Ilaris (Page 2 of 8)

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.

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 [see Warnings and Precautions (5.3)]
  • Macrophage Activation Syndrome [see Warnings and Precautions (5.5)]

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
ILARISN = 177 n (%)(IR)^ ILARISN = 50 n (%) (IR) PlaceboN = 50n (%) (IR) ILARISN = 43n (%) (IR) PlaceboN = 41n (%) (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 = 552n (%)(IR-w) Triamcinolone acetonide 40 mg *N = 431n (%)(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 109 /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 0.5×109 /L was observed in the ILARIS group and none in the placebo group.

Mild (less than LLN and greater than 75 x 109 /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.

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