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  • CLASSES

    Anti-Rheumtic Monoclonal Antibody Preparations
    Interleukin Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Human monoclonal antibody that inhibits interleukin-1 beta
    Approved for active systemic juvenile idiopathic arthritis, tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevanolate kinase deficiency (MKD), and familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS) including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS)
    Used in pediatric patients as young as 2 years of age
    May cause hypersensitivity reactions

    COMMON BRAND NAMES

    Ilaris

    HOW SUPPLIED

    Ilaris Subcutaneous Inj Pwd F/Sol: 180mg
    Ilaris Subcutaneous Inj Sol: 1mL, 150mg

    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, Adolescents, and Children 4 years and older and weight more than 40 kg

    150 mg subcutaneously every 8 weeks. The efficacy of canakinumab was evident in most patients during the pivotal clinical trial after only 1 dose; symptoms of Cryopyrin-Associated Periodic Syndromes (CAPS) diminished within 24 hours in responding patients. The median C-reactive protein (CRP) and serum amyloid A protein (SAA) concentrations fell to within the normal range. Most (81%) of patients who stopped receiving canakinumab experienced a disease flare; the median time until the disease flare was 100 days. All patients who continued therapy with canakinumab maintained normal CRP and SAA concentrations. Upon reinitiation canakinumab, patients who experienced a disease flare responded again. At the end of the 48-week trial, 30 of 31 patients had no or minimal disease activity, according to the physician's assessment.

    Adults, Adolescents, and Children 4 years and older and weight 15 to 40 kg

    2 mg/kg subcutaneously every 8 weeks. If response is inadequate in children in this weight range, may consider dose increase to 3 mg/kg subcutaneously every 8 weeks.

    For the treatment of active systemic juvenile idiopathic arthritis (SJIA).
    Subcutaneous dosage
    Children and Adolescents 2 years and older and weight 7.5 kg or more

    4 mg/kg (Max: 300 mg/dose) subcutaneously every 4 weeks.

    For the treatment of tumor necrosis factor receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), and familial mediterranean fever (FMF).
    Subcutaneous dosage
    Adults, Adolescents, and Children 2 years and older and weight more than 40 kg

    150 mg subcutaneously every 4 weeks. The dose can be increased to 300 mg subcutaneously every 4 weeks if the clinical response is not adequate. During clinical trials, canakinumab was superior to placebo in the proportion of patients who resolved their disease flare by Day 15 and had no new flare over the next 16 weeks of treatment.

    Adults, Adolescents, and Children 2 years and older and weight less than 40 kg

    2 mg/kg subcutaneously every 4 weeks. May increase to 4 mg/kg subcutaneously every 4 weeks if the clinical response is not adequate. During clinical trials, canakinumab was superior to placebo in the proportion of patients who resolved their disease flare by Day 15 and had no new flare over the next 16 weeks of treatment.

    MAXIMUM DOSAGE

    Adults

    CAPS:
    more than 40 kg: 150 mg/dose subcutaneously every 8 weeks.
    40 kg or less: 3 mg/kg/dose subcutaneously every 8 weeks.
    TRAPS, HIDS/MKD, FMF:
    more than 40 kg: 300 mg/kg/dose subcutaneously every 4 weeks.
    40 kg or less: 4 mg/kg/dose subcutaneously every 4 weeks.

    Geriatric

    CAPS:
    more than 40 kg: 150 mg/dose subcutaneously every 8 weeks.
    40 kg or less: 3 mg/kg/dose subcutaneously every 8 weeks.
    TRAPS, HIDS/MKD, FMF:
    more than 40 kg: 300 mg/kg/dose subcutaneously every 4 weeks.
    40 kg or less: 4 mg/kg/dose subcutaneously every 4 weeks.

    Adolescents

    CAPS:
    more than 40 kg: 150 mg/dose subcutaneously every 8 weeks.
    15 to 40 kg: 3 mg/kg/dose subcutaneously every 8 weeks.
    TRAPS, HIDS/MKD, FMF:
    more than 40 kg: 300 mg/kg/dose subcutaneously every 4 weeks.
    40 kg or less: 4 mg/kg/dose subcutaneously every 4 weeks.
    SJIA:
    7.5 kg or more: 4 mg/kg/dose (Max: 300 mg/dose) subcutaneously every 4 weeks.

    Children

    Less than 2 years: Safety and efficacy have not been established.
    CAPS:
    4 years and older and more than 40 kg: 150 mg/dose subcutaneously every 8 weeks.
    4 years and older and 15 to 40 kg: 3 mg/kg/dose subcutaneously every 8 weeks.
    TRAPS, HIDS/MKD, FMF:
    2 years and older and more than 40 kg: 300 mg/kg/dose subcutaneously every 4 weeks.
    2 years and older and 40 kg or less: 4 mg/kg/dose subcutaneously every 4 weeks.
    SJIA:
    2 years and older and 7.5 kg or more: 4 mg/kg/dose (Max: 300 mg) subcutaneously every 4 weeks.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No formal studies have been conducted to examine the pharmacokinetics or use of canakinumab in patients with hepatic impairment.

    Renal Impairment

    No formal studies have been conducted to examine the pharmacokinetics or use of canakinumab in patients with renal impairment.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Subcutaneous Administration

    Reconstitution:
    Using aseptic technique, slowly inject 1 mL of preservative-free sterile water for injection with a syringe and an 18-gauge, 2-inch needle.
    Slowly swirl the vial at a 45 degree angle for approximately 1 minute; allow to stand for 5 minutes.
    Gently turn the vial upside down and back again ten times; do not shake. Avoid touching the rubber stopper with your fingers.
    Allow to stand for about 15 minutes at room temperature to obtain a clear solution. Tap the side of the vial to remove any residual liquid from the stopper.
    The reconstituted solution has a final concentration of 150 mg/mL.
    The reconstituted solution should be essentially free from particulates, and should be clear to opalescent; do not use if particulate matter is present in the solution. The solution should be colorless or may have a slight brownish-yellow tint; do not use if the solution has a distinctly brown discoloration. It is not unusual to have slight foaming of the product upon reconstitution.
    Storage: If not used within 60 minutes of reconstitution, the solution should be stored in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F) and used within 4 hours.
     
    Subcutaneous injection:
    Using a sterile 1-mL syringe and needle, carefully withdraw the required volume depending on the dose to be administered.
    Discard any unused product; the vial is for single-use and does not contain any preservatives.
    Subcutaneously inject using a 27-gauge, 0.5-inch needle. Avoid injection into scar tissue as this may result in insufficient exposure to canakinumab.

    STORAGE

    Ilaris:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Store in carton until time of use
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatitis, human immunodeficiency virus (HIV) infection, immunosuppression, infection, tuberculosis

    Do not initiate canakinumab in patients with an active infection requiring medical intervention and discontinue therapy if a patient develops a serious infection. Patients should be cautioned not to receive canakinumab if they have a chronic or active infection, including human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C. Canakinumab is an IL-1 blocker that may cause immunosuppression and use is associated with an increased risk of serious infections. Canakinumab use may also increase the risk of tuberculosis (TB) or other atypical or opportunistic infections. Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported with the drug. Generally, the observed infections responded to standard therapy. Isolated cases of unusual or opportunistic infections (e.g., aspergillosis, atypical mycobacterial infections, cytomegalovirus, herpes zoster) were reported during treatment. Use caution when administering the drug to patients with infections, a history of recurring infections, or with underlying conditions that may predispose them to infections. Patients with underlying immune problems may be particularly at risk. Prior to initiating canakinumab, test patients for latent and active tuberculosis infection. The drug has not been studied in patients with a positive tuberculosis screen. Patients with positive tuberculosis screening or with known active or latent tuberculosis should be treated before canakinumab receipt, following current Centers for Disease Control (CDC) guidelines.

    Neoplastic disease

    The impact of anti-interleukin-1 therapy with canakinumab on the development of neoplastic disease is not known. However, treatment with immunosuppressants, including canakinumab, may result in an increase in the risk of certain malignancies.

    Vaccination

    Live vaccines should not be given to patients taking canakinumab; other forms of vaccination should be completed prior to initiation of therapy. Data are lacking on the efficacy of live vaccines and on the risks of secondary transmission of infection by live vaccines in patients receiving canakinumab. In addition, limited data are available on the effectiveness of vaccinations in patients receiving canakinumab; it is possible the drug may interfere with normal immune response to vaccine antigens. Interleukin-1 blockade may also interfere with immune response to infections. It is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive all recommended vaccinations (including pneumococcal vaccine and inactivated influenza vaccine; consult current recommendations of the Centers for Disease Control).

    Hepatic disease, renal impairment

    Use canakinumab with caution in patients with hepatic disease or renal impairment. No formal studies have been conducted to examine the pharmacokinetics or use of canakinumab in patients with renal or hepatic impairment.

    Pregnancy

    Pregnancy exposure data is insufficient to inform regarding drug-associated risk with canakinumab. Monoclonal antibodies, such as canakinumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential fetal effects are likely to be greater during the second and third trimesters. Canakinumab has been studied in marmoset monkeys using doses 11-fold the maximum recommended human dose (MRHD) and greater (based on a plasma area under the time-concentration curve, AUC comparison); delays in fetal skeletal development were reported. Doses producing exposures within the clinical exposure range at the MRHD were not evaluated.

    Breast-feeding

    No information is available regarding the presence of canakinumab in breast-milk, the effects on milk production, or the effects on the breast-fed infant. Excretion of the drug into mature breast milk is considered unlikely due to the drugs high molecular weight (145,157). Absorption is unlikely because canakinumab is a protein that will likely be destroyed in the infant's gastrointestinal tract. Because maternal antibodies are known to be present in colostrum, there is a potential of exposing a nursing infant to the drug during the first few days after birth. Thus, health care providers are advised to monitor nursing babies for signs of infection as well as other drug associated adverse effects including nasopharyngitis, diarrhea, rhinitis, nausea, headache, bronchitis, and gastroenteritis. The FDA-approved product label recommends considering the developmental and health benefits of breast-feeding, the mother's need for canakinumab therapy, and potential adverse effects of the drug or an inadequately treated condition on the breast-fed infant.

    Children, infants, neonates

    The safety and effectiveness of canakinumab in neonates, infants, and children < 2 years old have not been established. Clinical trials with canakinumab included a total of 23 pediatric patients with CAPS, ages 4 years—17 years (11 adolescents were treated with 150 mg SC, and 12 children were treated with 2 mg/kg based on body weight >= 15 kg and <= 40 kg ). Overall, the efficacy and safety of canakinumab in pediatric and adult patients were comparable.

    Intramuscular administration, intravenous administration

    Canakinumab injection is for subcutaneous use only. Do not inject via intravenous administration or intramuscular administration.

    ADVERSE REACTIONS

    Severe

    macrophage activation syndrome / Delayed / Incidence not known

    Moderate

    neutropenia / Delayed / 1.0-10.0
    antibody formation / Delayed / 1.5-3.1
    injection site reaction / Rapid / 0-2.0
    leukopenia / Delayed / Incidence not known
    immunosuppression / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 20.0-20.0
    rhinitis / Early / 17.0-17.0
    influenza / Delayed / 17.0-17.0
    abdominal pain / Early / 7.0-16.0
    nausea / Early / 14.0-14.0
    headache / Early / 14.0-14.0
    vertigo / Early / 9.0-14.0
    pharyngitis / Delayed / 11.0-11.0
    weight gain / Delayed / 11.0-11.0
    musculoskeletal pain / Early / 11.0-11.0
    infection / Delayed / 10.0
    cough / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known

    DRUG INTERACTIONS

    Anakinra: (Severe) The concomitant administration of canakinumab with other drugs that block interleukin (IL)-1, such as anakinra, has not been studied; however, based upon the potential for serious infection associated with the use of both drugs, concomitant administration of canakinumab with anakinra is not recommended.
    Bacillus Calmette-Guerin Vaccine, BCG: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Intranasal Influenza Vaccine: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Live Vaccines: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Measles/Mumps/Rubella Vaccines, MMR: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Rilonacept: (Severe) The concomitant administration of canakinumab with other drugs that block interleukin (IL)-1, such as rilonacept, has not been studied; however, based upon the potential for serious infection associated with the use of both drugs, concomitant administration of canakinumab with rilonacept is not recommended.
    Rotavirus Vaccine: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Rubella Virus Vaccine Live: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Smallpox Vaccine, Vaccinia Vaccine: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Tumor Necrosis Factor modifiers: (Severe) The concomitant administration of tumor necrosis factor (TNF) modifiers with other drugs that block interleukin (IL)-1, such as canakinumab, has not been studied; however, an increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Based upon the potential for similar interactions, concomitant administration of TNF inhibitors and canakinumab is not recommended.
    Typhoid Vaccine: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    Varicella-Zoster Virus Vaccine, Live: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).
    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 canakinumab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If canakinumab is initiated in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed.
    Yellow Fever Vaccine, Live: (Major) Do not administer live vaccines to a patient who is receiving canakinumab; other vaccination schedules should be complete as recommended prior to initiating canakinumab treatment. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving canakinumab. The immune response to vaccines or toxoids may be decreased, as canakinumab may interfere with normal immune response to new antigens. Limited data are available on the effectiveness of vaccination with inactivated antigens in patients receiving canakinumab. Because interleukin-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with canakinumab, adult and pediatric patients receive any recommended vaccination (including pneumococcal vaccine and inactivated influenza vaccines).

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy exposure data is insufficient to inform regarding drug-associated risk with canakinumab. Monoclonal antibodies, such as canakinumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential fetal effects are likely to be greater during the second and third trimesters. Canakinumab has been studied in marmoset monkeys using doses 11-fold the maximum recommended human dose (MRHD) and greater (based on a plasma area under the time-concentration curve, AUC comparison); delays in fetal skeletal development were reported. Doses producing exposures within the clinical exposure range at the MRHD were not evaluated.

    No information is available regarding the presence of canakinumab in breast-milk, the effects on milk production, or the effects on the breast-fed infant. Excretion of the drug into mature breast milk is considered unlikely due to the drugs high molecular weight (145,157). Absorption is unlikely because canakinumab is a protein that will likely be destroyed in the infant's gastrointestinal tract. Because maternal antibodies are known to be present in colostrum, there is a potential of exposing a nursing infant to the drug during the first few days after birth. Thus, health care providers are advised to monitor nursing babies for signs of infection as well as other drug associated adverse effects including nasopharyngitis, diarrhea, rhinitis, nausea, headache, bronchitis, and gastroenteritis. The FDA-approved product label recommends considering the developmental and health benefits of breast-feeding, the mother's need for canakinumab therapy, and potential adverse effects of the drug or an inadequately treated condition on the breast-fed infant.

    MECHANISM OF ACTION

    Canakinumab is a human monoclonal antibody against interleukin (IL)-1 beta. Binding of canakinumab to IL-1 beta blocks the interaction with IL-1 receptors. Excessive release of IL-1 beta drives inflammation in patients with cryopyrin-associated periodic syndromes (CAPS), which is a rare, genetic-based disease. Patients with the disease have mutations in the NLRP-3 (CIAS1) gene that encodes the protein cryopyrin. Cryopyrin binds with an intrinsic inhibitor and controls the activation of caspase-1. Caspase-1 cleaves pro-interleukin-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.
     
    Canakinumab has a disease-modifying effect through autocrine down-regulation of IL-1 beta production. IL-1 beta has been shown both in vivo and in vitro to stimulate its own production. Unbound IL-1 beta in the tissue stimulates production of C-reactive protein (CRP) and serum amyloid A protein (SAA), leading to an increased probability of a disease flare. Canakinumab binds to IL-1 beta and suppresses free IL-1 beta; this disrupts this feedback mechanism and hence reduces IL-1 production to a rate of that seen in healthy subjects.

    PHARMACOKINETICS

    Canakinumab is administered subcutaneously. Canakinumab binds to serum interleukin (IL)-1-beta. The volume of distribution at steady state varied with body weight and was estimated to be 6.01 liters in a typical patient with cryopyrin-associated periodic syndromes (CAPS) weighing 70 kg. The expected accumulation ratio was 1.3-fold after 6 months of 150 mg canakinumab subcutaneously every 8 weeks. Clearance of the drug also varied according to body weight and was estimated to be 0.174 L/day in a typical 70 kg patient with CAPS. After repeated administration, there was no indication of accelerated clearance or time-dependent change.

    Intravenous Route

    Canakinumab has been investigated as an intravenous infusion. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10 mg/kg given as intravenous infusion.

    Subcutaneous Route

    The peak serum canakinumab concentration (Cmax) of 16 +/- 3.5 mcg/mL occurred approximately 7 days after subcutaneous administration of a single, 150 mg dose in adult patients with cryopyrin-associated periodic syndromes (CAPS). The absolute bioavailability of subcutaneous canakinumab was estimated to be 70%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 150 to 300 mg as subcutaneous injection. The mean terminal half-life was 26 days.