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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, Subcutaneous:

Ilaris: 150 mg/mL (1 mL) [contains polysorbate 80]

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-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.

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 labeling 2017; 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.

Contraindications

Hypersensitivity to canakinumab or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Active, severe infections

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 labeling 2017).

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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Cryopyrin-associated periodic syndromes (CAPS): SubQ:

Children ≥4 years and Adolescents:

15 to 40 kg: 2 mg/kg every 8 weeks; may increase to 3 mg/kg if response inadequate; in clinical trials, dosage adjustments up to 8 mg/kg and/or increased dosing frequency were allowed for residual symptoms (Kuemmerle-Deschner 2011). For inadequate response, a dose titration schedule of 2 mg/kg every 7 days up to a maximum dose of 8mg/kg has been recommended (Ilaris Canadian product labeling 2017)

>40 kg: Refer to adult dosing

Familial Mediterranean Fever (FMF), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): SubQ: Children and Adolescents: Refer to adult dosing.

Systemic juvenile idiopathic arthritis (SJIA): SubQ: Children ≥2 years and ≥7.5 kg and Adolescents: 4 mg/kg every 4 weeks (maximum: 300 mg per dose)

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

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

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

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

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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

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

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. 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

>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% (Limited to important or life-threatening): 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 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 signs of common cold, headache, abdominal pain, diarrhea, muscle pain, flu-like symptoms, rhinorrhea, pharyngitis, or weight gain. Have patient report immediately to prescriber signs of infection, persistent cough, weight loss, dizziness, passing out, severe injection site irritation, difficulty swallowing, severe nausea, severe vomiting, 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.

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