Canakinumab Injection

Approximately 570 patients have been treated with ILARIS in interventional trials in CAPS, TRAPS, HIDS/MKD, FMF or SJIA. These clinical trials included approximately 350 children up to 17 years of age. The most frequently reported adverse drug reactions were infections predominantly of the upper respiratory tract. The majority of the events were mild to moderate although serious infections were observed.

Opportunistic infections have also been reported in patients treated with ILARIS [see WARNINGS AND PRECAUTIONS].

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.

Treatment Of Periodic Fever Syndromes: CAPS, TRAPS, HIDS/MKD, And FMF

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 three study periods.

Table 1: Number (%) of Patients with AEs by Preferred Terms, in Greater Than 10% of Patients in Parts 1 to 3 of the Phase 3 Trial for CAPS Patients

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 two cases. All events resolved with continued treatment with ILARIS.

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.

A Phase III 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.

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.

Treatment Of SJIA

A total of 201 SJIA patients aged 2 to less than 20 years have received ILARIS in clinical trials. The safety of ILARIS compared to placebo was investigated in two phase 3 studies [see Clinical Studies]. 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.

Adverse reactions are listed according to MedDRA version 15.0 system organ class.

Table 2: Tabulated Summary of Adverse Drug Reactions from Pivotal SJIA Clinical Trials

Hypersensitivity

During clinical trials, no anaphylactic reactions have been reported. In CAPS trials one patient discontinued and in TRAPS, HIDS/MKD, FMF, and SJIA trials no patients discontinued due to hypersensitivity reactions. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Immunogenicity

A biosensor binding assay or a bridging immunoassay was used to detect antibodies directed against canakinumab in patients who received ILARIS. Antibodies against ILARIS were observed in approximately 1.5% and 3.1% of the patients treated with ILARIS for CAPS and SJIA, respectively. No neutralizing antibodies were detected. No apparent correlation of antibody development to clinical response or adverse events was observed. The CAPS clinical studies employed the biosensor binding assay, and most of the SJIA clinical studies employed 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 and SJIA clinical studies or with the incidence of antibodies to other products may be misleading.

No TRAPS, HIDS/MKD and FMF patients treated with ILARIS doses of 150 mg and 300 mg over 16 weeks of treatment tested positive for anti-canakinumab antibodies.

Laboratory Findings

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 (4.0%) in the placebo group. Transient decreases in absolute neutrophil count (ANC) to less than 1x109/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 0.5x109/L was observed in the ILARIS group and none in the placebo group.

Mild (less than LLN and greater than 75x109/L) and transient decreases in platelet counts were observed in 3 (6.3%) ILARIS-treated patients versus 1 (2.0%) placebo-treated patient.

Hepatic Transaminases

Elevations of transaminases have been observed in patients treated with ILARIS.

In the randomized, placebo-controlled portion of SJIA Study 2, high ALT and/or AST greater than or equal to 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.

Bilirubin

Asymptomatic and mild elevations of serum bilirubin have been observed in patients treated with ILARIS without concomitant elevations of transaminases.

ILARIS®
(i-LAHR-us)
(canakinumab) for Injection, for Subcutaneous Use Injection

What is the most important information I should know about ILARIS?

ILARIS can cause serious side effects, including:

• Increased risk of serious infections. ILARIS can lower the ability of your immune system to fight infections. Your healthcare provider should:
  • test you for tuberculosis (TB) before you receive ILARIS
  • monitor you closely for symptoms of TB during treatment with ILARIS
  • check you for symptoms of any type of infection before, during, and after your treatment with ILARIS

Tell your healthcare provider right away if you have any symptoms of an infection such as fever, sweats or chills, cough, flu-like symptoms, weight loss, shortness of breath, blood in your phlegm, sores on your body, warm or painful areas on your body, diarrhea or stomach pain, or feeling very tired.

See “What are possible side effects of ILARIS?” for more information about side effects.

What is ILARIS?

ILARIS is a prescription medicine injected by your healthcare provider just below the skin (subcutaneous) used to treat:

• The following Periodic Fever Syndromes
  • Adults and children 4 years of age and older who have auto-inflammatory diseases called Cryopyrin-Associated Periodic Syndromes (CAPS), including:
    • Familial Cold Auto-inflammatory Syndrome (FCAS)
    • Muckle-Wells Syndrome (MWS)
  • Adults and children who have an auto-inflammatory disease called Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS)
  • Adults and children who have an auto-inflammatory disease called Hyperimmunoglobulin D Syndrome (HIDS) (also known as Mevalonate Kinase Deficiency (MKD).
  • Adults and children who have an auto-inflammatory disease called Familial Mediterranean Fever (FMF).
• Systemic Juvenile Idiopathic Arthritis (SJIA) in children 2 years of age and older.

It is not known if ILARIS is safe and effective when used to treat SJIA in children under 2 years of age or when used to treat CAPS in children under 4 years of age.

Who should not receive ILARIS?

• Do not receive ILARIS if you are allergic to canakinumab or any of the ingredients in ILARIS. See the end of this Medication Guide for a complete list of ingredients in ILARIS.

Before you receive ILARIS, tell your healthcare provider about all your medical conditions, including if you:

• think you have or are being treated for an active infection
• have symptoms of an infection
• have a history of infections that keep coming back
• have a history of low white blood cells
• have or have had HIV, Hepatitis B, or Hepatitis C
• are scheduled to receive any immunizations (vaccines). You should not get 'live vaccines' if you are receiving ILARIS.
• are pregnant or planning to become pregnant. It is not known if ILARIS will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while receiving ILARIS.
• are breastfeeding or planning to breastfeed. It is not known if ILARIS passes into your breast milk. You and your healthcare provider should decide if you will receive ILARIS or breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take:

• Medicines that affect your immune system
• Medicines called IL-1 blocking agents such as Kineret® (anakinra), Arcalyst® (rilonacept)
• Medicines called Tumor Necrosis Factor (TNF) inhibitors such as Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab), Simponi® (golimumab), or Cimzia® (certolizumab pegol)
• Medicines that effect enzyme metabolism

Ask your healthcare provider for a list of these medicines if you are not sure.

How should I receive ILARIS?

• ILARIS is given by your healthcare provider every 8 weeks for CAPS and every 4 weeks for TRAPS, HIDS/MKD, FMF, and SJIA.

What are the possible side effects of ILARIS?

ILARIS can cause serious side effects, including:

• See “What is the most important information I should know about ILARIS?”
• decreased ability of your body to fight infections (immunosuppression). For people treated with medicines that cause immunosuppression like ILARIS, the chances of getting cancer may increase.
• allergic reactions. Allergic reactions can happen while you are receiving ILARIS. Call your healthcare provider right away if you have any of these symptoms of an allergic reaction:
  • rash
  • itching and hives
  • difficulty breathing or swallowing
  • dizziness or feeling faint
• risk of infection with live vaccines. You should not get live vaccines if you are receiving ILARIS. Tell your healthcare provider if you are scheduled to receive any vaccines.

The most common side effects of ILARIS include:

When ILARIS is used for the treatment of CAPS:

• cold symptoms
• headache
• feeling like you are spinning (vertigo)
• diarrhea
• cough
• weight gain
• flu (influenza)
• body aches
• injection-site reactions(such as redness, swelling,warmth, or itching)
• runny nose
• nausea, vomiting, and diarrhea (gastroenteritis)
• nausea

When ILARIS is used for the treatment of TRAPS, HIDS/MKD, and FMF:

• cold symptoms
• runny nose
• nausea, vomiting, and diarrhea (gastroenteritis)
• Upper respiratory tract
• sore throat
• Injection-site reactions (such as infection redness, swelling, warmth, or itching)

When ILARIS is used for the treatment of SJIA:

• cold symptoms
• runny nose
• nausea, vomiting, and diarrhea (gastroenteritis)
• upper respiratory tract
• sore throat
• stomach pain infection
• pneumonia
• urinary tract
• injection-site reactions infection

Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of ILARIS. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of ILARIS.

Medicines are sometimes prescribed for purposes other than those listed in this Medication Guide. Do not use ILARIS for a condition for which it was not prescribed.

You can ask your healthcare provider or pharmacist for information about ILARIS that was written for health professionals.

What are the ingredients in ILARIS?

Active ingredient: canakinumab

Inactive ingredients:

Powder for Solution for Injection: L-histidine, L-histidine HCl monohydrate, polysorbate 80, sterile water for injection, sucrose

Solution for Injection: L-histidine, L-histidine HCl monohydrate, mannitol, polysorbate 80, sterile water for injection

What are Periodic Fever Syndromes?

Periodic Fever Syndromes is the name for several different autoinflammatory diseases, including CAPS, TRAPS, HIDS/MKD, and FMF. People with these diseases cannot keep certain chemicals made by their body (interleukin-1 beta, also called IL-1β) at the correct level. All these diseases have symptoms that often come and go, with irritated body parts (inflammation) and elevated body temperature (fever). These conditions have a dysregulation of IL-1β production and share similar clinical features of recurrent episodes of inflammation and fever such as rash, headache, pain (mostly in the joints, belly, eyes, muscles), fatigue, inflammation of other organs such as heart, lungs, spleen, and brain.

What is SJIA?

SJIA is an autoinflammatory disorder which can be caused by having too much or being too sensitive to certain proteins, including interleukin-1β (IL-1β), and can lead to symptoms such as fever, rash, headache, feeling very tired (fatigue), or painful joints and muscles.

What is Macrophage Activation Syndrome (MAS)?

MAS is a syndrome associated with SJIA and some other autoinflammatory diseases like HIDS/MKD that can lead to death. Tell your healthcare provider right away if your SJIA symptoms get worse or if you have any of these symptoms of an infection:

• a fever lasting longer than 3 days
• a cough that does not go away
• redness in one part of your body
• warm feeling or swelling of your skin

Canakinumab reduces the effects of a substance in the body that can cause inflammation.

Canakinumab is used to treat rare genetic conditions such as Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children who are at least 4 years old.

Canakinumab may also be used for other purposes not listed in this medication guide.

Avoid being near people who have colds, the flu, or other contagious illnesses. Contact your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while you are being treated with canakinumab. The live vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), oral polio, chickenpox (varicella), BCG (Bacillus Calmette and Guérin), and nasal flu vaccine.

Make sure you are current on all vaccines before you begin treatment with canakinumab.