Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Subcutaneous [preservative free]:
Ilaris: 150 mg/mL (1 mL) [contains polysorbate 80]
Solution Reconstituted, Subcutaneous [preservative free]:
Ilaris: 150 mg (1 ea [DSC]) [contains polysorbate 80]
Pharmacology
Mechanism of Action
Canakinumab reduces inflammation by binding to interleukin-1 beta (IL-1beta) (no binding to IL-1 alpha or IL-1 receptor antagonist [IL-1ra]) and preventing interaction with cell surface receptors. Cryopyrin-associated periodic syndromes (CAPS) refers to rare genetic syndromes caused by mutations in the nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3 (NLRP-3) gene or the cold-induced autoinflammatory syndrome-1 (CIAS1) gene. Cryopyrin, a protein encoded by this gene, regulates IL-1beta activation. Deficiency of cryopyrin results in excessive inflammation.
Pharmacokinetics/Pharmacodynamics
Distribution
Vdss: Children: 0.097 L/kg (3.2 L in 33 kg); Adults: CAPS: 0.086 L/kg (6 L in 70 kg); FMF, HIDS/MKD, TRAPS: 0.09 L/kg (6.34 L in 70 kg).
Excretion
Clearance: Varies according to body weight:
Children ≤40 kg: SJIA: 0.11 L/day in 33 kg
Children >40 kg and Adults: CAPS: 0.174 L/day in 70 kg
Children, Adolescents, and Adults: FMF, HIDS/MKD, TRAPS: 0.17 L/day in 70 kg
Onset of Action
Maximum effect: Within 8 days CRP and serum amyloid normalization
Time to Peak
Serum: Children ≥4 years: 2 to 7 days; Adults: ~7 days
Half-Life Elimination
Children ≥4 years: 22.9 to 25.7 days; Adults: 26 days
Protein Binding
Binds to serum IL-1 beta
Use: Labeled Indications
Periodic fever syndromes:
Cryopyrin-associated periodic syndromes: Treatment of cryopyrin-associated periodic syndromes (CAPS) in adults and children 4 years and older, including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). Note: Has also been studied in Neonatal-onset multisystem inflammatory disease (Ilaris Canadian product monograph; Sibley 2015).
Familial Mediterranean fever: Treatment of familial Mediterranean fever in adult and pediatric patients.
Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD): Treatment of hyperimmunoglobulin D (Hyper-IgD) Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients.
Tumor necrosis factor (TNF) receptor associated periodic syndrome: Treatment of TNF receptor associated periodic syndrome (TRAPS) in adult and pediatric patients.
Systemic juvenile idiopathic arthritis: Treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years and older.
Use: Off Label
Gout, treatment of acute flares (when conventional therapy is ineffective, contraindicated, or not tolerated)byes
Data from relatively small phase 3 study supports the use of canakinumab in the treatment of acute gout in patients with frequent flares (history of ≥3 in previous 12 months) and who are refractory to, intolerant of, or have contraindications to NSAIDs and/or colchicine. Of note, rate of infection was higher in the canakinumab group compared with the group receiving triamcinolone acetonide intramuscularly Schlesinger 2012. Additional data may be necessary to further define the role of canakinumab in this condition.
Based on European League Against Rheumatism (EULAR) evidence-based recommendations for the management of gout, interleukin-1 (IL-1) blockers (eg, canakinumab) may be considered for treating acute gout flares in patients with frequent flares and who have contraindications to other anti-gout therapies including colchicine, NSAIDS, and corticosteroids. Following flare treatment with interleukin-1 (IL-1) blockers, urate-lowering therapy should be adjusted to meet uricemia target levels.
Contraindications
Hypersensitivity to canakinumab or any component of the formulation
Canadian labeling: Additional contraindications (not in US labeling): Active, severe infections
Dosage and Administration
Dosing: Adult
Cryopyrin-associated periodic syndromes (CAPS): SubQ: 150 mg (>40 kg) or 2 mg/kg (15 to 40 kg) every 8 weeks; in clinical trials, dosage adjustments up to 600 mg (>40 kg) or 8 mg/kg (≤40 kg) and/or increased dosing frequency were allowed for residual symptoms (Kuemmerle-Deschner 2011). For inadequate response, a dose titration schedule of 150 mg or 2 mg/kg every 7 days up to a maximum dose of 600 mg or 8 mg/kg (15 to 40 kg) has been recommended (Ilaris Canadian product monograph).
Familial Mediterranean Fever (FMF), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): SubQ: 150 mg (>40 kg) or 2 mg/kg (≤40 kg) every 4 weeks; may increase to 300 mg (>40 kg) or 4 mg/kg (≤40 kg) every 4 weeks if response is not adequate.
Gout, treatment of acute flares (when conventional therapy is ineffective, contraindicated, or not tolerated) (off-label use): SubQ: 150 mg as a single dose (Schlesinger 2012). Additional data may be necessary to further define the role of canakinumab in this condition.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Cryopyrin-associated periodic syndromes (CAPS): Patient syndromes included in trials were: Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystemic inflammatory disease (CINCA/NOMID), and familial cold urticaria (FCU); data has shown that pediatric patients require higher doses than adults (Kuemmerle-Deschner 2011).
Manufacturer's labeling: Children ≥4 years and Adolescents:
15 to 40 kg: SubQ: Initial: 2 mg/kg/dose every 8 weeks; may increase to 3 mg/kg/dose if response inadequate
>40 kg: SubQ: 150 mg/dose every 8 weeks
Alternate dosing: Limited data available:
Children 2 to <4 years and weighing ≥7.5 kg: SubQ: 4 mg/kg/dose every 8 weeks; if no response after 7 days, may repeat 4 mg/kg dose, if response achieved then may continue patient on intensified maintenance of 8 mg/kg/dose every 8 weeks (Ilaris prescribing information, United Kingdom 2017)
Children ≥4 years and Adolescents:
7.5 kg to <15 kg: SubQ: 4 mg/kg/dose every 8 weeks. If no response after 7 days, may administered a second 4 mg/kg/dose, if full treatment response achieved then may continue patient on intensified maintenance of 8 mg/kg/dose every 8 weeks (Ilaris prescribing information, United Kingdom 2017)
15 kg to 40 kg: SubQ: 2 mg/kg/dose every 8 weeks. If response not satisfactory after 7 days, may repeat 2 mg/kg dose, if full treatment response achieved then may continue patient on intensified maintenance of 4 mg/kg/dose every 8 weeks. If after 7 days (ie, day 14) a satisfactory response still not achieved, may administer another 4 mg/kg dose, if full treatment response achieved then may continue patient on intensified maintenance of 8 mg/kg/dose every 8 weeks (Ilaris prescribing information, United Kingdom 2017; Kuemmerle-Deschner 2011). Another dose-escalation regimen describes titration in 2 mg/kg/dose increments every 7 days up to a maximum dose of 8 mg/kg/dose (Ilaris prescribing information, Canada 2017)
>40 kg: SubQ: 150 mg every 8 weeks. If response not satisfactory after 7 days, may repeat 150 mg/dose, if full treatment response achieved then may continue patient on intensified maintenance of 300 mg every 8 weeks. If after 7 days (ie, day 14) a satisfactory response still not achieved, may administer another 300 mg/dose, if full treatment response achieved then may continue patient on intensified maintenance of 600 mg every 8 weeks (Ilaris prescribing information, United Kingdom 2017; Kuemmerle-Deschner 2011). Another dose-escalation regimen describes titration in 150 mg increments every 7 days up to a maximum dose of 600 mg (Ilaris prescribing information, Canada 2017).
Familial Mediterranean Fever (FMF): Children ≥2 years and Adolescents: Note: In trial, canakinumab was used as monotherapy and in combination with daily colchicine. Patient weight:
7.5 to 40 kg: SubQ: Initial: 2 mg/kg/dose every 4 weeks; if inadequate response after 7 days may repeat dose (2 mg/kg) and increase maintenance dose to 4 mg/kg/dose every 4 weeks if full treatment response (Ilaris prescribing information, Canada 2017; Ilaris prescribing information, United Kingdom 2017)
>40 kg: SubQ: Initial: 150 mg every 4 weeks; if inadequate response after 7 days may repeat dose (150 mg) and increase maintenance dose to 300 mg every 4 weeks if full treatment response (Ilaris prescribing information, Canada 2017; Ilaris prescribing information, United Kingdom 2017)
Hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD): Children ≥2 years and Adolescents: Patient weight:
7.5 to 40 kg: SubQ: Initial: 2 mg/kg/dose every 4 weeks; if inadequate response after 7 days may repeat dose (2 mg/kg) and increase maintenance dose to 4 mg/kg/dose every 4 weeks if full treatment response (Ilaris prescribing information, Canada 2017; Ilaris prescribing information, United Kingdom 2017)
>40 kg: SubQ: Initial: 150 mg every 4 weeks; if inadequate response after 7 days may repeat dose (150 mg) and increase maintenance dose to 300 mg every 4 weeks if full treatment response (Ilaris prescribing information, Canada 2017; Ilaris prescribing information, United Kingdom 2017)
Juvenile idiopathic arthritis; systemic: Children ≥2 years weighing at least 7.5 kg and Adolescents: SubQ: 4 mg/kg/dose every 4 weeks; maximum dose: 300 mg
Tumor necrosis factor receptor associated periodic syndrome (TRAPS): Children ≥2 years and Adolescents: Patient weight:
7.5 to 40 kg: SubQ: Initial: 2 mg/kg/dose every 4 weeks; if inadequate response after 7 days may repeat dose (2 mg/kg) and increase maintenance dose to 4 mg/kg/dose every 4 weeks if full treatment response (Ilaris prescribing information, Canada 2017; Ilaris prescribing information, United Kingdom 2017)
>40 kg: SubQ: Initial: 150 mg every 4 weeks; if inadequate response after 7 days may repeat dose (150 mg) and increase maintenance dose to 300 mg every 4 weeks if full treatment response (Ilaris prescribing information, Canada 2017; Ilaris prescribing information, United Kingdom 2017)
Reconstitution
Powder: Reconstitute each vial by slowly injecting SWFI 1 mL. Swirl vial slowly at a 45-degree angle for ~1 minute (do not shake), then allow solution to sit for 5 minutes. Gently turn vial (without touching rubber stopper) upside down and back 10 times. Allow to sit at room temperature for ~15 minutes. Do not shake. Solution may have a slight brownish-yellow tint; do not use if distinctly brown in color or if particulate matter is present in the solution. Slight foaming upon reconstitution is not unusual. Each reconstituted vial results in a final concentration of 150 mg/mL.
Administration
SubQ: For subcutaneous injection only. Do not shake solution. Do not inject into scar tissue.
Storage
Store intact vial at 2°C to 8°C (36°F to 46°F); do not freeze. After reconstitution of powder, vials may be stored at room temperature for up to 1 hour or in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 4 hours. Protect from light prior to and after reconstitution. Discard any unused portion.
Drug Interactions
Anti-TNF Agents: May enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Avoid combination
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Interleukin-1 Inhibitors: May enhance the adverse/toxic effect of Canakinumab. Whether such a combination will also alter the therapeutic response to one or both agents is unclear. Avoid combination
Interleukin-1 Receptor Antagonist: May enhance the adverse/toxic effect of Canakinumab. Whether such a combination will also alter the therapeutic response to one or both agents is unclear. Avoid combination
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification
Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination
Adverse Reactions
>10%:
Central nervous system: Headache (14%), vertigo (9% to 14%)
Endocrine & metabolic: Weight gain (11%)
Gastrointestinal: Diarrhea (20%), upper abdominal pain (7% to 16%), nausea (14%), gastroenteritis (3% to 11%)
Infection: Infection (30% to 54%; serious infection: 2% to 5%), influenza (17%)
Local: Injection site reaction (≤12%)
Neuromuscular and skeletal: Musculoskeletal pain (11%)
Respiratory: Nasopharyngitis (11% to 34%), rhinitis (5% to 17%), bronchitis (11%), pharyngitis (3% to 11%)
1% to 10%:
Endocrine & metabolic: Decreased serum calcium (8% [Lachmann 2009])
Genitourinary: Proteinuria (8% [Lachmann 2009])
Hematologic & oncologic: Decreased white blood cell count (10%), eosinophilia (7% [Lachmann 2009]), decreased neutrophils (transient: ≤7%), decreased platelet count (mild and transient: ≤6%)
Hepatic: Increased serum bilirubin (7% [Lachmann 2009]), increased serum AST (≤4%), increased serum ALT (≤4%)
Immunologic: Antibody development (non-neutralizing: ≤3%)
Renal: Decreased creatinine clearance (8% [Lachmann 2009])
Respiratory: Upper respiratory tract infection (7%)
Frequency not defined: Hepatic: Increased serum transaminases
<1%, postmarketing, and/or case reports: Hypersensitivity reaction
Warnings/Precautions
Concerns related to adverse effects:
- Hematologic effects: A decrease in WBC, neutrophils, and platelets was observed in clinical trials; some changes were transient and/or mild (eg, thrombocytopenia). One case of neutropenia (ANC <1,500/mm3) was reported; monitor blood counts as indicated.
- Hypersensitivity: Hypersensitivity reactions (excluding anaphylactic reactions) have been reported with use; symptoms may be similar to those that are disease related.
- Infections: Caution should be exercised when considering use in patients with a history of new/recurrent infections, with conditions that predispose them to infections, or with latent or localized infections. Patients who develop a new infection while undergoing treatment should be monitored closely. If a patient develops a serious infection, therapy should be discontinued. Therapy should not be initiated in patients with active or chronic infections.
- Macrophage activation syndrome (MAS): MAS may develop in patients with SJIA and should be treated aggressively. Infection or worsening SJIA may be triggers for MAS.
- Malignancy: Use may impair defenses against malignancies; impact on the development and course of malignancies is not fully defined.
- Tuberculosis: Avoid use in patients with active tuberculosis (TB). Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to starting therapy. Treat latent TB infections prior to initiating canakinumab therapy. During and following treatment, monitor for signs/symptoms of active TB.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Dosage form specific issues:
- Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.
Other warnings/precautions:
- Immunizations: All patients should be brought up to date with all immunizations including pneumococcal and influenza vaccines before initiating therapy. Live vaccines should not be given concurrently; no data available on either the efficacy or on the risks concerning secondary transmission of infection by live vaccines in patients receiving therapy. Administration of inactivated (killed) vaccines while on therapy may not be effective.
Monitoring Parameters
CBC with differential, C-reactive protein (CRP), serum amyloid A protein A (SAA); signs of infection; latent TB screening (prior to initiating therapy).
Eye examinations for patients with CAPS (Caorsi 2013) and symptoms of disease for patients with CAPS or SJIA (Caorsi 2013; Lachmann 2009; Ruperto 2012) were also monitored in clinical trials.
Pregnancy
Pregnancy Considerations
Adverse events have been observed in animal reproduction studies. Canakinumab is a recombinant IgG monoclonal antibody; IgG is known to cross the placenta in a linear fashion as pregnancy progresses; potential fetal exposure is likely to be greater during the second and third trimesters.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience nausea, vomiting, injection site irritation, signs of common cold, headache, abdominal pain, diarrhea, muscle pain, flu-like symptoms, runny nose, sore throat, or weight gain. Have patient report immediately to prescriber signs of infection, weight loss, dizziness, passing out, abnormal heartbeat, or signs of macrophage activation syndrome (worsening of arthritis, fever for more than 3 days, persistent cough, redness in one part of your body, or a warm feeling or swelling of your skin) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
