Sylvant 100 mg/400 mg Solution

SYLVANT is indicated for the treatment of patients with multicentric Castlemanu2019s disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpesvirus-8 (HHV-8)-negative.

Posology

Dosage u2013 18 years and older

SYLVANT 11 mg/kg is given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure. Haematology laboratory tests should be performed prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. The doctor should consider delaying treatment if the treatment criteria outlined in Table 1 are not met, before administering SYLVANT. Dose reduction is not recommended.

Table 1 Treatment Criteria

• Laboratory parameter
• Requirements before first SYLVANT administration
• Retreatment criteria
• Absolute Neutrophil Count
• u2265 1,0 u00d7 109/L
• u2265 1,0 u00d7 109/L
• Platelet count
• u2265 75 u00d7 109/L
• u2265 50 u00d7 109/L
• Haemoglobin a
• < 170 g/L
• < 170 g/L

a SYLVANT may increase haemoglobin levels in MCD patients. 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 SYLVANT infusion, further administration of SYLVANT should be discontinued. Discontinuing the 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 65 years of age and older

No major age-related differences in pharmacokinetic (PK) or in safety profile were observed in clinical studies. No dose adjustment is required (see section 5.2).

Renal impairment

No formal studies have been conducted to investigate the pharmacokinetics of SYLVANT in patients with renal impairment. (see section 5.2).

Hepatic impairment

No formal studies have been conducted to investigate the pharmacokinetics of SYLVANT in patients with hepatic impairment. (see section 5.2.

Paediatric population (17 years of age and younger)

The safety and efficacy of SYLVANT have not been established in paediatric patients.

Method of administration

Intravenous infusion (I.V.) of SYLVANT should be administered by qualified healthcare professionals.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy and lactation.

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).

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, doctors should diligently monitor patients receiving treatment in order to detect serious infections.

Vaccinations

Live, attenuated vaccines should not be given concurrently or within 4 weeks before initiating SYLVANT, because clinical safety has not been established and because IL-6 inhibition may interfere with the normal immune response to new antigens.

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 I.V. infusion of SYLVANT, mild to moderate infusion reactions may occur. 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 with SYLVANT 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 medicine should be available to treat anaphylaxis if it occurs (see section 4.8).

Malignancy

SYLVANT 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 SYLVANT clinical 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 or suggestive of GI perforation.

Hepatic impairment

Following treatment with SYLVANT in clinical trials, transient or intermittent mild-to-moderate elevation of hepatic transaminases or other liver function tests such as bilirubin have been reported. SYLVANT u2013 treated patients with known hepatic impairment as well as patients with elevated transaminase or bilirubin levels should be monitored.

No formal interaction studies have been conducted with SYLVANT. In nonclinical studies, 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 SYLVANT with CYP450 substrates that have a narrow therapeutic index has the potential to change medicine therapeutic effects and toxicity due to alterations in the CYP450 pathways. Upon initiation or discontinuation of SYLVANT in patients being treated with concomitant medications that are CYP450 substrates and have a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or medicine concentration (e.g., ciclosporin or theophylline) is recommended. The dose of the concomitant medication should be adjusted as needed. The effect of SYLVANT on CYP450 enzyme activity can persist for several weeks after stopping therapy. Doctors should also exercise caution when SYLVANT is co administered with CYP3A4 substrate medicines where a decrease in effectiveness would be undesirable (e.g., oral contraceptives).

Paediatric population

No interaction studies have been performed in this population.

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 SYLVANT in pregnant women. Studies in animals with siltuximab have shown no adverse effect on pregnancy or on embryofetal development. The safety of SYLVANT in pregnancy has not been established. SYLVANT is contraindicated in pregnancy. It is not known whether siltuximab can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. Doctors should also exercise caution when SYLVANT is administered with CYP3A4 substrates where a decrease in effectiveness would be undesirable e.g. oral contraceptives (see section 4.5). Siltuximab crosses the placenta, as was observed in studies in monkeys. Consequently, infants born to women treated with SYLVANT may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants (see section 4.4).

Breastfeeding

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

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.

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

Summary of the safety profile

The most frequent side effects (> 20 % of patients) during treatment with SYLVANT in the MCD clinical trials were upper respiratory tract infection, pruritus, rash, arthralgia and diarrhoea. The most serious side effect associated with the use of SYLVANT was anaphylactic reaction.

Tabulated list of adverse reactions

Table 2 lists adverse reactions observed in MCD patients treated with SYLVANT 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 (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1000 and < 1/100); rare (u2265 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 SYLVANT treated patients in MCD clinical studies a

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

Gastrointestinal disorders

very common

Nausea, abdominal pain, vomiting, constipation, diarrhoea, gastroesophageal reflux disease, mouth ulceration

Skin and subcutaneous tissue disorders

very common

Rash, pruritus, eczema

Musculoskeletal and connective tissue disorders

very common

Arthralgia, pain in extremity

Renal and urinary disorders

very common

Renal impairment

General disorders and administration site conditions

very common

Localised oedema

Investigations

very common

Weight increased

a All patients with CD treated with SYLVANT at recommended dose of 11 mg/kg every 3 weeks [including crossover patients (N = 87)]

Description of selected adverse reactions

Infusion related reactions and hypersensitivity: In clinical studies, SYLVANT was associated with an infusion related reaction or hypersensitivity reaction in 5,1 % (severe reaction in 0,8 %) of patients treated with SYLVANT monotherapy. In long-term treatment of MCD patients with SYLVANT 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

No case of overdose has been reported. 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.