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  • CLASSES

    Anti-Rheumtic Monoclonal Antibodies
    Interleukin-1 Beta (IL-1 Beta) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Human monoclonal antibody that inhibits interleukin-1 beta
    Approved for active still's disease (including adult-onset still's disease and systemic juvenile idiopathic arthritis), tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevanolate kinase deficiency (MKD), familial Mediterranean fever (FMF), and cryopyrin-associated periodic syndromes (CAPS) including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS)
    Increases risk of serious infections; evaluate for latent TB before use

    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 Still's disease, including adult-onset Still's disease and systemic juvenile idiopathic arthritis (SJIA).
    Subcutaneous dosage
    Adults

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

    Children and Adolescents 2 years and older and weight 7.5 kg or more

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

    For the treatment of tumor necrosis factor receptor associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/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.

    INVESTIGATIONAL USE: For adjunctive use in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection†, the virus that causes coronavirus disease 2019 (COVID-19)†.
    Intravenous dosage
    Adults

    Efficacy has not been established. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommendation against the use of canakinumab outside of clinical trials. Dosing regimens being evaluated include: 4 mg/kg and 8 mg/kg IV once for patients 40 kg or less; 300 mg and 600 mg IV once for patients more than 40 kg; 450 mg IV once for patients 40 to 59 kg; 600 mg IV once for patients 60 to 80 kg; 750 mg IV once for patients more than 80 kg. All doses are to be diluted in 250 mL of 5% dextrose and infused over 2 hours.

    Subcutaneous dosage
    Adults

    Efficacy has not been established. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommendation against the use of canakinumab outside of clinical trials. A single 150 mg subcutaneous injection is being evaluated in a retrospective and prospective observational study.

    †Indicates off-label use

    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/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/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/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

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

    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 in patients with hepatic impairment.

    Renal Impairment

    No formal studies have been conducted 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.
    Canakinumab injection solution should be essentially free from particulates, clear to opalescent, colorless to slightly brownish-yellow tint. If the solution has a distinctly brown discoloration, is highly opalescent or contains visible particles, do not use.

    Subcutaneous Administration

    Health care providers should perform administration of canakinumab.
     
    Subcutaneous injection:
    Canakinumab solution has a concentration of 150 mg/mL. Do NOT shake.
    Using a sterile 1-mL syringe and 18-gauge, 2-inch needle, carefully withdraw the required volume depending on the dose to be administered.
    Subcutaneously inject using a 27-gauge, 0.5-inch needle. Avoid injection into scar tissue as this may result in insufficient exposure to canakinumab.
    Discard any unused product; the vial is for single-use and does not contain any preservatives.

    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

    General Information

    Canakinumab is contraindicated for use in patients with a confirmed hypersensitivity to canakinumab. Hypersensitivity reactions have been reported with canakinumab therapy. During clinical trials, no anaphylactic reactions have been reported. It should be recognized that symptoms of the underlying disease being treated may be similar to symptoms of hypersensitivity. If a severe hypersensitivity reaction occurs, discontinue canakinumab and initiate appropriate therapy.

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

    Patients who receive canakinumab are at an increased risk of developing serious infections. Canakinumab should not be initiated in patients with an active infection requiring medical intervention and therapy should be discontinued if a patient develops a serious infection. Infections, primarily 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) have been reported with canakinumab therapy. 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. Prior to initiation of canakinumab, evaluate patients for tuberculosis risk factors and test them for active or latent tuberculosis. 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 the current Centers for Disease Control (CDC) guidelines. Use caution in patients with infection, including human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C, history of recurring infections, or underlying conditions that may predispose them to infections.

    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.

    Infants, neonates, pregnancy

    Pregnancy exposure data from canakinumab case reports and postmarketing experience is insufficient to identify a drug-associated risk of major birth defects, miscarriage, and adverse maternal or fetal outcomes. Monoclonal antibodies, such as canakinumab, are actively transported across the placenta in increasing amount as the pregnancy progresses, with the largest amount transferred during the third trimester. Neonates and infants exposed in utero to monoclonal antibodies may experience immunosuppression. Due to the potential for impaired immune response, consider risks and benefits of live vaccine administration to infants exposed to canakinumab in utero for at least 4 to 12 months after the mother's last canakinumab dose. There are insufficient data on infant canakinumab serum levels at birth or duration canakinumab remains in infant serum after birth following canakinumab exposure in utero to identify the ideal time for live vaccine administration. 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 or the effects on milk production. A small number of published case reports do not demonstrate an association between maternal canakinumab use during breast-feeding and adverse effects in a breast-fed infant. Excretion of the drug into mature breast milk is considered unlikely due to the drug's high molecular weight. 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. Consider 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 breastfed infant.

    Children

    The safety and effectiveness of canakinumab in neonates, infants, and children less than 2 years old have not been established for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency (HIDS/MKD), Familial Mediterranean Fever (FMF), and Systemic Juvenile Idiopathic Arthritis (SJIA). The safety and effectiveness of canakinumab in pediatric patients less than 4 years old have not been established in Cryopyrin-Associated Periodic Syndrome (CAPS). Clinical trials with canakinumab included a total of 23 pediatric patients with CAPS, ages 4 years to 17 years (11 adolescents were treated with 150 mg subcutaneously, and 12 children were treated with 2 mg/kg based on body weight 15 kg to 40 kg ). Overall, the efficacy and safety of canakinumab in pediatric and adult patients were comparable. In the TRAPS, HIDS/MKD, and FMF clinical trial, 102 pediatric patients, ages 2 to 17 years were treated with canakinumab 2 mg/kg subcutaneously every 4 weeks. No clinically meaningful differences in efficacy, safety, and tolerability were found between adult and pediatric patients.

    ADVERSE REACTIONS

    Severe

    macrophage activation syndrome / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    neutropenia / Delayed / 6.0-6.5
    thrombocytopenia / Delayed / 0.6-6.3
    elevated hepatic enzymes / Delayed / 0-4.1
    antibody formation / Delayed / 1.5-3.1
    immunosuppression / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    diarrhea / Early / 20.0-20.0
    influenza / Delayed / 17.0-17.0
    rhinitis / Early / 5.3-17.0
    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 / 3.0-11.0
    weight gain / Delayed / 11.0-11.0
    musculoskeletal pain / Early / 11.0-11.0
    infection / Delayed / 10.0
    cough / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Major) Concomitant use of abatacept with biological DMARDs, such as canakinumab, is not recommended because of the possibility of additive immunosuppression and increased risk of infection. There is insufficient experience to assess the safety and efficacy of abatacept administered concurrently with canakinumab.
    Alfentanil: (Moderate) Monitor for an altered patient response to alfentanil if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as alfentanil, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Alfentanil is a CYP3A4 substrate and narrow therapeutic index drug.
    Anakinra: (Major) Concomitant use of anakinra with other drugs that also block interleukin (IL)-1, such as canakinumab, is not recommended; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    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).
    Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as canakinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk.
    Basiliximab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as basilixumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor for an altered patient response to ergotamine if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ergotamine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Ergotamine is a CYP3A4 substrate and a narrow therapeutic index drug.
    Brodalumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as brodalumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Carbamazepine: (Moderate) Monitor carbamazepine concentrations and watch for decreased efficacy of carbamazepine if coadministration with canakinumab is necessary; adjust carbamazepine dosage as necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as carbamazepine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. In vitro, canakinumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Carbamazepine is a substrate of both CYP1A2 and CYP3A4 and a narrow therapeutic index drug.
    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.
    Cisapride: (Moderate) Monitor for an altered patient response to cisapride if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cisapride, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Cisapride is a CYP3A4 substrate and a narrow therapeutic index drug.
    Cyclosporine: (Moderate) Monitor cyclosporine levels and adjust the dose of cyclosporine as appropriate if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as cyclosporine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Cyclosporine is a CYP3A4 substrate and a narrow therapeutic index drug.
    Daclizumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as daclizumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Dextromethorphan; Quinidine: (Moderate) Monitor quinidine levels and adjust the dose of quinidine as appropriate if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as quinidine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Quinidine is a CYP3A4 substrate and narrow therapeutic index drug.
    Dihydroergotamine: (Moderate) Monitor for an altered patient response to dihydroergotamine if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as dihydroergotamine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Dihydroergotamine is a CYP3A4 substrate and a narrow therapeutic index drug.
    Ergotamine: (Moderate) Monitor for an altered patient response to ergotamine if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ergotamine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Ergotamine is a CYP3A4 substrate and a narrow therapeutic index drug.
    Ergotamine; Caffeine: (Moderate) Monitor for an altered patient response to ergotamine if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ergotamine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Ergotamine is a CYP3A4 substrate and a narrow therapeutic index drug.
    Ethosuximide: (Moderate) Monitor for reduced efficacy of ethosuximide, monitor drug concentrations, and adjust the dose of ethosuximide as appropriate if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ergotamine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Ergotamine is a CYP3A4 substrate and a narrow therapeutic index drug.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if treatment with canakinumab is initiated for a patient on chronic everolimus therapy. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate. During chronic inflammation, increased levels of certain cytokines can decrease the formation of CYP450 enzymes. Thus, the formation of CYP3A4 could be normalized during canakinumab administration. The addition of canakinumab to everolimus therapy may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Fentanyl: (Moderate) Monitor for evidence of reduced pain control or opioid withdrawal if fentanyl coadministration with canakinumab is necessary; fentanyl dosage adjustment may be needed. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fentanyl, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Fentanyl is a CYP3A4 substrate and narrow therapeutic index drug.
    Fosphenytoin: (Moderate) Monitor fosphenytoin concentrations and watch for decreased efficacy of fosphenytoin if coadministration with canakinumab is necessary; adjust fosphenytoin dosage as necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as fosphenytoin, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Fosphenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
    Guselkumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as guselkumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    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).
    Ixekizumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as ixekizumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    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).
    Macitentan: (Major) Avoid coadministration of macitentan with canakinumab due to the potential for increases in macitentan exposure and adverse effects. Macitentan is a CYP3A4 and CYP2C9 substrate and canakinumab is a dual moderate CYP3A4 and CYP2C9 inhibitor. Concomitant use is predicted to increase macitentan exposure approximately 4-fold.
    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).
    Phenytoin: (Moderate) Monitor phenytoin concentrations and watch for decreased efficacy of phenytoin if coadministration with canakinumab is necessary; adjust phenytoin dosage as necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as phenytoin, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Phenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
    Pimozide: (Moderate) Monitor for an altered patient response to pimozide if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as pimozide, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Pimozide a substrate of both CYP2D6 and CYP3A4 and narrow therapeutic index drug.
    Quinidine: (Moderate) Monitor quinidine levels and adjust the dose of quinidine as appropriate if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as quinidine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Quinidine is a CYP3A4 substrate and narrow therapeutic index drug.
    Rilonacept: (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.
    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).
    Sarilumab: (Major) Avoid using sarilumab with other biological DMARDs including interleukin-1 receptor antagonists such as canakinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    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.
    Secukinumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as secukinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Siltuximab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as siltuximab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Sirolimus: (Moderate) Monitor sirolimus levels and adjust the dose of sirolimus as appropriate if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as sirolimus, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Sirolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (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).
    Tacrolimus: (Moderate) Monitor tacrolimus levels and adjust the dose of tacrolimus as appropriate if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tacrolimus, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Tacrolimus is a CYP3A4 substrate and narrow therapeutic index drug.
    Theophylline, Aminophylline: (Moderate) Monitor drug concentrations and watch for decreased efficacy of aminophylline or theophylline if coadministration with canakinumab is necessary; a dosage increase of these methylxanthines may be necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as aminophylline or theophylline, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Aminophylline and Theophylline are CYP1A2 substrates and narrow therapeutic index drugs.
    Thioridazine: (Moderate) Monitor for an altered patient response to thioridazine if coadministration with canakinumab is necessary. Canakinumab therapy may restore CYP450 activities to higher levels compared to pretreatment, thus leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index may have fluctuations in drug levels and therapeutic effect. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Thioridazine is a CYP2D6 substrate and narrow therapeutic index drug.
    Tildrakizumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as tildrakizumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Tizanidine: (Moderate) Monitor for reduced efficacy of tizanidine if coadministered with canakinumab. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as tizanidine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Tizanidine is a CYP1A2 substrate and narrow therapeutic index drug.
    Tocilizumab: (Major) Avoid using tocilizumab with other biological DMARDs including interleukin-1 receptor antagonists such as canakinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Tofacitinib: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as canakinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Tumor Necrosis Factor modifiers: (Major) Avoid concomitant administration of canakinumab with tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection. 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 canakinumab and TNF inhibitors 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).
    Upadacitinib: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as canakinumab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Ustekinumab: (Major) Avoid the concomitant use of canakinumab with other interleukin inhibitors, such as ustekinumab; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    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) Monitor the INR if canakinumab is coadministered with warfarin due to the potential for decreased warfarin efficacy; adjust the dose of warfarin as necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as warfarin, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab.
    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

    No information is available regarding the presence of canakinumab in breast-milk or the effects on milk production. A small number of published case reports do not demonstrate an association between maternal canakinumab use during breast-feeding and adverse effects in a breast-fed infant. Excretion of the drug into mature breast milk is considered unlikely due to the drug's high molecular weight. 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. Consider 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 breastfed 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 L in a typical patient with cryopyrin-associated periodic syndromes (CAPS) weighing 70 kg, 3.2 L in a patient weighing 33 kg with systemic juvenile idiopathic arthritis (SJIA), and 6.34 L for a patient weighing 70 kg with periodic fever syndrome. 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, 0.11 L/day in an SJIA patient weighing 33 kg, and 0.17 L/day in a periodic fever syndrome patient weighing 70 kg. After repeated administration, there was no indication of accelerated clearance or time-dependent change. The expected accumulation ratio was 1.3-fold for CAPS patients and 1.6-fold for SJIA patients after 6 months of 150 mg canakinumab subcutaneously every 8 weeks and 4 mg/kg subcutaneously every 4 weeks, respectively. The mean terminal half-life was 26 days in adults with CAPS receiving subcutaneous dosing. Canakinumab pharmacokinetics were similar between patients with SJIA and adult-onset Still's disease.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: various CYP isoenzymes
    The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as canakinumab, 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 canakinumab, in patients being treated with drugs with an NTI, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed.

    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 66%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 150 to 300 mg as a subcutaneous injection.