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.

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 )

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 patients with autoinflammatory conditions treated with ILARIS. If a severe hypersensitivity reaction occurs, immediately discontinue ILARIS; treat promptly and monitor until signs and symptoms resolve. 5.4 Immunizations Avoid administration of live vaccines concurrently with ILARIS [see Drug Interactions (7.2)] . Since no data are available on either the efficacy or on the risks of secondary transmission of infection by live vaccines in patients receiving ILARIS, avoid administering live vaccines concurrently with ILARIS. In addition, because ILARIS may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ILARIS. Limited data are available on the response to vaccinations with inactivated (killed) antigens in patients receiving ILARIS [ see Drug Interactions (7.2) ] . Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, adult and pediatric patients receive all recommended vaccinations, as appropriate and if feasible, including pneumococcal vaccine and inactivated influenza vaccine. See current recommended immunization schedules at the website of the Centers for Disease Control, http://www.cdc.gov/vaccines/schedules/index.html . 5.5 Macrophage Activation Syndrome Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with rheumatic conditions, in particular Still’s disease, and should be aggressively treated. Physicians should be attentive to symptoms of infection or worsening of Still’s disease, as these are known triggers for MAS. Eleven cases of MAS were observed in 201 SJIA patients treated with canakinumab in clinical trials. Based on the clinical trial experience, ILARIS does not appear to increase the incidence of MAS in Still’s disease patients, but no definitive conclusion can be made.

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.

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-site reactions were observed in 9% of patients in Part 1 with mild tolerability reactions; in Part 2, one patient each (7%) had a mild or a moderate tolerability reaction and, in Part 3, one patient had a mild local tolerability reaction. No severe injection-site reactions were reported, and none led to discontinuation of treatment. Treatment of TRAPS, HIDS/MKD, and FMF A Phase 3 trial (TRAPS, HIDS/MKD, and FMF Study 1) investigated the safety of ILARIS in 3 cohorts (TRAPS, HIDS/MKD, and FMF) as follows: a 12-week screening period (Part 1), followed by a 16-week, randomized, double-blind, placebo-controlled parallel-arm treatment period (Part 2), followed by a 24-week randomized withdrawal period (Part 3), followed by a 72-week, open-label treatment period (Part 4). All patients randomized to treatment with ILARIS in Part 2 received 150 mg subcutaneously every 4 weeks if body weight was greater than 40 kg (or 2 mg/kg every 4 weeks if body weight was less than or equal to 40 kg). In Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1, initially 90 patients were randomized to ILARIS treatment, and 91 patients were randomized to placebo. Of patients randomized to ILARIS, 55.6% remained on the initial dose through Week 16 with 6.7% receiving an additional ILARIS dose between Day 7 and Day 15. Of the patients randomized to placebo, 9.9% remained on placebo through Week 16 with 28.6% switching to active treatment with ILARIS by Day 15. Overall, there were 43 TRAPS, 68 HIDS/MKD, and 58 FMF patients in the safety set with a cumulative canakinumab exposure of 47.61 patient-years. The cumulative exposure in the placebo group was 8.03 patient-years. In Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1, a total of 22 TRAPS patients aged 3 to 76 years of age, 37 HIDS/MKD patients aged 2 to 43 years of age, and 31 FMF patients aged 2 to 60 years of age were initially randomized to treatment with ILARIS 150 mg every four weeks in the placebo-controlled period of the clinical trial. In addition, 4 non-randomized patients (2 FMF patients of age 20 and 29 years with non-exon 10 mutations and 2 HIDS/MKD patients both of 1 year of age) received open-label treatment in Part 2. The most commonly reported adverse reactions (greater than or equal to 10%) associated with ILARIS treatment in TRAPS, HIDS/MKD, and FMF patients were injection-site reactions and nasopharyngitis. The reported adverse reactions (greater than or equal to 3%) associated with ILARIS treatment in TRAPS, HIDS/MKD, and FMF patients were injection-site reactions (10.1%), and infections, including nasopharyngitis (10.7%), upper respiratory tract infection (7.1%), rhinitis (5.3%), gastroenteritis (3.0%), and pharyngitis (3.0%). Serious infections (e.g., conjunctivitis, pneumonia, pharyngitis, pharyngotonsillitis) were observed in approximately 2.4% (0.03 per 100 patient-days) of patients receiving ILARIS in Part 2 of the TRAPS, HIDS/MKD, and FMF Study 1. In the ILARIS treatment group, 1 TRAPS patient discontinued treatment due to adverse events, 2 HIDS/MKD patients discontinued treatment due to adverse events, and no FMF patients discontinued treatment due to an adverse event. Injection-Site Reactions In the TRAPS, HIDS/MKD, and FMF Study 1, subcutaneous injection-site reactions were observed in 10.1% of patients in Part 2 who had a mild or a moderate tolerability reaction. No severe injection-site reactions were reported and none led to discontinuation of treatment. Adverse Reactions from Clinical Trials for Treatment of Still’s Disease: SJIA and AOSD The safety of ILARIS compared to placebo in SJIA patients was investigated in two Phase 3 studies [see Clinical Studies (14.2)] . Patients in SJIA Study 1 received a single dose of ILARIS 4 mg/kg (n = 43) or placebo (n = 41) via subcutaneous injection and were assessed at Day 15 for the efficacy endpoints and had a safety analysis up to Day 29. SJIA Study 2 was a two-part study with an open-label, single-arm active treatment period (Part I) followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design (Part II). Overall, 177 patients were enrolled into the study and received ILARIS 4 mg/kg (up to 300 mg maximum) in Part I, and 100 patients received ILARIS 4 mg/kg (up to 300 mg maximum) every 4 weeks or placebo in Part II. Adverse drug reactions listed in Table 2 showed higher rates than placebo from both trials. The adverse drug reactions associated with ILARIS treatment in greater than 10% of SJIA patients were infections, abdominal pain, and injection-site reactions. Serious infections (e.g., pneumonia, varicella, gastroenteritis, measles, sepsis, otitis media, sinusitis, adenovirus, lymph node abscess, pharyngitis) were observed in approximately 4% to 5% (0.02 to 0.17 per 100 patient-days) of patients receiving ILARIS in both studies. Table 2: Tabulated Summary of Adverse Drug Reactions From Pivotal SJIA Clinical Trials n = number of patients. ^IR = Exposure adjusted incidence rate per 100 patient-days. *No injection-site reaction led to study discontinuation. SJIA Study 2 SJIA Study 1 Part I Part II ILARIS N = 177 n (%) (IR)^ ILARIS N = 50 n (%) (IR) Placebo N = 50 n (%) (IR) ILARIS N = 43 n (%) (IR) Placebo N = 41 n (%) (IR) Infections and infestations All infections (e.g., nasopharyngitis, [viral] upper respiratory tract infection, pneumonia, rhinitis, pharyngitis, tonsillitis, sinusitis, urinary tract infection, gastroenteritis, viral infection) 97 (54.8%) (0.91) 27 (54%) (0.59) 19 (38%) (0.63) 13 (30.2%) (1.26) 5 (12.2%) (1.37) Gastrointestinal disorders Abdominal pain (upper) 25 (14.1%) (0.16) 8 (16%) (0.15) 6 (12%) (0.08) 3 (7%) (0.25) 1 (2.4%) (0.23) Skin and subcutaneous tissue disorders Injection-site reaction* mild 19 (10.7%) 6 (12.0%) 2 (4.0%) 0 3 (7.3%) moderate 2 (1.1%) 1 (2.0%) 0 0 0 The safety profile of ILARIS in AOSD patients in a randomized, double-blind, placebo-controlled study (GDE01T) in 36 adult patients (aged 22 to 70 years) was similar to what was observed in SJIA patients. Adverse Reactions from Clinical Trials for Treatment of Gout Flares The safety of ILARIS compared to triamcinolone acetonide in patients with gout flares was assessed in four 12-week randomized, double-blind, active-controlled Phase 3 studies [see Clinical Studies (14.4) for details of the studies supporting efficacy] and in two 12-week double-blind active-controlled extension studies. In the ILARIS treatment groups 512 patients were treated up to 12 weeks and 165 of these patients up to 24 weeks. In the triamcinolone acetonide groups, 381 patients were treated up to 12 weeks and 152 of these patients up to 24 weeks. Patients received a single dose of ILARIS 150 mg (n = 467) via subcutaneous injection or triamcinolone acetonide 40 mg (n = 279) via intramuscular injection. Upon a new flare, 85 and 152 patients received at least one additional dose of ILARIS and triamcinolone acetonide, respectively. The most commonly reported adverse drug reactions were infections and infestations (see Table 3). The most common infections reported in more than 2% of patients in the ILARIS treatment groups were nasopharyngitis, upper respiratory tract infections, and urinary tract infections. The trends observed in all infections are aligned with the overall known safety profile of canakinumab. Serious adverse events were reported in 1.4% of the ILARIS-treated patients, all of which were single events. No serious adverse events were reported in the triamcinolone acetonide-treated group. Of the ILARIS-treated patients, 17% were 65 years of age and older, including 3% who were 75 years of age and older. No new safety findings were observed between these patients compared to patients under 65 years of age [see Use in Specific Populations (8.5) . Table 3: Tabulated Summary of Adverse Drug Reactions From Pivotal Gout Flare Clinical Trials Abbreviation: SOC, system organ class. * N = Number of patients at study entry. IR-w = Study size weighted incidence rate (i.e., number of patients with an event per 100 patient-years). System Organ Class Adverse reaction ILARIS 150 mg *N = 552 n (%) (IR-w) Triamcinolone acetonide 40 mg *N = 431 n (%) (IR-w) Infections and infestations All infections (e.g., nasopharyngitis, upper respiratory tract infection, urinary tract infections) 90 (16.3%) (59.0) 40 (9.3%) (32.1) Investigations Blood triglycerides increased 7 (1.3%) (3.8) 2 (0.5%) (1.3) Platelet count decreased 4 (0.7%) (2.5) 1 (0.2%) (1.0) Metabolism and nutrition disorders Hypertriglyceridemia 15 (2.7%) (9.5) 4 (0.9%) (3) Musculoskeletal and connective tissue disorders Back pain 17 (3.1%) (10.9) 7 (1.6%) (6.2) Nervous system disorders Dizziness 9 (1.6%) (5.8) 2 (0.5%) (1.7) Specific Adverse Reactions from Clinical Trials Hypersensitivity During clinical trials, no anaphylactic reactions attributable to treatment with canakinumab have been reported. In CAPS trials one patient discontinued and in TRAPS, HIDS/MKD, FMF, Still’s disease, and gout trials no patients discontinued due to hypersensitivity reactions. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS [see Contraindications (4) and Warnings and Precautions (5.3)] . Laboratory Abnormalities Hematology TRAPS, HIDS/MKD, and FMF Overall, in the TRAPS, HIDS/MKD, and FMF Study 1, neutrophil count decreased (greater than or equal to Grade 2) was reported in 6.5% of patients and platelet count decreased (greater than or equal to Grade 2) was reported in 0.6% of patients. SJIA During clinical trials with ILARIS, mean values decreased for white blood cells, neutrophils and platelets. In the randomized, placebo-controlled portion of SJIA Study 2, decreased white blood cell counts (WBC) less than or equal to 0.8 times lower limit of normal (LLN) were reported in 5 patients (10.4%) in the ILARIS group compared to 2 patients (4.0%) in the placebo group. Transient decreases in absolute neutrophil count (ANC) to less than 1 x 10 9 /L were reported in 3 patients (6.0%) in the ILARIS group compared to 1 patient (2.0%) in the placebo group. One case of ANC less than 0.5x10 9 /L was observed in the ILARIS group and none in the placebo group. Mild (less than LLN and greater than 75 x 10 9 /L) and transient decreases in platelet counts were observed in 3 (6.3%) ILARIS-treated patients versus 1 (2.0%) placebo-treated patient. Gout Flares In the pooled analysis of patients with gout flares from four 12-week randomized, double-blind, active-controlled Phase 3 studies and two 12-week active-controlled extension studies, transient cytopenias were observed. Leukopenia (WBC ≤ 0.8 x LLN) was reported in 6.4% of ILARIS-treated patients compared to 1.4% of triamcinolone acetonide-treated patients. Neutropenia (ANC < 0.9 x LLN) was reported in 15.9% of patients treated with ILARIS compared to 2.1% treated with triamcinolone acetonide. Thrombocytopenia (platelet counts < LLN) was observed in 16.3% of patients treated with ILARIS versus 12.5% of patients treated with triamcinolone acetonide. Uric Acid Gout Flares The proportion of patients with laboratory abnormalities (from normal at baseline to >ULN or from ≤9.9 mg/dl at baseline to > 9.9 mg/dl) and/or adverse reactions of increased uric acid levels were numerically higher in the ILARIS group (43.8% for ILARIS vs. 40.1% for (triamcinolone acetonide). Hepatic Transaminases Elevations of transaminases (ALT/AST) have been observed in patients treated with ILARIS. SJIA In the randomized, placebo-controlled portion of SJIA Study 2, high ALT and/or AST ≥ 3 times upper limit of normal (ULN) were reported in 2 (4.1%) ILARIS-treated patients and 1 (2.0%) placebo patient. All patients had normal values at the next visit. Gout Flares In the randomized double-blind studies up to 24 weeks high ALT and AST ≥ 3 times upper limit of normal (ULN) were reported in 1.6% and 0.5% of ILARIS-treated patients respectively, and 2.6% and 1.9% of the triamcinolone acetonide-treated patients, respectively. Bilirubin SJIA Asymptomatic and mild elevations of serum bilirubin have been observed in patients treated with ILARIS without concomitant elevations of transaminases. Hypertriglyceridemia Gout Flares The proportion of patients with hypertriglyceridemia events in the randomized double-blind studies up to 24 weeks was higher in the ILARIS group compared to the triamcinolone acetonide-treated group (5.6% vs. 1.9%). The majority of abnormal values were noted at a single visit. 6.2 Immunogenicity A biosensor binding assay or a bridging immunoassay was used to detect antibodies directed against canakinumab in patients who received ILARIS. Following treatment with ILARIS, antibodies against ILARIS were observed in approximately 1.4%, 1.2%, and 3.5% of the patients with CAPS, SJIA, and gout flares, respectively. Neutralizing antibodies were detected in < 1% of patients with gout flares. No apparent correlation of antibody development to clinical response or adverse events was observed. The CAPS clinical studies employed the biosensor binding assay, most of the SJIA clinical studies employed the bridging assay, and the gout clinical studies used initially the biosensor assay and for later studies or extensions the bridging assay. The data obtained in an assay are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, underlying disease, and the number of patients tested. For these reasons, comparison of the incidence of antibodies to canakinumab between the CAPS, SJIA, and gout flare clinical studies or with the incidence of antibodies to other products may be misleading. No TRAPS, HIDS/MKD, FMF, SJIA, or AOSD patients treated with ILARIS doses of 150 mg and 300 mg over 16 weeks of treatment tested positive for anti-canakinumab antibodies. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ILARIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.3)]

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.