COVID treatment

Note: For additional recommendations, please refer to the Ontario Science Table’s COVID-19 Clinical Practice Guideline

MILD DISEASE SEVERITY: Symptomatic hospitalized patients but do not require supplemental oxygen

Note: Asymptomatic individuals incidentally discovered to have positive COVID-19 diagnostic tests are not candidates for therapy in the mild illness category

Nirmatrelvir/ritonavir Dosing: eGFR 60 mL/min or greater: 300/100 mg twice daily; eGFR 30 to 59 mL/min: 150/100mg twice daily; eGFR less than 30 mL/min: not recommended by manufacturer; however, the following modified dosing schedule proposed by the Ontario Renal Network can be considered: 300/100 mg on day 1 then 150/100 mg once daily for 4 more days (to be dosed after dialysis if patient receiving dialysis). This medication is associated with significant drug interactions. For more information, please refer to: Nirmatrelvir/Ritonavir (Paxlovid): What Prescribers and Pharmacists Need to Know.

MODERATE SEVERITY & SEVERE / CRITICALLY ILL

Baricitinib dosing: eGFR 60 mL/min or greater: 4 mg PO/NG daily; eGFR 30 to 59 mL/min: 2 mg PO/NG daily; eGFR 15 to 29 mL/min: 2 mg PO/NG q48h; eGFR less than 15 mL/min: not recommended; renal replacement therapy: not recommended

Criteria for use: Infectious diseases approval is required. Sarilumab will only be considered when tocilizumab is unavailable.

• Mildly ill (i.e. non-hospitalized patients, hospitalized patients who do not require supplemental oxygen): Tocilizumab is not recommended outside of clinical trials for patients who are mildly ill with suspected or confirmed COVID-19.
• Moderately ill (i.e. hospitalized patients requiring low-flow supplemental oxygen): Tocilizumab is recommended for patients who are moderately ill with suspected or confirmed COVID-19, who:
• have evidence of systemic inflammation, defined as a CRP 75 mg/L or higher; AND
• have evidence of disease progression (i.e., increasing oxygen or ventilatory requirements) despite 24-48 hours of optimal dexamethasone therapy;
• AND are within 14 days of hospital admission (or within 14 days of a new COVID-19 diagnosis if nosocomially acquired).
• Critically ill (i.e. hospitalized patients requiring oxygen by high flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation): Tocilizumab is recommended for patients who are critically ill with suspected or confirmed COVID-19 who:
• are on optimal dexamethasone therapy; AND
• are within 14 days of hospital admission (or within 14 days of a new COVID-19 diagnosis if nosocomially acquired).

Exclusion criteria:

• Known hypersensitivity to tocilizumab and/or sarilumab
• ANC < 2 x10⁹/L
• PLT < 50 x10⁹/L
• AST/ALT > 5X ULN

Dose:

• Tocilizumab:

• Sarilumab: 400 mg IV x 1 dose

Adverse effects and monitoring:

*Note: IL-6 inhibitors are associated with reactivation of tuberculosis, hepatitis B and Strongyloides. Consider screening for latent infection if applicable.

Criteria for use: Infectious diseases approval is required. Baricitinib will only be considered when tocilizumab or sarilumab are unavailable.

• Mildly ill (i.e. non-hospitalized patients, hospitalized patients who do not require supplemental oxygen): Baricitinib is not recommended outside of clinical trials for patients who are mildly ill with suspected or confirmed COVID-19.
• Moderately ill (i.e. hospitalized patients requiring low-flow supplemental oxygen): Baricitinib is recommended for patients who are moderately ill with suspected or confirmed COVID-19, who:
• have evidence of systemic inflammation, defined as a CRP 75 mg/L or higher; AND
• have evidence of disease progression (i.e., increasing oxygen or ventilatory requirements) despite 24-48 hours of optimal dexamethasone therapy;
• AND are within 14 days of hospital admission (or within 14 days of a new COVID-19 diagnosis if nosocomially acquired).
• Critically ill (i.e. hospitalized patients requiring oxygen by high flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation): Baricitinib is recommended for patients who are critically ill with suspected or confirmed COVID-19 who:
• are on optimal dexamethasone therapy; AND
• are within 14 days of hospital admission (or within 14 days of a new COVID-19 diagnosis if nosocomially acquired).

Patients meeting the following criteria will be excluded from receiving baricitinib:

• Receipt of an IL-6 inhibitor (Note: tocilizumab or sarilumab are preferred over baricitinib if supply is available)
• Known hypersensitivity to baricitinib
• ANC less than 0.5 x10⁹/L
• Absolute lymphocyte count less than 0.2 x10⁹/L
• AST/ALT greater than 5X ULN
• eGFR less than 15 mL/min
• Pregnancy

*Note: Baricitinib is associated with reactivation of tuberculosis, hepatitis B and Strongyloides. Consider screening patients at risk for latent infection.

Dose:

• eGFR 60 mL/min or greater: 4 mg PO/NG daily
• eGFR 30 to 59 mL/min: 2 mg PO/NG daily
• eGFR 15 to 29 mL/min: 2 mg PO/NG q48h
• eGFR less than 15 mL/min: not recommended
• Renal replacement therapy: not recommended

Duration of therapy:

• 14 days or until hospital discharge, whichever is shorter

Adverse effects & monitoring:

The product monograph for remdesivir does not recommend use of remdesivir in patients with eGFR <30 ml/min, including those on renal replacement therapy. This is due to lack of data from randomized trials (which excluded patients with eGFR < 30 ml/min) in conjunction with theoretical concerns around nephrotoxic potential of the diluent (of sulfobutylether-β-cyclodextrin; SBECD) as well remdesivir’s active metabolite. These concerns have yet to be supported.

There is mounting experience and observational studies suggesting that full dose remdesivir is safe in patients with chronic kidney disease (CKD), including those on dialysis, particularly for the short durations commonly prescribed (3-5 days). Recognizing that patients with CKD are at high risk of poor outcomes secondary to COVID and the experience with using full doses without apparent toxicity, we are recommending full doses of remdesivir in patients with CKD (with the exception of outpatients receiving dialysis, where dosing post-dialysis may be used for ease of administration for presumed low severity of illness):

It is noted that Gilead (manufacturer of remdesivir) is currently conducting a clinical trial (https://clinicaltrials.gov/ct2/show/NCT04745351) assessing full dose of remdesivir in patients with CKD. Once the results are available, dosing in this population will be re-evaluated.

References:

• Schieber TJ, Bennett N, Aragon L, Ploetz J, Boyd S. Real-world risk evaluation of remdesivir in patients with an estimated glomerular filtration rate of less than 30 mL/min. Am J Health Syst Pharm. 2021;78(23):2101-2102. doi:10.1093/ajhp/zxab245
• Thakare S, Gandhi C, Modi T, et al. Safety of Remdesivir in Patients With Acute Kidney Injury or CKD. Kidney Int Rep. 2021;6(1):206-210. doi:10.1016/j.ekir.2020.10.005
• Aiswarya D, Arumugam V, Dineshkumar T, et al. Use of Remdesivir in Patients With COVID-19 on Hemodialysis: A Study of Safety and Tolerance. Kidney Int Rep. 2021;6(3):586-593. doi:10.1016/j.ekir.2020.12.003
• Cheng M, Fowler R, Murthy S, Pinto R, Sheehan NL, Tseng A. Remdesivir in Patients With Severe Kidney Dysfunction: A Secondary Analysis of the CATCO Randomized Trial. JAMA Netw Open.2022;5(8):e2229236. doi:10.1001/jamanetworkopen.2022.29236