Arcalyst (rilonacept)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Rilonacept, a dimeric fusion protein, is an interleukin-1 (IL-1) receptor antagonist (IL-1Ra).
Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human interleukin-1 type I receptor (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human immunoglobulin G1. The drug is an interleukin-1 alpha(IL-1alpha) and interleukin-1 beta (IL-1beta) cytokine trap. It also binds toreceptor antagonist (IL-1Ra)
Cryopyrin-associated periodic syndromes (CAPS) are rare genetic syndromes generally caused by mutations in theNLRP-3 gene. Inflammation in CAPS is usually associated with mutations in the NLRP-3 gene that encodes the protein cryopyrin, which is an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1beta).
Mutations in the NLRP-3 gene result in an overactive inflammasome, which causes excessive release of activated IL-1beta. Rilonacept blocks IL-1beta signaling by acting as a soluble decoy receptor that binds IL-1beta and prevents its interaction with cell surface receptors. The drug also bindsIL-1alpha and interleukin-1 receptor antagonist(IL-1Ra) to a lesser extent.
Deficiency of interleukin-1 receptor antagonist (DIRA) is an autoinflammatory, autosomal recessive disorder caused by loss of function mutations in the IL1RN gene, which encodes IL-1Ra, resulting in unopposed signaling of the proinflammatory cytokines IL-1alpha and IL-1beta through the IL-1 receptor. IL-1 is a key cytokine in inflammatory processes and has been implicated as a causative factor in pericarditis. IL-1alpha and IL-1beta bind to IL-1receptor type-1, which triggers a cascade of inflammatory mediators.
Preformed IL-1alpha is released by inflamed pericardial cells and may contribute to the maintenance and amplification of inflammation via activation of the NLRP3 inflammasome, which further augments the inflammatory response by production of IL-1beta in a cascade amplification system.
Concentrations of serum amyloid A (SAA) and C-reactive protein (CRP), indicators of inflammatory disease activity, are elevated in patients with CAPS. CRP is also an indicator of inflammation in DIRA and recurrent pericarditis. Elevated SAA concentrations have been associated with the development of systemic amyloidosis in patients with CAPS.
In a placebo-controlled study of patients with FCAS or MWS, treatment with rilonacept resulted in sustained reductions in mean serum SAA and CRP concentrations compared with placebo. Maintenance of CRP reduction was observed in a clinical trial of pediatric patients with DIRA. In a clinical trial of patients with recurrent pericarditis treated with rilonacept, resolution of acute episodes along with a rapid and sustained reduction in CRP were observed.
The median time to normalization of CRP was 7 days.
Following multiple-dose subcutaneous administration of rilonacept (160 mg once weekly for up to 48 weeks) in patients with CAPS, steady-state concentrations of the drug were reached by 6 weeks of therapy; the average steady-state trough concentration of rilonacept in adult patients was approximately 24 mcg/mL. In patients with recurrent pericarditis, the average trough levels were approximately 23 mcg/mL at steady-state and the in vivo circulation half-life was approximately 7 days following a 320 mg loading dose and weekly subcutaneous doses of 160 mg for up to 36 weeks. Steady state appeared to be reached by approximately 2 weeks.
In pediatric patients with DIRA (3-6 years of age and body weight 12.7-19.9 kg), the average steady-state trough levels of rilonacept ranged from 63.5-74 mg/mL following 6-24 monthsof treatment with weekly doses of 4.4 mg/kg.
The relative bioavailability of rilonacept following subcutaneous administration is estimated to be approximately 50%. Based on population-based pharmacokinetic parameters in patients with CAPS, the terminal half-life of the drug is 7.72 days. Pharmacokinetic data are not available for patients with hepatic impairment.
In patients with end-stage renal disease on hemodialysis, the pharmacokinetics of a single dose of rilonacept demonstrated 21% higher mean rilonacept concentrations on day 3 after hemodialysis compared to day 3 pre-dialysis; the difference was not consideredclinically important. Terminal half-life was similar in hemodialysis patients compared to patients with normal renal function (7.63 versus 7.72 days, respectively). The effects of age, gender, or body weight on the pharmacokinetics of rilonacept have not been systematically evaluated.
However, limited dataindicate that steady-state trough concentrations are similar between male and female patients. Age (26-78 years old) and body weight (50-120 kg) did not appear to have substantial effects on trough rilonacept concentrations. The effects of race could not be assessed because lownumbers of non-Caucasian patients participated in the clinical study.
USES: Rilonacept is used to treat a certain type heart disease (recurrent pericarditis). This medication reduces the risk of the heart disease from coming back. This medication is also used to treat a certain group of inherited disorders called cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome and Muckle-Wells syndrome.
Rilonacept works by blocking a certain natural protein in your body (interleukin-1) that may worsen the symptoms of CAPS. Rilonacept does not cure CAPS, but it can help lessen the symptoms, including rash, joint pain, fever, and tiredness. This medication is also used to treat a condition of a lack of the natural protein interleukin-1 receptor antagonist (Deficiency of Interleukin-1 Receptor Antagonist-DIRA).
Generic name: rilonacept
Pronunciation: (ri-LON-a-sept)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Arcalyst
Indications
The following indications are listed for Arcalyst:
- Deficiency Of Interleukin-1 Receptor Antagonist
- Familial Cold Autoinflammatory Syndrome
- Muckle-Wells Syndrome
- Recurrent Pericarditis
Also known as: Amyloid Nephropathy With Deafness And Urticaria, Cryopyrin-Associated Periodic Syndrome-1, Cryopyrin-Associated Periodic Syndrome-2, Familial Amyloid Nephropathy With Urticaria And Deafness, Familial Cold Urticaria, Familial Cold-Induced Auto-Inflammatory Syndrome, Interleukin-1 Receptor Antagonist Deficiency, Recurring Pericarditis, Relapsing Pericarditis, Sterile Multifocal Osteomyelitis With Periostitis And Pustulosis, Uda Syndrome, Urticaria-Deafness-Amyloidosis Syndrome.
Dosing
No dosing information is available for this tab.
Rilonacept is administered by subcutaneous injection; the drug should not be given by IM, IV, or intra-arterial injection. The first injection of rilonacept should be performed under the supervision of the clinician; subsequent injections of the drug may be self-administered if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug after appropriate training and with medical follow-up as necessary.
Injectrilonacept subcutaneously into the upper arms, thighs, or abdomen (avoid the 2-inch area around the navel); rotateinjection sites to prevent irritation and to allow complete absorption of the drug. If the patient is self-administering the drug, injection sites in the abdomen and thigh are preferred; the upper arm may be used if another person is administering the injection. Injections should not be made into areas where the skin is bruised, red, swollen, tender, or hard. Prior to administration, cleanthe area around the injection sitewith alcohol and allow to air dry completely. Gently pinchthe tissue around the injection site, and insertthe needleat a 90degrees angle; for small children or patients with little fat under the skin, the needle may need to be inserted at a 45degrees angle. Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, the reconstituted solution may no longer be used; discontinuethe procedure, discardthe syringe and needle, and reconstitutea new dose. If no blood appears, injectthe reconstituted solutionby pushing the plunger down at a slow, steady rate; it may take up to 30 seconds to inject the entire dose. Once the entire dose has been injected, removethe needle, and coverthe injection sitewith a piece of sterile gauze for several seconds. Dividedoses exceeding 2 mLequally into 2 syringes and inject into 2 separate sites.
If a once-weekly dose is missed, administer the injection within 7 days from the missed dose and resume the original schedule. If the missed dose is not administered within 7 days, administer the dose, starting a new schedule based on this date.
Store rilonacept under refrigeration (2-8oC) in its original carton prior to use to protect the drug from light.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Specific drug interaction studies have not been conducted to date.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
None.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse reactions reported by patients with CAPS and recurrent pericarditis receiving rilonacept are injection-site reactions and upper respiratory tract infection.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Rilonacept has been evaluated in 6 pediatric patients 12-16 years of age withCAPS receiving the drug at a dosage of 2.2 mg/kg (up to a maximum dose of 160 mg) once weekly by subcutaneous injection for 24 weeks during the open-label extension phase of a study. These patients demonstrated improvement from baseline in symptom scores and objective markers of inflammation (e.g., serum amyloid A (SAA), C-reactive protein (CRP)). Adverse effects were similar to those observed in adults and included injection site reactions and upper respiratory symptoms. Mean trough drug concentrations (20 mcg/mL) were similar to those observed in adults with CAPS (24 mcg/mL).
In a phase 3 study in patients with recurrent pericarditis (RHAPSODY), 7 patients,12-17 years of age, were treated for a median duration of 15 weeks with an initial rilonacept loading dose of 4.4 mg/kg (up to a maximum of 320 mg) followed by weekly doses of 2.2 mg/kg (up to a maximum to 160 mg). No apparent differences in efficacy, safety, or tolerability were observed across age groups.
Rilonacept treatment may have contributed to alterations in bone ossification in the fetus when administered to pregnant primates; it is not known if rilonacept will affect bone development in pediatric patients. Pediatric patients receiving the drug should undergo appropriate monitoring for growth and development.
The manufacturer states that the safety and efficacy of rilonacept in pediatric patients <12 years of age with CAPS or recurrent pericarditis have not been established.
The safety and effectiveness in pediatric patients with DIRA weighing >=10 kg have been established. For those weighing <10 kg, safety and effectiveness have not been established for this indication.
The risk of rilonacept use during human pregnancy is unknown. There are limited available data regarding use of rilonacept in pregnant women to inform 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 CAPS. In an animal reproduction study, no treatment-related effects of rilonacept on fetal survival or malformations were observed at exposure levels up to 11 times the maximum recommended human dosage (MRHD). Increased incidence of lumbar ribs was observed at approximately 2 times the MRHD 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. Whether these findings are related to drug treatment is unclear as these findings were not evident in fetuses from pregnant monkeys that had higher exposures (11 times the MRHD) during the period of organogenesis.
Published data suggest that increased maternal levels of IL-1beta, which induces inflammation that occurs in CAPS, may be associated with pre-term birth.
The presence of rilonacept in human or animal milk, its effects on the breastfed infant, and its effects on milk production are unknown. Consider the benefits of breastfeeding on the infant and the clinical need for rilonacept for the mother.
The manufacturer makes no specific dosage recommendations for geriatric patients.
In placebo-controlled clinical trials in patients with CAPS and other indications, 78 patients randomized to rilonacept treatment were >=65 years of ageand 6 patients were >=75 years of age. In the CAPS clinical trial, efficacy, safety, and tolerability generally were similar in geriatric patients and younger adults; however, only 10 patients >=65 years of age participated in the trial. In an open-label extension study of CAPS, a 71-year-old female patient developed bacterial meningitis and later died; this death was considered probably related to the immunosuppression from rilonacept therapy. Age did not appear to have a significant effect on steady-state trough concentrations of rilonacept in the CAPS clinical study.
ICD codes
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Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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