Canakinumab (Monograph)
Brand name: Ilaris
Drug class: Other Miscellaneous Therapeutic Agents
Introduction
Interleukin-1 beta (IL-1β) blocker; a recombinant human anti-human IL-1β monoclonal antibody.
Uses for Canakinumab
Periodic Fever Syndromes
Management of periodic fever syndromes including cryopyrin-associated periodic syndromes (CAPS), such as familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), in adults and children ≥4 years of age.
Also used for tumor necrosis factor receptor associated periodic syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), and Familial Mediterranean Fever (FMF) in adult and pediatric patients.
Designated an orphan drug by FDA for use in these conditions.
Guidelines recommend use of interleukin (IL)-1 inhibitors including anakinra, rilonacept, and canakinumab for patients with CAPS.
Colchicine is the mainstay therapy for FMF; however, IL-1 inhibitors have been effective in patients with inadequate response to colchicine.
Recommended therapies for TRAPS include corticosteroids, tumor necrosis factor (TNF) blockers, and IL-1 inhibitors.
Trials of corticosteroids and inflammatory cytokine inhibitors are recommended for HIDS/MKD; some experts note benefit observed with TNF-α and IL-1ß inhibitors.
Still's Disease
Treatment of active Still’s disease, including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) in patients ≥2 years of age.
Designated an orphan drug by FDA for use in these conditions.
Guidelines conditionally recommend NSAIAs, IL-1 inhibitors, and IL-6 inhibitors (anakinra, canakinumab, tocilizumab, or other agents) as initial therapy in patients with SJIA without macrophage activation syndrome (MAS).
In patients with MAS, IL-1 inhibitors and IL-6 inhibitors are conditionally recommended over calcineurin inhibitors alone; glucocorticoids are also conditionally recommended as initial treatment.
For AOSD, some experts state that corticosteroids are first-line treatment, with refractory disease treated with IL-1 inhibitors, IL-6 inhibitors, and TNF-blocking agents.
Other Uses
Has been used for the treatment of acute gout flares† [off-label]Ϯ.
Canakinumab Dosage and Administration
General
Pretreatment Screening
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Confirm absence of active infection. Evaluate for and, if necessary, treat latent tuberculosis infection before initiating canakinumab.
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Ensure that patients receive all recommended vaccinations, including pneumococcal and inactivated influenza vaccines, before treatment with canakinumab.
Patient Monitoring
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Monitor patients with Still's disease for worsening of underlying symptoms and symptoms of infection as these are known triggers for macrophage activation syndrome.
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Monitor all patients for signs and symptoms of infection suggestive of tuberculosis.
Administration
Sub-Q Administration
Administer by sub-Q injection only.
Injections should be performed by a clinician; do not self-administer.
Do not inject into scar tissue; this may result in insufficient exposure to the drug. Do not inject into areas where skin is already swollen or erythematous.
Administration
Solution should be clear to opalescent, colorless to slightly brownish-yellow, and essentially free from particulates. Do not use if the solution has a distinctly brown discoloration, is highly opalescent, or contains visible particles.
Using a sterile 1-mL syringe and 18-gauge, 2 inch needle, withdraw the required volume for administration. Use a 27-gauge, ½-inch needle for the sub-Q injection.
Discard unused portions of the reconstituted solution; the solution contains no preservatives.
Dosage
Pediatric Patients
Cryopyrin-associated Periodic Syndromes
Sub-Q
Children ≥4 years of age who weigh >40 kg : 150 mg once every 8 weeks.
Children ≥4 years of age who weigh 15–≤40 kg : 2 mg/kg once every 8 weeks. In patients with inadequate response, may increase dosage to 3 mg/kg once every 8 weeks.
Tumor Necrosis Factor Receptor Associated Periodic Syndrome, Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency, Familial Mediterranean Fever
Sub-Q
Children who weigh >40 kg: 150 mg once every 4 weeks. Increase to 300 mg every 4 weeks if response is not adequate.
Children who weigh ≤40 kg: 2 mg/kg once every 4 weeks. In patients with inadequate response, may increase dosage to 4 mg/kg once every 4 weeks.
Still's Disease
Sub-Q
Children ≥2 years of age who weigh ≥7.5 kg: 4 mg/kg (maximum 300 mg) every 4 weeks.
Adults
Cryopyrin-associated Periodic Syndromes
Sub-Q
Adults who weigh >40 kg : 150 mg once every 8 weeks.
Adults who weigh 15–≤40 kg : 2 mg/kg once every 8 weeks.
Tumor Necrosis Factor Receptor Associated Periodic Syndrome, Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency, Familial Mediterranean Fever
Sub-Q
Adults who weigh >40 kg: 150 mg once every 4 weeks. Increase to 300 mg every 4 weeks if response is not adequate.
Adults who weigh ≤40 kg: 2 mg/kg once every 4 weeks. Increase to 4 mg/kg once every 4 weeks if response is inadequate.
Still's Disease
Sub-Q
Adults who weigh ≥7.5 kg: 4 mg/kg (maximum 300 mg) every 4 weeks.
Special Populations
Geriatric Patients
No specific dosage recommendations at this time.
Hepatic Impairment
No specific dosage recommendations at this time.
Renal Impairment
No specific dosage recommendations at this time.
Cautions for Canakinumab
Contraindications
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Confirmed hypersensitivity to canakinumab or any ingredient in the formulation.
Warnings/Precautions
Serious Infections
IL-1 blockade may interfere with immune response to infections; associated with an increased risk of serious infections. Potentially serious infections, predominantly involving the upper respiratory tract, reported. Unusual or opportunistic infections not reported during premarketing studies. Isolated cases of unusual or opportunistic infections (e.g., aspergillosis, atypical mycobacterial infections, cytomegalovirus, herpes zoster) reported.
Do not initiate canakinumab in patients with an active infection requiring medical treatment or a chronic infection (e.g., HIV, HBV, or HCV infection); discontinue therapy if a serious infection occurs. Use with caution in patients with infections, a history of recurring infections, or underlying conditions which may predispose them to infections.
May increase risk of tuberculosis or other atypical or opportunistic infections. Evaluate patients for new tuberculosis or reactivation of latent tuberculosis prior to initiation of canakinumab therapy. Not studied in patients with latent tuberculosis infection; safety in such patients not known. When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to canakinumab therapy. Instruct patients to seek medical advice if signs, symptoms, or high risk exposure suggestive of tuberculosis (e.g., persistent cough, weight loss, subfebrile temperature) appear during or after canakinumab treatment.
Immunosuppression
Effect on the development of malignancies not known. However, possible increased risk of malignancies in patients receiving immunosuppressive agents, including canakinumab.
Hypersensitivity
Hypersensitivity reactions reported. If hypersensitivity occurs, discontinue drug and initiate appropriate therapy.
Immunizations
Avoid live vaccines during canakinumab therapy.
Vaccine efficacy may be reduced. Review vaccination status of all patients and administer all age-appropriate vaccines, including pneumococcal vaccine and influenza virus vaccine inactivated, prior to initiation of canakinumab therapy.
Macrophage Activation Syndrome
Life-threatening macrophage activation syndrome reported in patients with Still's disease. Monitor patients with Still's disease for worsening of symptoms and for infection.
Immunogenicity
Antibodies to canakinumab observed in clinical study of patients treated for CAPS; no detected neutralizing antibodies or impact on the drug's efficacy, safety, and tolerability detected. No neutralizing antibodies were detected. No anti-canakinumab antibodies detected in clinical studies of 150 mg and 300 mg canakinumab for TRAPS, HIDS/MKD, FMF, SJIA, or AOSD.
Specific Populations
Pregnancy
Data are limited regarding use of canakinumab in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Delayed fetal skeletal development reported in some animal studies of exposure to canakinumab above maximum recommended human dose either prenatally or during organogenesis.
Consider risks and benefits of administering live vaccines to infants who were exposed to canakinumab in utero for at least 4–12 months following the mother's last dose of canakinumab.
Lactation
Not known whether canakinumab is distributed into milk. Consider benefits of breastfeeding to infant and benefit of treatment to mother.
Pediatric Use
Evaluated in 23 pediatric patients 4–17 years of age with CAPS; symptoms and objective markers of inflammation improved in most patients and overall efficacy and safety were similar to those observed in adults. Safety and efficacy not established in children <4 years of age with CAPS.
Evaluated in 102 pediatric patients 2–17 years of age with TRAPS, HIDS/MKD, and FMF; clinical symptoms and objective markers of inflammation improved in a majority of pediatric patients with no meaningful differences in efficacy, safety, and tolerability between pediatric and adult patients.
Safety and efficacy not established in children <2 years of age with SJIA.
Avoid live virus vaccines and administer all required vaccinations prior to initiation of treatment.
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.
Hepatic Impairment
Pharmacokinetics not studied in patients with hepatic impairment.
Renal Impairment
Pharmacokinetics not studied in patients with renal impairment.
Common Adverse Effects
Adverse effects (>10% of patients receiving canakinumab for CAPS): nasopharyngitis, diarrhea, influenza, rhinitis, headache, nausea, bronchitis, gastroenteritis, musculoskeletal pain, pharyngitis, vertigo, weight gain.
Adverse effects (≥10% of patients receiving canakinumab for TRAPS, HIDS/MKD, and FMF): injection site reactions and nasopharyngitis.
Adverse effects (≥10% of patients receiving canakinumab for Still's disease): infections (nasopharyngitis and upper respiratory tract infections), abdominal pain, injection site reactions.
Drug Interactions
No formal drug interaction studies to date.
Drugs Metabolized by Hepatic Microsomal Enzymes
Because increased levels of cytokines (e.g., IL-1) during chronic inflammation may suppress formation of CYP isoenzymes, antagonism of IL-1 activity by canakinumab may normalize formation of CYP enzymes.
Drugs metabolized by CYP isoenzymes that have a low therapeutic index: monitor therapeutic effect and/or serum concentrations following initiation of canakinumab; adjust dosage of the CYP substrate as needed.
Immunizations
Data not available regarding efficacy of inactivated vaccines in patients receiving canakinumab.
Do not administer live vaccines to patients receiving canakinumab. Data not available regarding efficacy of live vaccines or risk of secondary transmission of infection by live vaccines in patients receiving the drug.
Manufacturer makes no specific recommendations regarding the length of time to wait between discontinuance of canakinumab and administration of a live vaccine or the length of time to wait between administration of a live vaccine and initiation of canakinumab therapy.
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
IL-1 blocking agents (e.g., anakinra, rilonacept) |
Potential pharmacologic interaction |
Concomitant use not recommended |
TNF blocking agents (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab) |
Potential for increased risk of serious infections and neutropenia |
Concomitant use not recommended |
Warfarin |
Possible effect on warfarin metabolism (increased levels of IL-1 during chronic inflammation may suppress formation of CYP isoenzymes, antagonism of IL-1 activity by canakinumab may normalize formation of CYP enzymes) |
Monitor therapeutic effect of warfarin; adjust warfarin dosage as needed |
Canakinumab Pharmacokinetics
Absorption
Bioavailability
Absolute bioavailability following sub-Q injection approximately 66%. Peak plasma concentrations achieved in approximately 7 days in adults and approximately 2–7 days in pediatric patients with CAPS.
AUC and peak plasma concentrations increase in proportion to dose over a sub-Q dosage range of 150–300 mg.
Onset
Improvement in symptom scores and objective markers of inflammation occurs within approximately 1 week following initiation of therapy in most patients with CAPS.
Distribution
Extent
Not known whether canakinumab is distributed into milk.
Elimination
Half-life
Terminal half-life approximately 26 days in adults with CAPS.
Special Populations
Pharmacokinetic data not available for patients with hepatic or renal impairment.
No gender- or age-related differences in pharmacokinetics observed after correction for body weight.
Stability
Storage
Parenteral
Injection, for Sub-Q use
2–8°C in original carton to protect from light.
Actions
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Recombinant human anti-human interleukin-1 beta (IL-1β) monoclonal antibody belonging to the IgG1/κ isotype subclass.
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Binds to IL-1β and neutralizes its activity by blocking its interaction with IL-1 receptors; does not bind interleukin-1 alpha (IL-1α) or interleukin-1 receptor antagonist (IL-1Ra). Mutations in the NLRP-3 gene in patients with CAPS result in an overactive inflammasome, which causes excessive release of activated IL-1β.
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Still's disease driven by innate immunity by means of proinflammatory cytokines such as IL-1 β.
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Results in normalization of serum concentrations of SAA and CRP, indicators of inflammatory disease activity. Elevated SAA concentrations have been associated with the development of systemic amyloidosis in patients with CAPS.
Advice to Patients
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Provide a copy of the manufacturer’s patient information to all patients and advise of the importance to read the information.
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Inform patients of the importance of discussing any questions pertaining to the manufacturer's patient information.
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Inform patients of the risk of injection site reactions (e.g., pain, erythema, swelling, pruritus, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, hemorrhage). Instruct patient to inform their clinician of any persistent injection site reaction.
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Inform patients of the risk of serious infection. Instruct patients to inform their clinicians immediately if any signs or symptoms of infection (e.g., fever, cough, redness in one part of the body, warmth or swelling of the skin) occur.
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Instruct patients to inform their clinician if they have an active infection, have a history of recurrent infection, have had human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
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Advise patients that they should not take canakinumab if they have an active or chronic infection.
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Instruct patients to contact their clinician immediately if they develop signs of an allergic reactions, such as difficulty breathing or swallowing, nausea, dizziness, skin rash, itching, hives, palpitations, or low blood pressure.
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Advise patients to review their vaccination status with their clinician and receive all age-appropriate vaccines prior to initiation of canakinumab therapy.
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Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription (e.g., IL-1 antagonists such as anakinra, rilonacept; TNF-blocking agents such as etanercept, infliximab, certolizumab, golimumab, or adalimumab; immunizations; corticosteroids) and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illnesses (e.g., active or chronic infections).
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Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.
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Importance of informing patients of other important precautionary information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Canakinumab can only be obtained through designated specialty pharmacies and distributors. Contact the manufacturer for additional information regarding enrollment.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Parenteral |
Injection, for subcutaneous use |
150 mg/mL |
Ilaris (available in single-dose vials) |
Novartis |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions July 26, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
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