Canakinumab (Monograph)

Brand name: Ilaris
Drug class: Interleukin Antagonists

Medically reviewed by Drugs.com on Jul 26, 2023. Written by ASHP.

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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 of 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.

Gout Flares

Treatment of adults with gout flares in whom NSAIAs and colchicine are contraindicated, not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are inappropriate.

Guidelines conditionally recommend an IL-1 inhibitor (e.g., canakinumab) over no therapy for patients with a gout flare who are unable to tolerate, had an ineffective response,or have contraindications to first-line treatments (e.g., colchicine, NSAIAs, glucocorticoids).

Canakinumab Dosage and Administration

General

Pretreatment Screening

• Confirm absence of active infection. Evaluate for and, if necessary, treat latent tuberculosis infection before initiating canakinumab.

• Ensure that patients receive all recommended vaccinations, including pneumococcal and inactivated influenza vaccines, before treatment with canakinumab.

Patient Monitoring

• Monitor patients with Still's disease for worsening of underlying symptoms and symptoms of infection as these are known triggers for macrophage activation syndrome.

• 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

4 mg/kg (maximum 300 mg) every 4 weeks.

Gout Flares

Sub-Q

150 mg. If retreatment required, there should be an interval of ≥12 weeks before a new dose may be administered.

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

• Confirmed hypersensitivity to canakinumab or any ingredient in the formulation.

Warnings/Precautions

Serious Infections

Canakinumab has been associated with an increased risk of serious infections. Potentially serious infections, predominantly involving the upper respiratory tract, reported. 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. Symptoms of underlying disease may be similar to symptoms of hypersensitivity. 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 rheumatic conditions, particularly Still's disease; if MAS develops, it should be aggressively treated. Monitor patients with Still's disease for worsening of symptoms and for infection (known triggers for MAS).

Immunogenicity

Antibodies to canakinumab observed in clinical studies of patients treated for CAPS, SJIA, and gout flares. Neutralizing antibodies detected in <1% of patients with gout flares and no correlation of antibody development to clinical response or adverse events observed. No anti-canakinumab antibodies detected in clinical studies of 150 mg and 300 mg doses of 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 breast-feeding 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.

Safety and efficacy not established in pediatric patients for treatment of gout flares.

Avoid live virus vaccines in pediatric patients receiving canakinumab and in infants exposed in utero following maternal administration. Administer all required vaccinations prior to initiation of treatment.

Geriatric Use

Insufficient experience in patients ≥65 years of age with CAPS, TRAPS, HIDS/MKD, FMF, and Still's disease to determine whether geriatric patients respond differently than younger adults.

In clinical studies for treatment of gout flares, 85 (17.3%) patients were ≥65 years of age and 16 (3.3%) patients were ≥75 years of age. The efficacy profile was similar between patients 65 to 75 years of age and those <65 years of age. Studies did not include sufficient numbers of patients ≥75 years of age to determine whether they respond differently than younger patients. No new safety findings were reported in these age groups.

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.

Adverse effects (≥2% of patients receiving canakinumab for gout flares): nasopharyngitis, upper respiratory tract infections, urinary tract infections, hypertriglyceridemia, back pain.

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

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.

Pharmacokinetic properties in pediatric populations are similar in patients with CAPS, TRAPS, HIDS/MKD, FMF, and SJIA.

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

• Recombinant human anti-human interleukin-1 beta (IL-1β) monoclonal antibody belonging to the IgG1/κ isotype subclass.

• 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.

• Concentrations of serum amyloid A (SAA) and C-reactive protein (CRP), indicators of inflammatory disease activity, are elevated in patients with CAPS. Canakinumab results in normalization of serum concentrations of SAA and CRP. Elevated SAA concentrations have been associated with the development of systemic amyloidosis in patients with CAPS.

• Still's disease is a severe autoinflammatory disease driven by innate immunity by means of proinflammatory cytokines such as IL-1 β. In patients with SJIA, the median percent reduction in CRP from baseline to day 15 was 91%.

• Gout flares are characterized by activation of resident macrophages and infiltrating neutrophils in the joint, with concomitant overproduction of IL-1β resulting in an acute painful inflammatory response. In patients with gout flares, CRP and SAA were rapidly reduced following canakinumab treatment, and reductions were sustained throughout the 24-week observation period.

Advice to Patients

• Provide a copy of the manufacturer’s patient information to all patients and advise of the importance of reading the information.

• 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 patients to inform their clinician of any persistent injection site reaction.

• 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.

• Instruct patients to inform their clinician if they have an active infection, have a history of recurrent infection, or have had human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.

• Advise patients that they should not take canakinumab if they have an active or chronic infection.

• 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.

• Advise patients to review their vaccination status with their clinician and receive all age-appropriate vaccines prior to initiation of canakinumab therapy.

• 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).

• Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.

• Inform 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.

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