Arcalyst

1 INDICATIONS AND USAGE ARCALYST (rilonacept) is an interleukin-1 blocker indicated for: Treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS), and Muckle-Wells Syndrome (MWS) in adults and children 12 years and older ( 1.1 , 14.1 ) Maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing 10 kg or more ( 1.2 , 14.2 ) Treatment of recurrent pericarditis (RP) and reduction in risk of recurrence in adults and children 12 years and older ( 1.3 , 14.3 ) 1.1 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. 1.2 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. 1.3 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.

2 DOSAGE AND ADMINISTRATION Administer by subcutaneous injection ( 2.1 ) CAPS, FCAS, MWS, and RP ( 2.2 ): Adults: – Loading dose: 320 mg, delivered as two 160 mg (2 mL) injections. – Maintenance dose: 160 mg (2 mL) injection once weekly. Pediatric patients 12 years to 17 years: – Loading dose: 4.4 mg/kg, up to a maximum of 320 mg, delivered as 1 or 2 injections (not to exceed 2 mL/injection). – Maintenance dose: 2.2 mg/kg, up to a maximum of 160 mg (2 mL) injection, once weekly. DIRA ( 2.3 ): Adults and pediatric patients weighing 10 kg or more: – 4.4 mg/kg up to a maximum of 320 mg, delivered as 1 or 2 injections (2 mL/injection) once weekly. 2.1 General Dosing Information ARCALYST is for subcutaneous use only. 2.2 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. Continue dosing with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL. 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. 2.3 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 [see Drug Interactions (7.1) ] . 2.4 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. 2.5 Administration Using aseptic technique, withdraw 2.3 mL of preservative-free Sterile Water for Injection through an 18-gauge, 1- or 1½-inch needle attached to a 3-mL syringe and inject the preservative-free Sterile Water for Injection, USP, into the drug product vial for reconstitution. The needle and syringe used for reconstitution with preservative-free Sterile Water for Injection, USP, should then be discarded and should not be used for subcutaneous injections. After the addition of preservative-free Sterile Water for Injection, USP, reconstitute the vial contents by shaking the vial for approximately one minute and then allowing it to sit for one minute. The resulting 80mg/mL solution is sufficient to allow a withdrawal volume of up to 2 mL for subcutaneous administration. The reconstituted solution is viscous, clear, colorless to pale yellow, and free from particulates. Prior to injection, inspect the reconstituted solution for any discoloration or particulate matter. Discard the solution if either is observed. Using aseptic technique, withdraw the recommended dose volume, up to 2 mL (160 mg), of the solution with a new 18-gauge, 1- or 1½-inch needle attached to a new 3-mL syringe. For the subcutaneous injection, replace the needle with a new 26-gauge, ½-inch needle. EACH VIAL SHOULD BE USED FOR A SINGLE DOSE ONLY. Discard the vial after withdrawal of drug. After reconstitution, ARCALYST may be kept at room temperature, but keep it protected from light, and use the solution within three hours after reconstitution. Discard unused portions of ARCALYST. Rotate the sites for subcutaneous injection, such as the abdomen, thigh, or upper arm. Injections should never be administered at sites that are bruised, red, tender, or hard.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Serious Infections : Serious, life-threatening infections have been reported in patients taking ARCALYST. Do not initiate treatment with ARCALYST in patients with active or chronic infections. Discontinue treatment if a patient develops a serious infection. ( 5.1 ) Hypersensitivity Reactions : If a hypersensitivity reaction occurs, discontinue administration of ARCALYST and initiate appropriate therapy. ( 5.3 ) Immunizations : Avoid live vaccines. Update recommended vaccinations prior to initiation of therapy per current guidelines. ( 5.5 ) 5.1 Serious Infections Interleukin-1 (IL-1) blockade may interfere with the immune response to infections. Treatment with another medication that works through inhibition of IL-1 has been associated with an increased risk of serious infections, and serious infections have been reported in patients taking ARCALYST [see Clinical Studies (14) ] . There was a greater incidence of infections in CAPS and RP patients on ARCALYST compared with placebo. In the controlled portion of the CAPS study [see Clinical Studies (14.1) ] , severe infection (bronchitis) was reported in one patient receiving ARCALYST. In an open-label extension study in CAPS, one patient developed bacterial meningitis and died [see Adverse Reactions (6.1) ] . In clinical studies, ARCALYST has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of an IL-1 blocker in combination with TNF inhibitors. ARCALYST is not recommended for use with TNF inhibitors because this may increase the risk of serious infections. 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 ARCALYST that block IL-1 increases the risk of TB or other atypical or opportunistic infections. Refer to current practice guidelines for evaluation and treatment of possible latent tuberculosis infections before initiating therapy with ARCALYST. Treatment with ARCALYST should not be initiated in patients with an active or chronic infection. Discontinue ARCALYST if a patient develops a serious infection. 5.2 Risk of Malignancy The impact of treatment with ARCALYST on the development of malignancies is not known. Treatment with immunosuppressants, including ARCALYST, may result in an increase in the risk of malignancies. 5.3 Hypersensitivity Reactions Hypersensitivity reactions associated with ARCALYST occurred in clinical trials. If a hypersensitivity reaction occurs, discontinue ARCALYST and initiate appropriate therapy. 5.4 Lipid Profile Changes Cholesterol and lipid levels may be reduced in patients with chronic inflammation. Increases in non-fasting lipid profile parameters occurred in patients treated with ARCALYST in clinical trials. Monitor patients' lipid profiles and consider lipid-lowering therapies if needed, based on cardiovascular risk factors and current guidelines [see Adverse Reactions (6.1) ] . 5.5 Immunizations Since no data are available on the risks of secondary transmission of infection by live vaccines in patients receiving ARCALYST, avoid administration of live vaccines during treatment with ARCALYST. No data are available on the effectiveness of vaccines in patients receiving ARCALYST. Since ARCALYST may interfere with normal immune response to new antigens, vaccines may not be effective in patients receiving ARCALYST. Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ARCALYST, adult and pediatric patients receive all recommended vaccinations, as per current immunization guidelines, including pneumococcal vaccine and inactivated influenza vaccine.

7 DRUG INTERACTIONS 7.1 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 [see Warnings and Precautions (5.1) ] . 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. 7.2 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. Serious Infections [see Warnings and Precautions (5.1) ] Risk of Malignancy [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Lipid Profile Changes [see Warnings and Precautions (5.4) ] The most common adverse reactions reported by patients with CAPS and RP treated with ARCALYST are injection-site reactions and upper respiratory tract infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Kiniksa at 1-833-KINIKSA (1-833-546-4572) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. The data described herein reflect exposure to ARCALYST in over 2,000 patients who received at least one dose, including approximately 1700 exposed to 160 mg or more, of whom 151 patients were exposed for at least 6 months and 111 patients for at least one year. 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 [see Clinical Studies (14) ] . Table 1 reflects the frequency of adverse events reported by at least two patients during Part A. Table 1: Most Frequent Adverse Reactions in Patients with CAPS (Part A, Reported by at Least Two Patients) Adverse Event ARCALYST 160 mg (n = 23) Placebo (n= 24) Any AE 17 (74%) 13 (54%) Injection-site reactions 11 (48%) 3 (13%) Upper respiratory tract infection 6 (26%) 1 (4%) Nausea 1 (4%) 3 (13%) Diarrhea 1 (4%) 3 (13%) Sinusitis 2 (9%) 1 (4%) Abdominal pain upper 0 2 (8%) Cough 2 (9%) 0 Hypoesthesia 2 (9%) 0 Stomach discomfort 1 (4%) 1 (4%) Urinary tract infection 1 (4%) 1 (4%) DIRA In a 2-year, open-label study, 6 pediatric patients with DIRA, 3 years to 6 years of age, received a 2.2 to 4.4 mg/kg dose of ARCALYST once weekly [see Clinical Studies (14.2) ] . The safety profile was generally consistent with that seen in patients with CAPS. The most common adverse reactions were upper respiratory infection (6 of 6), rash (5 of 6), otitis media (3 of 6), pharyngitis (3 of 6) and rhinorrhea (3 of 6). 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 [see Clinical Studies (14.3) ]. Of the patients, 49 (57%) were female and 37 (43%) were male; 93% were White/Caucasian. 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. 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 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 [see Adverse Reactions (6) ] . 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 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 6 weeks of open-label therapy. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. 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 any point in time, 26 out of 86 (30%) subjects tested positive at any assessment and of these, 6 tested positive for neutralizing antibodies (NAb). At the last assessment, 10 subjects remained positive for anti-drug antibodies (ADA) and 1 subject remained positive for NAb. There was no correlation of antibody activity and either clinical effectiveness or safety.

8.1 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 0, 5, 15 or 30 mg/kg given twice a week from gestation days 20 to 48. The study 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 MRHD (on a mg/kg basis with maternal subcutaneous doses up to 30 mg/kg). Increased incidences of lumbar ribs, a skeletal variation, were observed in fetuses at doses approximately 2 times the MRHD and higher (on a mg/kg basis with maternal subcutaneous doses of 5 mg/kg and higher) that slightly exceeded incidences in both control animals and the historical control database. 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 6 times the MRHD (on a mg/kg basis with a maternal subcutaneous dose of 15 mg/kg). 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 (on a mg/kg basis with a maternal subcutaneous dose of 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 0, 20, 100 or 200 mg/kg), there was a small increase in the number of stillbirths in dams treated with 200 mg/kg three times per week.