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Six serious adverse reactions were reported by four patients during the clinical program. These serious adverse reactions were Mycobacterium intracellulare infection; gastrointestinal bleeding and colitis; sinusitis and bronchitis; and Streptococcus pneumoniae meningitis.

The most commonly reported adverse reaction associated with ARCALYST (rilonacept) was injection-site reaction (ISR). The next most commonly reported adverse reaction was upper respiratory infection.

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.

The data described herein reflect exposure to ARCALYST (rilonacept) in 600 patients, including 85 exposed for at least 6 months and 65 exposed for at least one year. These included patients with CAPS, patients with other diseases, and healthy volunteers. Approximately 60 patients with CAPS have been treated weekly with 160 mg of ARCALYST (rilonacept) . The pivotal trial population included 47 patients with CAPS. These patients were between the ages of 22 and 78 years (average 51 years).Thirty-one patients were female and 16 were male. All of the patients were White/Caucasian. Six pediatric patients (12-17 years)were enrolled directly into the open-label extension phase.

Clinical Trial Experience

Part A of the clinical trial was conducted in patients with CAPS who were naïve to treatment with ARCALYST (rilonacept) . Part A of the study was a randomized, double-blind, placebo-controlled, six-week study comparing ARCALYST to placebo [see Clinical Studies].Table 1 reflects the frequency of adverse events reported by at least two patients during Part A.

Table 1: Most Frequent Adverse Reactions (Part A, Reported by at Least Two Patients)

Adverse Event ARCALYST (rilonacept)
160 mg
(n = 23)
Placebo
(n = 24)
Any AE 17 (74%) 13 (54%)
Injection-site reactions 11 (48%) 13 (13%)
Upper respiratory tract infection 16 (26%) 11 ( 4%)
Nausea 1 ( 4%) 13 (13%)
Diarrhea 11 (14%) 13 (13%)
Sinusitis 2 ( 9%) 11 ( 4%)
Abdominal pain upper 10 12 ( 8%)
Cough 2 ( 9%) 0
Hypoesthesia 12 (19%) 10
Stomach discomfort 1 ( 4%) 1 ( 4%)
Urinary tract infection 11 (14%) 1 (14%)

Injection-Site Reactions

In patients with CAPS, the most common and consistently reported adverse event associated with ARCALYST (rilonacept) was injection-site reaction (ISR).The ISRs included erythema, swelling, pruritis, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth and hemorrhage. Most injection-site reactions lasted for one to two days. No ISRs were assessed as severe, and no patient discontinued study participation due to an ISR.

Infections

During Part A, the incidence of patients reporting infections was greater with ARCALYST (rilonacept) (48%) than with placebo (17%). In Part B, randomized withdrawal, the incidence of infections were similar in the ARCALYST (rilonacept) (18%) and the placebo patients (22%). Part A of the trial was initiated in the winter months, while Part B was predominantly performed in the summer months.

In placebo-controlled studies across a variety of patient populations encompassing 360 patients treated with rilonacept and 179 treated with placebo, the incidence of infections was 34% and 27% (2.15 per patient-exposure year and 1.81 per patient-exposure year), respectively, for rilonacept and placebo.

Serious Infections

One subject receiving ARCALYST (rilonacept) for an unapproved indication in another study developed an infection in his olecranon bursa with Mycobacterium intracellulare. The patient was on chronic glucocorticoid treatment. The infection occurred after an intraarticular glucocorticoid injection into the bursa with subsequent local exposure to a suspected source of mycobacteria. The patient recovered after the administration of the appropriate antimicrobial therapy. One patient treated for another unapproved indication developed bronchitis/sinusitis, which resulted in hospitalization. One patient died in an open-label study of CAPS from Streptococcus pneumoniae meningitis.

Malignancies

[see WARNINGS AND PRECAUTIONS].

Hematologic Events

One patient in a study in an unapproved indication developed transient neutropenia (ANC < 1 x 109/L) after receiving a large dose (2000 mg intravenously) of ARCALYST (rilonacept) . The patient did not experience any infection associated with the neutropenia.

Immunogenicity

Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in patients with CAPS after treatment with ARCALYST (rilonacept) . Nineteen of 55 subjects (35%) who had received ARCALYST (rilonacept) for at least 6weeks tested positive for treatment-emergent binding antibodies on at least one occasion. Of the 19, seven tested positive at the last assessment (Week 18 or 24 of the open-label extension period), and five subjects tested positive for neutralizing antibodies on at least one occasion. There was no correlation of antibody activity and either clinical effectiveness or safety.

The data reflect the percentage of patients whose test results were positive for antibodies to the rilonacept receptor domains in specific assays, and are highly dependent on the sensitivity and specificity of the assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to rilonacept with the incidence of antibodies to other products may be misleading.

Lipid profiles

Cholesterol and lipid levels may be reduced in patients with chronic inflammation. Patients with CAPS treated with ARCALYST (rilonacept) experienced increases in their mean total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. The mean increases from baseline for total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were 19 mg/dL, 2 mg/dL, 10 mg/dL, and 57 mg/dL respectively after 6weeks of open-label therapy. Physicians should monitor the lipid profiles of their patients (for example after 2-3 months) and consider lipid-lowering therapies as needed based upon cardiovascular risk factors and current guidelines.