Ilaris Drug Information

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.

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.

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.

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.

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. 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.

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.

All events resolved with continued treatment with ILARIS. 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).

The cumulative exposure in the placebo group was 8.03 patient-years. 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. 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. 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. 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).

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 patient-days of patients receiving ILARIS in both studies.

Table 2: Tabulated Summary of Adverse Drug Reactions From Pivotal SJIA Clinical Trials All infections (e.g., nasopharyngitis, upper respiratory tract infection, pneumonia, rhinitis, pharyngitis, tonsillitis, sinusitis, urinary tract infection, gastroenteritis, viral infection) Gastrointestinal disorders Abdominal pain (upper) 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 and in two 12-week double-blind active-controlled extension studies. 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. No new safety findings were observed between these patients compared to patients under 65 years of age.

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. One case of ANC less than 0.5x10 9 /L was observed in the ILARIS group and none in the placebo group.

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.

All patients had normal values at the next visit. 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.

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.

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)

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. 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.

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.

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.

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 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 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. 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.

The majority of patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g., Serum Amyloid A and C-Reactive Protein). Overall, the efficacy and safety of ILARIS in pediatric and adult patients were comparable. Infections of the upper respiratory tract were the most frequently reported infection.

The safety and effectiveness of ILARIS in CAPS patients less than 4 years of age has not been established. The safety and effectiveness of ILARIS in SJIA patients less than 2 years of age have not been established. The TRAPS, HIDS/MKD, and FMF trial included a total of 102 pediatric patients (TRAPS, HIDS/MKD and FMF patients) with an age range from 2 to 17 years who received ILARIS.

The safety and effectiveness of ILARIS for the treatment of gout flares in the pediatric population have not been established. Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, pediatric patients receive all recommended vaccinations. Avoid use of live virus vaccines concurrently with ILARIS treatment in pediatric patients or in infants exposed in utero following maternal administration.

Confirmed hypersensitivity to canakinumab or to any of the excipients.

No confirmed case of overdose has been reported. In the case of overdose, it is recommended that the subject be monitored for any signs and symptoms of adverse reactions or effects, and appropriate symptomatic treatment be instituted immediately.