Sylvant

Get emergency medical help if you have any of these signs of an allergic reaction: hives; chest tightness, difficult breathing; swelling of your face, lips, tongue, or throat.

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy or light-headed, or have a chest tightness, trouble breathing, or swelling in your face.

Call your doctor at once if you have:

• bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
• signs of infection, such as fever, chills, painful mouth sores, pain when swallowing, cold or flu symptoms, cough, trouble breathing; or
• signs of a kidney problem--little or no urinating; painful or difficult urination; swelling in your feet or ankles; severe pain in your side or lower back.

Common side effects may include:

• weight gain;
• itching or rash;
• cold symptoms such as stuffy nose, sneezing, sore throat; or
• high levels of uric acid in your blood (can lead to kidney problems or gout symptoms such as joint stiffness, pain, or swelling).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Sylvant, there are no specific foods that you must exclude from your diet when receiving this medication.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based your weight.

The recommended dose of Sylvant for the treatment of multicentric Castleman's disease (MCD) is 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks.

• Keep all appointments with your doctor.

Siltuximab is injected into a vein through an IV. A healthcare provider will give you this injection once every 3 weeks. Follow your doctor's dosing instructions very carefully.

Before each injection, your doctor may perform blood tests to make sure you do not have conditions that would prevent you from safely using siltuximab.

Siltuximab must be given slowly and the IV infusion can take at least 1 hour to complete.

Siltuximab can lower blood cells that help your body fight infections. Your blood will need to be tested often. Your siltuximab treatments may be delayed based on the results of these tests.

No formal drug interaction studies to date.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increased metabolism of drugs metabolized by CYP isoenzymes.1 Because IL-6 may downregulate CYP isoenzymes, inhibition of IL-6 by siltuximab may restore CYP enzyme activity to higher levels.1 Effects on CYP enzyme activity may persist for several weeks after drug discontinuance.1

Drugs metabolized by CYP isoenzymes that have a low therapeutic index: Monitor therapeutic effect and/or serum concentrations following initiation or discontinuance of siltuximab and adjust dosage, if necessary.1

CYP3A4 substrates: Caution advised when a reduction in efficacy of the substrate would be undesirable.1

Specific Drugs

If you will be using this medicine for a long time, it is very important that your doctor check you at regular visits for any problems or unwanted effects that may be caused by this medicine. Blood tests may be needed to check for unwanted effects.

Make sure your doctor knows if you are pregnant or planning to become pregnant. You must use an effective form of birth control to keep from getting pregnant during therapy and for 3 months after the last dose of this medicine.

Your body's ability to fight infection may be reduced while you are using siltuximab. It is very important that you call your doctor at the first sign of any infection. Check with your doctor right away if you have any of the following symptoms while receiving this medicine: a fever, chills, cough, flu-like symptoms, or unusual tiredness or weakness.

While you are being treated with siltuximab, do not have any immunizations (vaccines) without your doctor's approval. Live virus vaccines should not be given with this medicine or soon after you receive it.

This medicine may cause a serious allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor right away if you have a rash, itching, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are receiving this medicine.

Siltuximab may cause an infusion reaction while you are receiving it or right after the infusion ends. Check with your doctor or nurse right away if you have back pain, chest pain or discomfort, fast or uneven heartbeat, nausea or vomiting, trouble breathing, or redness of the face, neck, arms, and upper chest.

This medicine may increase your risk of gastrointestinal perforation. Tell your doctor right away if you have any of the following symptoms: severe abdominal or stomach pain or cramps, bloody, black, or tarry stools, or vomiting of material that looks like coffee grounds.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• If you have an allergy to siltuximab or any other part of Sylvant (siltuximab).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have an infection.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with Sylvant.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Dizziness or passing out.
• Very bad belly pain.
• Upset stomach or throwing up.
• Back pain.
• Chest pain.
• A heartbeat that does not feel normal.
• Flushing.
• Swelling.
• Any unexplained bruising or bleeding.

Sylvant is 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.

Limitation 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.

Sylvant (siltuximab) is a human-mouse chimeric monoclonal antibody that binds human interleukin-6 (IL-6). Sylvant is produced by Chinese hamster ovary cells.

Sylvant is supplied as a sterile, white, preservative free, lyophilized powder in single-use vials.

Each Sylvant 100 mg single-use vial contains 100 mg siltuximab, 3.7 mg L-histidine (from L-histidine and L-histidine monohydrochloride monohydrate), 0.8 mg polysorbate 80, and 169 mg sucrose.

Each Sylvant 400 mg single-use vial contains 400 mg siltuximab, 14.9 mg L-histidine (from L-histidine and L-histidine monohydrochloride monohydrate), 3.2 mg polysorbate 80, and 677 mg sucrose.

Following reconstitution with Sterile Water for Injection, USP (per section 2.2), the resulting pH is approximately 5.2. The resulting solution contains 20 mg/mL siltuximab to be administered by intravenous infusion following dilution [see Dosage and Administration (2)].

Study 1

The clinical efficacy and safety of Sylvant for the treatment of patients with MCD was established in Study 1, a Phase 2, multinational, randomized (2:1) double blind, placebo controlled study. In this study 53 patients were randomized to Best Supportive Care (BSC) and Sylvant at a dose of 11 mg/kg every 3 weeks and 26 patients were randomized to BSC and placebo. The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The histological subtype of MCD was similar in both treatment arms, with 33% hyaline vascular subtype, 23% plasmacytic subtype and 44% mixed subtype. 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.

The major efficacy outcome of the study was durable tumor and symptomatic response, defined as tumor response (PR and CR based on modified International Working Group response criteria for malignant lymphoma) assessed by independent review and complete resolution or stabilization of MCD symptoms. Thirty-four MCD related signs and symptoms prospectively identified were collected and graded according to the NCI-CTCAE v 4, by investigators. A durable response was defined as tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. The durable tumor and symptomatic response in the Sylvant arm was 34% compared to 0% in the placebo arm (95% CI: 11.1, 54.8; p=0.0012).

Other analyses included tumor response, time to treatment failure and an increase in hemoglobin of 1.5 g/dL or more, in patients who were anemic at time of study entry, at week 13. The results are summarized in Table 5.

A consistent treatment effect was confirmed on subgroup analysis for all parameters evaluated with the exception of the hyaline vascular histological subtype. There were no patients with hyaline vascular histology who demonstrated a durable tumor and symptomatic response. However, activity was suggested in this subtype based on change in hemoglobin and median time to treatment failure.

At the time of the analysis, overall survival data were not mature. One year survival rate was 100% in the Sylvant arm and 92% in the placebo arm.

NDC 57894-420-01

Single Use Only
Discard Unused Portion

Sylvant®
(siltuximab)

For Injection

100 mg

For Intravenous
Infusion Only

Reconstitution: Reconstitute with
5.2 mL Sterile Water for Injection, USP.
Dilution: Must be further diluted with
5% Dextrose Injection, USP.

Janssen Biotech, Inc.
Rx Only

Sylvant (siltuximab) inhibits a certain protein in the body called interleukin-6 (IL-6). High levels of IL-6 can cause an overgrowth of cells in the lymph system (part of your immune system).

Sylvant is used to treat Multicentric Castleman's Disease (MCD). MCD is a rare condition in which the body produces too much of a certain type of white blood cell. MCD can increase your risk of certain cancers by changing the way your immune system works.

Sylvant is not for use in people who have human immunodeficiency virus (HIV) or human herpesvirus-8.

Do not receive a "live" vaccine while using Sylvant. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Other drugs may interact with siltuximab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Applies to siltuximab: intravenous powder for injection

General

The most common adverse reactions were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 63%)
Common (1% to 10%): Lower respiratory tract infection, oropharyngeal pain[Ref]

Dermatologic

Very common (10% or more): Rash (28%), pruritus (28%)
Common (1% to 10%): Skin hyperpigmentation, eczema, psoriasis, dry skin[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 32%), abdominal pain/abdominal distention (12%)
Common (1% to 10%): Constipation
Frequency not reported: Gastrointestinal perforation[Ref]

Metabolic

Very common (10% or more): Weight increased (19%), hyperuricemia (11%)
Common (1% to 10%): Hypertriglyceridemia, hypercholesterolemia, decreased appetite, dehydration[Ref]

Cardiovascular

Very common (10% or more): Edema (26%)
Common (1% to 10%): Hypotension[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Anaphylactic reaction[Ref]

Other

Very common (10% or more): Fatigue (21%)
Common (1% to 10%): Infusion related reaction[Ref]

Infusion related reactions included back pain, chest pain/discomfort, nausea and vomiting, flushing, erythema, and palpitations.[Ref]

Musculoskeletal

Very common (10% or more): Pain in extremities (21%), arthralgia (21%)[Ref]

Renal

Common (1% to 10%): Renal impairment[Ref]

Hematologic

Common (1% to 10%): Thrombocytopenia[Ref]

Nervous system

Common (1% to 10%): Headache[Ref]

Immunologic

Uncommon (0.1% to 1%): Positive test for anti-siltuximab (the active ingredient contained in Sylvant) antibodies[Ref]

Some side effects of Sylvant may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.