Arcalyst Drug Information

Cryopyrin-Associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome ARCALYST ® (rilonacept) is an interleukin-1 blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS), and Muckle-Wells Syndrome (MWS) in adults and pediatric patients 12 years and older.

Deficiency of IL-1 Receptor Antagonist ARCALYST is indicated for the maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing at least 10 kg.

Recurrent Pericarditis ARCALYST is indicated for the treatment of recurrent pericarditis (RP) and reduction in risk of recurrence in adults and pediatric patients 12 years and older.

General Dosing Information ARCALYST is for subcutaneous use only.

Cryopyrin-Associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome and Recurrent Pericarditis Adults: Initiate treatment with a loading dose of 320 mg delivered as two, 2-mL subcutaneous injections of 160 mg each, administered on the same day at two different injection sites. Continue dosing with a once-weekly injection of 160 mg administered as a single, 2-mL subcutaneous injection. Pediatric patients 12 years to 17 years: Initiate treatment with a loading dose of 4.4 mg/kg, up to a maximum dose of 320 mg, administered as one or two subcutaneous injections, not to exceed single-injection volume of 2 mL per injection site.

If the initial dose is given as two injections, administer on the same day at two different sites. If a once-weekly dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to administer the dose, starting a new schedule based on this date.

Deficiency of IL-1 Receptor Antagonist Adults

The recommended dose of ARCALYST is 320 mg, once weekly, administered as two subcutaneous injections on the same day at two different sites with a maximum single-injection volume of 2 mL. ARCALYST should not be given more often than once weekly. Pediatric patients weighing 10 kg or more: The recommended dose of ARCALYST is 4.4 mg/kg (up to a maximum of 320 mg), once weekly, administered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL.

If the dose is given as two injections, administer both on the same day, each one at a different site. When switching from another IL-1 blocker, discontinue the IL-1 blocker and begin ARCALYST treatment at the time of the next dose.

Preparation for Administration

Reconstitute each single-dose vial of ARCALYST with 2.3 mL of preservative-free Sterile Water for Injection, USP (supplied separately) prior to subcutaneous administration of the drug.

Clinical Trial Experience

Clinical trials are conducted under widely varying conditions and, as such, adverse reaction rates observed cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. These included patients with CAPS and RP, patients with other diseases, and healthy volunteers. CAPS Approximately 60 patients with CAPS were treated weekly with 160 mg of ARCALYST.

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 to17 years) were enrolled directly into the open-label extension phase of the trial. Part A of the clinical trial was conducted in patients with CAPS who were naïve to treatment with ARCALYST.

Part A of the study was a randomized, double-blind, placebo-controlled, six-week study comparing ARCALYST to placebo. Table 1 reflects the frequency of adverse events reported by at least two patients during Part A. The safety profile was generally consistent with that seen in patients with CAPS.

RP In the RP phase 3 study, a total of 86 patients received at least one dose of ARCALYST with a median treatment duration of 9 months. The mean age was 44.7 years. Seven patients (8%) were aged 12-17 years old.

No new adverse reactions were identified in this study. Adverse Reactions of Special Interest Injection-Site Reactions In patients with CAPS or RP, the most common and consistently reported adverse event associated with ARCALYST was injection-site reaction (ISR). The ISRs included erythema, swelling, pruritus, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth and hemorrhage.

Most injection-site reactions lasted for one to two days. Infections During Part A in the CAPS study, the incidence of patients reporting infections was greater with ARCALYST (48%) than with placebo (17%). In Part B, randomized withdrawal, the incidence of infections was similar in the ARCALYST (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. Serious Infections Six serious infections were reported by four patients during the CAPS clinical program: Mycobacterium intracellulare infection; gastrointestinal bleeding and colitis; sinusitis and bronchitis; and Streptococcus pneumoniae meningitis. One patient receiving ARCALYST 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. Changes in Hematologic Parameters Laboratory Changes One patient in a study in an unapproved indication developed transient neutropenia (ANC < 1 × 10 9 /L) after receiving a large dose (2000 mg intravenously) of ARCALYST.

The patient did not experience any infection associated with the neutropenia. Lipid Profile Changes Patients with CAPS treated with ARCALYST experienced increases in their mean total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

The data reflect the percentage of patients whose test results were positive for antibodies to the rilonacept receptor domains in specific assays. Additionally, 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 in other studies or to other products may be misleading.

Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in patients with CAPS after treatment with ARCALYST. Nineteen of 55 patients (35%) who had received ARCALYST for at least 6 weeks 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 patients tested positive for neutralizing antibodies on at least one occasion.

There was no correlation of antibody activity and either clinical effectiveness or safety. In the Phase 3 study of patients with RP, there were no patients who tested positive for antibodies at baseline. At the last assessment, 10 subjects remained positive for anti-drug antibodies (ADA) and 1 subject remained positive for NAb.

TNF-Blocking Agent and IL-1 Blocking Agent

Specific drug interaction studies have not been conducted with ARCALYST. Concomitant administration of another drug that blocks IL-1 with a TNF-blocking agent in another patient population has been associated with an increased risk of serious infections and an increased risk of neutropenia. The concomitant administration of ARCALYST with TNF-blocking agents may also result in similar toxicities and is not recommended.

The concomitant administration of ARCALYST with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacologic interactions between rilonacept and a recombinant IL-1ra, concomitant administration of ARCALYST and other agents that block IL-1 or its receptors is not recommended.

Cytochrome P450 Substrates

The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as rilonacept, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin).

Upon initiation of ARCALYST in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed, and the individual dose of the medicinal product may need to be adjusted.

Pregnancy Risk Summary Rare pregnancy outcomes reported postmarketing and from clinical trials, with very limited use of ARCALYST in pregnant women, are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the mother and fetus associated with Cryopyrin Associated Periodic Syndromes (CAPS) (see Clinical Considerations ). In an animal reproduction study, subcutaneous administration of rilonacept to pregnant monkeys during the period of organogenesis was complicated by losses of drug exposure as the study progressed, due to anti-drug antibody formation at all doses, but a dose-related increase in exposure was still evident.

There were no treatment-related effects on fetal survival or development of malformations with doses up to 11 times the maximum recommended human dose (MRHD). Increased incidences of lumbar ribs, a skeletal variation, were observed in fetuses at doses approximately 2 times the MRHD and higher that slightly exceeded incidences in both control animals and the historical control database ( see Data ). There were findings of multiple fusion and absence of the ribs and thoracic vertebral bodies and arches in one fetus of the only pregnant monkey with exposure to rilonacept during the later period of gestation associated with a dose approximately 6 times the MRHD ( see Data ).

The relationship of these findings in a single fetus to drug treatment was unclear, as these findings were not evident in fetuses from pregnant monkeys that had higher exposures to rilonacept during the period of organogenesis associated with a dose approximately 11 times the MRHD. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and of miscarriage is 15%–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased maternal levels of interleukin (IL)-1β, which induces inflammation that occurs in CAPS, may be associated with pre-term birth. Data Animal Data In an embryo-fetal development study, pregnant cynomolgus monkeys received rilonacept at subcutaneous doses of mg/kg given twice a week from gestation days 20 to 48.

There were no treatment-related effects on fetal survival or development of malformations with doses up to 11 times the MRHD (on a mg/kg basis with maternal subcutaneous doses up to 30 mg/kg). All doses of rilonacept reduced maternal serum levels of estradiol up to 64% compared to controls. In pre- and postnatal development studies in the mouse model using a murine analog of rilonacept (subcutaneous doses of mg/kg), there was a small increase in the number of stillbirths in dams treated with 200 mg/kg three times per week.

Pediatric Use Cryopyrin-Associated Periodic Syndromes (CAPS) and Recurrent Pericarditis (RP) Safety and effectiveness in pediatric patients with CAPS and RP below the age of 12 years have not been established. These patients showed improvement from baseline in their symptom scores and in objective markers of inflammation (e.g., Serum Amyloid A and C-Reactive Protein). The adverse reactions included injection-site reactions and upper respiratory symptoms as were commonly seen in adult patients.

These patients were treated for a median time of 15 weeks. There were no apparent differences in efficacy, safety or tolerability across age groups. When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus.

It is not known if ARCALYST will alter bone development in pediatric patients. Pediatric patients treated with ARCALYST should undergo appropriate monitoring for growth and development. Deficiency of Interleukin-1 Receptor Antagonist (DIRA) Safety and effectiveness in pediatric patients with DIRA weighing 10 kg or more have been established.

Safety and effectiveness of ARCALYST have not been established in pediatric patients weighing less than 10 kg for maintenance of remission of DIRA.

There have been no reports of overdose with ARCALYST. Maximum weekly doses of up to 320 mg have been administered subcutaneously for up to approximately 18 months in a small number of patients with CAPS and up to 6 months in patients with an unapproved indication in clinical trials without evidence of dose-limiting toxicities. In addition, ARCALYST given intravenously at doses up to 2000 mg monthly in another patient population for up to six months was tolerated without dose-limiting toxicities.

The maximum amount of ARCALYST that can be safely administered has not been determined. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.