Brand Information

Strength	Rate	Packing Style
mg	0.00	unit injection

Indication:

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

SYLVANT® safely and effectively. See full prescribing information for SYLVANT. SYLVANT (siltuximab) for injection, for intravenous use

Initial U.S. Approval: 2014

RECENT MAJOR CHANGES

Dosage and Administration (2.2) 05/2018 Contraindications 05/2018 Warnings and Precautions, Infusion Related Reactions and Hypersensitivity 05/2018

INDICATIONS AND USAGE

SYLVANT is an interleukin-6 (IL-6) antagonist indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.

Limitations of Use -

SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.

DOSAGE AND ADMINISTRATION

For intravenous infusion only. Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks.

Proprietary Name- SYLVANT INJECTION*

Established Name- Siltuximab

Applicant- JANSSEN BIOTECH.INC

Indication- Treatment of patients with multicentric Castlemans Disease

(MCD) who are human immunodeficiency virus(HIV) -negative

and human herpes virus -8 (HHV-8)- negative

Approval Date- 23/4/2014

Approved by U.S.FDA (Ref- FDA approved List- 2014)

Adverse Reaction:

ADVERSE REACTIONS

The most common adverse reactions (>10% of patients) were rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia.

.

Contra-Indications:

CONTRAINDICATIONS

Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT. (4) ---

WARNINGS AND PRECAUTIONS

Concurrent Active Severe Infections: Do not administer SYLVANT to patients with severe infections, monitor for infections, institute prompt treatment, and interrupt SYLVANT until resolution of infection.

Vaccinations: Do not administer live vaccines because IL-6 inhibition may interfere with the normal immune response to new antigens.

Infusion Related Reactions: Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.

Gastrointestinal (GI) perforation: Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation.

ADVERSE REACTIONS

The most common adverse reactions (>10% of patients) were rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia. To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA1088 or www.fda.gov/medwatch.

Dosages/ Overdosage Etc:

Indication- Treatment of patients with multicentric Castlemans Disease

(MCD) who are human immunodeficiency virus(HIV) -negative

and human herpes virus -8 (HHV-8)- negative

INDICATIONS AND USAGE

SYLVANT is an interleukin-6 (IL-6) antagonist indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.

Limitations of Use -

SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.

DOSAGE AND ADMINISTRATION

For intravenous infusion only. Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks.

DOSAGE FORMS AND STRENGTHS

For injection ? 100 mg of lyophilized powder in a single-dose vial. (3) ? 400 mg of lyophilized powder in a single-dose vial.

Patient Information:

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Instruct the patient of the risks of SYLVANT treatment.

Infections Inform patients that SYLVANT may lower their resistance to infections.

Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.

Vaccination-

Inform the patient that they should discuss the recommended vaccinations prior to treatment with SYLVANT.

Allergic Reactions -

Advise patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions during the infusion. Signs include: difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips or skin rash.

Pregnancy

Advise patients of childbearing potential to avoid pregnancy which may include use of contraception during treatment and for 3 months after SYLVANT therapy.

Other Medical Conditions

Advise patients to report any signs of new or worsening medical conditions.

Manufactured by:

Janssen Biotech, Inc., Horsham, PA 19044

U.S. License No. 1864

At: Cilag AG, Schaffhausen, Switzerland

Product of the Netherlands

© Janssen Biotech, Inc. 2015

Pharmacology/ Pharmacokinetics:

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Siltuximab binds human IL-6 and prevents the binding of IL-6 to both soluble and membranebound IL-6 receptors. IL-6 has been shown to be involved in diverse normal physiologic processes such as induction of immunoglobulin secretion. Overproduction of IL-6 has been linked to systemic manifestations in patients with MCD.

2. Pharmacodynamics -

Cardiac Electrophysiology:

The effect of multiple doses of SYLVANT (15 mg/kg every 3 weeks for 4 cycles) on the QTc interval was evaluated in an open label, single arm study in 30 patients with Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Indolent Multiple Myeloma. No large changes in the mean QTc interval (i.e., > 20 ms) were detected in the study.

3.Pharmacokinetics -

The pharmacokinetics of siltuximab were evaluated in patients with multicentric Castleman’s disease and hematological and non-hematological malignancies. The serum siltuximab pharmacokinetics are adequately described by a linear two-compartment intravenous model with first-order elimination.

Distribution

Following SYLVANT administration (11 mg/kg, once every 3 weeks as 1-hour intravenous infusion) in patients with multicentric Castleman’s disease, the maximum serum siltuximab concentration (Cmax) occurred close to the end of infusion.

At steady state, the serum mean Cmax value for siltuximab is 332 mcg/mL (42% CV), and the serum mean predose trough value is 84 mcg/mL (78% CV).

Elimination

Based on the population pharmacokinetic analysis, the clearance of siltuximab in patients is 0.23 L/day (51% CV). Based on population pharmacokinetic analysis (n=378), body weight was identified as the only statistically significant covariate for siltuximab clearance. Therefore, the body weight based dosing is appropriate.

The mean terminal half-life (t1/2) for siltuximab in patients after the first intravenous infusion of 11 mg/kg is 20.6 days (range: 14.2 to 29.7 days).

Specific Populations Age and Gender

Based on population pharmacokinetic analysis, age [range: 18 to 85 years (n=378)] and gender [female (n=175), male (n=203)] do not affect exposure of siltuximab.

Renal Impairment

A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 377 patients enrolled in clinical trials, including 176 with normal renal function (CLCr = 90 mL/min), 122 with mild renal impairment (CLCr 60 to <90 mL/min), 75 with moderate renal impairment (CLCr 30 to <60 mL/min), and 3 with severe renal impairment (CLCr 15 to 29 mL/min).

The apparent clearance of siltuximab was similar in patients with preexisting mild, moderate and severe renal impairment (CLCr 15 to <90 mL/min) compared to patients with normal renal function.

The potential effect of end stage renal disease on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient.

Hepatic Impairment

A population pharmacokinetic analysis (based on pre-existing hepatic function) was carried out with data from 377 patients enrolled in clinical trials, including 302 with normal hepatic function, 72 with mild hepatic impairment (Child-Pugh A), and 3 with moderate hepatic impairment (Child-Pugh B).

The apparent clearance of siltuximab was similar in patients with pre-existing mild and moderate hepatic impairment (Child-Pugh Class A and B) compared to patients with normal hepatic function.

Pregnancy and lactation:

USE IN SPECIFIC POPULATIONS

1. Pregnancy -

Pregnancy Category

Risk-Summary -

There are no adequate or well-controlled studies in pregnant women.

In animal reproduction studies, administration of a human antibody to IL-6 to pregnant cynomolgus monkeys caused decreases in globulin levels in pregnant animals and in the offspring.

SYLVANT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Advise patients of childbearing potential to avoid pregnancy. Women of childbearing potential should use contraception during and for 3 months after treatment.

2. Nursing Mothers

It is not known whether siltuximab is excreted in human milk or absorbed systemically after ingestion.

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.

3.Pediatric Use -

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

4.Geriatric Use

Of the patients treated with SYLVANT monotherapy in clinical studies 127 (35%) were 65 years and older.

No overall differences in safety profile were observed between these patients and younger patients, and other reported clinical experience has not identified differences in the safety profile between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

5. Patients with Renal Impairment

Based on a population pharmacokinetic analysis using data from clinical trials in patients, no significant difference in siltuximab clearance was observed in patients with pre-existing renal impairment (creatinine clearance (CLCr) = 15 mL/min) compared to patients with baseline normal renal function (CLCr = 90 mL/min).

No initial dosage adjustment is necessary for patients with CLCr = 15 mL/min.

6.Patients with Hepatic Impairment

Based on a population pharmacokinetic analysis using data from clinical trials in patients, no significant difference in siltuximab clearance was observed in patients with pre-existing mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) compared to patients with baseline normal hepatic function.

No initial dosage adjustment is necessary for patients with mild to moderate hepatic impairment. Patients with baseline severe hepatic impairment (Child-Pugh Class C) were not included in clinical trials

SYLVANT INJECTION*

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Patient Information

Pharmacology/ Pharmacokinetics

Pregnancy and lactation