Tocilizumab

by Douglas Black, Pharm.D. last updated 2022-01-07 15:25:04.626391-05:00 © Antimicrobial Therapy, Inc.
IL-6 Inhibitor, Tocilizumab
Actemra
  • Tocilizumab is a recombinant humanized anti-interleukin 6 (IL-6) monoclonal antibody.
  • Tocilizumab binds to both soluble and membrane-bound IL-6 receptors, and has been shown to inhibit IL-6-mediated signaling through those receptors.
  • The most recent IDSA guidelines make a conditional recommendation, low certainty of evidence, for use of Tocilizumab in addition to standard of care, including corticosteroids, for progressive severe or critical disease in patients with COVID-19 pneumonia.  (Link to most recently published IDSA review of IL-6 inhibitor studies here.) Revised NIH guidelines make similar recommendations.  
  • Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid at an equivalent dose).  Use of Tocilizumab should be avoided in patients with any of the following: (1) significant immunosuppression, particularly in those with a history of recent use of other biologic immunomodulating drugs; (2) alanine transaminase >5 times the upper limit of normal; (3) high risk for gastrointestinal perforation; (4) an uncontrolled, serious bacterial, fungal, or non-SARS-CoV-2 viral infection; (5) absolute neutrophil count <500 cells/µL; or (6) platelet count <50,000 cells/µL.
  • Clinical trial results:
    • Roche announced in a press release of that its phase III tocilizumab failed to meet its primary endpoint (7- category ordinal scale based on need for supplemental oxygen requirements, and intensive care and/or ventilator use) in hospitalized adult patients with severe COVID-19 associated pneumonia. 
    • Phase III double-blind randomized trial (N Engl J Med. 2020; 383:2333) of tocilizumab compared to placebo for hospitalized, moderately ill patients with confirmed COVID-19 found no difference in intubation or death, worsening of disease; or time to discontinuation of supplemental oxygen.
    • Randomized controlled trial (N Engl J Med. 2021; 384:20) of tocilizumab versus placebo for hospitalized patients with COVID-19 pneumonia found that tocilizulmab reduced likelihood of progression to the composite outcome of mechanical ventilation or death, but did not improve survival.
      • Randomized ongoing international, multifactorial, adaptive platform trial (NEJM 2021, Feb 25; NEJMoa2100433. doi: 10.1056/NEJMoa2100433) of ICU patients receiving high-flow nasal cannula oxygen support, non-invasive or mechanical ventilation, or pressor support reported improved outcomes, including mortality with Tocilizumab (353 patients).
      • RECOVERY open-label trial (pre-print in medRxIV, not peer reviewed) of 2022 patients randomized to tocilizumab compared with 2094 patients randomized to usual care (82% of patients overall were taking a systemic corticosteroids) reported a mortality benefit at 28 days with tocilizumab , 596 deaths (29%) vs. 694 deaths (33%) (p=0·007). Tocilizumab also increased the probability of discharge alive within 28 days from 47% to 54% (p<0·0001). Trends toward benefit, not reaching statistical significance in most cases, were seen in several patient subgroups , including those requiring only supplemental oxygen and non-invasive ventilation, but not mechanical ventilation.  Tocilizumab in combination with corticosteroids  reduced mortality compared to those receiving corticosteroids and usual care 457/1664 (27%) vs. 565/1721 (33%), RR= 0.80 (95% CI 0.70−0.90)], but not in those not receiving corticosteroids).
  • On June 24 2021, the US FDA issued an EUA for tocilizumab for the treatment of hospitalized adults and pediatric patients (2 years of age and older) with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO. FDA news release here. Healthcare provider fact sheet here.
  • Tocilizumab is not authorized for use in outpatients with COVID-19.
  • Black box warning (from FDA-approved prescribing information): Serious infections due to bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens.
  • COVID-19, hospitalized adults and pediatric patients (≥2 years of age):
    • Weight <30 kg: 12 mg/kg as a single IV infusion over 60 minutes.
    • Weight ≥30 kg: 8 mg/kg as a single IV infusion over 60 minutes.
    • Maximum dosage: 800 mg per infusion.
    • If clinical signs or symptoms worsen or do not improve after the initial dose, consider administering an additional dose at least 8 hours after the initial dose.
  • Preparation:
    • Weight <30 kg: use 50 mL bag of 0.9% or 0.45% sodium chloride for injection.
    • Weight ≥30 kg: use 100 mL bag of 0.9% or 0.45% sodium chloride for injection.
    • Drug is supplied in 20 mg/mL vials (multiple sizes) for further dilution.
    • Withdraw a volume from the bag equal to the volume of tocilizumab required for the patient's dose (0.4 mL/kg for an 8 mg/kg dose, 0.6 mL/kg for a 12 mg/kg dose), then slowly add the tocilizumab. Mix by inverting the bag to avoid foaming.
  • Stability of diluted infusion solution:
    • Using 0.9% sodium chloride: 24 hours at room temperature or 2-8°C. Protect from light.
    • Using 0.45% sodium chloride: 4 hours at room temperature, or 24 hours at 2-8°C. Protect from light.
  • Age ≥2 years: see Adult Dose.
  • No dosage adjustment in patients with mild or moderate renal impairment.
  • No data in patients with severe impairment.
  • Not recommended in patients with active hepatic disease or hepatic impairment.
  • Serious infections due to bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens.
  • Gastrointestinal perforations.
  • Hepatotoxicity.
  • Neutropenia, thrombocytopenia.
  • Lipid abnormalities.
  • Hypersensitivity reactions, including anaphylaxis.
  • Demyelinating disorders.
  • Malignancy.
Class  IgG monoclonal antibody
PK/PD Index  No data
Pharmaceutical
Preparation
 Injectable
Usual Adult Dose  See Adult Dosing above
Pregnancy Risk Summary Animal data suggested potential risk to fetus. Human data insufficient.
Food Effect1  Not applicable
Oral
Absorption2 (%)
 Not applicable
Peak Serum Level3
(μg/mL)
151
(8 mg/kg SD)
Protein Binding
(%)
 No data
Average Serum
Half-life4
 About 21.5 days (terminal)
Biliary Penetration5 (%)  No data
CSF/Blood
Penetration6 (%)
 No data
Therapeutic Levels in CSF7  No data
Volume of Distribution8
(Vd)
8.75 L
AUC9
(μg*hr/mL)
 No data
CYP450, Transporter
Interactions
 See Major Drug Interactions
  • Notes:
    • 1 Adult preparations unless otherwise noted.
    • 2 Absorption under optimal conditions.
    • 3 Total drug; adjust for protein binding to determine free drug concentration.
      • SD = after single dose
      • SS = steady state after multiple doses
    • 4 Assumes CrCl > 80 mL/min
    • 5 Peak concentration in bile/peak concentration in serum x 100
    • 6 CSF levels with inflammation
    • 7 Judgment based on drug dose & organism susceptibility. CSF concentration ideally ≥10x above MIC.
    • 8 Volume of Distribution (Vd):
      • V/F = Vd/oral bioavailability
      • Vss = Vd at steady state
      • Vss/F = Vd at steady state/oral bioavailability
    • 9 Area under the plasma concentration versus time curve
  • Hepatic CYP450 enzymes are down-regulated by infection and inflammatory stimuli, including cytokines such as IL-6. Therefore, treatment with tocilizumab may restore CYP450 activity, leading to increased metabolism (and decreased activity) of CYP450 substrates. For example, a 28% and 57% decrease in omeprazole and simvastatin exposure, respectively, has been observed one week after a single dose of tocilizumab.
  • Exercise caution when using tocilizumab in patients receiving CYP450 substrates with a narrow therapeutic index.
  • The effect of tocilizumab on CYP450 activity may persist for several weeks after stopping therapy.
  • Supplied as 80 mg/4 mL, 200 mg/10 mL, and 400 mg/20 mL single-dose vials for further dilution before IV administration.
  • Storage: 2-8ºC.