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Canakinumab

Pronunciation

(can a KIN ue mab)

Index Terms

  • ACZ885

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Subcutaneous [preservative free]:

Ilaris: 180 mg (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • Ilaris

Pharmacologic Category

  • Interleukin-1 Beta Inhibitor
  • Interleukin-1 Inhibitor
  • Monoclonal Antibody

Pharmacology

Canakinumab reduces inflammation by binding to interleukin-1 beta (IL-1β) (no binding to IL-1 alpha or IL-1 receptor antagonist) 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-1β activation. Deficiency of cryopyrin results in excessive inflammation.

Distribution

Vdss: Children: 0.097 L/kg (3.2 L in 33 kg); Adults: 0.086 L/kg (6 L in 70 kg)

Excretion

Clearance: Varies according to body weight (NCT 00685373, 2011):

Children ≤40 kg: 0.083 L/day (0.11 L/day in 33 kg)

Children >40 kg and Adults: 0.18 L/day (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: 2-7 days; Adults: ~7 days

Half-Life Elimination

Children ≥4 years: 23 to 26 days; Adults: 26 days

Protein Binding

Binds to serum IL-1 beta

Special Populations: Children

CAPS patients: Tmax is 2-7 days and half-life ranged from 22.9-25.7 days

SJIA patients: AUC and Cmax comparable across age groups following 4 mg/kg every 4 weeks.

Use: Labeled Indications

Cryopyrin-associated periodic syndromes:

U.S. labeling: 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).

Canadian labeling: Treatment of cryopyrin-associated periodic syndromes (CAPS) in adults and children 2 years and older, including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). May also be used in Neonatal-Onset Multisystem Inflammatory Disease (NOMID) although clinical data has not confirmed improvement of CNS symptoms in this patient population.

Systemic juvenile idiopathic arthritis: Treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years and older.

Contraindications

Confirmed hypersensitivity to canakinumab or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Active, severe infections

Dosing: Adult

Cryopyrin-associated periodic syndromes (CAPS): Adults >40 kg: SubQ:

U.S. labeling: 150 mg every 8 weeks

Canadian labeling: 150 mg every 8 weeks; if inadequate response after 7 days may consider further titration by 150 mg every 7 days up to a maximum dose of 600 mg. The dose at which a satisfactory response is achieved should be maintained and administered every 8 weeks.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Cryopyrin-associated periodic syndromes (CAPS): SubQ:

U.S. labeling:

Children ≥4 years and Adolescents:

15 to 40 kg: 2 mg/kg every 8 weeks; may increase to 3 mg/kg if response inadequate

>40 kg: 150 mg every 8 weeks

Canadian labeling:

Children ≥2 years and Adolescents:

15 to 40 kg: Initial: 2 mg/kg every 8 weeks; if inadequate response after 7 days may consider further titration by 2 mg/kg every 7 days up to a maximum dose of 8 mg/kg (do not exceed 600 mg). The dose at which a satisfactory response is achieved should be maintained and administered every 8 weeks.

>40 kg: 150 mg every 8 weeks; if inadequate response after 7 days may consider further titration by 150 mg every 7 days up to a maximum dose of 600 mg. The dose at which a satisfactory response is achieved should be maintained and administered every 8 weeks.

Systemic juvenile idiopathic arthritis (SJIA): SubQ: Children ≥2 years and ≥7.5 kg (U.S. labeling) or >9 kg (Canadian labeling) and Adolescents: 4 mg/kg every 4 weeks (maximum: 300 mg per dose)

Dosing: Renal Impairment

U.S. labeling: There are no dosage adjustments provided in the manufacturer’s labeling.

Canadian labeling: No dosage adjustment necessary; limited data in this population.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Reconstitution

Reconstitute vial with SWFI 1 mL. After reconstituting with SWFI, swirl the vial 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 until solution is clear. 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. Each reconstituted vial results in a final concentration of 150 mg/mL.

Administration

SubQ: Do not inject into scar tissue.

Storage

Store powder in refrigerator at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. After reconstitution, vials may be stored at controlled room temperature for up to 1 hour or in a refrigerator for up to 4 hours.

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

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. 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

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

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. Avoid combination

Adverse Reactions

Adverse events reported in treatment of CAPS unless otherwise noted.

>10%:

Central nervous system: Headache (14%), vertigo (9% to 14%)

Endocrine & metabolic: Weight gain (11%)

Gastrointestinal: Diarrhea (20%), upper abdominal pain (SJIA 7% to 16%), nausea (14%), gastroenteritis (11%)

Infection: Infection (SJIA 30% to 55%; serious 4% to 5%), influenza (17%)

Local: Injection site reaction (SJIA ≤14%; CAPS 7% to 9%)

Neuromuscular and skeletal: Musculoskeletal pain (11%)

Respiratory: Nasopharyngitis (34%), rhinitis (17%), bronchitis (11%), pharyngitis (11%)

1% to 10%:

Endocrine & metabolic: Decreased serum calcium (≤8% [Lachmann, 2009])

Genitourinary: Proteinuria (≤8% [Lachmann, 2009])

Hematologic & oncologic: Decreased white blood cell count (SJIA 10%), eosinophilia (3% to 7% [Lachmann, 2009]), decreased neutrophils (transient; SJIA 6%), thrombocytopenia (mild, transient; SJIA 6%)

Hepatic: Increased serum bilirubin (≤7% [Lachmann, 2009]), increased serum AST (3% to 6% [Lachmann, 2009]), increased serum transaminases (SJIA 4%), increased serum alkaline phosphatase (3% [Lachmann, 2009]), increased serum ALT (3% [Lachmann, 2009])

Immunologic: Antibody development (non-neutralizing; SJIA 3%; CAPS 2%)

Renal: Decreased creatinine clearance (3% to 8% [Lachmann, 2009]) )

<1% (Limited to important or life-threatening): Hypersensitivity reaction, increased blood pressure, neutropenia (SJIA)

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity reactions (excluding anaphylactic reactions) have been reported with use; symptoms may be similar to those that are disease related. Use is contraindicated in patients with known hypersensitivity to canakinumab.

• 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.

• Neutropenia: Neutropenia (ANC <1500/mm3) has been reported with use. The Canadian labeling recommends assessing the neutrophil counts prior to initiating canakinumab, after 1 to 2 months of therapy, and periodically thereafter. Patients with neutropenia prior to initiation are not recommended for therapy. In addition, if a patient becomes neutropenic, close monitoring of the ANC and consideration of treatment discontinuation is also recommended (Ilaris Canadian product monograph, 2013).

• 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: 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; there is no data available concerning secondary transmission of 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); Canadian labeling also recommends blood pressure monitoring, annual lipid screening, and monitoring of neutrophil counts (at baseline, after 1-2 months and periodically thereafter)

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 Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. The Canadian product labeling recommends women of reproductive potential use effective contraception during treatment and for 3 months after the last dose.

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 headache, abdominal pain, diarrhea, rhinorrhea, pharyngitis, or weight gain. Have patient report immediately to prescriber signs of infection, severe dizziness, passing out, severe injection site irritation, dysphagia, severe nausea, severe vomiting, arrhythmia, or signs of macrophage activation syndrome (worsening of arthritis, fever for more than 3 days, cough that does not go away, 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 healthcare 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.

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