
reaction in 5.1% (severe reaction in 0.8%) of patients treated with siltuximab monotherapy. 
 
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). 
 
 
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. 
 
4.9 Overdose 
 
No case of overdose has been reported in clinical trials.  In the event of an overdose, the patient should 
be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment 
should be instituted immediately. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunosuppresants, interleukin inhibitors, ATC code: L04AC11. 
 
Mechanism of action 
Siltuximab is a human-mouse chimeric monoclonal antibody that forms high affinity, stable 
complexes with soluble bioactive forms of human IL-6. Siltuximab prevents the binding of human 
IL-6 to both soluble and membrane-bound IL-6 receptors (IL-6R), thus inhibiting the formation of the 
hexameric signaling complex with gp130 on the cell surface. Interleukin-6 is a pleiotropic 
pro-inflammatory cytokine produced by a variety of cell types including T-cells and B-cells, 
lymphocytes, monocytes and fibroblasts, as well as malignant cells. IL-6 has been shown to be 
involved in diverse normal physiologic processes such as induction of immunoglobulin secretion, 
initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic 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 CD. 
 
Pharmacodynamic effects 
In vitro, siltuximab dose-dependently inhibited the growth of an IL-6-dependent murine plasmacytoma 
cell line in response to human IL-6. In cultures of human hepatoma cells, IL-6-stimulated production 
of the acute-phase protein serum amyloid A was dose-dependently inhibited by siltuximab. Similarly, 
in cultures of human Burkitt’s B-lymphoma cells, the production of immunoglobulin M protein in 
response to IL-6 was dose-dependently inhibited by siltuximab. 
 
Biomarkers 
It is well established that IL-6 stimulates the acute-phase expression of C-reactive protein (CRP). The 
mechanism of action of siltuximab is neutralisation of IL-6 bioactivity, which can be measured 
indirectly by suppression of CRP. Siltuximab treatment in MCD results in rapid and sustained 
decreases in CRP serum concentrations. Measurement of IL-6 concentrations in serum or plasma 
during treatment should not be used as a pharmacodynamic marker, as siltuximab-neutralised 
antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods. 
 
Clinical efficacy and safety 
Study 1 
A Phase 2, multinational, randomised (2:1) double-blind, placebo-controlled study was conducted to 
assess the efficacy and safety of siltuximab (11 mg/kg every 3 weeks) compared with placebo in 
combination with best supportive care in patients with MCD. Treatment was continued until treatment 
failure (defined as disease progression based on increase in symptoms, radiologic progression or 
deterioration in performance status) or unacceptable toxicity. A total of 79 patients with symptomatic 
MCD were randomised and treated. Median age was 47 years (range 20-74) in the siltuximab arm and 
48 years (range 27-78) in the placebo arm. More male patients were enrolled in the placebo arm (85% 
in placebo vs. 56% in the siltuximab group). ECOG performance status score (0/1/2) at baseline was 
42%/45%/13% in the siltuximab arm and 39%/62%/0% in the placebo arm, respectively. At baseline, 
55% of patients in the siltuximab arm and 65% of patients in the placebo arm had received prior 
systemic therapies for MCD and 30% of patients in the siltuximab arm and 31% in the placebo arm 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


8 

were using corticosteroids. Histological subtype was similar in both treatment arms, with 33% hyaline 
vascular subtype, 23% plasmacytic subtype and 44% mixed subtype. 
The primary endpoint of the study was durable tumour and symptomatic response, defined as tumour 
response assessed by independent review and complete resolution or stabilisation of prospectively 
collected MCD symptoms, for at least 18 weeks without treatment failure. 
 
In Study 1 a statistically significant difference in independently reviewed durable tumour and 
symptomatic response rate in the siltuximab arm compared with the placebo arm (34% vs. 0%, 
respectively; 95% CI: 11.1, 54.8; p = 0.0012) was observed. The overall tumour response rate was 
evaluated based on modified Cheson criteria both by independent review and investigator assessment. 
 
Key efficacy results from Study 1 are summarised in Table 3. 
 
Table 3: Efficacy endpoints from study 1 
Efficacy endpoints Siltuximab+BSC* Placebo+BSC P-valuea 
Primary efficacy endpoint 
Durable tumour & symptomatic response 
(independent review) 18/53 (34.0%) 0/26 (0%) 0.0012 

Secondary efficacy endpoints 
Durable tumour & symptomatic response 
(investigator review) 24/53 (45.3%) 0/26 (0%) < 0.0001 

Best tumour response (independent review) 20/53 (37.7%) 1/26 (3.8%) 0.0022 
Best tumour response (investigator assessment) 27/53 (50.9%) 0/26 (0%) < 0.0001 

Time to treatment failure Not reached 134 days 0.0084; HR 0.418 
Haemoglobin increase > 15 g/L (0.9 mmol/L) 
at Week 13/haemoglobin response-evaluable 
population 

19/31 (61.3%) 0/11 (0%) 0.0002 

Duration of tumour & symptomatic response 
(days) - independent review; median (min, 
max) 

340 (55, 676)b N/Ac N/A 

Durable complete symptomatic responsed 13/53 (24.5%) 0/26 (0%) 0.0037 
Duration of durable complete symptomatic 
response (days) median (min, max) 472 (169, 762)

e N/A N/A 
* Best Supportive Care 
a Adjusted for corticosteroid use at randomisation 
b At the time of primary analysis data for 19 of 20 tumour and symptomatic responders were censored due to on-going 

response 
c N/A = “Not applicable”, there were no responders in the placebo arm, therefore, duration is not applicable 
d Complete symptomatic response is defined as a 100% reduction in the baseline MCD overall symptom score sustained 

for at least 18 weeks prior to treatment failure 
e Data from 11 of 13 complete symptomatic responders were censored due to on-going response 

 
MCD-related signs and symptoms were prospectively collected. A total score of all symptoms 
(referred to as the MCD-related Overall Symptom Score) is the sum of the severity grades 
(NCI-CTCAE grade) of the MCD-related signs and symptoms [general MCD-related (fatigue, 
malaise, hyperhidrosis, night sweats, fever, weight loss, anorexia, tumour pain, dyspnea, and pruritus), 
autoimmune phenomena, fluid retention, neuropathy, and skin disorders]. The percent change from 
baseline in MCD-related signs and symptoms and MCD-related overall symptom score at each cycle 
was calculated. Complete symptom response was defined as a 100% reduction from the baseline 
overall in the MCD-related overall symptom score sustained for at least 18 weeks prior to treatment 
failure. 
Haemoglobin response was defined as a change from baseline of ≥ 15 g/L (0.9 mmol/L) at Week 13. 
A statistically significant difference (61.3% vs. 0% respectively; p = 0.0002) in the haemoglobin 
response in the siltuximab arm compared with the placebo arm was observed. 
 



9 

Subgroup analyses 
Analyses for both primary and secondary endpoints on various subgroups including age (< 65 years 
and ≥ 65 years); race (White and Non-White); region (North America, Europe, Middle East and 
Africa, and Asia Pacific); baseline corticosteroid use (yes and no); prior therapy (yes and no); and 
MCD histology (plasmatic and mixed histology) consistently showed that the treatment effect 
favoured the siltuximab arm except for the hyaline vascular subgroup in which no patient achieved the 
definition of the primary endpoint. A consistent treatment effect favouring siltuximab treated patients 
across all major secondary endpoints was shown in the hyaline vascular subgroup. Select efficacy 
results from Study 1 in the hyaline vascular subgroup are summarised in Table 4. 
 
Table 4: Select efficacy endpoints for hyaline vascular subgroup from study 1 
Efficacy endpoints Siltuximab+BSC* Placebo+BSC 95% CIa 

Primary efficacy endpoint 
Durable tumour & symptomatic response 
(independent review) 

0/18 (0%) 0/8 (0%) (N/A; N/A)b 

Secondary efficacy endpoints 
Durable tumour & symptomatic response 
(investigator review) 3/18 (16.7%) 0/8 (0%) (-25.7; 55.9) 

Best tumour response (independent 
review) 1/18 (5.6%) 1/8 (12.5%) (-46.7; 35.3) 

Best tumour response (investigator 
assessment) 4/18 (22.2%) 0/8 (0%) (-20.3; 60.6) 

Time to treatment failure 206 days 70 days (0.17; 1.13)c 
Haemoglobin increase > 15 g/L 
(0.9 mmol/L) at Week 13/haemoglobin 
response-evaluable population 

3/7 (42.9%) 0/4 (0%) (-22.7; 83.7) 

Durable complete symptomatic responsed 3/18 (16.7%) 0/8 (0%) (-25.7; 55.9) 
* Best Supportive Care 
a 95% confidence interval for the for the difference in proportions 
b N/A = “Not applicable”, there were no responders therefore 95% CI is not applicable 
c 95% confidence interval for the hazard ratio 
d Complete symptomatic response is defined as a 100% reduction in the baseline MCD overall symptom score sustained 

for at least 18 weeks prior to treatment failure 
 
Study 2 
In addition to Study 1, efficacy data are available in patients with CD from a single arm Phase 1 study 
(Study 2). In this study 37 patients with CD (35 MCD patients) were treated with siltuximab. In the 
16 patients with MCD treated with 11 mg/kg every 3 weeks, overall tumour response rate by 
independent review was 43.8% with 6.3% complete response. All tumour responses were durable for 
> 18 weeks. In this study, 16 of the 35 MCD patients were hyaline vascular subtype; 31% of these 
patients had a radiologic response based on independent review and 88% showed clinical benefit 
response as defined in the protocol. 
 
Study 3 
An open-label, multicentre, non-randomised Phase 2 study assessed the safety and efficacy of 
extended treatment with siltuximab in 60 patients with MCD who were previously enrolled in Study 1 
(41 patients) or Study 2 (19 patients). 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. After 
a median of 6 years of follow-up, none of the 60 patients had died and maintenance of disease control 
was demonstrated in 58 of 60 patients. 
 
Highest total dose in clinical trials 
The highest total amount of siltuximab administered in any clinical trial so far per dose was 2,190 mg 
(11 mg/kg). 
 



10 

Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
siltuximab in all subsets of the paediatric population in CD (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Following the first administration of siltuximab (doses ranging from 0.9 to 15 mg/kg), the area under 
the concentration-time curve (AUC) and maximal serum concentration (Cmax) increased in a 
dose-proportional manner and clearance (CL) was independent of dose. Following the single dose 
administration at the recommended dose regimen (11 mg/kg given once every 3 weeks), the clearance 
was 3.54 ± 0.44 mL/kg/day and half-life was 16.3 ± 4.2 days. Following the repeat dose administration 
at the recommended dose, siltuximab clearance was found to be time-invariant, and systemic 
accumulation was moderate (accumulation index of 1.7). Consistent with half-life after the first dose, 
serum concentrations reached steady-state levels by the sixth infusion (intervals every 3 weeks) with 
mean (± SD) peak and trough concentrations of 332 ± 139 and 84 ± 66 mcg/mL, respectively. 
 
Immunogenicity 
As with all therapeutic proteins, there is potential for the generation of anti-medicine antibodies 
(immunogenicity). The immunogenicity of siltuximab has been evaluated using antigen-bridging 
enzyme immunoassay (EIA) and electrochemiluminescence (ECL)-based immunoassay (ECLIA) 
methods. 
 
In clinical studies including monotherapy and combination studies, samples from a total of 
432 patients were available for anti-siltuximab antibody testing with 189 patients having at least one 
sample tested with the high medicinal product-tolerant ECLIA assay. The incidence rate of detectable 
anti-siltuximab antibodies was 0.9% (4/432) overall and 2.1% (4/189) in patients with at least once 
sample tested with the high medicinal product tolerant ECLIA assay. Further immunogenicity 
analyses were conducted for all positive samples from the 4 patients with detectable anti-siltuximab 
antibodies. None of these patients had neutralising antibodies. No evidence of altered safety or 
efficacy was identified in the patients who developed antibodies to siltuximab. 
 
Special populations 
Cross-study population PK analyses were performed using data from 378 patients with a variety of 
conditions who received single-agent siltuximab at doses ranging from 0.9 to 15 mg/kg. The effects of 
various covariates on siltuximab PK were assessed in the analyses. 
 
Siltuximab clearance increased with increasing body weight; however, no dose adjustment is required 
for body weight since administration is on an mg/kg basis. The following factors had no clinical effect 
on the clearance of siltuximab: gender, age, and ethnicity. The effect of anti-siltuximab antibody status 
was not examined, as there were insufficient numbers of anti-siltuximab antibody positive patients. 
 
Elderly 
The population PK of siltuximab were analysed to evaluate the effects of demographic characteristics. 
The results showed no significant difference in the PK of siltuximab in patients older than 65 years 
compared to patients age 65 years or younger. 
 
Renal impairment 
No formal study of the effect of renal impairment on the pharmacokinetics of siltuximab has been 
conducted. For patients with baseline calculated creatinine clearance of 12 mL/min or greater, there 
was no meaningful effect on siltuximab PK. Four patients with severe renal impairment (creatinine 
clearance 12 to 30 mL/min) were included in the data set. 
 
Hepatic impairment 
No formal study of the effect of hepatic impairment on the pharmacokinetics of siltuximab has been 
conducted. For patients with baseline alanine transaminase up to 3.7 times the upper limit of normal 



11 

baseline albumin ranging from 15 to 58 g/L, and baseline bilirubin ranging from 1.7 to 42.8 mg/dL 
there was no meaningful effect on siltuximab PK. 
 
Paediatric population 
The safety and efficacy of siltuximab have not been established in paediatric patients. 
 
5.3 Preclinical safety data 
 
The repeat-dose toxicology studies conducted in young cynomolgus monkeys at doses of 9.2 and 
46 mg/kg/week (up to 22-fold greater exposure than in patients receiving 11 mg/kg every 3 weeks) 
with siltuximab showed no signs indicative of toxicity. A slight reduction in T-cell dependent antibody 
response and a reduction in the size of the splenic germinal centers following Keyhole limpet 
hemocyanin (KLH) immunisation was observed which were considered to be pharmacological 
responses of IL-6 inhibition and not of toxicological significance. 
 
Siltuximab (9.2 and 46 mg/kg/week) did not produce any toxicity of the reproductive tract in 
cynomolgus monkeys. In mice dosed subcutaneously with an anti-mouse IL-6 monoclonal antibody, 
no effects on male or female fertility were observed. 
 
During an embryo-fetal development study where siltuximab was administered intravenously to 
pregnant cynomolgus monkeys (gestation day 20 – 118) at doses of 9.2 and 46 mg/kg/week, no 
maternal or fetal toxicity was observed. Siltuximab crossed the placenta during gestation whereby fetal 
serum concentrations of siltuximab at gestation day (GD) 140 were similar to maternal concentrations. 
Histopathological examination of lymphoid tissues from GD140 fetuses showed no morphological 
abnormalities in the development of the immune system. 
 
Rodent carcinogenicity studies have not been conducted with siltuximab. Evidence from studies 
conducted with siltuximab and other IL-6 inhibitors suggest that the potential for siltuximab to cause 
carcinogenicity is low. However, there is also evidence to suggest that IL-6 inhibition may suppress 
immune responses, immune surveillance and lower defense against established tumours. Therefore, an 
increased susceptibility to specific tumours cannot be entirely ruled out. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Histidine 
Histidine hydrochloride monohydrate 
Polysorbate 80 
Sucrose 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
Unopened vial 
3 years 
 
After reconstitution and dilution 
Chemical and physical in-use stability has been demonstrated for up to 8 hours at room temperature 
(see section 6.6). 
 



12 

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes 
the risk of microbial contamination, the product should be used immediately. 
If not used immediately, in-use storage times and conditions are the responsibility of the user. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the original package in order to protect from 
light. 
 
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
SYLVANT 100 mg powder for concentrate for solution for infusion 
8 mL Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off button 
containing 100 mg of siltuximab. Pack size of 1 vial.  
 
SYLVANT 400 mg powder for concentrate for solution for infusion 
30 mL Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off button 
containing 400 mg of siltuximab. Pack size of 1 vial.  
 
6.6 Special precautions for disposal and other handling 
 
This medicinal product is for single use only. 
 
• Use aseptic technique. 
• Calculate the dose, total volume of reconstituted SYLVANT solution required and the number 

of vials needed. The recommended needle for preparation is 21-gauge 1½ inch (38 mm). 
Infusion bags (250 mL) 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 SYLVANT to come to room temperature (15°C to 25°C) over approximately 
30 minutes. SYLVANT should remain at room temperature for the duration of the preparation. 

 
Each 100 mg vial should be reconstituted with 5.2 mL of single-use water for injections to yield 
a 20 mg/mL solution. 

 
Each 400 mg vial should be reconstituted with 20 mL of single-use water for injections to yield 
a 20 mg/mL solution. 

 
• Gently swirl (DO NOT SHAKE OR VORTEX OR SWIRL VIGOROUSLY) the reconstituted 

vials to aid the dissolution of the powder. Do not remove contents until all of the powder has 
been completely dissolved. The 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 if foreign particles and/or solution discolouration are present. 

• Dilute the total volume of the reconstituted solution dose to 250 mL with sterile dextrose 5%, by 
withdrawing a volume equal to the volume of reconstituted SYLVANT from the dextrose 5%, 
250 mL bag. Slowly add the total volume of reconstituted SYLVANT solution to the 250 mL 
infusion bag. Gently mix. 

• The reconstituted solution should be kept for no more than 2 hours prior to addition into the 
intravenous 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. SYLVANT does not contain preservatives; 
therefore do not store any unused portion of the infusion solution for re-use. 



13 

• No physical biochemical compatibility studies have been conducted to evaluate the 
co-administration of SYLVANT with other medicinal products. Do not infuse SYLVANT 
concomitantly in the same intravenous line with other agents. 

• Any unused product or waste material should be disposed of in accordance with local 
requirements. 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
 
EUSA Pharma  
(Netherlands) B.V.  
Johannes Vermeerplein 11  
1071 DV  
Amsterdam  
Netherlands 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
SYLVANT 100 mg powder for concentrate for solution for infusion 
EU/1/14/928/001 
 
SYLVANT 400 mg powder for concentrate for solution for infusion 
EU/1/14/928/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 22 May 2014 
Date of latest renewal: 2 April 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



15 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturers of the biological active substances 
 
Janssen Biotech Inc. 
200 Great Valley Parkway 
Malvern 
Pennsylvania 
19355 
United States 
 
Janssen Sciences Ireland UC 
Barnahely 
Ringaskiddy 
Co. Cork 
Ireland 
 
Janssen Biologics B.V. 
Einsteinweg 101 
NL-2333 CB Leiden 
The Netherlands 
 
Name and address of the manufacturer responsible for batch release 
 
Janssen Biologics B.V. 
Einsteinweg 101 
NL-2333 CB Leiden 
The Netherlands 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal products subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 



16 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
A registry should be conducted to collect information on patients with 
Castleman’s disease, who are candidates to receive Sylvant or are 
currently receiving treatment with Sylvant. The registry should be 
continued for the either 100 patients, or 5 years, whichever is greater. 
The MAH should provide tabulated data to the CHMP every 
12 months in line with the periodic safety update report (PSUR) cycle 
including data for only those patients who are candidates for 
treatment with siltuximab. 

Protocol: 
31/12/2014 
 
First tabulated update: 
30/11/2015 (aligned with 
expected PSUR cycle) 

 



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



19 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
SYLVANT 100 mg powder for concentrate for solution for infusion 
SYLVANT 400 mg powder for concentrate for solution for infusion 
siltuximab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 100 mg of siltuximab. After reconstitution the solution contains 20 mg siltuximab 
per mL. 
Each vial contains 400 mg of siltuximab. After reconstitution the solution contains 20 mg siltuximab 
per mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: histidine, histidine hydrochloride monohydrate, polysorbate 80, sucrose. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
 
Read the package leaflet before use. 
Intravenous infusion after reconstitution and dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 



20 

 
Do not freeze. 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
 
EUSA Pharma  
(Netherlands) B.V.  
Johannes Vermeerplein 11  
1071 DV  
Amsterdam  
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/928/001 (100 mg) 
EU/1/14/928/002 (400 mg) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



21 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
SYLVANT 100 mg powder for concentrate 
SYLVANT 400 mg powder forconcentrate 
siltuximab 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



23 

Package leaflet: Information for the patient 
 

SYLVANT 100 mg powder for concentrate for solution for infusion 
 

siltuximab 
 
This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how 
to report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist, or nurse. 
- If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What SYLVANT is and what it is used for 
2. What you need to know before you are given SYLVANT 
3. How SYLVANT is given 
4. Possible side effects 
5. How to store SYLVANT 
6. Contents of the pack and other information 
 
 
1. What SYLVANT is and what it is used for 
 
What SYLVANT is 
SYLVANT is a medicine that contains the active substance siltuximab. 
Siltuximab is a monoclonal antibody (a specialised type of protein) that binds selectively to an antigen 
(a target protein) in the body called interleukin-6 (IL-6). 
 
What SYLVANT is used for 
SYLVANT is used to treat multicentric Castleman’s disease (MCD) in adult patients who do not have 
human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8) infection. 
Multicentric Castleman’s disease causes benign tumours (non-cancerous growths) to develop in the 
lymph nodes in the body. Symptoms of this disease may include feeling tired, sweating at night, 
having a tingling feeling, and loss of appetite. 
 
How SYLVANT works 
Patients with MCD produce too much IL-6 and this is thought to contribute to the abnormal growth of 
certain cells in lymph nodes. By binding to IL-6, siltuximab blocks its activity and stops abnormal cell 
growth. This helps reduce the size of the affected lymph nodes, which reduces the symptoms of the 
illness and should help you carry out your normal daily tasks. 
 
 
2. What you need to know before you are given SYLVANT 
 
You should not be given SYLVANT if: 
You are severely allergic to siltuximab or any of the other ingredients of this medicine (listed in 
section 6). 
 
Warnings and precautions 
Talk to your doctor, pharmacist, or nurse before you are given SYLVANT if: 
• you have an infection at the moment – this is because SYLVANT may lower your ability to feel 

or fight infections, and infections may get worse. 



24 

• you are due to have a vaccination or may need to have one in the near future – this is because 
some vaccines should not be given with SYLVANT. 

• you have high level of fats in your blood (hypertriglyceridaemia) – this is because SYLVANT 
may increase these levels. Your doctor may prescribe medicines to correct this. 

• you have a condition such as stomach ulcer or diverticulitis that may increase the risk of getting 
a tear in the stomach or gut (gastrointestinal perforation). Signs of such a tear developing 
include stomach pain getting worse, feeling sick (nausea), change in bowel habits and fever – if 
you get any of these, contact your doctor right away. 

• you have liver disease or changes that show up in blood tests of the liver. Your doctor will 
monitor you and your liver function. 
 

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist, or nurse before 
you are given SYLVANT. 
 
Allergic reactions 
Tell your doctor straight away if you have a severe allergic reaction during or after the infusion. Signs 
include: difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling 
of the lips or skin rash. 
 
Infections 
You may be more likely to get infections while you are being treated with SYLVANT. 
These infections may be serious, such as pneumonia or blood poisoning (also called “sepsis”). 
 
Tell your doctor straight away if you get any signs of infection during treatment with SYLVANT. 
Signs include: cough, flu-like symptoms, feeling unwell, red or hot skin, fever. Your doctor may stop 
your treatment with SYLVANT straight away. 
 
Children and adolescents 
It is not known if SYLVANT is safe and effective in this population, therefore SYLVANT should not 
be given to children and adolescents. 
 
Other medicines and SYLVANT 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines.  
In particular, tell your doctor or pharmacist if you are taking any of the following medicines: 
• theophylline, used to treat asthma 
• warfarin, a blood thinner 
• cyclosporin, used during and after organ transplants 
• oral contraceptives, used to prevent pregnancy. 
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before you are 
given SYLVANT. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think that you might be pregnant or are planning to have a baby, 
ask your doctor or pharmacist for advice before you are given this medicine. 
• SYLVANT is not recommended for use during pregnancy. It is not known if SYLVANT may 

affect the baby or a pregnant or breast-feeding woman. 
• You must not become pregnant while you are being treated with SYLVANT and for 3 months 

after your treatment has finished. You should use effective methods of contraception during this 
time. 

• In some cases, if you are pregnant and need treatment for MCD, your doctor may advise that the 
benefit of taking SYLVANT for your health outweighs the possible risks to your unborn baby, 
including increased risk of infection and use of certain vaccines in babies born to mothers 
exposed to SYLVANT while pregnant. 

•  



25 

• It is not known if. SYLVANT passes into breast milk. You and your doctor should decide if you 
will continue to take SYLVANT, or breast-feed and discontinue SYLVANT. 

 
Driving and using machines 
SYLVANT is not likely to affect your ability to drive, cycle, or use any tools or machines. 
 
 
3. How SYLVANT is given 
 
SYLVANT will be given to you by your doctor or nurse, in a hospital or clinic only. 
• The recommended dose is 11 milligrams per kilogram of body weight, given once every 

3 weeks. 
• SYLVANT will be given as an “intravenous infusion” (a drip into a vein, usually in your arm). 
• It will be given slowly over a period of 1 hour. 
• During the infusion with SYLVANT, you will be monitored for side effects. 
• You will receive treatment until you and your doctor agree that you will no longer benefit from 

the treatment. 
 
If you are given more SYLVANT than you should 
As this medicine will be given to you by your doctor or nurse, it is unlikely that you will be given too 
much. If you think you have been given too much SYLVANT, tell your doctor or nurse straight away. 
It is not known what the possible side effects could be from having too much SYLVANT. 
 
If you stop treatment with SYLVANT 
You should not stop using SYLVANT without discussing with your doctor first. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The 
following side effects may happen with this medicine. 
 
Tell your doctor straight away if you notice the following side effects, as he or she may need to 
stop your treatment: 
Common (may affect up to 1 in 10 people): 
• severe allergic reaction – the signs may include: difficulty breathing, chest tightness, wheezing, 

severe dizziness or light-headedness, swelling of the lips or skin rash. 
 
Other side effects include: 
Talk to your doctor, pharmacist or nurse if you notice any of the following side effects: 
 
Very common (may affect more than 1 in 10 people): 
• drop in the number of white blood cells (neutropenia) 
• drop in the number of platelets (thrombocytopenia) 
• itching 
• rash, itchy skin rash (eczema) 
• high fat levels in your blood (hypertriglyceridaemia) 
• high level of 'uric acid' in the blood, which may cause gout 
• abnormal kidney function test 
• swelling in the arms, legs, neck or face 
• high blood pressure 
• respiratory infections – such as of the nose, sinuses or throat 
• urinary tract infection 
• common cold 



26 

• sore throat 
• stomach pain or discomfort, constipation, diarrhoea, heartburn, ulcers (sores) in the mouth, 

nausea, vomiting 
• feeling dizzy 
• headache 
• joint pain, arm or leg pain 
• weight gain. 
 
Common (may affect up to 1 in 10 people): 
• high level of cholesterol in the blood 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store SYLVANT 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date 
refers to the last day of that month.  
 
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect 
from light. 
 
Do not use if you see opaque or foreign particles and/or if the solution appears discoloured after 
reconstitution. 
 
 
6. Contents of the pack and other information 
 
What SYLVANT contains 
• The active substance is siltuximab. Each single-use vial contains 100 mg siltuximab. After 

reconstitution the solution contains 20 mg siltuximab per mL. 
• The other ingredients (excipients) are histidine, histidine hydrochloride monohydrate, 

polysorbate 80, and sucrose. 
 
What SYLVANT looks like and contents of the pack 
• SYLVANT is supplied as a glass vial containing a white powder for concentrate for solution for 

infusion (powder for concentrate). 
• SYLVANT is available in packs containing 1 vial. 
 
Marketing Authorisation Holder 
 
EUSA Pharma  
(Netherlands) B.V.  
Johannes Vermeerplein 11  
1071 DV  
Amsterdam  
Netherlands 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


27 

Manufacturer 
Janssen Biologics B.V. 
Einsteinweg 101 
2333 CB Leiden 
The Netherlands 
 
 
This leaflet was last revised in MM/YYYY 
 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
 
The following information is intended for healthcare professionals only: 
 
This medicinal product is for single use only. 
 
1. Use aseptic technique. 
2. Calculate the dose, total volume of reconstituted SYLVANT solution required and the number 

of vials needed. The recommended needle for preparation is 21-gauge 1½ inch (38 mm). 
Infusion bags (250 mL) 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. 

3. Allow vial(s) of SYLVANT to come to room temperature (15°C to 25°C) over approximately 
30 minutes. SYLVANT should remain at room temperature for the duration of the preparation. 
Each vial should be reconstituted with 5.2 mL of single-use water for injections to yield a 
20 mg/mL solution. 

4. Gently swirl (DO NOT SHAKE OR VORTEX OR SWIRL VIGOROUSLY) the reconstituted 
vials to aid the dissolution of the powder. Do not remove contents until all of the powder has 
been completely dissolved. The 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 if foreign particles and/or solution discolouration are present. 

5. Dilute the total volume of the reconstituted solution dose to 250 mL with sterile Dextrose 5%, 
by withdrawing a volume equal to the volume of reconstituted SYLVANT from the Dextrose 
5%, 250 mL bag. Slowly add the total volume of reconstituted SYLVANT solution to the 
250 mL infusion bag. Gently mix. 

6. The reconstituted solution should be kept for no more than 2 hours prior to addition into the 
intravenous 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. SYLVANT does not contain preservatives; 
therefore do not store any unused portion of the infusion solution for re-use. 

7. No physical biochemical compatibility studies have been conducted to evaluate the 
co-administration of SYLVANT with other medicinal products. Do not infuse SYLVANT 
concomitantly in the same intravenous line with other agents. 

8. Any unused product or waste material should be disposed of in accordance with local 
requirements. 

 
Traceability 
In order to improve the traceability of biological medicinal products, the tradename and the batch 
number of the administered product should be clearly recorded. 

 

http://www.ema.europa.eu/


28 

Package leaflet: Information for the patient 
 

SYLVANT 400 mg powder for concentrate for solution for infusion 
 

siltuximab 
 
This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how 
to report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist, or nurse. 
- If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What SYLVANT is and what it is used for 
2. What you need to know before you are given SYLVANT 
3. How SYLVANT is given 
4. Possible side effects 
5. How to store SYLVANT 
6. Contents of the pack and other information 
 
 
1. What SYLVANT is and what it is used for 
 
What SYLVANT is 
SYLVANT is a medicine that contains the active substance siltuximab. 
Siltuximab is a monoclonal antibody (a specialised type of protein) that binds selectively to an antigen 
(a target protein) in the body called interleukin-6 (IL-6). 
 
What SYLVANT is used for 
SYLVANT is used to treat multicentric Castleman’s disease (MCD) in adult patients who do not have 
human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8) infection. 
Multicentric Castleman’s disease causes benign tumours (non-cancerous growths) to develop in the 
lymph nodes in the body. Symptoms of this disease may include feeling tired, sweating at night, 
having a tingling feeling, and loss of appetite. 
 
How SYLVANT works 
Patients with MCD produce too much IL-6 and this is thought to contribute to the abnormal growth of 
certain cells in lymph nodes. By binding to IL-6, siltuximab blocks its activity and stops abnormal cell 
growth. This helps reduce the size of the affected lymph nodes, which reduces the symptoms of the 
illness and should help you carry out your normal daily tasks. 
 
 
2. What you need to know before you are given SYLVANT 
 
You should not be given SYLVANT if: 
You are severely allergic to siltuximab or any of the other ingredients of this medicine (listed in 
section 6). 
 
Warnings and precautions 
Talk to your doctor, pharmacist, or nurse before you are given SYLVANT if: 
• you have an infection at the moment – this is because SYLVANT may lower your ability to feel 

or fight infections, and infections may get worse. 



29 

• you are due to have a vaccination or may need to have one in the near future – this is because 
some vaccines should not be given with SYLVANT. 

• you have high level of fats in your blood (hypertriglyceridaemia) – this is because SYLVANT 
may increase these levels. Your doctor may prescribe medicines to correct this. 

• you have a condition such as stomach ulcer or diverticulitis that may increase the risk of getting 
a tear in the stomach or gut (gastrointestinal perforation). Signs of such a tear developing 
include stomach pain getting worse, feeling sick (nausea), change in bowel habits and fever – if 
you get any of these, contact your doctor right away. 

• you have liver disease or changes that show up in blood tests of the liver. Your doctor will 
monitor you and your liver function.  

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist, or nurse before 
you are given SYLVANT. 
 
Allergic reactions 
Tell your doctor straight away if you have a severe allergic reaction during or after the infusion. Signs 
include: difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling 
of the lips or skin rash. 
 
Infections 
You may be more likely to get infections while you are being treated with SYLVANT. 
These infections may be serious, such as pneumonia or blood poisoning (also called “sepsis”). 
 
Tell your doctor straight away if you get any signs of infection during treatment with SYLVANT. 
Signs include: cough, flu-like symptoms, feeling unwell, red or hot skin, fever. Your doctor may stop 
your treatment with SYLVANT straight away. 
 
Children and adolescents 
It is not known if SYLVANT is safe and effective in this population, therefore SYLVANT should not 
be given to children and adolescents. 
 
Other medicines and SYLVANT 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 
In particular, tell your doctor or pharmacist if you are taking any of the following medicines: 
• theophylline, used to treat asthma 
• warfarin, a blood thinner 
• cyclosporin, used during and after organ transplants 
• oral contraceptives, used to prevent pregnancy. 
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before you are 
given SYLVANT. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think that you might be pregnant or are planning to have a baby, 
ask your doctor or pharmacist for advice before you are given this medicine. 
• SYLVANT is not recommended for use during pregnancy. It is not known if SYLVANT may 

affect the baby or a pregnant or breast-feeding woman. 
• You must not become  pregnant while you are being treated with SYLVANT and for 3 months 

after your treatment has finished. You should use effective methods of contraception during this 
time. 

• In some cases, if you are pregnant and need treatment for MCD, your doctor may advise that the 
benefit of taking SYLVANT for your health outweighs the possible risks to your unborn baby, 
including increased risk of infection and use of certain vaccines in babies born to mothers 
exposed to SYLVANT while pregnant. 

•  
• It is not known if. SYLVANT passes into breast milk. You and your doctor should decide if you 

will continue to take SYLVANT, or breast-feed and discontinue SYLVANT. 



30 

 
Driving and using machines 
SYLVANT is not likely to affect your ability to drive, cycle, or use any tools or machines. 
 
 
3. How SYLVANT is given 
 
SYLVANT will be given to you by your doctor or nurse, in a hospital or clinic only. 
• The recommended dose is 11 milligrams per kilogram of body weight, given once every 

3 weeks. 
• SYLVANT will be given as an “intravenous infusion” (a drip into a vein, usually in your arm). 
• It will be given slowly over a period of 1 hour. 
• During the infusion with SYLVANT, you will be monitored for side effects. 
• You will receive treatment until you and your doctor agree that you will no longer benefit from 

the treatment. 
 
If you are given more SYLVANT than you should 
As this medicine will be given to you by your doctor or nurse, it is unlikely that you will be given too 
much. If you think you have been given too much SYLVANT, tell your doctor or nurse straight away. 
It is not known what the possible side effects could be from having too much SYLVANT. 
 
If you stop treatment with SYLVANT 
You should not stop using SYLVANT without discussing with your doctor first. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The 
following side effects may happen with this medicine. 
 
Tell your doctor straight away if you notice the following side effects, as he or she may need to 
stop your treatment: 
Common (may affect up to 1 in 10 people): 
• severe allergic reaction – the signs may include: difficulty breathing, chest tightness, wheezing, 

severe dizziness or light-headedness, swelling of the lips or skin rash. 
 
Other side effects include: 
Talk to your doctor, pharmacist or nurse if you notice any of the following side effects: 
 
Very common (may affect more than 1 in 10 people): 
• drop in the number of white blood cells (neutropenia) 
• drop in the number of platelets (thrombocytopenia) 
• itching 
• rash, itchy skin rash (eczema) 
• high fat levels in your blood (hypertriglyceridaemia) 
• high level of 'uric acid' in the blood, which may cause gout 
• abnormal kidney function test 
• swelling in the arms, legs, neck or face 
• high blood pressure 
• respiratory infections – such as of the nose, sinuses or throat 
• urinary tract infection 
• common cold 
• sore throat 



31 

• stomach pain or discomfort, constipation, diarrhoea, heartburn, ulcers (sores) in the mouth, 
nausea, vomiting 

• feeling dizzy 
• headache 
• joint pain, arm or leg pain 
• weight gain. 
 
Common (may affect up to 1 in 10 people): 
• high level of cholesterol in the blood 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store SYLVANT 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date 
refers to the last day of that month.  
 
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect 
from light. 
 
Do not use if you see opaque or foreign particles and/or if the solution appears discoloured after 
reconstitution. 
 
 
6. Contents of the pack and other information 
 
What SYLVANT contains 
• The active substance is siltuximab. Each single-use vial contains 400 mg siltuximab. After 

reconstitution the solution contains 20 mg siltuximab per mL. 
• The other ingredients (excipients) are histidine, histidine hydrochloride monohydrate, 

polysorbate 80, and sucrose. 
 
What SYLVANT looks like and contents of the pack 
• SYLVANT is supplied as a glass vial containing a white powder for concentrate for solution for 

infusion (powder for concentrate). 
• SYLVANT is available in packs containing 1 vial. 
 
Marketing Authorisation Holder 
 
EUSA Pharma  
(Netherlands) B.V.  
Johannes Vermeerplein 11  
1071 DV  
Amsterdam  
Netherlands 
 
Manufacturer 
Janssen Biologics B.V. 
Einsteinweg 101 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


32 

2333 CB Leiden 
The Netherlands 
 
 
This leaflet was last revised in MM/YYYY 
 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
 
The following information is intended for healthcare professionals only: 
 
This medicinal product is for single use only. 
 
1. Use aseptic technique. 
2. Calculate the dose, total volume of reconstituted SYLVANT solution required and the number 

of vials needed. The recommended needle for preparation is 21-gauge 1½ inch (38 mm). 
Infusion bags (250 mL) 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. 

3. Allow vial(s) of SYLVANT to come to room temperature (15°C to 25°C) over approximately 
30 minutes. SYLVANT should remain at room temperature for the duration of the preparation. 
Each vial should be reconstituted with 20.0 mL of single-use water for injections to yield a 
20 mg/mL solution. 

4. Gently swirl (DO NOT SHAKE OR VORTEX OR SWIRL VIGOROUSLY) the reconstituted 
vials to aid the dissolution of the powder. Do not remove contents until all of the powder has 
been completely dissolved. The 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 if foreign particles and/or solution discolouration are present. 

5. Dilute the total volume of the reconstituted solution dose to 250 mL with sterile Dextrose 5%, 
by withdrawing a volume equal to the volume of reconstituted SYLVANT from the Dextrose 
5%, 250 mL bag. Slowly add the total volume of reconstituted SYLVANT solution to the 
250 mL infusion bag. Gently mix. 

6. The reconstituted solution should be kept for no more than 2 hours prior to addition into the 
intravenous 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. SYLVANT does not contain preservatives; 
therefore do not store any unused portion of the infusion solution for re-use. 

7. No physical biochemical compatibility studies have been conducted to evaluate the 
co-administration of SYLVANT with other medicinal products. Do not infuse SYLVANT 
concomitantly in the same intravenous line with other agents. 

8. Any unused product or waste material should be disposed of in accordance with local 
requirements. 

 
Traceability 
In order to improve the traceability of biological medicinal products, the tradename and the batch 
number of the administered product should be clearly recorded. 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET