Tocilizumab

Kathryn Dzintars, Pharm.D., BCPS

INDICATIONS

FDA

  • Rheumatoid arthritis
  • Polyarticular juvenile idiopathic arthritis
  • Systemic juvenile idiopathic arthritis

NON-FDA APPROVED USES

  • Chimeric antigen receptor therapy (CAR-T) T cell-induced severe cytokine release syndrome (CRS)
  • Severe or life-threatening cytokine release syndrome associated with SARS-CoV-2

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

Actemra

Tocilizumab

Genentech

IV

Vial

80mg/4mL

$553.39

200mg/10mL

$1,383.48

400mg/20mL

$2,766.96

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

USUAL ADULT DOSING

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.)
    • Dose can be repeated 8 - 12 hours after 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

DOSING IN HEMODIALYSIS

  • No data are available.

DOSING IN PERITONEAL DIALYSIS

  • No data are available.

DOSING IN RENAL REPLACEMENT THERAPY

  • No data are available.

Other Adult Renal Dosing Information

  • No dose adjustment is required for patients with mild renal impairment; tocilizumab has not been studied in patients with a CrCl < 30 mL/min.

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

  • Data on the use of tocilizumab in pediatric patients for the management of CRS associated with SARS-CoV-2 infection is not available.

ADVERSE DRUG REACTIONS

GENERAL

  • Tocilizumab is contraindicated in patients with a known hypersensitivity to the agent.
  • Serious and sometimes fatal infections due to various bacterial, viral, fungal and opportunistic pathogens have occurred in patients receiving immunosuppressive agents.

OCCASIONAL

  • Neutropenia, thrombocytopenia
  • Elevated liver enzymes
  • Lipid abnormalities

RARE

  • Gastrointestinal perforation

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

MECHANISM

  • Tocilizumab binds to both soluble and membrane-bound IL-6 receptor and inhibits IL-6 mediated signaling. IL-6 is a pro-inflammatory cytokine that is elevated in cytokine release syndrome.

PHARMACOKINETIC PARAMETERS

Absorption

  • N/A

Metabolism and Excretion

  • N/A

Protein Binding

  • N/A

Cmax, Cmin, and AUC

  • N/A

T1/2

  • 13 days

Distribution

  • N/A

DOSING FOR DECREASED HEPATIC FUNCTION

  • Tocilizumab is not recommended for patients with active hepatic disease or hepatic impairment.

PREGNANCY RISK

  • Pregnancy Category C; adequate, well-controlled studies have not been conducted in pregnant women.
  • In general, as with monoclonal antibodies, more transfer across the placenta occurs as the pregnancy progresses.

BREAST FEEDING COMPATIBILITY

  • It is not known if tocilizumab is present in breast milk; however, IgG is excreted in human milk and it is expected that tocilizumab may be present.

COMMENTS

  • Some patients infected with SARS-CoV-2, or the novel coronavirus, can develop an uncontrolled immune response, which can lead to significant complications including the 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. Definitive evidence is lacking (as of 3/23/20).
  • 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 Italian Society of Infectious and Tropical Diseases (SIMIT) has incorporated tocilizumab into its treatment recommendations (Handbook for the care of people with the disease from COVID-19 Version 2.0; March 13, 2020).

References

  1. 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.

  2. 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.

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Last updated: March 23, 2020