Rilonacept

Class: Other Miscellaneous Therapeutic Agents
Chemical Name: Interleukin 1 receptor accessory protein (human extracellular domain fragment) fusion protein with type I interleukin 1 receptor (human extracellular domain fragment) fusion protein with immunoglobulin G1 (human Fc fragment), homodimer
Molecular Formula: C9030H13932N2400O2670S74
CAS Number: 501081-76-1
Brands: Arcalyst

Introduction

Interleukin-1 (IL-1) receptor antagonist (IL-1Ra); dimeric fusion protein.1 2 3 4 5 13

Uses for Rilonacept

Cryopyrin-associated Periodic Syndromes

Long-term5 management of cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), in adults and children ≥12 years of age;1 2 3 4 5 6 13 designated an orphan drug by FDA for use in these conditions.5 6

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Results in improvements in each of 5 components of a composite symptom score (joint pain, rash, fever or chills, eye redness or pain, and fatigue).1 2 Also results in decreases in mean concentrations of acute phase reactants (serum amyloid A [SAA] and C-reactive protein [CRP]).1 2

Rilonacept Dosage and Administration

Administration

Sub-Q Administration

Administer by sub-Q injection only; do not give by IM, IV, or intra-arterial injection.1 3

Perform the first injection of rilonacept under the supervision of a clinician;1 subsequent injections 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.1 3

Inject sub-Q into the upper arms, thighs, or abdomen (avoid the 2-inch area around the navel); rotate injection sites to prevent irritation and to allow complete absorption of the drug.1 3

Injection sites in the abdomen and thigh are preferred if the patient is administering the drug; if another person is administering the injection, may use the upper arm.1 3 Do not inject into areas where the skin is bruised, red, swollen, tender, or hard.1 3

Gently pinch tissue around the injection site and insert needle at a 90° angle (45° angle may be appropriate for small children and thin individuals).1 3 After pulling back the plunger to ensure that blood is not aspirated, inject drug at a slow, steady rate; up to 30 seconds may be required to inject the entire dose.1 3

Divide doses exceeding 160 mg (2 mL) equally into 2 syringes and inject on the same day into 2 separate sites.1 3

Reconstitution

Reconstitute the appropriate number of vials of the drug based on the indicated dosage of rilonacept.1

Prior to administration, reconstitute rilonacept lyophilized powder for injection using proper aseptic technique by adding 2.3 mL of preservative-free sterile water for injection (using a 3-mL syringe with a 27-gauge, ½-inch needle) to a vial labeled as containing 220 mg of rilonacept to provide a solution containing 80 mg/mL.1 3

Hold the vial sideways (not upright) and shake back and forth (side-to-side) for approximately one minute, then allow to sit for one minute.1 3 If the powder is not completely dissolved, shake the vial for approximately 30 seconds more and then allow to sit for one minute;3 repeat the process until the powder is completely dissolved and the solution is clear.1 3 The reconstituted solution should be viscous, clear, colorless to pale yellow, and essentially free from particulates.1 3

Discard the needle and syringe used for reconstitution; do not use for sub-Q injection.1

Before administration, withdraw the appropriate dose of rilonacept (up to 160 mg or 2 mL) into a new 3-mL syringe using a new 27-gauge, ½-inch needle.1 Discard unused portions of the reconstituted solution since the solution contains no preservatives.1

Dosage

Pediatric Patients

Cryopyrin-associated Periodic Syndromes
Sub-Q

Usual loading dose in children 12–17 years of age: 4.4 mg/kg (up to 320 mg) given as 1 or 2 injections (maximum 160 mg [2 mL] per injection).1

Usual maintenance dosage in children 12–17 years of age: 2.2 mg/kg (up to 160 mg) given as a single injection once weekly beginning 1 week after the loading dose.1

Safety and efficacy of lower doses or longer dosing intervals not established.10

Adults

Cryopyrin-associated Periodic Syndromes
Sub-Q

Usual loading dose: 320 mg given as 2 divided injections of 160 mg each.1

Usual maintenance dosage: 160 mg given as a single injection once weekly beginning 1 week after the loading dose.1

Safety and efficacy of lower doses or longer dosing intervals not established.10

Prescribing Limits

Pediatric Patients

Cryopyrin-associated Periodic Syndromes
Sub-Q

Children 12–17 years of age: Maximum loading dose of 320 mg; maximum maintenance dose of 160 mg.1 Do not administer more frequently than once weekly.1 Maximum safe dosage not established.1

Adults

Cryopyrin-associated Periodic Syndromes
Sub-Q

Do not administer more frequently than once weekly.1 Maximum safe dosage not established.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1

Renal Impairment

No specific dosage recommendations at this time1

Geriatric Patients

Dosage adjustment not required in patients ≥65 years of age.1

Cautions for Rilonacept

Contraindications

  • No known contraindications.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions reported rarely.1

If hypersensitivity reactions (e.g., rash, swollen face, difficulty breathing) occur, discontinue drug and initiate appropriate therapy as indicated.1 3

Infectious Complications

IL-1 blockade may interfere with immune response to infections.1 3 Increased incidence of infections reported,1 2 including serious, potentially life-threatening infections (e.g., Mycobacterium intracellulare infection, sinusitis and bronchitis, Streptococcus pneumoniae meningitis).1 2

Infections may occur at any time during therapy.10 Do not initiate rilonacept in patients with an active or chronic infection; discontinue therapy in patients who develop a serious infection.1

May increase the risk of tuberculosis or other atypical or opportunistic infections.1 Evaluate and treat patients for latent tuberculosis prior to initiation of rilonacept therapy.1

Immunosuppression and Malignancies

Effect on active and/or chronic infections and on development of malignancies not known.1 However, possible increased risk of malignancies with treatment with immunosuppressive agents, including rilonacept.1 11

Immunization

Vaccine efficacy may be reduced; avoid live vaccines during rilonacept therapy.1 (See Vaccines under Interactions.)

Review vaccination status of all patients and administer all age-appropriate vaccines, including pneumococcal vaccine and influenza virus vaccine inactivated, prior to initiation of rilonacept therapy.1

Lipid Abnormalities

Increases in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations reported.1 Monitor lipoprotein concentrations (e.g., after 2–3 months) and initiate antilipemic therapy as needed based on cardiovascular risk factors and current clinical guidelines.1

Immunologic Effects

Development of antibodies to rilonacept has been reported;1 however, no correlation between antibody activity and efficacy or safety of rilonacept.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether rilonacept is distributed into milk.1 Caution if used in nursing women.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

Evaluated in 6 pediatric patients 12–16 years of age with CAPS;1 10 symptom scores and objective markers of inflammation improved in these children and adverse effects were similar to those observed in adults.1

In animal studies, rilonacept may have contributed to alterations in bone ossification in the fetus; not known if rilonacept will affect bone development in pediatric patients.1 Pediatric patients receiving the drug should undergo appropriate monitoring for growth and development.1

Geriatric Use

Efficacy, safety, and tolerability profile in those ≥65 years of age generally similar to that in younger adults.1 Fatal bacterial meningitis reported in a 71-year-old woman in a clinical study.1 10 11 (See Infectious Complications under Cautions.)

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment.1

Renal Impairment

Pharmacokinetics not evaluated in patients with renal impairment.1

Common Adverse Effects

Injection site reactions (e.g., erythema, swelling, pruritus, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth, hemorrhage), upper respiratory tract infections, sinusitis, cough, hypoesthesia.1 2

Interactions for Rilonacept

No formal drug interaction studies to date.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Increased levels of cytokines (e.g., IL-1) during chronic inflammation suppress the formation of CYP isoenzymes; drugs that bind to IL-1, including rilonacept, are expected to normalize CYP enzyme formation.1

If rilonacept is initiated in a patient already receiving a CYP isoenzyme substrate that has a narrow therapeutic margin, monitor efficacy or concentrations of the concomitant drug and adjust dosage of the concomitant drug as needed.1

Vaccines

Data not available on the effects of live virus vaccines in patients receiving rilonacept; administration of live vaccines not recommended.1 Data not available regarding whether rilonacept would affect the rate of secondary transmission of vaccine virus following administration of a live virus vaccine or regarding any other effect of vaccination on patients receiving the drug.1 (See Immunization under Cautions.)

Specific recommendations regarding the length of time to wait between discontinuance of rilonacept and administration of a live vaccine or the length of time to wait between administration of a live vaccine and initiation of rilonacept therapy not available.16

Specific Drugs

Drug

Interaction

Comments

IL-1 blocking agents (e.g., anakinra, canakinumab)

Potential pharmacologic interaction1 10 15

Concomitant use of rilonacept with other agents that block IL-1 or its receptors not recommended1 10 15

Immunosuppressive agents

Potential for increased immunosuppressive effects 10

TNF-blocking agents (e.g., adalimumab, etanercept, infliximab)

Possible increased risk of serious infections and increased risk of neutropenia1 8 9

Concomitant use not recommended1

Warfarin

Possible effect on warfarin metabolism; because increased levels of IL-1 during chronic inflammation may suppress formation of CYP isoenzymes, binding of rilonacept to IL-1 may normalize formation of CYP enzymes1

Monitor efficacy of warfarin; adjust warfarin dosage as needed1

Rilonacept Pharmacokinetics

Absorption

Bioavailability

Relative bioavailability following sub-Q administration is approximately 50%.16 Peak plasma concentrations achieved in approximately 3.6 days in healthy individuals.16 Steady-state concentrations reached by 6 weeks in patients with CAPS.1

Onset

Improvement in symptom scores occurs within several days following initiation of therapy in most patients.1 2 5

Special Populations

Following sub-Q administration for 24 weeks in pediatric patients 12–16 years of age with CAPS, mean trough drug concentrations were similar to those observed in adults with CAPS.1

No significant difference in steady-state trough concentrations observed between geriatric patients and younger adults.1

Distribution

Extent

Not known whether rilonacept is distributed into milk.1

Elimination

Half-life

Terminal half-life approximately 8.6 days in adult patients.16

Terminal half-life approximately 6.3 days in pediatric patients.16

Special Populations

Pharmacokinetic data not available for patients with hepatic or renal impairment.1

Effects of age, gender, or body weight on the pharmacokinetics of rilonacept not systematically evaluated.1

Stability

Storage

Parenteral

Powder for Injection

2–8°C in original carton to protect from light.1

Following reconstitution, store at room temperature, protect from light, and use within 3 hours.1 Discard unused portion of vial after a single withdrawal of drug.1

Actions

  • Dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human IL-1 type I receptor (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human immunoglobulin G1.1 2 4

  • IL-1 receptor antagonist (IL-1Ra) used for the management of CAPS, including FCAS and MWS.1 2 3 4 5 6 13

  • Blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell surface receptors;1 2 also binds IL-1α and IL-1Ra to a lesser extent.1 4 Mutations in the NLRP-3 gene in patients with CAPS result in an overactive inflammasome, causing excessive release of activated IL-1β.1

  • Results in sustained reductions in mean concentrations of SAA and CRP, indicators of inflammatory disease activity.1 Elevated SAA concentrations have been associated with the development of systemic amyloidosis in patients with CAPS.1

Advice to Patients

  • Importance of providing a copy of the manufacturer’s patient information to all patients.1 3 Importance of discussing any questions pertaining to the manufacturer’s patient information.1 3

  • Importance of instructing patient and/or caregiver regarding proper dosage and administration of rilonacept (including the use of aseptic technique and safe disposal of vials, needles, and syringes) if clinician has determined that the drug can safely and effectively be self-administered in the patient’s home by the patient, family member, or other responsible individual.1 3

  • Risk of injection site reactions (e.g., erythema, swelling, pruritus, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth, hemorrhage).1 Importance of not injecting into areas where the skin is bruised, red, swollen, tender, or hard.1 Importance of informing clinician of any persistent injection site reaction.1

  • Risk of serious, potentially life-threatening infection.1 Importance of informing clinicians promptly if any signs or symptoms of infection (e.g., fever, cough, flu-like symptoms, open sores) occur.1 3

  • Risk of hypersensitivity reactions.1 Importance of immediately contacting a clinician or seeking immediate medical attention if any signs or symptoms of hypersensitivity (e.g., rash, swollen face, difficulty breathing) occur.1

  • Possible changes in blood cholesterol and triglyceride concentrations; importance of adherence to laboratory appointment schedules.1

  • Importance of reviewing vaccination status with clinician and receiving all age-appropriate vaccines prior to initiation of rilonacept therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., IL-1 antagonists, TNF-blocking agents, immunizations, corticosteroids) or OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illnesses (e.g., active or chronic infections, asthma, diabetes mellitus).1 3

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 3

  • Importance of informing patients of other important precautionary information.1 3 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Rilonacept

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for subcutaneous use

220 mg

Arcalyst

Regeneron

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Regeneron Pharmaceuticals, Inc. Arcalyst (rilonacept) for subcutaneous injection prescribing information. Tarrytown, NY; 2009 Apr 24.

2. Hoffman HM, Throne ML, Amar NJ et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008; 58:2443-52. [PubMed 18668535]

3. Regeneron Pharmaceuticals, Inc. Arcalyst (rilonacept) for subcutaneous injection patient information. Tarrytown, NY; 2009 Apr 24.

4. Goldbach-Mansky R, Schroff SD, Wilson M et al. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum. 2008; 58:2432-42. [PubMed 18668591]

5. Food and Drug Administration. FDA News: FDA approves new orphan drug for treatment of rare inflammatory syndromes: Arcalyst is first treatment for extremely rare condition called cryopyrin-associated periodic syndrome or CAPS. Rockville, MD; 2008 Feb 28. From the FDA website.

6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; from FDA website.

7. Shinkai K, McCalmont TH, Leslie KS. Cryopyrin-associated periodic syndromes and autoinflammation. Clin Dermatology. 2007; 33:1-9.

8. Amgen Inc. Kineret (anakinra) injection prescribing information. Thousand Oaks, CA; 2008 Oct.

9. Genovese MC, Cohen S, Moreland L et al. and the 20000223 Study Group. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004; 50:1412-9. [PubMed 15146410]

10. Burkhart KK. Rilonacept: Medical review(s), FDA approval package. Application number BL 125249/0. Rockville, MD: US Food and Drug Administration; 2007 Dec 18. From FDA web site.

11. Rappaport BA. Rilonacept: Summary review, FDA approval package. Application number BL 125249/0. Rockville, MD: US Food and Drug Administration; 2008 Feb 8. From FDA web site.

12. Regeneron Pharmaceuticals, Inc. Cryopyrin associated periodic syndromes (CAPS): physician backgrounder. 2008. From the CAPS community website (). Accessed 2008 Oct 30.

13. Church LD, McDermott MF. Rilonacept in cryopyrin-associated periodic syndromes: the beginning of longer-acting interleukin-1 antagonism. Nat Clin Pract Rheumatol. 2008 Nov 18; Epub ahead of print.

14. Thornton BD, Hoffman HM, Bhat A et al. Successful treatment of renal amyloidosis due to familial cold autoinflammatory syndrome using an interleukin 1 receptor antagonist. Am J Kidney Dis. 2007; 49:477-81. [PubMed 17336710]

15. Novartis Pharmaceuticals Corporation. Ilaris (canakinumab) for subcutaneous injection prescribing information. East Hanover, NJ; 2009 Jun.

16. Regeneron Pharmaceuticals, Inc., Tarrytown, NY: Personal communication.

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