Ilaris

        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.        

        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.

       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.        

        General Dosing Information

ILARIS IS FOR SUBCUTANEOUS USE ONLY.

        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.

       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.

        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.        

        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.

        Lactation

Risk Summary

There is no information regarding the presence of canakinumab in human milk or the effects on milk production. There are a small number of published case reports that do not establish an association between maternal canakinumab use during lactation and adverse effects on breastfed infants. Maternal IgG is known to be present in human milk. The effects of canakinumab in breast milk and possible systemic exposure in the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ILARIS and any potential adverse effects on the breastfed infant from ILARIS or from the underlying maternal condition.

        Pediatric Use

The CAPS trials with ILARIS included a total of 23 pediatric patients with an age range from 4 years to 17 years (11 adolescents were treated subcutaneously with 150 mg, and 12 children were treated with 2 mg/kg based on body weight greater than or equal to 15 kg and less than or equal to 40 kg). The majority of patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g., Serum Amyloid A [SAA] 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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

The safety and effectiveness of ILARIS in SJIA patients less than 2 years of age have not been established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].

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. Overall, there were no clinically meaningful differences in the efficacy, safety and tolerability profile of ILARIS in pediatric patients compared to the overall TRAPS, HIDS/MKD, and FMF populations (comprised of adult and pediatric patients, N = 169). The majority of pediatric patients achieved improvement in clinical symptoms and objective markers of inflammation [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

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 [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

        Geriatric Use

Clinical studies of ILARIS in patients with CAPS, TRAPS, HIDS/MKD, FMF and Still’s disease, did not include sufficient numbers of patients 65 years and older to determine whether they respond differently from younger patients.

In the clinical studies for gout flares, of the total number of ILARIS- treated patients (n=491), 85 (17.3 %) were 65 years of age and older, while 16 (3.3 %) were 75 years of age and older [see Clinical Studies (14.4)]. Overall, the efficacy profile of ILARIS in patients with gout flares was comparable between the age group of patients less than 65 years of age, and of patients 65 to 75 years of age. The studies did not include sufficient numbers of patients 75 years and older to determine whether they respond differently from younger patients. No new safety findings were observed in patients across these age groups [see Adverse Reactions (6.1)].

        Renal Impairment

No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with renal impairment.

        Hepatic Impairment

No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with hepatic impairment.

        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. 

        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. 

        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.

        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.        

        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.