Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: EUSA Pharma (Netherlands) B.V., Johannes Vermeerplein 11, 1071 DV, Amsterdam, Netherlands
Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.
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).
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.
Live, attentuated vaccines should not be given concurrently or within 4 weeks before initiating SYLVANT as clinical safety has not been established.
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.
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).
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 (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.
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.
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 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).
No interaction studies have been performed in this population.
Women of childbearing potential must use effective contraception during and up to 3 months after treatment (see section 4.5).
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).
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.
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).
Siltuximab has no or negligible influence on the ability to drive and use machines.
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).
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:
Very common: Upper respiratory tract infection, urinary tract infection, nasopharyngitis
Very common: Neutropenia, thrombocytopenia
Common: Anaphylactic reaction
Very common: Hypertriglyceridaemia, hyperuricaemia
Common: Hypercholesterolaemia
Very common: Dizziness, headache
Very common: Oropharyngeal pain
Very common: Hypertension
Very common: Nausea, abdominal pain, vomiting, constipation, diarrhoea, gastroesophageal reflux disease, mouth ulceration
Very common: Rash, pruritus, eczema
Very common: Arthralgia, pain in extremity
Very common: Renal impairment
Very common: Localised oedema
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)].
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 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 professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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