Tocilizumab

Aka: Tocilizumab, Actemra

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II. Indications

  1. Severe Cytokine Release Syndrome (CRS)
    1. CAR T-Cell Therapy Related CRS (FDA approved use of Tocilizumab)
    2. COVID-19 related CRS (experimental Tocilizumab use in 2020)
  2. Rheumatologic Conditions
    1. Rheumatoid Arthritis (refractory, moderate to severe)
    2. Giant Cell Arteritis
    3. Polyarticular Juvenile Idiopathic Arthritis
    4. Systemic Juvenile Idiopathic Arthritis

III. Contraindications

  1. Live Vaccines
  2. Active liver disease or hepatic dysfunction

IV. Mechanism

  1. See Interleukin-6 Receptor Antagonist
  2. Interleukin-6 (IL-6)
    1. Pro-inflammatory Cytokine synthesized and release by immune cells
  3. Interleukin-6 Receptor Antagonist
    1. Monoclonal antibodies bind and block IL-6
    2. Blockade of of IL-6 decreases production of proinflammatory Cytokines and acute phase reactants

V. Medications

  1. Intravenous solution for injection (single dose vials 20 mg/ml): 80 mg, 200 mg and 400 mg
  2. Subcutaneous prefilled syringes or ACTPen Autoinjector (162 mg/0.9 ml)
    1. Keep refrigerated
    2. Allow to warm to room Temperature for 30 minutes before injection (reduces pain)

VI. Dosing: Adult

  1. Rheumatoid Arthritis
    1. Subcutaneous (SQ)
      1. Start 162 mg SQ every 2 weeks (every 1 week if weight >100 kg)
      2. May be titrated to weekly dosing if needed
    2. Intravenous (IV)
      1. Start 4 mg/kg IV every 4 weeks
      2. May increase to 8 mg/kg (up to 800 mg) IV every 4 weeks
  2. Giant Cell Arteritis
    1. Subcutaneous (SQ)
      1. Start 162 mg SQ every week (may be given every 2 weeks if needed)
      2. Combined with Corticosteroid
  3. Cytokine Release Syndrome (CAR T-Cell Therapy Related)
    1. Intravenous: 8 mg/kg (up to 800 mg) IV (or for <30 kg, use 12 mg/kg)
    2. May repeat every 8 hours for up to 3 doses if no initial response

VII. Dosing: Child (age >=2 years)

  1. FDA Approved for age >=2 years
  2. Polyarticular Juvenile Idiopathic Arthritis
    1. Subcutaneous (SQ)
      1. Weight <30 kg: 162 mg SQ every 3 weeks
      2. Weight >=30 kg: 162 mg SQ every 2 weeks
    2. Intravenous (IV)
      1. Weight <30 kg: 10 mg/kg IV every 4 weeks
      2. Weight >=30 kg: 8 mg/kg IV every 4 weeks
  3. Systemic Juvenile Idiopathic Arthritis
    1. Subcutaneous (SQ)
      1. Weight <30 kg: 162 mg SQ every 2 weeks
      2. Weight >=30 kg: 162 mg SQ every 1 week
    2. Intravenous (IV)
      1. Weight <30 kg: 12 mg/kg IV every 2 weeks
      2. Weight >=30 kg: 8 mg/kg IV every 2 weeks
  4. Cytokine Release Syndrome (CAR T-Cell Therapy Related)
    1. Intravenous (IV)
      1. Weight <30 kg: 12 mg/kg IV once
      2. Weight >=30 kg: 8 mg/kg (up to 800 mg) IV once
      3. May repeat every 8 hours for up to 3 doses if no initial response

VIII. Adverse Effects

  1. Severe infections (esp. opportunistic Viral Infections, Bacterial Infections, invasive Fungal Infections)
  2. Reactivated Herpes Zoster
  3. Reactivated Tuberculosis
  4. Neutropenia
    1. Avoid if Absolute Neutrophil Count (ANC) <2000
  5. Thrombocytopenia
    1. Avoid if Platelet Count <100,000
  6. Increased liver enzymes (AST, ALT)
    1. Avoid starting if serum transaminases are >1.5 times normal
    2. Stop if serum transaminases increase >5 times normal
  7. Hyperlipidemia
  8. GI perforation
    1. Higher risk in Rheumatoid Arthritis patients with a history of Diverticulitis

IX. Safety

  1. Unknown safety in pregnancy
    1. Fetal exposure increases after 20 weeks gestation
  2. Unknown safety in Lactation
  3. Monitoring
    1. Timing
      1. Adults: Labs after 4-8 weeks and then every 3 months
      2. Children: Monitoring intervals vary by indication (see other references)
    2. Complete Blood Count (Neutrophils, Platelets)
    3. Serum transaminases (AST, ALT)
    4. Lipid panel
    5. Infection signs

X. Drug Interactions

  1. Broad effects on multiple CYP450 enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4)
  2. May affect drug levels of agents with a narrow therapeutic range
    1. Warfarin
    2. Cyclosporine
    3. Theophylline

XI. Resources

  1. Tocilizumab (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e5365ff-cb2a-4b16-b2c7-e35c6bf2de13

XII. References

  1. Kamer and LoVecchio (2020) Crit Dec Emerg Med 34(8): 24

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