Ilaris

1 INDICATIONS AND USAGE ILARIS is an interleukin-1β blocker indicated for the treatment of: • Periodic Fever Syndromes ( 1.1 ): - Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older, including: ◾ Familial Cold Auto-inflammatory Syndrome (FCAS) ◾ Muckle-Wells Syndrome (MWS) - Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients - Hyperimmunoglobulin D Syndrome (HIDS)/ Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients - Familial Mediterranean Fever (FMF) in adult and pediatric patients • Active Still’s Disease, including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) in patients 2 years of age and older ( 1.2 ) • Gout flares in adults in whom non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate ( 1.3 ) 1.1 Periodic Fever Syndromes ILARIS ® (canakinumab) is an interleukin-1β (IL-1β) blocker indicated for the treatment of the following autoinflammatory Periodic Fever Syndromes: Cryopyrin-Associated Periodic Syndromes (CAPS) ILARIS is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and pediatric patients 4 years of age and older, including: Familial Cold Autoinflammatory Syndrome (FCAS) Muckle-Wells Syndrome (MWS) Tumor Necrosis Factor Receptor (TNF) Associated Periodic Syndrome (TRAPS) ILARIS is indicated for the treatment of Tumor Necrosis Factor (TNF) Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients. Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) ILARIS is indicated for the treatment of Hyperimmunoglobulin D (Hyper-IgD) Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients. Familial Mediterranean Fever (FMF) ILARIS is indicated for the treatment of Familial Mediterranean Fever (FMF) in adult and pediatric patients. 1.2 Still’s Disease (Adult-Onset Still’s Disease [AOSD] and Systemic Juvenile Idiopathic Arthritis [SJIA]) ILARIS is indicated for the treatment of active Still’s Disease, including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) in patients 2 years of age and older. 1.3 Gout Flares ILARIS is indicated for the symptomatic treatment of adult patients with gout flares in whom non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate.

2 DOSAGE AND ADMINISTRATION • CAPS: Recommended weight-based dosage is: - For patients > 40 kg: 150 mg subcutaneously, every 8 weeks - For patients ≥ 15 kg and < 40 kg: 2 mg/kg subcutaneously, every 8 weeks. For pediatric patients 15 kg to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. ( 2.2 ) • TRAPS, HIDS/MKD, and FMF: Recommended weight-based dosage is: - For patients > 40 kg: Starting dosage is 150 mg subcutaneously every 4 weeks. The dosage can be increased to 300 mg every 4 weeks if the clinical response is not adequate. ( 2.3 ) - For patients ≤ 40 kg: Starting dosage is 2 mg/kg subcutaneously every 4 weeks. The dosage can be increased to 4 mg/kg every 4 weeks if the clinical response is not adequate. ( 2.3 ) Still’s disease (AOSD and SJIA): Recommended weight-based dosage for patients ≥ 7.5 kg is 4 mg/kg (maximum dose of 300 mg), subcutaneously, every 4 weeks. ( 2.4 ) Gout Flares: Recommended dosage is 150 mg subcutaneously. In patients who require re-treatment, there should be an interval of at least 12 weeks before a new dose of ILARIS may be administered. ( 2.5 ) 2.1 General Dosing Information ILARIS IS FOR SUBCUTANEOUS USE ONLY. 2.2 Recommended Dosage for Cryopyrin-Associated Periodic Syndromes (CAPS) The recommended weight-based dosage of ILARIS is: For patients with CAPS > 40 kg: 150 mg subcutaneously, every 8 weeks For patients with CAPS ≥ 15 kg and ≤ 40 kg: 2 mg/kg subcutaneously, every 8 weeks. For pediatric patients with CAPS 15 kg to 40 kg with an inadequate response, the dosage can be increased to 3 mg/kg subcutaneously, every 8 weeks. 2.3 Recommended Dosage for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency (HIDS/MKD), and Familial Mediterranean Fever (FMF) The recommended weight-based dosage of ILARIS for patients with TRAPS, HIDS/MKD, and FMF is: For patients > 40 kg: 150 mg subcutaneously, every 4 weeks. The dosage can be increased to 300 mg every 4 weeks if the clinical response is not adequate. For patients ≤ 40 kg: 2 mg/kg administered subcutaneously, every 4 weeks. The dosage can be increased to 4 mg/kg every 4 weeks if the clinical response is not adequate. 2.4 Recommended Dosage for Still’s Disease, Including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) The recommended weight-based dosage of ILARIS for patients with Still’s Disease (AOSD and SJIA) weighing ≥ 7.5 kg is 4 mg/kg (maximum dose of 300 mg) administered subcutaneously every 4 weeks. 2.5 Recommended Dosage for Gout Flares The recommended dose of ILARIS for adult patients with a gout flare is 150 mg administered subcutaneously. In patients who require re-treatment, there should be an interval of at least 12 weeks before a new dose of ILARIS may be administered. 2.6 Administration Instructions for ILARIS Injection STEP 1: ILARIS injection has a concentration of 150 mg/mL. Do not shake. The solution should be essentially free from particulates, clear to opalescent, colorless to slightly brownish-yellow tint. If the solution has a distinctly brown discoloration, is highly opalescent or contains visible particles, do not use. STEP 2: Using a sterile 1-mL syringe and 18-gauge x 2” needle, carefully withdraw the required volume depending on the dose to be administered and subcutaneously inject using a 27-gauge x 0.5” needle. Avoid injection into scar tissue as this may result in insufficient exposure to ILARIS. Discard unused product or waste material in accordance with the local requirements.

5 WARNINGS AND PRECAUTIONS Serious Infections: ILARIS has been associated with an increased incidence of serious infections. Exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. Discontinue ILARIS if a patient develops a serious infection. Avoid administering ILARIS to patients during an active infection requiring medical intervention. ( 5.1 ) Hypersensitivity Reactions and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) can occur; discontinue ILARIS, treat promptly, and monitor until reaction resolves. ( 5.3 ) Immunizations: Avoid administration of live vaccines concurrently with ILARIS. Update all recommended vaccinations prior to initiation of therapy with ILARIS. ( 5.4 ) 5.1 Serious Infections ILARIS has been associated with an increased risk of serious infections. Exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. Avoid administering ILARIS to patients during an active infection requiring medical intervention. Discontinue ILARIS if a patient develops a serious infection. Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported with ILARIS. Generally, the observed infections responded to standard therapy. Isolated cases of unusual or opportunistic infections (e.g., aspergillosis, atypical mycobacterial infections, cytomegalovirus, herpes zoster) were reported during ILARIS treatment. A causal relationship of ILARIS to these events cannot be excluded. In clinical trials, ILARIS has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Coadministration of ILARIS with TNF inhibitors is not recommended because this may increase the risk of serious infections [ see Drug Interactions (7.1) ] . Drugs that affect the immune system by blocking TNF have been associated with an increased risk of new tuberculosis and reactivation of latent tuberculosis (TB). It is possible that use of IL-1 inhibitors, such as ILARIS, increases the risk of reactivation of tuberculosis or of opportunistic infections. Prior to initiating immunomodulatory therapies, including ILARIS, evaluate patients for active and latent tuberculosis infection. Appropriate screening tests should be performed in all patients. ILARIS has not been studied in patients with a positive tuberculosis screen, and the safety of ILARIS in individuals with latent tuberculosis infection is unknown. Treat patients testing positive in tuberculosis screening according to standard medical practice prior to therapy with ILARIS. Instruct patients to seek medical advice if signs, symptoms, or high-risk exposure suggestive of tuberculosis (e.g., persistent cough, weight loss, subfebrile temperature) appear during or after ILARIS therapy. Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ILARIS. 5.2 Immunosuppression The impact of treatment with anti-interleukin-1 (IL-1) therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including ILARIS, may result in an increase in the risk of malignancies. 5.3 Hypersensitivity Reactions Hypersensitivity reactions have been reported with ILARIS. During clinical trials, no anaphylactic reactions attributable to treatment with canakinumab have been reported. It should be recognized that symptoms of the underlying disease being treated may be similar to symptoms of hypersensitivity [see Adverse Reactions (6.1)] . Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), characterized by serious skin eruptions, has been reported in…

4 CONTRAINDICATIONS Confirmed hypersensitivity to canakinumab or to any of the excipients [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)] . Confirmed hypersensitivity to canakinumab or to any of the excipients. ( 4 )

7 DRUG INTERACTIONS Interactions between ILARIS and other medicinal products have not been investigated in formal studies. 7.1 TNF-Blocker and IL-1 Blocking Agent An increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors in another patient population. Use of ILARIS with TNF inhibitors may also result in similar toxicities and is not recommended because this may increase the risk of serious infections [ see Warnings and Precautions (5.1) ] . The concomitant administration of ILARIS with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacological interactions between ILARIS and a recombinant IL-1ra, concomitant administration of ILARIS and other agents that block IL-1 or its receptors is not recommended. 7.2 Immunization No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving ILARIS. Therefore, avoid administration of live vaccines concurrently with ILARIS. It is recommended that, if possible, pediatric and adult patients complete all immunizations in accordance with current immunization guidelines prior to initiating ILARIS therapy [ see Warnings and Precautions (5. 4 ) ] . 7.3 Cytochrome P450 Substrates The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus, it is expected that for a molecule that binds to IL-1, such as canakinumab, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of canakinumab, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed, and the individual dose of the medicinal product may need to be adjusted as needed.

8.1 Pregnancy Risk Summary Available human data from postmarketing experience and published case reports on ILARIS use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, and adverse maternal or fetal outcomes. Canakinumab, like other monoclonal antibodies, is actively transported across the placenta mainly during the third trimester of pregnancy and may cause immunosuppression in the in utero exposed infant ( see Clinical Considerations ). In an animal embryo-fetal development study with marmoset monkeys, there was no evidence of embryotoxicity or fetal malformations with subcutaneous administration of canakinumab during the period of organogenesis and later in gestation at doses that produced exposures approximately 11 times the exposure at the maximum recommended human dose (MRHD) and greater. Delays in fetal skeletal development were observed in marmoset monkeys following prenatal exposure to ILARIS at concentrations approximately 11 times the MRHD and greater. Similar delays in fetal skeletal development were observed in mice administered a murine analog of ILARIS during the period of organogenesis. Delays in skeletal ossification are changes from the expected ossification state in an otherwise normal structure/bone: these findings are generally reversible or transitory and not detrimental to postnatal survival ( see Animal Data ). The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Because IL-1 blockade may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants who were exposed to ILARIS in utero for at least 4 to 12 months following the mother’s last dose of ILARIS. The ideal time to avoid live vaccines in infants exposed to ILARIS in utero is unknown, as there are insufficient data regarding infant serum levels of canakinumab at birth and the duration of persistence of canakinumab in infant serum after birth is also unknown. Data Animal Data In an embryo-fetal development study, pregnant marmoset monkeys received canakinumab from gestation days 25 to 109 at doses that produced exposures approximately 11 times that achieved with MRHD and greater (on a plasma area under the curve [AUC] basis with maternal subcutaneous doses of 15, 50, or 150 mg/kg twice weekly). ILARIS did not elicit any evidence of embryotoxicity or fetal malformations. There were increases in the incidence of incomplete ossification of the terminal caudal vertebra and misaligned and/or bipartite vertebra in fetuses at all dose levels when compared to concurrent controls suggestive of delay in skeletal development in the marmoset. Since ILARIS does not cross-react with mouse or rat IL-1β, pregnant mice were subcutaneously administered a murine analog of ILARIS at doses of 15, 50, or 150 mg/kg during the period of organogenesis on gestation days 6, 11, and 17. The incidence of incomplete ossification of the parietal and frontal skull bones of fetuses was increased in a dose-dependent manner at all dose levels tested.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions (5.1)] Immunosuppression [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Macrophage Activation Syndrome [see Warnings and Precautions (5.5)] CAPS: The most common adverse reactions (>10%) are nasopharyngitis, diarrhea, influenza, rhinitis, nausea, headache, bronchitis, gastroenteritis, pharyngitis, weight increased, musculoskeletal pain, and vertigo. ( 6 ) TRAPS, HIDS/MKD, and FMF: The most common adverse reactions (≥10%) are injection-site reactions and nasopharyngitis. ( 6 ) Still’s Disease: The most common adverse drug reactions (>10%) are infections (nasopharyngitis and upper respiratory tract infections), abdominal pain, and injection-site reactions. ( 6 ) Gout Flares: The most common adverse reactions (>2%) reported by are nasopharyngitis, upper respiratory tract infections, urinary tract infections, hypertriglyceridemia, and back pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions from Clinical Trials for Treatment of Periodic Fever Syndromes: CAPS, TRAPS, HIDS/MKD, and FMF Treatment of CAPS The data described herein reflect exposure to ILARIS in 104 adult and pediatric CAPS patients, including 20 FCAS, 72 MWS, 10 MWS/NOMID (Neonatal Onset Multisystem Inflammatory Disorder) overlap, 1 non-FCAS non-MWS, and 1 misdiagnosed in placebo-controlled (35 patients) and uncontrolled trials. Sixty-two patients were exposed to ILARIS for at least 6 months, 56 for at least 1 year, and 4 for at least 3 years. A total of 9 serious adverse reactions were reported for CAPS patients. Among these were vertigo (2 patients), infections (3 patients), including intra-abdominal abscess following appendectomy (1 patient). The most commonly reported adverse reactions associated with ILARIS treatment in greater than 10% of the CAPS patients were nasopharyngitis, diarrhea, influenza, rhinitis, nausea, headache, bronchitis, gastroenteritis, pharyngitis, weight increased, musculoskeletal pain, and vertigo. One patient discontinued treatment due to potential infection. CAPS Study 1 investigated the safety of ILARIS in an 8-week, open-label period (Part 1), followed by a 24-week, randomized withdrawal period (Part 2), followed by a 16-week, open-label period (Part 3). All patients were treated with ILARIS 150 mg subcutaneously or 2 mg/kg if body weight was greater than or equal to 15 kg and less than or equal to 40 kg (see Table 1). Since all CAPS patients received ILARIS in Part 1, there are no controlled data on adverse events (AEs). Data in Table 1 are for all AEs for all CAPS patients receiving canakinumab. In CAPS Study 1, no pattern was observed for any type or frequency of adverse events throughout the 3 study periods. Table 1: Adverse Reactions in ≥ 10% of Patients in Parts 1 to 3 of the Phase 3 Trial for Patients with CAPS Adverse reactions ILARIS N = 35 n (%) n (%) of patients with adverse reactions 35 (100) Nasopharyngitis 12 (34) Diarrhea 7 (20) Influenza 6 (17) Rhinitis 6 (17) Nausea 5 (14) Headache 5 (14) Bronchitis 4 (11) Gastroenteritis 4 (11) Pharyngitis 4 (11) Weight increased 4 (11) Musculoskeletal pain 4 (11) Vertigo 4 (11) Vertigo Vertigo has been reported in 9% to 14% of patients in CAPS studies, exclusively in MWS patients, and reported as a serious adverse event in 2 cases. All events resolved with continued treatment with ILARIS. Injection-Site Reactions In CAPS Study 1, subcutaneous injection-s…