INDICATIONS

FORMS

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

The dosing provided here can be considered for the management of severe or life-threatening CRS associated with COVID-19

• ≥ 30kg: 8 mg/kg IV x1 dose (Maximum single dose is 800mg.)
  • The dose can be repeated 8 - 12 hours after the preceding dose two additional times for a total of 3 doses.
• < 30kg: 12 mg/kg IV x1 dose (Maximum single dose is 800mg.)

ADULT RENAL DOSING

PEDIATRIC DOSING

ADVERSE DRUG REACTIONS

DRUG INTERACTIONS

• Tocilizumab is known to restore CYP450 enzyme activity to higher levels through IL-6 inhibition. Use caution when administering tocilizumab with CYP3A4 substrates where a decrease in effectiveness is not desired. The effect of tocilizumab may persist for days to weeks after cessation of tocilizumab therapy.

PHARMACOLOGY

COMMENTS

• The most favorable results for IL-6 inhibitors come from case series and cohort studies, with mixed results from RCTs. Risks and benefits of tocilizumab therapy should be weighed prior to administering tocilizumab.
• Some patients infected with SARS-CoV-2 can develop an uncontrolled immune response, which can lead to significant complications including cytokine release syndrome and severe lung damage. This same syndrome develops in cancer patients after receiving CAR-T therapy. Tocilizumab has been reported as helpful in these patients to downregulate the inflammatory response.
• A small, non-peer-reviewed case series of 21 patients at The First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital) who were given tocilizumab in addition to routine therapy demonstrated that fever returned to normal and remarkable improvement in other symptoms in just a few days. Of note, ALL patients had IL-6 levels done prior to tocilizumab therapy, and all patients had an elevated level (132.4 ± 278.5 pg/mL).
• The Roche EMPACTA study of tocilizumab reported a reduction in mechanical ventilation in patients with COVID-19 pneumonia in a double-blind RCT of 389 patients. The hazard ratio of the primary outcome of progression to mechanical ventilation or death was 0.56 (p=0.04) among participants randomized to the tocilizumab arm compared to the placebo arm. However, the time to improvement was not significantly different between arms, and mortality was similar (10.4% in the tocilizumab arm and 8.6% in the placebo arm).
• The REMAP-CAP study, an international adaptive clinical trial platform for testing multiple COVID-19 therapeutics, included tocilizumab or sarilumab compared to standard care (i.e., no placebo arm). Data have been released as a pre-print pending peer review. Participants were adults admitted to an intensive care unit with COVID-19 who were receiving respiratory or cardiovascular support in the form of high-flow oxygen, noninvasive or invasive mechanical ventilation or pressor drug therapies (19%); 77% of participants received a corticosteroid. In a preliminary analysis, the median organ support-free days within 21 days of randomization were 10 for tocilizumab and 0 for standard care. Hospital mortality was 28% for tocilizumab and 36% for standard care.
• The RECOVERY trial, a multi-site factorial design RCT in the United Kingdom, included tocilizumab. Participants were first randomized to one of the following: usual care, dexamethasone, lopinavir-ritonavir, hydroxychloroquine, azithromycin, or colchicine. Participants were subsequently considered for randomization to tocilizumab or no-tocilizumab if they had clinical progression as indicated by SpO₂ < 92% on room air, requiring oxygen therapy, or CRP ≥75 mg/L. A total of 4,116 participants were randomized 1:1 to tocilizumab or no-tocilizumab. Of these, 55% were receiving high-flow oxygen or invasive or noninvasive mechanical ventilation, and 45% were receiving supplemental oxygen via nasal cannula. The primary endpoint, 28-day mortality, occurred among 29% of the tocilizumab group and 33% of the no-tocilizumab group (p=0.007). In subgroup analysis, tocilizumab was found to be most effective when used concomitantly with corticosteroids and when given within 7 days of symptom onset.

References

1. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021.  [PMID:33631065]

   Comment: The REMAP-CAP study, an international adaptive clinical trial platform for testing multiple COVID-19 therapeutics, included tocilizumab or sarilumab compared to standard care (i.e., no placebo arm).91 Data have been released as a pre-print pending peer review. Participants were adults admitted to an intensive care unit with COVID-19 who were receiving respiratory or cardiovascular support in the form of high-flow oxygen, non-invasive or invasive mechanical ventilation, or pressor drug therapies (19%); 77% of participants received a corticosteroid. In a preliminary analysis, the median organ support-free days within 21 days of randomization were 10 for tocilizumab and 0 for standard care. Hospital mortality was 28% for tocilizumab and 36% for standard care. Based on Bayesian analysis, a hazard ratio for the comparison with the control group was 1.61 (95% CI 1.25 - 2.08) and a posterior probability of superiority of more than 99.9%.
   

2. Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384(1):20-30.  [PMID:33332779]

   Comment: The Roche EMPACTA study of tocilizumab reported a reduction in mechanical ventilation in patients with COVID-19 pneumonia in a double-blind RCT of 389 patients.88 The hazard ratio of the primary outcome of progression to mechanical ventilation or death was 0.56 (p=0.04) among participants randomized to the tocilizumab arm compared to the placebo arm. However, the time to improvement was not significantly different between arms, and mortality was similar (10.4% in the tocilizumab arm and 8.6% in the placebo arm).
   

3. Le RQ, Li L, Yuan W, et al. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. Oncologist. 2018;23(8):943-947.  [PMID:29622697]

   Comment: Summary of two, independent cohorts discussing the role of tocilizumab for the management of CRS secondary to CAR-T therapy. Assesses drug dosing recommended in this module.
   

4. Horby PW, Pessoa-Amorim G, Peto L, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021:2021.2002.2011.21249258. https://www.medrxiv.org/content/medrxiv/early/2021/02/11/2021.02.11.212492...

   Comment: The RECOVERY trial, a multi-site factorial design RCT in the United Kingdom, included tocilizumab.92 Participants were first randomized to one of the following: usual care, dexamethasone, lopinavir-ritonavir, hydroxychloroquine, azithromycin, or colchicine. Participants were subsequently considered for randomization to tocilizumab or no-tocilizumab if they had clinical progression as indicated by SpO2 < 92% on room air, requiring oxygen therapy, or CRP ≥75 mg/L. A total of 4,116 participants were randomized 1:1 to tocilizumab or no- tocilizumab. Of these, 55% were receiving high-flow oxygen or invasive or non-invasive mechanical ventilation, and 45% were receiving supplemental oxygen via nasal cannula. The primary endpoint, 28-day mortality, occurred among 29% of the tocilizumab group and 33% of the no-tocilizumab group (p=0.007). In subgroup analysis, tocilizumab was found to be most effective when used concomitantly with corticosteroids and when given within 7 days of symptom onset.
   

5. Xu, Xiaoling et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. http://chinaXiv:202003.00026v1. Accessed 13 March 2020.

   Comment:
   
   Case series of 21 patients administered tocilizumab for the management of severe or critical cytokine release syndrome secondary to SARS-CoV-2 infection. All enrolled patients had symptoms per clinical criteria set forth by the Diagnosis Treatment Protocol for Novel Coronavirus Pneumonia (6th ed) of the National Health Commission of the People’s Republic of China. Severe disease was defined as any of the following conditions being met (1) RR >/= 30 breaths/min,(2) SpO2 < /= 93% on room air,or (3) PaO2/FiO2 < /= 300 mmHg. A critical case was defined as (1) requiring mechanical ventilation, (2) shock or (3) ICU admission plus organ failure. Standard of care included lopinavir, methylprednisolone, other symptom relievers, and oxygen therapy. IL-6 levels were obtained prior to the administration of tocilizumab. The standard starting dose was 400 mg with a second dose given 12 hours later if the patient was still febrile. The average age of the patients was 56.8 +/- 16.5 years, and 18/21 patients were male. 17 patients were considered severe, and 4 were critical. 20 patients needed some form of oxygen therapy, with 2 patients requiring mechanical ventilation. All patients had abnormal imaging on CT, most with ground-glass opacities with focal consolidation. Fever was the first symptom to drop dramatically after administration of tocilizumab, with other clinical symptoms improving thereafter. Oxygen requirements decreased. WBCs returned to normal by Day 5. Mean hospitalization was an additional 13 days after tocilizumab therapy. All 21 patients survived. These findings need to be validated in a large-scale, randomized trial as significant bias might exist.