Sylvant

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Siltuximab 100 mg;  ;  
Available from:
Link Pharmaceuticals Ltd
INN (International Name):
Siltuximab 100 mg
Dosage:
100 mg
Pharmaceutical form:
Powder for infusion concentrate
Composition:
Active: Siltuximab 100 mg     Excipient: Histidine Polysorbate 80 Sucrose
Prescription type:
Prescription
Manufactured by:
Janssen Sciences Ireland UC
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.
Product summary:
Package - Contents - Shelf Life: Vial, glass, Type 1 - 1 dose units - 36 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light 2 hours reconstituted stored at or below 25°C. prior to dilution 6 hours diluted stored at or below 25°C
Authorization number:
TT50-9608
Authorization date:
2014-08-08

Read the complete document

SYLVANT

MARCH 2021 CMI 3

SYLVANT

®

Siltuximab

Consumer Medicine Information

What is in this leaflet

This leaflet answers some of the

common questions about

SYLVANT. It does not contain all

of the available information. It does

not take the place of talking to your

doctor or pharmacist.

If you have any concerns about

using SYLVANT, ask your doctor

or pharmacist.

Your doctor and pharmacist have

more information.

Keep this information handy. You

can refer to it later if you have any

questions.

Please also refer to Consumer

Medicine Information documents of

other medicines your doctor may

have prescribed for use in

combination with SYLVANT.

What SYLVANT is

used for

SYLVANT is a prescription

medicine used to treat multicentric

Castleman’s disease (MCD) in

patients who do not have human

immunodeficiency virus (HIV) and

human herpesvirus-8 (HHV-8)

infection.

Multicentric Castleman’s disease

causes non-cancerous growths

(tumours) to develop in the lymph

nodes in the body. This disease may

also make you feel tired, sweat at

night, have a tingling feeling, and a

loss of appetite.

Ask your doctor if you have any

questions about why it has been

prescribed for you.

How it works

SYLVANT contains the active

ingredient siltuximab. SYLVANT

blocks the action of a specific protein

called “interleukin-6”, which can

cause inflammation. Blocking this

protein helps to reduce the size of the

affected lymph nodes and reduce the

symptoms of the illness such as

feeling tired. This should help you

carry out your normal daily tasks.

Before you use

SYLVANT

When you must not use it

Do not use SYLVANT if you know

you are allergic to siltuximab or

any of the other ingredients listed

at the end of this leaflet.

Symptoms of an allergic reaction

may include skin rash, itching or

hives on the skin, shortness of breath,

wheezing or difficulty breathing,

swelling of the face, lips, tongue or

other parts of the body.

Do not use it after the expiry date

printed on the pack.

Do not use it if the packaging is

torn or shows signs of being

tampered with.

Before you start to use it

SYLVANT should be used with

caution in some patients.

Tell your doctor, pharmacist or

nurse before you are given

SYLVANT, if:

you have an infection at the

moment.

you are due to have a vaccine or

may need to have one in the near

future – this is because some

vaccines should not be given with

SYLVANT.

you have high levels of fats in

your blood (hyperlipidaemia) –

this is because SYLVANT may

increase these levels. Your doctor

may prescribe medicines to

correct this.

you had a risk of getting a hole or

tear in the stomach or gut

(gastrointestinal perforation) such

as intestinal ulcers or

diverticulitis. Signs of this

include stomach pain getting

worse, feeling sick (nausea),

change in bowel habits and fever.

you have kidney disease.

you have liver disease or changes

that show up in blood tests of the

liver.

you get any new health problems

or any of them get worse.

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.

SYLVANT

MARCH 2021 CMI 3

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including any that you

buy without a prescription from

your pharmacy, supermarket or

health food shop.

SYLVANT might interact with other

medicines. Using SYLVANT with

certain other medicines may result in

greater or lesser effects or even side

effects from these medicines. Tell

your doctor about everything you are

taking including prescription and

non-prescription medicines, vitamins

and herbal supplements so that your

doctor can tell you whether you can

continue the medicines you are

taking or reduce the dose.

Be sure to tell your doctor if you are

taking:

theophylline, used to treat asthma

warfarin (a blood thinner), used

to stop your blood from clotting

cyclosporin, used during and after

organ transplants

oral contraceptives to prevent

pregnancy

If you are not sure if any of the above

apply to you, talk to your doctor or

pharmacist before you are given

SYLVANT.

How SYLVANT is

given

SYLVANT will be prepared and

given to you by a healthcare

professional. SYLVANT is

administered as an intravenous

infusion, which means that the

medicine will be administered to you

through a needle placed in a vein in

your arm. The infusion will be given

to you over a period of about 1 hour.

SYLVANT will be given every 3

weeks. During the infusion with

SYLVANT, you will be monitored

for side effects.

Follow your doctor's instructions

carefully and do not stop receiving

SYLVANT infusions without

consulting your doctor first.

You will receive treatment until

you and your doctor agree that you

will no longer benefit from the

treatment.

If you forget to use it

If you forget or miss your

appointment to be given SYLVANT,

make another appointment as soon as

possible.

Overdose

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 or anybody else has

been given too much SYLVANT,

contact your doctor, pharmacist or

the Poisons Information Centre who

will advise you what to do. The side

effects of having too much

SYLVANT are not known.

You can contact the Poisons

Information Centre by dialling:

Australia: 13 11 26

New Zealand: 0800 POISON or

0800 764 766

You may need urgent medical

attention.

While you are using

SYLVANT

Things you must do

Follow your doctor's instructions

carefully.

Tell your doctor if you are

pregnant or are planning to

become pregnant before using

SYLVANT. SYLVANT is not

recommended for use during

pregnancy.

It is not known if SYLVANT

may affect the baby of 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.

It is not known if SYLVANT

passes into breast milk.You and

your doctor should decide if you

will take SYLVANT or

breast-feed. You should not do

both.

Tell all of your doctors, dentists,

and pharmacists who are treating

you that you are taking SYLVANT

before taking any new medicines

that they may prescribe for you.

Ask your doctor or pharmacist

before taking any other medicines.

These include herbal treatments and

those bought in a pharmacy or

supermarket.

Allergic reactions

Tell your doctor or nurse

immediately 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 immediately, 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 giving you

SYLVANT right away.

SYLVANT

MARCH 2021 CMI 3

Things you must not do

Do not miss or stop the treatment

without consulting your doctor

first.

Do not give SYLVANT to anyone

else, even if they have the same

condition as you.

Things to be careful of

SYLVANT is not likely to affect you

being able to drive or use tools or

machines.

Side Effects

All medicines may have some

unwanted side effects although not

everyone will get them. Sometimes

they are serious, but most of the time

they are not. Your doctor has

weighed the risks of using this

medicine against the benefits they

expect it will have for you.

Do not be alarmed by this list of

possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to

answer any questions you may

have about the risks of SYLVANT

treatment.

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are receiving

SYLVANT.

Tell your doctor if you notice any

of the following and they worry

you:

respiratory infections

itching

rash

These are mild side effects of

SYLVANT but may require medical

attention.

Other side effects from SYLVANT

are a drop in number of white blood

cells, low blood platelet count, itchy

skin rash (eczema), high fat levels in

your blood, high level of cholesterol

in the blood, high levels 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, urinary

tract infection, common cold, sore

throat, stomach pain or discomfort,

constipation, diarrhea, heartburn,

ulcers (sores) in the mouth, nausea,

vomiting, feeling dizzy, headache,

joint pain, arm or leg pain and weight

gain. If these or any other effects

occur, talk to your doctor without

delay.

Tell your doctor immediately, or

go to Accident and Emergency at

your nearest hospital if you notice

signs of severe allergic

(hypersensitivity) reaction like

difficulty breathing, chest

tightness, wheezing, severe

dizziness or light-headedness,

swelling of the lips, or skin rash.

As with other medications similar

to SYLVANT, allergic reactions

may occur. These may be serious

side effects of SYLVANT. You may

need urgent medical attention and

your doctor may need to stop your

treatment.

Tell your doctor if you notice

anything else that is making you

feel unwell.

Other side effects not listed above

may occur in some consumers.

Do not hesitate to report any other

side effects to your doctor or

pharmacist.

After using it

Storage

SYLVANT must be stored in the

refrigerator (2ºC-8ºC). Heat and

dampness can destroy some

medicines.

SYLVANT should not be used after

the expiration date stated on the label

and carton even if it is stored

properly.

Keep it where young children

cannot reach it.

Product Description

What it looks like

SYLVANT is supplied in a vial as a

powder for concentrate for solution

for infusion. Each vial contains either

100 mg or 400 mg of siltuximab.

Ingredients

The active ingredient in SYLVANT

is siltuximab. The other ingredients

in SYLVANT are histidine,

polysorbate-80, and sucrose.

Sponsor

Link Pharmaceuticals Ltd.

Suite 32

Level 26, PwC Tower

188 Quay Street

Auckland 1010

Telephone: +64 (9) 358 7146

Medical Information

Email: medinfo@linkhealthcare.co

Registration Numbers

100mg vials

AUST R 229996

400mg vials

AUST R 229997

This leaflet was prepared in March

2021.

Read the complete document

SYLVANT DATA SHEET – 22Mar2021

Page 1 of 13

SYLVANT

Siltuximab

NEW ZEALAND DATA SHEET

1. PRODUCT NAME

SYLVANT 100 mg powder for infusion concentrate

SYLVANT 400 mg powder for infusion concentrate

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

SYLVANT is a chimeric (human murine) immunoglobulin G1k (IgG1k) monoclonal antibody

against human Interleukin-6 (IL-6) produced in a Chinese Hamster Ovary (CHO) cell line.

SYLVANT 100 mg powder for infusion concentrate

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 infusion concentrate

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.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for infusion 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 DOSE AND METHOD OF ADMINISTRATION

The recommended dose is 11 mg/kg siltuximab given over 1 hour as an intravenous infusion

administered every 3 weeks until treatment failure.

Intravenous

infusion

(IV)

SYLVANT

should

administered

qualified

healthcare

professionals.

Appropriate

personnel

medicinal

product

should

available

treat

anaphylaxis if it occurs.

SYLVANT DATA SHEET – 22Mar2021

Page 2 of 13

Treatment criteria

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 prescriber 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

≥1.0 × 10

≥ 1.0 × 10

Platelet count

≥ 75 × 10

≥ 50 × 10

Haemoglobina

< 170 g/L

< 170 g/L

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

Renal Impairment

No formal studies have been conducted to investigate the pharmacokinetics of SYLVANT in

patients with renal impairment. No dose adjustments can be recommended (see section 4.4).

Hepatic Impairment

No formal studies have been conducted to investigate the pharmacokinetics of SYLVANT in

patients with hepatic impairment. No dose adjustments can be recommended (see section 4.4).

Method of administration

SYLVANT 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. See section 6.1.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

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).

SYLVANT DATA SHEET – 22Mar2021

Page 3 of 13

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, 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 IV 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

therapeutic

administration

antihistamines,

acetaminophen,

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 medication should be

available to treat anaphylaxis if it occurs (see section 4.8).

Appropriate personnel and medicinal product should be available to treat anaphylaxis if it occurs.

Malignancy

Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience

with siltuximab, the present data do not suggest any increased risk of malignancy.

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 or suggestive of GI

perforation.

Special populations

Paediatric Use

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

Use in the Elderly

population

siltuximab

were

analysed

evaluate

effects

demographic

characteristics. The results showed no significant difference in the PK of siltuximab in patients

older than 65 years. No major age related differences in pharmacokinetic (PK) or in safety profile

were observed in clinical studies. No dose adjustment is required.

SYLVANT DATA SHEET – 22Mar2021

Page 4 of 13

Renal Impairment

No formal studies have been conducted to investigate the pharmacokinetics of SYLVANT in

patients with renal impairment. For subjects 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 studies have been conducted to investigate the pharmacokinetics of SYLVANT in

patients with hepatic impairment. For subjects with baseline alanine transaminase ranging from

0.1 to 3.7 times the upper limit of normal and baseline albumin ranging from 1.5 to 5.8 g/dL, there

was no meaningful effect on siltuximab PK.

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-treated patients with known hepatic impairment as well as patients with

elevated transaminase or bilirubin levels should be monitored.

4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS

No formal drug-drug 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 drug 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 drug concentration (e.g.,

cyclosporine 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. Prescribers should also exercise caution when SYLVANT

is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be

undesirable (e.g., oral contraceptives).

4.6 FERTILITY, PREGNANCY AND LACTATION

Pregnancy

Category C

There are no data from the use of SYLVANT in pregnant women. No maternal or foetal toxicity

was observed in cynomolgus monkeys after intravenous administration of siltuximab. It is not

known whether siltuximab can cause foetal harm when administered to a pregnant woman or can

affect reproduction capacity. SYLVANT should be given to a pregnant woman only if the benefit

clearly outweighs the risk. Women of childbearing potential must use effective contraception

during and up to 3 months after treatment. Prescribers 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). As with other immunoglobulin G

antibodies, siltuximab crosses the placenta as 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.

Breast-feeding

It is not known whether siltuximab or its metabolites are excreted in human milk. Because many

drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse

reactions in nursing infants from SYLVANT, a decision should be made whether to discontinue

nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

SYLVANT DATA SHEET – 22Mar2021

Page 5 of 13

Fertility

Effects of siltuximab on fertility have not been evaluated in human patients. In cynomolgus

monkeys dosed intravenously with siltuximab, no histopathological changes were noted in the

reproductive tissues. In mice dosed subcutaneously with an anti-mouse IL-6 monoclonal

antibody, no effects on male or female fertility were observed.

4.7 EFFECT ON ABILITY TO DRIVE AND OPERATE MACHINERY

No studies of the effects on the ability to drive and use machines have been performed. It is not

known if SYLVANT has an effect on motor skills.

4.8 UNDESIRABLE EFFECTS

Data from all patients treated with SYLVANT 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.

In Study 1, a randomised placebo controlled Phase 2 study in (MCD), 53 patients were

randomised to the SYLVANT treatment arm and treated at the recommended dose,

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 SYLVANT.

In Study 2, a Phase 1 study, 16 of 37 patients with CD were treated with SYLVANT, at the

recommended dosage of 11 mg/kg every 3 weeks.

In Study 3, an open-label, multicenter, non-randomized 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.

The most frequent adverse reactions (> 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 adverse reaction associated with the use of SYLVANT was anaphlyactic

reaction.

Adverse reactions observed in MCD patients treated with SYLVANT at the recommended dosage

of 11 mg/kg every 3 weeks are summarised in Table 2.

Table 2:

Adverse Reactions in SYLVANT Treated Patients in MCD Clinical Studies

SYLVANT + BSC

a

N=87

Placebo + BSC

b

N=26

All Grades

(%)

Grade 3-4 (%)

All Grades

(%)

Grade 3-4 (%)

Infections and infestations

Nasopharyngitis

17.2%

0.0%

3.8%

0.0%

Upper respiratory tract infection

42.5%

0.0%

15.4%

3.8%

Urinary tract infection

10.3%

0.0%

0.0%

0.0%

Blood and lymphatic system disorders

Neutropenia

10.3%

3.4%

7.7%

3.8%

Thrombocytopenia

12.6%

2.3%

3.8%

3.8%

Immune system disorders

Anaphylactic reaction

1.1%

1.1%

0.0%

0.0%

Metabolism and nutrition disorders

Hypertriglyceridemia

17.2%

2.3%

0.0%

0.0%

Hyperuricemia

13.8%

3.4%

0.0%

0.0%

Hypercholesterolemia

9.2%

0.0%

0.0%

0.0%

SYLVANT DATA SHEET – 22Mar2021

Page 6 of 13

SYLVANT + BSC

a

N=87

Placebo + BSC

b

N=26

All Grades

(%)

Grade 3-4 (%)

All Grades

(%)

Grade 3-4 (%)

Nervous system disorders

Dizziness

19.5%

1.1%

7.7%

0.0%

Headache

13.8%

1.1%

3.8%

0.0%

Vascular disorders

Hypertension

18.4%

8.0%

3.8%

0.0%

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain

13.8%

0.0%

3.8%

0.0%

Gastrointestinal disorders

Nausea

19.5%

4.6%

19.2%

0.0%

Abdominal pain

15.9%

0.0%

3.8%

3.8%

Vomiting

17.2%

3.4%

7.7%

0.0%

Constipation

19.5%

0.0%

3.8%

0.0%

Diarrhea

28.7%

1.1%

19.2%

3.8%

Gastroesophageal reflux disease

10.3%

0.0%

0.0%

0.0%

Mouth ulceration

13.8%

0.0%

3.8%

0.0%

Skin and subcutaneous tissue disorders

Rash

21.8%

0.0%

3.8%

0.0%

Pruritus

32.2%

0.0%

15.4%

0.0%

Eczema

11.5%

0.0%

0.0%

0.0%

Musculoskeletal and connective tissue disorders

Arthralgia

20.7%

0.0%

7.7%

0.0%

Pain in extremity

10.3%

0.0%

0.0%

0.0%

Renal and urinary disorders

Renal impairment

10.3%

2.3%

0.0%

0.0%

General disorders and administration site conditions

Localised oedema

14.9%

2.3%

3.8%

0.0%

Investigations

Weight increased

17.2%

2.3%

0.0%

0.0%

All patients with CD treated with SYLVANT at recommended dosage of 11 mg/kg every 3 weeks

[including crossover patients (N=87)], BSC=Best Supportive Care

All patients with CD treated with placebo (N=26)

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 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).

4.9 OVERDOSE

No case of overdose has been reported. Repeated dosing of 15 mg/kg every 3 weeks has been

administered without additional adverse drug reactions.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

SYLVANT DATA SHEET – 22Mar2021

Page 7 of 13

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 signalling complex with gp130 on the cell surface. IL-6 is a pleiotropic pro-

inflammatory cytokine produced by a variety of cell types including T 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,

stimulation

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

growth

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 (IgM) 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 SYLVANT (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 SYLVANT 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 SYLVANT arm). ECOG performance

status score (0/1/2) at baseline was 42%/45%/13% in SYLVANT arm and 39%/62/0% in the

placebo arm respectively. At baseline 55% of patients in the SYLVANT arm and 65% of patients

in the placebo arm had received prior systemic therapies for MCD and 30% of patients in the

SYLVANT arm and 31% in the placebo arm were using corticosteroids. Histological subtype was

similar in both treatment arms, with 33% hyaline vascular subtype, 23% plasmacytic subtype and

44% mixed subtype. Disease related baseline laboratory parameters are summarised in Table 3.

CRP and erythrocyte sedimentation rate (ESR) showed wide variability across both treatment

arms.

SYLVANT DATA SHEET – 22Mar2021

Page 8 of 13

Table 3: Disease Related Baseline Laboratory Parameters

SYLVANT + BSC

Placebo + BSC

Patients in Intent To Treat population

Haemoglobin (g/L) Mean (SD)

115.8 (24.70)

130.0 (25.70)

Platelets (109/L) Mean ( SD)

323.2 (156.58)

302.6 (123.54)

Albumin (g/dL) Mean (SD)

3 5 (0.76)

3.6 (0.46)

ESR (mm/hr) Mean (SD)

68.3 (48.66)

34.6 (35.06)

CRP (mg/L) Mean (SD)

43.2 (53.63)

24.8 (34.53)

Fibrinogen (µmol/L) Mean (SD)

16.9 (7.52)

15.3 (7.48)

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.

Study 1 demonstrated a statistically significant improvement in independently reviewed durable

tumour and symptomatic response rate in the SYLVANT arm compared with the placebo arm

(34% vs. 0%, respectively; 95% CI: 11.1, 54.8; p=0.0012). Sensitivity analyses further supported

the primary endpoint analysis showing a significantly higher investigator assessed durable tumour

and symptom response rate of 45% in SYLVANT treated patients compared with 0% in placebo

treated patients (p <0.0001). 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 4.

Table 4: Efficacy Endpoints From Study 1

Efficacy Endpoints

SYLVANT+BSC

a

Placebo+BSC

p-value

b

Primary Efficacy Endpoint

Durable tumour & symptomatic

response (independent review)

18/53 (34.0%)

0/26 (0%)

0.0012

Secondary Efficacy Endpoints

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 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)

Durable complete symptomatic

response

13/53 (24.5%)

0/26 (0%)

0.0037

Duration of durable complete

symptomatic response (days) median

(min, max)

472 (169, 762)

Best Supportive Care

Adjusted for corticosteroid use at randomisation

At the time of primary analysis data for 19 of 20 tumour and symptomatic responders were censored due to on-

going response

N/A=“Not applicable”, there were no responders in the placebo arm, therefore, duration is not applicable

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

Data from 11 of 13 durable complete symptomatic responders

were censored due to on-going response

SYLVANT DATA SHEET – 22Mar2021

Page 9 of 13

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, dyspnoea, and

pruritus) autoimmune phenomena, fluid retention, neuropathy, and skin disorders] and was

calculated. The percent change

from baseline in MCD-related

signs

and symptoms

MCD-related overall symptom score at each cycle was calculated. Complete symptom response

was defined as a 100% reduction from the baseline 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 ≥ 15g/L at week 13. Mean

haemoglobin by cycle during the blinded treatment period is presented in Figure 1.

Figure 1: Mean haemoglobin by cycle during the blinded treatment period

One-year survival rate was 100% in the SYLVANT arm and 92% in the placebo arm.

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, EMEA, 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

SYLVANT arm except for the hyaline vascular subgroup. A consistent treatment effect favouring

SYLVANT 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 5.

SYLVANT DATA SHEET – 22Mar2021

Page 10 of 13

Table 5:

Select Efficacy Endpoints for Hyaline Vascular Subgroup from Study 1

Efficacy endpoints

SYLVANT+BSC

Placebo+BSC

95% CI

a

Primary efficacy endpoint

Durable tumour & symptomatic

response (independent review)

0/18 (0%)

0/8 (0%)

(N/A, N/A)

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)

Haemoglobin increase > 15 g/L

at Week 13/haemoglobin

response-evaluable population

3/7 (42.9%)

0/4 (0%)

(-22.7; 83.7)

Durable complete symptomatic

response

3/18 (16.7%)

0/8 (0%)

(-25.7; 55.9)

95% confidence interval for the for the difference in proportions

N/A = “Not applicable”, there were no responders therefore 95% CI is not applicable

95% confidence interval for the hazard ratio

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 were treated with SYLVANT. 35 of whom had MCD.

In total, 16 patients with MCD were treated with 11 mg/kg every 3 weeks. Patient demographics

and disease characteristics for patients treated at 11 mg/kg every 3 weeks were similar to those

in Study 1. Median age was 51 years (21-76) and 50% were male. ECOG performance status

score (0/1/2) at baseline was 6%/69%/25% respectively. Sixty-nine percent of patients had

received prior systemic therapies for MCD. Histological subtype was 44% hyaline vascular

subtype, 50% plasmacytic subtype and 6% mixed subtype. The mean (SD) haemoglobin level

was 125 (23) g/L.

The clinical benefit observed in Study 1 was supported by Study 2. Median duration of SYLVANT

treatment was 1278 days and mean number of SYLVANT administrations was 51 in SYLVANT

patients. 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. For patients with haemoglobin below lower limit of normal

at baseline, the haemoglobin response rate at Week 13 was 50%. The 1-year survival rate of

SYLVANT treated patients was 100%.

Study 3

An open-label, multicenter, non-randomized Phase 2 study assessed the safety and efficacy of

extended treatment with siltuximab in 60 patients with MCD who were previously enrolled in

Study CNTO328MCD2001 (41 patients) or Study C0328T03 (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.

SYLVANT DATA SHEET – 22Mar2021

Page 11 of 13

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 (C

) 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 every

week

infusion

with

mean

peak

trough

concentrations

84 ± 66 mcg/mL, respectively.

Immunogenicity

As with all therapeutic proteins, there is potential for the generation of anti-drug 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 single agent and combination studies 4 of 432 (0.9%) evaluable

patients tested positive for anti-siltuximab antibodies. Further immunogenicity analyses were

conducted for all positive samples from the 4 patients with detectable anti-siltuximab antibodies.

None of these patients had neutralizing 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 pharmacokinetics 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, ethnicity and use of corticosteroids.

The effect of anti-siltuximab antibody status was not examined as there were insufficient numbers

of anti-siltuximab antibody positive patients.

5.3 PRECLINICAL SAFETY DATA

Genotoxicity

Formal genotoxicity studies have not been performed for siltuximab.

Carcinogenicity

Formal carcinogenicity studies have not been performed for siltuximab.

6. PHARMACEUTICAL PARTICULARS

6.1 LIST OF EXCIPIENTS

Histidine

Polysorbate-80

Sucrose.

6.2 INCOMPATIBILITIES

In the absence of compatibility studies, this medicinal product must not be mixed with other

medicinal products.

SYLVANT DATA SHEET – 22Mar2021

Page 12 of 13

6.3 SHELF LIFE

36 months

After reconstitution and dilution

Chemical and physical in use stability has been demonstrated for 8 hours at room temperature.

Unless

method

opening

reconstitution

dilution

precludes

risk

microbial

contamination, the product should be used immediately after reconstitution.

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. Keep out of the sight and reach of children.

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 infusion concentrate

The product is supplied (as a sterile, single-use lyophilised dosage form) in an 8 mL Type 1 glass

vial with an elastomeric closure and an aluminium seal with a flip-off button.

SYLVANT 400 mg powder for infusion concentrate

The product is supplied (as a sterile, single-use lyophilised dosage form) in an 30 mL Type 1

glass vial with an elastomeric closure and an aluminium seal with a flip-off button.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING

This 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 1-½ inch.

Infusion bags (250 mL) must contain Dextrose 5% and must be made of made of Polyvinyl

chloride

(PVC),

Polyolefin

(PO),

polypropylene

(PP),

polyethylene

(PE).

Alternatively, PE bottles may be used.

Allow vial(s) of SYLVANT to come to room temperature over approximately 30 minutes.

SYLVANT should remain at room temperature for the duration of the preparation.

For 100 mg and 400 mg vials: Each vial should/must be reconstituted as instructed in

Table

6.

Table 6:

Reconstitution Instructions

Strength

Amount of Sterile Water for

Injection, required for

reconstitution

Post-reconstitution

concentration

100 mg vial

5.2 mL

20 mg/mL

400 mg vial

20.0 mL

20 mg/mL

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

vials to aid the dissolution of the lyophilised powder. Do not remove contents until all of

the solids have been completely dissolved. The lyophilised powder should dissolve in less

than 60 minutes. Inspect the vials for particulate matter and discoloration prior to dose

preparation. Do not use if visibly opaque or foreign particles and/or solution discoloration

are present. Dilute the total volume of the reconstituted SYLVANT solution dose to 250 mL

SYLVANT DATA SHEET – 22Mar2021

Page 13 of 13

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 product SYLVANT should be kept for no more than two hours prior to

addition into the IV 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 reuse.

No physical biochemical compatibility studies have been conducted to evaluate the co-

administration of SYLVANT with other agents. 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. MEDICINE SCHEDULE

Prescription Medicine

8. SPONSOR

Link Pharmaceuticals Ltd.

Suite 32

Level 26, PwC Tower

188 Quay Street

Auckland 1010

Telephone: +64 (9) 358 7146

Medical Information

Email: medinfo@linkhealthcare.co

9. DATE OF FIRST APPROVAL

2 July 2015

10. DATE OF REVISION OF THE TEXT

22 March 2021

SUMMARY TABLE OF CHANGES

Section

changes

Summary of new information

Datasheet reformat

Addition of a warning for hepatic impairment

Addition of several new adverse reactions from MCD Studies. Revisions to

the frequencies of existing adverse reactions. Revisions to add information

pertaining to the patients enrolled in Study 3.

Addition of results of overall survival data (Study 3).

Revisions to the existing immunogenicity information.

Update to sponsor details due to product transfer.

Update to Medical Information contact details.

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