Siltuximab

Pregnancy Category: C

Lactation: Unknown if distributed in human breast milk; because many drugs and immunoglobulins are excreted in human milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• medications that use the enzyme CYP450 such as:

  • warfarin (Coumadin, Jantoven)
  • cyclosporine (Neoral, Sandimmune, Gengraf)
  • theophylline
  • lovastatin (Mevacor)
  • atorvastatin (Lipitor)
  • oral contraceptives

This is not a complete list of siltuximab drug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Siltuximab falls into category C. There are no well-controlled studies that have been done in pregnant women. Siltuximab should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

• Keep all appointments with your doctor.

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.

Multicentric Castleman's Disease (MCD)

Treatment of MCD in patients who are HIV-negative and human herpes virus type 8 (HHV-8)-negative1 2 (designated an orphan drug by FDA for this use).3

MCD is a rare lymphoproliferative disorder associated with excessive release of IL-6 and other proinflammatory cytokines.5 17 18 20 23 Pathogenesis not fully understood, but excessive production and dysregulation of IL-6 appear to play a prominent role and lead to stimulation of the production of acute phase reactants in the liver.5 17 20

Common systemic manifestations of MCD include fever, night sweats, anorexia, weight loss, weakness and fatigue, edema, effusions, pruritus, pain, and/or dyspnea.5 17 18 20 Laboratory abnormalities may include anemia, elevated concentrations of inflammatory markers (e.g., C-reactive protein [CRP]), hypergammaglobulinemia, and hypoalbuminemia.5 17 20

Manufacturer states siltuximab not studied for use in HIV- and HHV-8-positive patients with MCD† because the drug did not bind to virally produced IL-6 in a nonclinical study.1 Some clinicians suggest that anti-IL6 therapy may help to decrease IL-6 activity and help control the disease.17 20 21 22 Very limited clinical experience treating HIV- and HHV-8-associated MCD with anti-IL-6 therapy;17 20 21 22 clinical trials needed to determine whether siltuximab is effective in this population.17 20 (See Actions.)

Contraindications

• Severe hypersensitivity reaction to siltuximab or any ingredient in the formulation.1 (See Infusion-related Reactions and Hypersensitivity under Cautions.)

Warnings/Precautions

Concurrent Active Severe Infections

Siltuximab may mask signs and symptoms of acute inflammation (i.e., suppression of fever and acute phase reactants [e.g., CRP]).1

Do not administer siltuximab in patients with severe infections until the infection resolves.1

Closely monitor patients for possible infections.1 If an infection develops, promptly initiate anti-infective therapy and withhold siltuximab until the infection resolves.1

Immunization

Inhibition of IL-6 may interfere with the normal immune response to new antigens.1 Do not administer live vaccines to patients receiving siltuximab.1 (See Advice to Patients.)

Infusion-related Reactions and Hypersensitivity

Anaphylactic reaction reported rarely.1 If signs of anaphylaxis or other severe allergic reactions occur, immediately and permanently discontinue siltuximab therapy.1 (See Contraindications under Cautions.)

Infusion-related reactions (including back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations) reported in 4.8% of patients receiving siltuximab monotherapy.1

If mild or moderate infusion-related reactions occur, temporarily interrupt the siltuximab infusion; if reaction resolves, may resume infusion at a slower infusion rate.1 Consider treatment with antihistamines, acetaminophen, and corticosteroids.1 If unable to tolerate the infusion following these interventions, discontinue siltuximab.1

If severe infusion reactions or cytokine release syndromes occur, permanently discontinue therapy.1 (See Infusion-Related Reactions and Hypersensitivity under Dosage and Administration.)

GI Perforation

GI perforation reported in siltuximab-treated patients in clinical trials; however, no cases were reported in MCD trials of the drug.1

Use with caution in patients who may be at increased risk for GI perforation (e.g., those with diverticulitis or ulcers).1 Promptly evaluate patients if manifestations suggestive of GI perforation occur (e.g., stomach pain, nausea, change in bowel habits, fever).1 19

Immunogenicity

Potential for immunogenicity.1 Development of anti-siltuximab antibodies reported in 1 of 411 patients (0.2%) receiving siltuximab in clinical studies.1 No evidence of altered toxicity of the drug observed in the patient who developed the antibodies.1

Specific Populations

Category C.1

No adequate and well-controlled studies in pregnant women.1 Maternal and fetal toxicity was not observed when siltuximab was administered to pregnant animals; however, siltuximab crossed the placenta and fetal serum concentrations were similar to maternal concentrations.1 Administration of a human antibody to IL-6 to pregnant animals caused decreased globulin concentrations in pregnant animals and offspring.1

Possible increased risk of infection in infants born to pregnant women treated with siltuximab; use live vaccines with caution in these infants.1

Avoid pregnancy during therapy.1 Use during pregnancy only if potential benefit justifies the potential risk to the fetus.1 Use contraception during siltuximab treatment and for 3 months following discontinuance of the drug.1

Not known whether distributed into human milk or absorbed systemically after ingestion.1 Discontinue nursing or the drug.1

MCD usually affects adults.17 18 Safety and efficacy of siltuximab not established in pediatric patients <18 years of age.1 2

No overall differences in safety relative to younger patients, but increased sensitivity cannot be ruled out.1

Insufficient experience in patients ≥65 years of age with MCD to determine whether they respond differently than younger adults.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Clearance not substantially affected by mild or moderate hepatic impairment (Child-Pugh class A or B).1

Not studied in patients with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Dosage and Administration.)

Clearance not substantially affected by mild, moderate, or severe renal impairment (Clcr 15–89 mL/minute).1

Effect of end-stage renal disease on pharmacokinetics not known; clinical and pharmacokinetic data are very limited.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Rash (e.g., maculopapular, papular, generalized, pruritic),1 2 pruritus,1 2 upper respiratory tract infection,1 2 weight gain,1 2 localized edema,2 abdominal pain,2 thrombocytopenia,2 nasopharyngitis,2 hyperuricemia.1 2

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

• Importance of advising patients about potential benefits and risks of siltuximab.1 Importance of patients reading the manufacturer's patient information prior to initiation of therapy and each time they receive an infusion of the drug.1

• Risk of increased susceptibility to infection.1 Instruct patients to immediately contact their clinician if symptoms suggesting an infection occur to ensure rapid evaluation and appropriate treatment.1

• Importance of advising patients that they should not receive live vaccines during siltuximab therapy.1 Importance of informing clinician of recent or scheduled vaccinations and of discussing recommended vaccinations with their clinician prior to beginning siltuximab therapy.1

• Risk of infusion-related and allergic reactions.1 Importance of immediately reporting signs and symptoms of such reactions, including dizziness, lightheadedness, wheezing, swelling of the lips, rash, breathing difficulty, or chest pain or tightness.1

• Importance of advising patients to report any new or worsening medical conditions to their clinician.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of advising women not to breast-feed during therapy.1 Necessity of advising women of childbearing potential to use effective contraception while receiving siltuximab and for 3 months after the drug is discontinued.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., infections, GI disease).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Hard stools (constipation).
• Loose stools (diarrhea).
• Headache.
• Feeling tired or weak.
• Joint pain.
• Throat pain.
• Belly pain.
• Weight gain.
• Signs of a common cold.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• CNTO 328

Chimeric monoclonal antibody which binds with high affinity and specificity to IL-6; prevents IL-6 from binding to both soluble and membrane-bound IL-6 receptors. Overproduction of IL-6 may lead to systemic manifestations in multicentric Castleman disease (MCD) patients by inducing C-reactive protein (CRP) synthesis (Kurzrock, 2010). Lowering serum IL-6 levels may improve systemic symptoms of Castleman disease.

Distribution

4.5 L

Half-Life Elimination

~21 days (range: 14.2 to 29.7 days)

Castleman disease: Treatment of multicentric Castleman disease (MCD) in patients who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative

Limitations of use: Has not been studied in patients with MCD who are HIV positive or HHV-8 positive because in a nonclinical study, siltuximab did not bind to virally produced IL-6

Severe hypersensitivity to siltuximab or any component of the formulation

Mild to severe renal impairment (CrCl 15 mL/min to under 90 mL/min): No adjustment recommended.
End stage renal disease (CrCl less than 15 mL/min): Data not available

Administration Advice:
-If treatment criteria are not met a delay in treatment may be necessary; dose should not be reduced.
-Do not administer to patients with severe infections until the infection resolves.
-Perform hematology lab tests prior to each dose for the first 12 months and every 3 dosing cycles thereafter.
-Absolute Neutrophil Count should be 1.0 x 10(9)/L or higher before administration.
-Platelet count should be 75 × 10(9)/L or higher before first dose and 50 × 10(9)/L or higher before subsequent doses.
-Hemoglobin should be less than 17 g/dL before administration.
-Administer in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
-Stop infusion if patient develops signs of anaphylaxis. Discontinue further therapy.
-Stop infusion if patient develops mild to moderate infusion reactions. If reaction resolves, infusion may be restarted at a lower infusion rate. Consider medication with antihistamines, acetaminophen, and corticosteroids. Discontinue if patient does not tolerate infusion following these interventions.

Storage requirements:
-Refrigerate; protect from light.

Reconstitution/preparation techniques: The manufacturer product information should be consulted.

IV compatibility:
-Do not infuse concomitantly in the same intravenous line with other agents.

Patient advice:
-May lower resistance to infections. Contact your doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.
-Discuss recommended vaccinations prior to treatment.
-Seek immediate medical attention for 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.
-Patients of childbearing potential should avoid pregnancy which may include use of contraception during treatment and for 3 months after siltuximab therapy.