canakinumab (Rx)

>10%

Nasopharyngitis (34%)

Diarrhea (20%)

Influenza (17%)

Rhinitis (17%)

Headache (14%)

Nausea (14%)

Vertigo (9-14%)

Gastroenteritis (11%)

Pharyngitis (11%)

Weight increase (11%)

Bronchitis (11%)

Musculoskeletal pain (11%)

WBC count ≤0.8x LLN (10.4%)

1-10%

Injection site pain (9%)

Decreased platelets (6.3%)

ANC <1x 10⁹/L (6%)

Increased AST/ALT (4.1%)

Frequency Not Defined

Mild bilirubin elevation

Contraindications

Hypersensitivity

Cautions

Risk of serious infections, including opportunistic infections and reactivation of latent hepatitis or TB; interrupt therapy if serious infection develops; infections, predominantly of upper respiratory tract, in some instances serious, reported in isolated cases of unusual or opportunistic infections including aspergillosis, atypical mycobacterial infections, cytomegalovirus, herpes zoster; causal relationship of therapy to infections cannot be excluded

Hypersensitivity reported postmarketing; disease symptoms may be similar to symptoms of hypersensitivity; if a severe hypersensitivity reaction occurs, therapy should be discontinued and appropriate therapy initiated

May impair defenses against malignancies

Macrophage activation syndrome (MAS) is a life-threatening disorder that may develop with rheumatic conditions, particularly with Still disease or SJIA; it should be aggressively treated; it is important to be attentive to symptoms of infection or worsening of Still’s disease, as these are known triggers for MAS; based on clinical trials, canakinumab did not increase incidence of MAS;

Drug interaction overview

• IL-1 or TNF blockers

  • Avoid coadministration
  • Coadministration with other IL-1 antagonists or TNF inhibitors increases risk of neutropenia and serious infection

• Live vaccines

  • Avoid coadministration
  • Data are not available on effects of live vaccination or secondary infection transmission by live vaccines if administered while on canakinumab
  • Recommended to complete immunization before initiating canakinumab

• CYP450 substrates

  • CYP450 enzymes are suppressed by increased levels of cytokines (eg, IL-1) during chronic inflammation
  • CYP450 enzymes are expected to normalize once IL-1 levels decrease
  • Monitor CYP450 substrates with narrow therapeutic indices, where the dose is individually adjusted (eg, warfarin); dose adjustment may be necessary

Pregnancy

Limited human data from postmarketing reports on use in pregnant women are not sufficient to inform a drug associated risk

Monoclonal antibodies, such as canakinumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential fetal exposure is likely to be greater during the second and third trimesters of pregnancy

Animal data

• Studies with marmoset monkeys showed no evidence of embryotoxicity or fetal malformations with during organogenesis and later in gestation at doses that produced exposures ~11 times the exposure at the maximum recommended human dose (MRHD) and greater
• Delays in fetal skeletal development were observed in marmoset monkeys following prenatal exposure at concentrations ~11 times the MRHD and greater; similar delays in fetal skeletal development were observed in mice administered a murine analog of canakinumab during organogenesis

Lactation

Data are not available regarding presence in human milk, effects on breastfed infants, or effects on milk production

Human IgG is known to be present in human milk; effects of canakinumab in breast milk and possible systemic exposure in the breastfed infant are unknown; the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Recombinant, human monoclonal antibody that binds to human interleukin (IL)-1β and neutralizes its activity by blocking its interaction with IL-1 receptors; does not bind IL-1α or IL-1 receptor antagonist (IL-1ra)

Absorption

Absolute bioavailability: 66%

Peak plasma concentration: 16 mcg/mL

Peak plasma time

• Adults: ~7 days
• Pediatric patients: 2-7 days

Distribution

Vd (steady-state)

• CAPS (70-kg patient): 6.01 L
• SJIA (33-kg patient): 3.2 L
• Periodic fever syndrome (70-kg patient): 6.34 L

Elimination

Clearance

• CAPS (70-kg patient): 0.174 L/day
• SJIA (33-kg patient): 0.11 L/day
• Periodic fever syndrome (70-kg patient): 0.17 L/day

Half-life

• Adults, 150-mg dose: 26 days
• Children and adolescents, 150-mg or 2-mg/kg dose: 22.9-25.7 days

SC Preparation

Reconstitute lyophilized powder with 1 mL sterile water for injection to obtain 150 mg/mL solution

Swirl the vial slowly at an angle of about 45° for ~1 minute and allow to stand for 5 minutes

Do not shake; gently turn the vial upside down and back again 10 times; avoid touching the rubber stopper with your fingers

Allow stand for 15 minutes at room temperature

Do not shake

Do not use if particulate matter is present in the solution

Tap the side of the vial to remove any residual liquid from the stopper

The reconstituted solution should be clear to opalescent, colorless to a slightly brownish yellow tint, and essentially free from particulates

If the solution has a distinctly brown discoloration, do not use

Slight foaming of the product upon reconstitution is not unusual

Protect from light

Reconstituted solution can be kept at room temperature if used within 1 hr; otherwise, refrigerate at 2-8°C (36-46°F) and use within 4 hr

SC Administration

Using a sterile 1-mL syringe and needle, carefully withdraw the required volume depending on the dose to be administered and inject SC using a 27-gauge x 0.5-inch needle

Avoid injecting scar tissue as this may result in insufficient exposure

Discard any unused product or waste material in accordance with local requirements

Storage

Unopened vial

• Refrigerate at 2-8°C (36-46° F)
• Do not freeze
• Store in the original carton to protect from light

Reconstituted vial

• Room temperature if used within 1 hr; otherwise, refrigerate at 2-8°C (36-46°F) and use within 4 hr