Arcalyst
(rilonacept)Dosage & Administration
Administer by subcutaneous injection
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Arcalyst Prescribing 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. 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.
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)].
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.
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.
For injection: 220 mg of rilonacept as a white to off-white lyophilized powder for reconstitution in single-dose vials.
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.
Lactation
Risk Summary
There is no information on the presence of rilonacept in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ARCALYST and any potential adverse effects on the breastfed child from ARCALYST or from the underlying maternal condition.
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.
Six pediatric patients with CAPS between the ages of 12 and 16 were treated with ARCALYST at a weekly subcutaneous dose of 2.2 mg/kg (up to a maximum of 160 mg) for 24 weeks during the open-label extension phase. 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.
The trough drug levels for four pediatric patients measured at the end of the weekly dose interval (mean 20 mcg/mL, range 3.6 to 33 mcg/mL) were similar to those observed in adult patients with CAPS (mean 24 mcg/mL, range 7 to 56 mcg/mL).
In the Phase 3 study RHAPSODY, 7 patients aged 12 years to 17 years were treated with ARCALYST subcutaneously with an initial loading dose of 4.4 mg/kg (up to a maximum of 320 mg) followed by 2.2 mg/kg (up to a maximum of 160 mg) weekly. 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. [see Use in Specific Populations (8.1)]
Deficiency of Interleukin-1 Receptor Antagonist (DIRA)
Safety and effectiveness in pediatric patients with DIRA weighing 10 kg or more have been established [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. Safety and effectiveness of ARCALYST have not been established in pediatric patients weighing less than 10 kg for maintenance of remission of DIRA.
Geriatric Use
In the placebo-controlled clinical studies, 78 patients randomized to treatment with ARCALYST were ≥ 65 years of age, and 6 were ≥ 75 years of age. In the CAPS clinical trial, efficacy, safety and tolerability were generally similar in elderly patients as compared to younger adults; however, only ten patients ≥ 65 years old participated in the trial. In an open-label extension study of CAPS, a 71-year-old woman developed bacterial meningitis and died [see Adverse Reactions (6.1)]. Age did not appear to have a significant effect on steady-state trough concentrations in the clinical study.
Patients with Renal Impairment
No studies have been conducted to evaluate the pharmacokinetics of rilonacept administered subcutaneously in patients with renal impairment.
Patients with Hepatic Impairment
No studies have been conducted to evaluate the pharmacokinetics of rilonacept administered subcutaneously in patients with hepatic impairment.
None.
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.
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.
Hypersensitivity Reactions
Hypersensitivity reactions associated with ARCALYST occurred in clinical trials. If a hypersensitivity reaction occurs, discontinue ARCALYST and initiate appropriate therapy.
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)].
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.