By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved tocilizumab injection to treat COVID-19 among hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen. The agency issued an emergency use authorization for the solution in March 2020.1 Tocilizumab is a recombinant, humanized, IgG1k monoclonal antibody that binds soluble and membrane-bound interleukin-6 receptors.2 Since its approval in 2010, tocilizumab injection has been indicated for numerous conditions, including rheumatoid arthritis, giant cell arteritis, systemic juvenile idiopathy arthritis, cytokine release syndrome, and systemic sclerosis-associated intestinal lung disease. It is marketed as Actemra.
INDICATIONS
Tocilizumab can be prescribed to hospitalized adult patients with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation.2
DOSAGE
Administer 8 mg/kg as a single 60-minute intravenous infusion.2 If symptoms do not improve or the patient’s condition deteriorates, administer a second dose (at least eight hours after the first dose). The solution is available as 20 mg/mL (4 mL, 10 mL, and 20 mL single-dose vials).
POTENTIAL ADVANTAGES
Tocilizumab led to improved survival rates and shorter median time to hospital discharge in one study, and reduced the likelihood of progression to the composite outcome of mechanical ventilation or death in another.2-4
POTENTIAL DISADVANTAGES
Tocilizumab does not appear to benefit patients not receiving systemic corticosteroids.2,3 Neutrophil counts lower than 1,000 cells/mcL occurred in 3.4% of tocilizumab-treated patients compared to 0.5% of placebo-treated patients.2 Rates of platelet counts lower than 50,000 cells/mcL were 3.2% vs. 1.5%, respectively.2 Alanine transaminase or aspartate aminotransferase five times or higher of the upper limit of normal were 11.7% vs. 9.9%, respectively. As infection and inflammation down-regulates CYP450 enzyme activity, tocilizumab may restore CYP450 activities to higher levels and affect drugs that are substrates for these isoenzymes.2
COMMENTS
Hyperactivation of the humoral immune pathway (including IL-6) is associated with severe and fatal COVID-19 infections. Higher mean IL-6 levels have been associated with increased likelihood of mortality.5 The efficacy of tocilizumab was based on a randomized, controlled, open-label study and a randomized, double-blind, placebo-controlled study.2-4 The Randomised Evaluation of COVID-19 Therapy study was conducted among subjects with clinically suspected or laboratory-confirmed SARS-CoV-2 infection and clinical evidence indicative of progressive COVID-19 (oxygen saturation < 92% on room air) or on oxygen therapy (41% non-invasive respiratory support, 14% invasive mechanical ventilation), and C-reactive protein (CRP) levels ≥ 75 mg/L.2,3 Subjects were randomized to tocilizumab plus standard of care (SOC; n = 2,022) or SOC only (n = 2,094). A second dose of tocilizumab could be given 12-24 hours later at the discretion of the attending clinician. At baseline, 82% received systemic corticosteroids. The median CRP level was 143 mg/L (interquartile range, 107-204). The primary efficacy endpoint was time to death through day 28. A secondary outcome was duration of hospital stay. Mortality rates overall were 30.7% for tocilizumab + SOC vs. 34.9% for SOC only (HR, 0.85; 95% CI, 0.76-0.94) and 29% vs. 34.9%, respectively, for those receiving systemic corticosteroids. Rates were 39% vs. 34.6% for those not receiving systemic corticosteroids at randomization. Patients randomized to tocilizumab were more likely to be discharged within 28 days (57% vs. 50%; P < 0.0001).
In the second study involving ethnic minorities (Evaluating Minority Patients with Actemra), tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death by day 28 in hospitalized patients with COVID-19 pneumonia.2,4 The patient population was 56% Hispanic or Latino, 12.7% American Indian or Alaska Native, and 14.9% Black. In patients randomly assigned to tocilizumab (n = 249), 12% progressed vs. 19.3% for the placebo group (n = 128). There was no statistical difference in survival (10.4% vs. 8.6%).
CLINICAL IMPLICATIONS
The Infectious Diseases Society of America recommends tocilizumab for hospitalized adults with progressive severe or critical COVID-19 who record elevated markers of systemic inflammation (CRP ≥ 75 mg/L), in addition to standard of care (i.e., steroids) rather than standard of care alone. Note that these recommendations are conditional, with low certainty of evidence.6
NIH recommends tocilizumab in combination with dexamethasone for hospitalized patients with significantly worsening symptoms. Alternatively, or if tocilizumab is not available, they recommend a similar IL-6 blocker, sarilumab.7 The cost for a single dose of tocilizumab for a 70 kg patient is $3,541.
REFERENCES
1. Hoffmann-La Roche, Ltd. c/o Genentech, Inc. Letter to the U.S. Food & Drug Administration re: Emergency use authorization 099. Dec. 21, 2022.
2. Genentech, Inc. Tocilizumab prescribing information. December 2022.
3. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet 2021;397:1637-1645.
4. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021;384:20-30.
5. Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J Med Virol 2020;92:2283-2285.
6. Infectious Diseases Society of America. IDSA guidelines on the treatment and management of patients with COVID-19. Updated Nov. 21, 2022.
7. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines.
The FDA has approved tocilizumab injection to treat COVID-19 among hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen.
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