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  • CLASSES

    Interleukin-1 Beta (IL-1 Beta) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Interleukin-1 inhibitor
    Used for cryopyrin-associated periodic syndromes (CAPS) including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), deficiency of IL-1 receptor antagonist (DIRA), and recurrent pericarditis
    Increases risk of serious infections; do not use in patients with active or chronic infection

    COMMON BRAND NAMES

    Arcalyst

    HOW SUPPLIED

    Arcalyst Subcutaneous Inj Pwd F/Sol: 220mg

    DOSAGE & INDICATIONS

    For the treatment of cryopyrin-associated periodic syndromes (CAPS) including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells syndrome (MWS).
    Subcutaneous dosage
    Adults

    320 mg subcutaneously (two 160 mg-injections) once, then 160 mg subcutaneously once weekly starting on day 8.

    Children and Adolescents 12 to 17 years

    4.4 mg/kg/dose (Max: 320 mg/dose) subcutaneously (1 or 2 injections, Max: 160 mg/injection) once then, 2.2 mg/kg/dose (Max: 160 mg/dose) subcutaneously once weekly starting on day 8.

    For the maintenance of remission of deficiency of interleukin-1 receptor antagonist (DIRA).
    Subcutaneous dosage
    Adults

    320 mg subcutaneously (two 160 mg-injections) once weekly. When switching from another IL-1 blocker, give first dose when the next dose of the previous IL-1 blocker would be due.

    Infants, Children, and Adolescents weighing 10 kg or more

    4.4 mg/kg/dose (Max: 320 mg/dose) subcutaneously (1 or 2 injections; Max: 160 mg/injection) once weekly. When switching from another IL-1 blocker, give first dose when the next dose of the previous IL-1 blocker would be due.

    For the treatment of recurrent pericarditis (RP) and for reduction in risk of recurrence of pericarditis.
    Subcutaneous dosage
    Adults

    320 mg subcutaneously (two 160 mg-injections) once, then 160 mg subcutaneously once weekly starting on day 8.

    Children and Adolescents 12 to 17 years

    4.4 mg/kg/dose (Max: 320 mg/dose) subcutaneously (1 or 2 injections, Max: 160 mg/injection) once then, 2.2 mg/kg/dose (Max: 160 mg/dose) subcutaneously once weekly starting on day 8.

    MAXIMUM DOSAGE

    Adults

    320 mg/week subcutaneously.

    Geriatric

    320 mg/week subcutaneously.

    Adolescents

    4.4 mg/kg/week (Max: 320 mg/week) subcutaneously.

    Children

    weighing 10 kg or more: 4.4 mg/kg/week (Max: 320 mg/week) subcutaneously.
    weighing less than 10 kg: Safety and efficacy have not been established.

    Infants

    weighing 10 kg or more: 4.4 mg/kg/week (Max: 320 mg/week) subcutaneously.
    weighing less than 10 kg: Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    If a once weekly dose is missed, administer the injection within 7 days from the missed dose and then resume the original schedule. If the missed dose is not administered within 7 days, administer the dose and start a new schedule based on this date.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Administer as a subcutaneous injection only. Do not inject into an artery, vein, or muscle.

    Subcutaneous Administration

    Only an individual trained in subcutaneous drug delivery should administer the injection. The initial injection should be given by a trained health care professional. A patient or caregiver who is properly trained in injection technique may self-inject, if their prescriber deems the action appropriate.
    See the manufacturer's "Instructions for Use" for detailed information regarding proper reconstitution and administration.
     
    Reconstitution
    Reconstitute each vial with 2.3 mL of the supplied preservative-free sterile water for injection. Shake the vial for approximately 1 minute and let it sit for 1 minute. If the powder has not completely dissolved, shake the vial quickly back and forth for an additional 30 seconds. Let the vial sit for about 1 minute. Repeat until the solution has completely dissolved.
    The reconstituted drug solution is viscous, clear, colorless to pale yellow, and essentially free from particulates. Do not use if there is discoloration or particulate matter in the solution.
    The reconstituted drug solution of 80 mg/mL is sufficient to allow a withdrawal volume of up to 2 mL. Use a new syringe and needle to withdraw the dose for subcutaneous administration. Discard unused portions; no preservatives are contained in the vial or diluent.
    Storage: Reconstituted product may be kept at room temperature for up to 3 hours as long as it is protected from light.
     
    Subcutaneous Injection
    The maximum single injection volume is 2 mL (160 mg). If the initial dose is 320 mg, then 2 injections are needed. Give both injections on same day but at 2 different sites.
    Proper injection sites are the front of the thighs and the abdomen. Avoid injecting the area that is 2 inches around the navel. If someone other than the patient is administering the injection, then the upper arm may also be used. Do not inject at sites that are bruised, red, tender, or hard.
    Rotate sites with each injection.
    Hold the syringe in 1 hand like you would hold a pencil.
    Gently squeeze and hold firm the area of cleaned skin, and insert the needle using a quick dart like motion at a 90-degree angle. For children or patients with little subcutaneous fat, insert the needle at a 45-degree angle.
    After the needle is completely in the skin, release the pinched skin. Ensure that rilonacept is not injected into a blood vessel. If no blood appears, slowly inject the solution at a steady rate, pushing the plunger all the way down; this may take up to 30 seconds.
    Pull the needle out of the skin and do not replace the needle cover. Place a gauze pad over the injection site for several seconds.
    Discard used vials, syringes, and needles in an FDA-cleared sharps disposal container.

    STORAGE

    Arcalyst:
    - Protect from light
    - Reconstituted product should be used within 3 hours
    - Store in original container
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Acquired immunodeficiency syndrome (AIDS), bone marrow suppression, diabetes mellitus, hepatitis, human immunodeficiency virus (HIV) infection, immunosuppression, infection, tuberculosis

    Interleukin-1 (IL-1) blockade may interfere with the immune response to infections. The impact of treatment with rilonacept on active and/or chronic infections, such as hepatitis, is not known. Rilonacept should not be initiated in patients with an active or chronic infection. Patients who receive rilonacept are at increased risk for developing a serious infection. If a patient develops a serious infection, discontinue rilonacept. Patients with a history of recurrent infections or with underlying conditions that may predispose them to infections (e.g., patients with advanced or uncontrolled diabetes mellitus, immunosuppression, bone marrow suppression, acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection), or those who have lived in tuberculosis or histoplasmosis endemic areas may not be appropriate candidates for rilonacept therapy. Medicines that block IL-1, like rilonacept, may increase the risk of tuberculosis or other atypical or opportunistic infections. Follow current practice guidelines to evaluate and to treat possible latent tuberculosis infections before rilonacept initiation. In clinical studies, the incidence of infections was greater with rilonacept compared to placebo. The risk of serious infections may be increased if rilonacept is coadministered with tumor necrosis factor (TNF) inhibitors.

    Asthma

    Cautious use of rilonacept in patients with asthma is advised. Patients with asthma may have an increased risk of infection. Upper respiratory infection (e.g., bronchitis) and cough were common adverse effects seen in the clinical trial.

    Hamster protein hypersensitivity

    Rilonacept is expressed in recombinant Chinese hamster ovary cells and may be inappropriate for use by patients with hamster protein hypersensitivity. Hypersensitivity reactions to rilonacept occurred in clinical trials. If a hypersensitivity reaction occurs, discontinue rilonacept and initiate appropriate therapy.

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    Cholesterol and lipid concentrations may be reduced in patients with chronic inflammation. Rilonacept treatment may cause elevations in cholesterol and lipid concentrations, resulting in hypercholesterolemia, hyperlipidemia, or hypertriglyceridemia. Patients treated with rilonacept experienced increases in their mean total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. Monitor serum lipid profiles and consider lipid-lowering medications as needed based upon cardiovascular risk factors and current guidelines.

    Vaccination

    Avoid use of live vaccines concurrently with rilonacept. No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving rilonacept. No data are available on the effectiveness of vaccination with inactivated (killed) antigens in patients receiving rilonacept. Since rilonacept may interfere with normal immune response mechanisms to new antigens, vaccination may not be effective. It is recommended that all adult and pediatric patients receive all recommended vaccinations, including pneumococcal vaccine and inactivate influenza vaccine, prior to initiation of rilonacept therapy. The interval between vaccinations and initiation of rilonacept therapy should be in accordance with current vaccination guidelines regarding immunosuppresive agents.

    New primary malignancy

    The impact of rilonacept on the development of a new primary malignancy is unknown. However, treatment with immunosuppressants, including rilonacept, may result in an increase in the risk of malignancies. Consider the risk and benefits of rilonacept continuation in patients who develop a malignancy.

    Pregnancy

    Available data from clinical trials and postmarketing reports with rilonacept are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes when the drug is used during pregnancy. Published data suggest that increased maternal levels of interleukin (IL)-1 beta, which induces inflammation in cryopyrin-associated periodic syndromes (CAPS), may be associated with pre-term birth. When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus. It is not known if rilonacept will alter bone development in pediatric patients with in utero exposure to the drug. In an animal reproduction study, subcutaneous administration of rilonacept to pregnant cynomolgus 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. 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. 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.

    Breast-feeding

    There is no data on the presence of rilonacept in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Caution is advised when administering to nursing women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If this drug is used in a woman who is breast-feeding, the infant should be monitored for signs of immunosuppression or infection.

    Children, infants

    Monitor infants, children, and adolescents treated with rilonacept for appropriate growth and development. When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus. It is not known if rilonacept will alter bone development in pediatric patients.

    Geriatric

    Cautious use of rilonacept in geriatric patients may be warranted; limited data are available. In clinical studies, 70 patients treated with rilonacept were 65 years of age or older and 6 were 75 years of age or older. Efficacy, safety, and tolerability of rilonacept was found to be similar between elderly patients and younger adults in the CAPS clinical trial. In an open-label extension study of CAPS, a 71 year-old woman developed bacterial meningitis and died. Age did not appear to have a significant effect on rilonacept steady-state trough concentrations.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 30.0-35.0
    meningitis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 48.0-48.0
    infection / Delayed / 18.0-48.0
    sinusitis / Delayed / 9.0-9.0
    cough / Delayed / 9.0-9.0
    hypoesthesia / Delayed / 9.0-9.0
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    rhinorrhea / Early / Incidence not known
    diarrhea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    dyspepsia / Early / Incidence not known

    DRUG INTERACTIONS

    Adalimumab: (Contraindicated) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors.
    Anakinra: (Major) Concomitant use of anakinra with other drugs that also block interleukin (IL)-1, such as rilonacept, is not recommended; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Antithymocyte Globulin: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Azathioprine: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Basiliximab: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Canakinumab: (Major) Concomitant use of canakinumab with other drugs that block interleukin (IL)-1, such as rilonacept, is not recommended; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Certolizumab pegol: (Contraindicated) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cyclosporine: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Dexamethasone: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Etanercept: (Contraindicated) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors.
    Golimumab: (Contraindicated) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors.
    Infliximab: (Contraindicated) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors.
    Intranasal Influenza Vaccine: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Live Vaccines: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Methotrexate: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Methylprednisolone: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Prednisone: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Rotavirus Vaccine: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Tumor Necrosis Factor modifiers: (Contraindicated) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors.
    Typhoid Vaccine: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Warfarin: (Moderate) The formation of CYP450 enzymes is suppressed by increased concentrations of cytokines (e.g., IL-1) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during rilonacept receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If rilonacept is initiated in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed.
    Yellow Fever Vaccine, Live: (Contraindicated) Do not administer live vaccines to a patient who is receiving rilonacept. No data are available regarding the use of live vaccines during rilonacept treatment. Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Available data from clinical trials and postmarketing reports with rilonacept are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes when the drug is used during pregnancy. Published data suggest that increased maternal levels of interleukin (IL)-1 beta, which induces inflammation in cryopyrin-associated periodic syndromes (CAPS), may be associated with pre-term birth. When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus. It is not known if rilonacept will alter bone development in pediatric patients with in utero exposure to the drug. In an animal reproduction study, subcutaneous administration of rilonacept to pregnant cynomolgus 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. 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. 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.

    There is no data on the presence of rilonacept in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Caution is advised when administering to nursing women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If this drug is used in a woman who is breast-feeding, the infant should be monitored for signs of immunosuppression or infection.

    MECHANISM OF ACTION

    Rilonacept is an interluekin-1 (IL-1) alpha and IL-1 beta cytokine trap. It blocks IL-1 signaling by acting as a soluble decoy receptor that binds both IL-1 alpha and IL-1 beta and prevents its interaction with cell surface receptors. Rilonacept also binds IL-1 receptor antagonist (IL-1ra). Structurally, rilonacept is a dimeric fusion protein that consists of the ligand-binding domains of the extracellular portions of the human IL-1 receptor component and IL-1 receptor accessory protein linked in-line to the Fc portion of human IgG1. IL-1 is a key cytokine that mediates the pathophysiology of many inflammatory processes.
     
    Binding of IL-1 beta by rilonacept and thus, interruption of IL-1 beta signaling, is beneficial in patients with cryopyrin-associated periodic syndromes (CAPS). In excess, IL-1 has been shown to be a key driver of inflammation in CAPS, which is caused by a range of mutations in the gene CIAS1 that encodes the protein cryopyrin. Cryopyrin binds with an intrinsic inhibitor and controls the activation of caspase-1. Caspase-1 cleaves pro-IL-1 beta and IL-18 into the biologically active forms. Patients with CAPS have increased caspase activity and thus, increased biologically active IL-1 beta. Enhanced caspase-1 activity with subsequent enhanced IL-1 beta and IL-18 release has been demonstrated in a patient with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome.
     
    Deficiency of IL-1 receptor antagonist (DIRA) is due to loss of function mutations in the IL1RN gene, which encodes IL-1ra, resulting in unopposed signaling of the proinflammatory cytokines IL-1 alpha and IL-1 beta through the IL-1 receptor. Rilonacept binds IL-1 alpha, IL-1 beta, and IL-1ra.
     
    IL-1 has been implicated as a causative factor in pericarditis. IL-1 alpha and IL-1 beta bind to universally expressed cell surface receptor, IL-1 receptor type-1, triggering a cascade of inflammatory mediators. Pre-formed IL-1 alpha is released by damaged/inflamed pericardial cells and may contribute to the maintenance and amplification of inflammation via activation of the NLRP3 inflammasome, which then augments the inflammatory response by production if IL-1 beta in a cascade amplification system.

    PHARMACOKINETICS

    Rilonacept is administered subcutaneously. Rilonacept has an approximate bioavailability of 50% after subcutaneous administration. In adult patients with cryopyrin-associated periodic syndromes (CAPS), the terminal half-life was 8.86 days. In patients with pericarditis, the circulation half-life was approximately 7 days. Limited data is available on whether rilonacept penetrates into the brain; however, it may be unlikely to cross the blood-brain barrier due to its size (251 kDa).
     
    Rilonacept receipt led to sustained reductions from baseline in mean serum C-reactive protein (CRP) and serum amyloid A to normal concentrations during the clinical trial in patients with cryopyrin-associated periodic syndromes (CAPS). In most patients, symptom reduction occurred within days of rilonacept initiation. Reduction of CRP was also observed in patients with deficiency of IL-1 receptor antagonist (DIRA) and pericarditis.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: various CYP isoenzymes
    The formation of CYP450 enzymes is suppressed by increased concentrations 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 (NTI), where the dose is individually adjusted (e.g. warfarin). Upon initiation of rilonacept in patients being treated with drugs with an NTI, perform therapeutic monitoring of the effect or drug concentration and adjust the individual dose of the medicinal product as needed.

    Subcutaneous Route

    In adults with cryopyrin-associated periodic syndromes (CAPS), the average trough concentration of rilonacept was approximately 24 mcg/mL (range, 20 to 27 mcg/mL) at steady-state after weekly subcutaneous doses of 160 mg for up to 48 weeks. Steady-state appeared to be reached by 6 weeks. A proportional increase in the Cmax and AUC has been observed with increased rilonacept doses up to a maximum of 320 mg.
     
    In patients with pericarditis, the average trough concentration of rilonacept was approximately 23 mcg/mL at steady-state after 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.