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COVID-19 is an emerging, rapidly evolving situation. Get the latest from the CDCNIH, and the Liverpool drug interaction group


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Tocilizumab for Covid-19

IL-6 receptor antibody; Disease modifying anti-rheumatic drug


(Updated April 21, 2020)



TOP FIVE THINGS TO KNOW ABOUT TOCILIZUMAB AND OLDER ADULTS


  1. Tocilizumab remains off label use for severe or critical COVID-19 cases.
  2. In trials of patients with rheumatoid arthritis, adults aged 65 years and over had a greater frequency of serious infections than patients under the age of 65.
  3. Serious drug-induced liver injury, in some cases resulting in acute liver failure requiring a transplant, has been reported in patients treated with tocilizumab. The drug is generally not recommended in patients with active liver disease and transaminase levels greater than 3-times the upper limit of normal. However, because most patients with cytokine release syndrome will have elevated transaminases, decision to treat should consider potential benefit versus risk.
  4. CYP450 drug metabolism may be broadly induced by tocilizumab. Because the drug has a long half-life (~ 13 days), some patients may require dose adjustments to stay within therapeutic range.
  5. Increased risk of serious infection including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving tocilizumab for approved indications.  


Mechanism of Action:  Tocilizumab is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody. Several clinical trials of the drug are being conducted for managing patients with Covid-19. In preliminary data from a non-peer reviewed, open-label trial of 21 patients with severe or critical COVID-19 infection, patients demonstrated rapid fever reduction and a reduced need for supplemental oxygen within several days of receiving tocilizumab, administered as a single 400 mg dose by intravenous infusion. The dose was repeated within 12 hours in 3 patients because of ongoing fever. Presently, the drug is reserved for patients with severe disease and evidence of cytokine release syndrome, which may manifest clinically as rapidly worsening respiratory gas exchange, rapidly worsening gas exchange requiring > 6 L of oxygen, serum IL-6 > three times the upper limit of normal, ferritin >300 ug/L with doubling within 24 hours or ferritin >600 ug/L at presentation and LDH >250 U/L. The goal of therapy is to improve oxygenation and time to symptom resolution in patients at high risk of cytokine storm.


Dosage: COVID (off label; current clinical trial data): 8 mg/kg as one dose; can be repeated 8 to 12 hours later if continued clinical deterioration or inadequate response to first dose. The total dose should not exceed 800 mg, and the drug should not be administered more than twice. There are no studies to help guide dosing in patients with renal or hepatic insufficiency. However, Health Canada advised withholding in patients with transaminase levels > 3 times the upper limit of normal to minimize the risk of drug-induced liver injury.


Drug Interactions: Pharmacokinetic: Inhibition of IL-6 may induce the expression of cytochrome P-450 enzymes, increasing the metabolism of CYP substrates. When starting or stopping therapy with tocilizumab, patients taking medications that are metabolised by CYP3A4, 1A2, 2C9 or 2C19 may have to have doses increased to maintain therapeutic effect). Given half-life of 13 days, the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy. In patients with rheumatoid arthritis, tocilizumab decreased simvastatin exposure 57%.


Adverse effects:  Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions. Note these are taken from clinical trials conducted in patients with rheumatoid arthritis and other inflammatory conditions for which the drug is approved. Serious infections and malignancies can occur with this drug. Serious drug-induced liver injury, in some cases resulting in acute liver failure requiring a transplant, has been reported in patients treated with tocilizumab. Serious infections. Gastrointestinal perforations rare (caution diverticulitis and other symptomatic lower GI conditions).


Monitoring: Ferritin, platelets, IL-6 (if available), liver function tests, fibrinogen, procalcitonin (if available, to help rule out bacterial superinfection, C-reactive protein).


Pharmacokinetics:

Absorption: Not applicable.

Distribution: Vd: 6.4 L
Metabolism: Information not available.

Elimination: The total clearance of tocilizumab is concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. At low concentrations, concentration-dependent nonlinear clearance is dominant. At high concentrations, linear clearance dominates.

Half-life: With intravenous administration, half-life is concentration-dependent, ranging from 11 days for 4 mg/kg and up to 13 days for 8 mg/kg every 4 weeks.


References:
  1. Xu X, Han M, Li T et al. Effective treatment of severe COVID-19 patients with Tocilizumab. Available at: file:///C:/Users/owner/Downloads/202003.00026v1.pdf. Accessed March 26, 2019.
  2. Actemra product information. Hoffman La Roche Limited. 2019
  3. Health Canada. Important Safety Information on ACTEMRA® (tocilizumab) - Risk of Hepatotoxicity. Available: https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/69991a-eng.php. Accessed March 26, 2019.

COVID-19 is an emerging, rapidly evolving situation. Get the latest from CDC: https://www.coronavirus.gov and NIH: https://www.nih.gov/coronavirus  and the Liverpool drug interaction group: http://www.covid19-druginteractions.org

This document is for informational purposes only and is not intended as, and should not be interpreted as, medical advice or other professional advice. Clinical judgement is still required. GeriMedRisk does not endorse the use of any of these therapies for COVID, but offers this information in the hopes of decreasing the risk of harmful drug-drug interactions or adverse drug events. We will do our best to update this information.


Last updated: April 21, 2020 - 2:36 PM                                                                                                                                                                      
                                                                                                                                                                                                       
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