3.       PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion (powder for concentrate).

4.4     Special warnings and precautions for use

 Traceability statement moverd from bottom of section 4.4 to top of the section

4.6     Fertility, pregnancy and lactation

Administartive change- ‘Women of childbearing potential’ text moved

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 drug reactions (ADRs), occurring in > 20% of siltuximab‑treated patients in Castleman’s disease (CD) clinical studies. The most serious adverse reactionADR 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 reactionsADRs 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).

In Study 1, a randomised, placebo‑controlled Phase 2 study in MCD, 53 patients were randomised to the siltuximab treatment arm and treated at the recommended dosage of 11 mg/kg every 3 weeks and 26 patients were randomised to the placebo arm. Of the 26 placebo‑treated patients, 18 patients subsequently crossed‑over to receive siltuximab.

In Study 2, a Phase 1 study, 16 of 37 patients with CD were treated with siltuximab, at the recommended dosage of 11 mg/kg every 3 weeks.

In Study 3, an open-label, multicentre, non-randomised Phase 2 study in 60 patients with MCD who were previously enrolled in Study 1 (41 patients) or Study 2 (19 patients), patients were treated with siltuximab, at the recommended dosage of 11 mg/kg every 3 weeks.

Tabulated list of adverse reactions

Table 2 lists adverse reactionsADRs 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 reactionsundesirable effects are presented in order of decreasing seriousness.

4.9     Overdose

No case of overdose has been reported in clinical trials. Repeated dosing of 15 mg/kg every 3 weeks has been administered without additional adverse drug reactions. 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.

6.1     List of excipients

L‑Histidine

L‑Histidine monohydrochloride monohydrate

Polysorbate 80

Sucrose

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.

• Section 4.4 revision to hepatic impairment paragraph to include post clinical trials’ reports of “transient or intermittent mild-to-moderate elevation of hepatic transaminase levels or other liver function tests”; addition of mandatory traceability statement.
• Section 4.8 addition of adverse reactions from Study 3: very common: urinary tract infection, hyperuricaemia, dizziness, headache, oropharyngeal pain, nausea, vomiting, constipation, diarrhoea, gastroesophageal reflux disease, mouth ulceration, rash, eczema, arthralgia, pain in extremity; common: hypercholesterolaemia. Deletion of maculopapular rash.
• Section 5.1 addition of information on Study 3.
• Section 5.2 revision to immunogenicity section.

6.3     Shelf life

Unopened vial

Addiotnal text in bold

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).