Ilaris (Novartis Pharmaceuticals Canada, Powder For Solution) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ILARIS (canakinumab) is an interleukin-1 beta (IL-1β) inhibitor indicated for the treatment of the following autoinflammatory Periodic Fever Syndromes.

Cryopyrin-Associated Periodic Syndromes (CAPS)

ILARIS is indicated for the ongoing management of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children aged 2 years and older, including:

• Familial Cold Autoinflammatory Syndrome (FCAS)/ Familial Cold Urticaria (FCU),
• Muckle-Wells Syndrome (MWS)

ILARIS may also be used in Neonatal-Onset Multisystem Inflammatory Disease (NOMID)/ Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA). Clinical data have not confirmed improvement in CNS symptoms in patients with this phenotype.

Tumor Necrosis Factor receptor 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 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.

ILARIS can be given as monotherapy or in combination with colchicine.

ILARIS is also indicated for the treatment of:

Systemic Juvenile Idiopathic Arthritis (SJIA)

ILARIS is indicated for the treatment of active Systemic Juvenile Idiopathic Arthritis (SJIA) in patients aged 2 years and older.

Geriatrics (> 65 years of age):

Clinical studies of ILARIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Pediatrics (<18 years of age):

CAPS, TRAPS, HIDS/MKD, and FMF: ILARIS is not recommended for use in children below age of 2 years due to lack of clinical data.

SJIA: The safety and efficacy of ILARIS in patients below age of 2 years and with a body weight under 9 kg have not been established.

CONTRAINDICATIONS

Patients who are hypersensitive to canakinumab or to any ingredient in the formulation of ILARIS or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. A risk for hypersensitivity reactions, which is not uncommon for injectable proteins, cannot be excluded.

Patients who have active, severe infections (see ADVERSE REACTIONS, Serious infections).

WARNINGS AND PRECAUTIONS

Serious infections

ILARIS is associated with an increased incidence of serious infections. Therefore patients should be monitored carefully for signs and symptoms of infections during and after treatment with ILARIS. Physicians should exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. Treatment with ILARIS should not be initiated or continued in patients with active infection requiring medical intervention.

Serious infections were observed in 28.6% of the 2-3 years age group and in 21.4% of the 4-11 year old age group vs. 2.7% in adult CAPS patients. The severe phenotype and disease severity in young children may have played a role in this difference.

Isolated cases of unusual or opportunistic infections (including aspergillosis, atypical mycobacterial infections, herpes zoster) have been reported during ILARIS treatment however no cases have been confirmed to be opportunistic in CAPS patients. A causal relationship of ILARIS to these events cannot be excluded.

Drugs that affect the immune system by blocking TNF have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as ILARIS that block IL-1 increases the risk of TB or other atypical or opportunistic infections.

Prior to initiating immunomodulatory therapies, including ILARIS, patients should be tested for latent tuberculosis infection. 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. Patients testing positive in tuberculosis screening should be treated by standard medical practice

prior to therapy with ILARIS.

In approximately 12% of CAPS patients tested with a PPD skin test in clinical trials, follow-up testing yielded a positive test result while treated with ILARIS without clinical evidence of a latent or active tuberculosis infection. Before initiation of therapy, all patients must be evaluated for both active and latent tuberculosis infection. Particularly in adult patients, this evaluation should include a detailed medical history and appropriate screening tests. Patients must be monitored closely for signs and symptoms of tuberculosis during and after treatment with ILARIS. In the event of conversion from a negative to a positive PPD test, especially in high-risk patients, alternative means of screening for a tuberculosis infection should be considered.

Concomitant use of ILARIS with tumour necrosis factor (TNF) inhibitors is not recommended because this may increase the risk of serious infections (see DRUG INTERACTIONS).

Cardiovascular

In clinical trials for CAPS, notable changes from baseline in systolic and diastolic blood pressure values were more frequently seen in patients in the canakinumab group than in patients in the placebo group. Blood pressure should be monitored in patients on ILARIS treatment (see ADVERSE REACTIONS, Vital Signs and Physical Findings).

Neutropenia

Neutropenia (absolute neutrophil count [ANC] < 1.5 x 10⁹/l) has been observed with medicinal products that inhibit IL-1, including ILARIS. Treatment with ILARIS should not be initiated in patients with neutropenia. It is recommended that neutrophil counts be assessed prior to initiating treatment, after 1 to 2 months, and periodically thereafter while receiving ILARIS. If a patient becomes neutropenic the ANC should be monitored closely and treatment discontinuation should be considered.

Hypersensitivity reactions

Hypersensitivity reactions with ILARIS therapy have been reported. The majority of these events were mild in severity. During clinical trials, no anaphylactoid or anaphylactic reactions have been reported. However, the risk for severe hypersensitivity reactions, which is not uncommon for injectable proteins, cannot be excluded (see CONTRAINDICATIONS and ADVERSE REACTIONS).

Hepatic function

Rare, mild, transient and asymptomatic cases of elevations of serum transaminases or bilirubin have been reported in clinical trials for CAPS (see ADVERSE REACTIONS, Hepatobiliary Events, and Abnormal Hematologic and Clinical Chemistry Findings).

Vaccinations

Live vaccines should not be given concurrently with ILARIS (see DRUG INTERACTIONS).

Since ILARIS may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ILARIS. No data are available on the effectiveness of

vaccinations with inactivated (killed) antigens in patients receiving ILARIS.

Prior to initiation of ILARIS therapy, adult and pediatric patients should receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine. In a dedicated study in healthy volunteers, a normal antibody-response to vaccination with meningococcal and influenza antigen was observed.

Lymphoid organ toxicity

Minimal to slight lymphoid hyperplasia of the spleen and lymph nodes has been infrequently observed in animal studies. Enlargement of lymphoid organs (lymph nodes, spleen), in patients treated with ILARIS, should be assessed for their etiology.

Macrophage activation syndrome (in SJIA patients)

Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with rheumatic conditions, in particular SJIA, and should be aggressively treated. Physicians should be attentive to symptoms of infection or worsening of SJIA, as these are known triggers for MAS. Eleven cases of MAS were observed in 201 SJIA patients treated with ILARIS in clinical trials. Based on clinical trial experience, ILARIS does not appear to increase the incidence of MAS in SJIA patients, but no definitive conclusion can be made.

Malignancies

Malignancy events have been reported in patients treated with ILARIS. The risk for the development of malignancies with anti-interleukin (IL)-1 therapy is unknown.

Special Populations

Pregnant Women and Women of Child-Bearing Potential: There are no adequate and well-controlled studies of ILARIS in pregnant women or women of child-bearing potential. There is a limited amount of data from the use of ILARIS in this population. Women should use effective contraceptives during treatment with ILARIS and for up to 3 months after the last dose.

A significant shift in the litter size was observed in marmosets treated with 150 mg/kg of canakinumab. Singlet pregnancy that was seen in 0% of animals in the control group, increased to 21% in the treated group and triplet pregnancy in control vs. treated group was down from 45% to 7%. This shift could be an indication of impaired fertility. Delayed ossification was seen in study 0680148 in a mouse model. Because animal reproduction studies are not always predictive of the human response, the risk for the foetus/mother is unknown, therefore, ILARIS should not be given to pregnant women or women who desire to become pregnant, unless clearly needed (see TOXICOLOGY).

Animal studies indicate that canakinumab crosses the placenta and is detectable in the foetus. No human data are available, but as canakinumab is an immunoglobulin of the G class (IgG1), human transplacental transfer is expected. The clinical impact of this is unknown. However, administration of live vaccines to infants exposed to canakinumab in utero is not recommended for 16 weeks following the mother’s last dose of ILARIS before childbirth. Women who received ILARIS during pregnancy should be instructed to inform the baby’s healthcare

professional before any vaccinations are given to their infant.

Nursing Women: It is not known whether canakinumab is excreted in human milk. Animal studies have shown that a murine anti-murine IL-1 beta antibody had no undesirable effects on development in nursing mouse pups and that the antibody was transferred to them (see TOXICOLOGY).

Breast-feeding is not recommended during ILARIS therapy.

Pediatrics (<18years of age):

CAPS, TRAPS, HIDS/MKD, and FMF: ILARIS is not recommended for use in children below age of 2 years due to lack of clinical data.

SJIA: The safety and efficacy of ILARIS in patients below age of 2 years and with a body weight < 9 kg have not been established.

Geriatrics (> 65 years of age): Clinical studies of ILARIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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

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

Monitoring and Laboratory Tests (CAPS)

Annual monitoring for changes in lipid profile are recommended.

ADVERSE REACTIONS

Periodic Fever Syndromes

Cryopyrin-Associated Periodic Syndromes (CAPS)

Adverse Drug Reaction Overview

The data described herein reflect exposure to ILARIS in 194 adult and pediatric CAPS patients (31 FCAS, 110 MWS, 52 NOMID, and 1 miss-classified with cold-induced urticaria) in placebo-controlled and uncontrolled studies. One hundred and seventy-seven (177) patients were exposed to ILARIS for at least 24 weeks, 127 for at least 48 weeks and 8 for at least 144 weeks. A total of 16 patients reported serious adverse drug reactions during the clinical trial program in CAPS, including vertigo (2 patients), increased transaminases (1 patient) and infection (13 patients). The infections included 3 cases of pneumonia considered to be typical and successfully treated, one case of abdominal abscess following appendectomy, bronchitis, cellulitis, chronic tonsillitis,

lower respiratory tract infection, sepsis and tonsillitis. Serious infections were observed in 2 (28.6%) of the 2-3 years age group and in 7 (25%) of the 4-11 year old age group vs. 2.7% in adult CAPS patients. The severe phenotype and disease severity in young children may have played a role in this difference. The following were identified as the infectious agents and none were reported more than once: Epstein-Barr virus, H1N1 influenza virus, mumps virus, parvovirus and Staphylococcus. The most commonly reported adverse reaction associated with ILARIS treatment in the CAPS patients were upper respiratory tract infections and nasopharyngitis. No impact on the type or frequency of adverse drug reactions was seen with longer-term treatment. One (1) patient discontinued treatment due to infection.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

To date, 211 patients with CAPS have received ILARIS, including 86 children (aged 28 days to 17 years) in completed clinical trials.

The safety of ILARIS compared with placebo was investigated in a pivotal phase III trial (Study D2304) that consisted of an 8-week, open-label period (Part I), followed by a 24-week, randomized, double-blind and placebo-controlled withdrawal period (Part II), followed by a 16-week open-label period (Part III). All patients were treated with ILARIS 150 mg subcutaneously or 2 mg/kg if body weight was ≥15 kg and ≤40 kg (see Table 1).

In placebo-controlled period in Part II of Study D2304 (canakinumab; n=15 vs. placebo; n=16), with a mean duration of 168.4 days (mean 3 doses) in ILARIS patients and 109.9 days (mean 2.3 doses) in placebo patients, there were more patients in the canakinumab treatment group reporting adverse events in the immune system disorders (13.3% vs. 0), infections and infestations (80% vs. 56.3%), injury, poisoning and procedural complications (26.7% vs. 12.5%), nervous system disorders (26.7% vs. 0), psychiatric disorders (20.0% vs. 6.3%) and respiratory, thoracic and mediastinal disorders (33.3% vs. 6.3%) in system organ classes than in the placebo group.

In all 5 CAPS clinical trials (Study D2304, D2102, D2306, D2308, and D2201), a total of 194 unique CAPS patients analysed for safety included 31 FCAS, 110 MWS, 52 NOMID and 1 mis-diagnosed patient with an overall exposure of 269.46 patient-years and a treatment duration of greater than 4 years, with age ranging from 2 to 91 years of age at time of treatment-start with canakinumab. This includes 69 pediatric (2 to 17 years of age; median: 11years) patients.

Adverse events (AEs) were reported in 88.2% in Study A2102, and in 82.9% (Part I), 100% in canakinumab group and 87.5% in placebo group (Part II) and 77.4% (Part III) of Study D2304. A total of 11 patients reported serious adverse drug reactions during the clinical trial program in