Treatments of Interest for COVID-19
(Updated January 3, 2022)
The chart below provides information or resources on pharmacotherapy of interest for COVID-19, the disease caused by the SARS-CoV-2 virus. Additional resources on pharmacotherapy, supportive therapy, and vaccines, many of which are frequently updated, include:
- The American Society of Health-System Pharmacists evidence table of COVID-19 treatments (https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table).
- The British Columbia Ministry of Health guidance on current research on COVID-19 treatments (http://www.bccdc.ca/health-professionals/clinical-resources/covid-19-care/clinical-care/treatments).
- The NIH general treatment guidelines (https://covid19treatmentguidelines.nih.gov/).
- IDSA treatment and management guidelines (https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/).
- WHO guidance on drugs for COVID-19 (https://www.bmj.com/content/370/bmj.m3379).
- The Surviving Sepsis Campaign COVID-19 guidelines (https://sccm.org/SurvivingSepsisCampaign/Guidelines/COVID-19).
For guidance from the USP on sterile compounding during the pandemic, including preparation of COVID-19 treatments such as monoclonal antibodies, see https://www.usp.org/compounding.
Our chart, COVID Pharmacotherapy FAQs: Addressing Patient Questions, provides information to help answer and correct misconceptions about pharmacotherapy as it relates to COVID-19.
**Search www.clinicaltrials.gov for the latest information on COVID-19 clinical trials.**
TREATMENTS OF INTEREST
Pertinent Information or Resources
Note that DOSES provided are examples only for ADULTS; the optimal dose has not been determined for any treatment.
Anakinra is an IL-1 antagonist. IL-1 may have a role in ARDS.65
Early evidence suggested that anakinra 5 mg/kg twice daily intravenously in moderate to severe ARDS (non-ventilator) and inflammation (elevated C-reactive protein and/or ferritin) (n=29) was associated with improved survival compared to a similar historical cohort (90% vs 56%, p = 0.009).65 These patients also received hydroxychloroquine and lopinavir/ritonavir.65 A lower dose of anakinra (100 mg twice daily subcutaneously) did not seem to provide benefit.65
Preliminary evidence from case reports suggest benefit in patients with severe COVID-19 and secondary hemophagocytic lymphohistiocytosis.19
In REMAP-CAP, anakinra was not effective in critically ill patients receiving respiratory or cardiovascular support.77
Macrolides have in vitro antiviral (e.g., Zika, Ebola), anti-inflammatory, and immunomodulatory activity.2,7
Insufficient evidence to support widespread use [Evidence level C].2,28
Was used in a small, widely publicized study with hydroxychloroquine in six patients to prevent bacterial superinfection in COVID-19 patients (see hydroxychloroquine, below).2 Subsequent observational data including 74 additional patients suggests that the combination can reduce viral load and perhaps improve the clinical course, but there was no comparator group.28 Also see the hydroxychloroquine section below for information on its use in a U.S. cohort study.75
NIH guidelines recommend against the use of azithromycin in hospitalized patients, or in outpatients for the treatment of COVID-19.50
When used with hydroxychloroquine or chloroquine (and other QT prolonging medications), QT prolongation is of increased concern.2,6
Inhibits SARS-CoV-2 in vitro, but clinical trials have not shown benefit against other viruses.5 Also has immunomodulating effects.26 Early reports suggested that for COVID-19 pneumonia, chloroquine could speed clinical improvement and viral clearance.3
The FDA has revoked its EUA for chloroquine because it is unlikely to be effective, based on data from the EUA and elsewhere.73 In addition to efficacy concerns, the FDA’s revocation of its EUA for chloroquine was based on adverse effects; its known and potential benefits no longer outweigh the known and potential side effects (e.g., serious cardiac events and other serious side effects).33
The FDA recommends against chloroquine use for COVID-19 outside of a clinical trial.33 NIH guidance recommends against use of chloroquine for treatment of COVID-19 in hospitalized or nonhospitalized patients.50
When used with azithromycin (and other QT-prolonging medications), QT prolongation is of increased concern.2,4,6,41
Based on its anti-inflammatory effect, there has been interest in using colchicine to alter the clinical course of COVID-19 in both inpatients and higher-risk outpatients.
The open-label GRECCO-19 study randomized patients to colchicine plus standard care or standard care (n = 105). The clinical primary endpoint, which included measurements of inflammation and clinical deterioration, occurred in 14% of the control group vs 1.8% in the colchicine group (p=0.02).9 This study’s findings are considered “hypothesis-generating” only.9
In a placebo-controlled study in patients hospitalized with moderate to severe COVID-19 (n = 75), at day seven, only 42% of colchicine patients were still in the hospital vs 72% of the placebo group. Also, at day seven, only 9% of colchicine patients still required supplemental oxygen vs 42% of placebo patients.118
The large RECOVERY trial discontinued its colchicine arm in hospitalized COVID-19 patients due to futility in regard to mortality benefit.117
In the large (n=4,159) ColCORONA study, colchicine (0.5 mg twice daily for three days, then once daily for 27 days) given to high-risk outpatients (e.g., diabetes, uncontrolled hypertension) with COVID-19 slightly reduced the composite primary endpoint of death or hospitalization vs placebo (4.6% vs 6%; OR 0.75, 95% CI 0.57 to 0.99, p=0.042), driven mainly by a reduction in hospitalization.114 Patients with severe kidney or liver disease were excluded. More cases of pulmonary embolism occurred in the colchicine group (11 vs 2).114 Limitations include the statistical analysis and study termination before the pre-planned number of patients were recruited.
Keep in mind colchicine’s toxicities and drug interactions. See our chart, Colchicine Dosing and Interactions, for details.
Convalescent Plasma (COVID-19)
Studies of convalescent plasma show mixed results. Small case series in patients hospitalized with severe COVID-19 showed promise.62-64
Analysis of a cohort of patients from the Mayo Clinic-led expanded access program found a small mortality benefit in patients who received high-titer convalescent plasma within three days of diagnosis and who were not receiving mechanical ventilation.69
Compared to usual care, convalescent plasma did not reduce mortality or severe illness in the open-label PLACID trial (n=464). Only 67 patients received high-titer plasma.95 Furthermore, a placebo-controlled trial (n= 333) found no benefit on clinical status or mortality. It is unclear how many patients received high-titer plasma in this study.105
The large open-label RECOVERY trial found no benefit of high-titer convalescent plasma (n = 5,795) on all-cause mortality (primary outcome) or discharge at day 28 vs usual care (n = 5,763). Almost all patients were receiving supplemental oxygen and corticosteroids at randomization. Among those not on mechanical ventilation, convalescent plasma did not affect a composite endpoint of death or progression to mechanical ventilation.14
There is very limited published data on convalescent plasma for pediatric patients.23
Convalescent plasma appears well-tolerated.62-64 Concerns include allergic reactions, fluid overload, transfusion-related lung injury, and viral infections.70 Risks do not appear different from other types of plasma.83,86
The FDA has issued an EUA for use of high-titer convalescent plasma early in the course of the disease (e.g., patients who do not require intubation), and for hospitalized patients with impaired humoral immunity, based on limited evidence that the therapeutic window may be longer in patients with suppressed humoral immunity.70
The NIH recommends against use of high-tier convalescent plasma in patients without impaired immunity, except in a clinical trial in patients who do not require mechanical ventilation.50 (See clinicaltrials.gov and https://covidcp.org/ for more information.) They recommend neither for nor against use in patients with impaired immunity.50
The FDA has a fact sheet for healthcare professionals on convalescent plasma, including criteria for use, adverse effects, dosing, and more (https://www.fda.gov/media/141478/download). A fact sheet for patients and parents/caregivers is available at https://www.fda.gov/media/141479/download.
A fact sheet explaining how the EUA differs from the discontinued expanded access program is available at https://www.uscovidplasma.org/pdf/EAP%20vs%20EUA.pdf.
Convalescent plasma is no longer being collected by Canadian Blood Services or by the American Red Cross.71,142 For potential remaining donation opportunities in the U.S., see https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma.
In one institution in China, methylprednisolone use in patients with COVID-19 ARDS was associated with reduced mortality.16 This and other cohort studies were limited by confounding, and inclusion of patients with various disease severities and concomitant treatments.46
Data from the open-label RECOVERY trial, in which 2,104 patients were randomized to oral or intravenous dexamethasone 6 mg/day for 10 days, suggests a mortality benefit for COVID-19 patients requiring supplemental oxygen, especially for those requiring ventilation, over usual care (n = 4,321).31 NNT = 8 to prevent one death in ventilated patients, or 34 in patients requiring oxygen but not ventilation. It did not provide a mortality benefit (and there was a nonstatistically significant trend toward harm) for patients not requiring oxygen. It also did not provide a mortality benefit for early disease (symptoms for a week or less). This suggests that dexamethasone’s mechanism involves an anti-inflammatory effect rather than an antiviral effect, because inflammation is more common in advanced disease, while viral replication is at maximum in early disease.
The open-label REMAP-CAP study (n=403) randomized COVID-19 patients admitted to intensive care for respiratory or cardiovascular support to hydrocortisone 50 to 100 mg every six hours for seven days, hydrocortisone started only if shock was clinically evident, or no hydrocortisone.68 Analysis suggests hydrocortisone was probably superior to no hydrocortisone in regard to organ support-free days at 21 days, but the study was stopped early.
The open-label CoDEX study (n=299) randomized COVID-19 patients with moderate to severe ARDS to dexamethasone 20 mg once daily for five days, then 10 mg once daily for five days.56 Ventilator-free survival days through day 28 were greater with dexamethasone (6.6 vs 4, p=0.04). However, 35% of the usual care patients received at least one dose of corticosteroids. Mortality was not affected, but this may be because the study was stopped early after the results of RECOVERY were released.
In a placebo-controlled study of corticosteroids for COVID-19 (CAPE COVID) (n=149), a hydrocortisone infusion was not superior to placebo in regard to death or need for respiratory support (mechanical ventilation or high-flow oxygen) at day 21.52 However, the study was likely underpowered to show a difference, and was stopped early pending RECOVERY publication.
The Brazilian MetCOVID study (n=416) did not find a mortality benefit for a five-day course of methylprednisolone over placebo.78 However, in a subgroup analysis, 28-day mortality was lower in the methylprednisolone group in patients <60 years of age (46.6% vs 61.9%). Most patients received mechanical ventilation or non-invasive oxygen, but patients not on oxygen with low oxygen saturation were not included. Mortality was relatively high in this study compared to the RECOVERY study. Patients with septic shock were allowed to receive hydrocortisone, which could have affected results.
In a WHO meta-analysis that included data from RECOVERY, CAPE COVID, CoDEX, REMAP-CAP, and three other studies (n=1,703), mortality at 28 days was lower in critically ill patients who received corticosteroids vs those who did not receive them (32% vs 40%)(OR 0.66, 95% CI 0.53 to 0.82, p<0.001).45 Including data from ventilator patients from MetCOVID did not affect results. Neither choice of corticosteroid (dexamethasone or hydrocortisone) nor days from symptom onset (>7 days vs ≤7 days) seems to affect efficacy. Benefit might be greater in patients not receiving mechanical ventilation. Based on these results, WHO strongly recommends systemic corticosteroids (dexamethasone 6 mg once daily or equivalent, via oral or intravenous route) for seven to ten days for severe/critical COVID-19, with glucose monitoring.51
The IDSA suggests dexamethasone 6 mg/day x 10 days (or until discharge, if earlier), for patients hospitalized with severe COVID-19 (oxygen saturation ≤94% on room air including those on supplementation oxygen), and recommends it for critical illness (mechanical ventilation or extracorporeal membrane oxygenation). If dexamethasone is not available, methylprednisolone 32 mg or prednisone 40 mg daily can be used.46 NIH guidelines similarly recommend dexamethasone 6 mg/day (or equivalent) for 10 days or until discharge (whichever comes first) in COVID-19 patients who require oxygen, mechanical ventilation, or ECMO.50 Corticosteroids are not recommended for COVID-19 patients not requiring treatment with supplemental oxygen.46,50
Harms of corticosteroids include hyperglycemia, agitation, confusion, and infection risk.46
Inhaled corticosteroids should be continued in asthma or COPD patients with COVID-19.50 The effect of inhaled corticosteroids on COVID-19 severity or viral clearance is unknown.50
In an open-label study (n=146) of outpatients with mild COVID-19, starting inhaled budesonide (Pulmicort Turbuhaler 800 mcg twice daily) within seven days of symptom onset and continuing until recovery or need for urgent care or hospitalization reduced the need for urgent care or hospitalization (NNT = 8).92 Patients were young (mean age 45 years), with few comorbidities.
A combination of inhaled and intranasal ciclesonide was not effective vs placebo for symptom resolution in relatively young (median age 35 years) COVID-19 outpatients (n=203).143
Dapagliflozin is being studied in COVID-19 patients with respiratory failure and with hypertension, diabetes, heart disease, or advanced renal disease to prevent organ failure, based on its known renal and cardiac benefit (DARE-19 study).
See www.clinicaltrials.gov for more information.
Interest in famotidine as a COVID-19 treatment stems from observations in China that patients who were taking famotidine who were infected with COVID-19 had better outcomes.55
In a retrospective U.S. study (n = 1,620), famotidine use (10 to 40 mg/day; n = 84) within 24 hours of admission was associated with reduced risk of death or intubation in hospitalized COVID-19 patients.67 But in a subsequent retrospective study in which famotidine users were matched to non-users to control for 12 potential confounders, famotidine was not associated with reduced risk of death. In fact, among patients not receiving famotidine at home 30-day mortality was higher.94
The IDSA suggests against use of famotidine for COVID-19 outside of a clinical trial.46 See www.clinicaltrials.gov for more information.
Favipiravir is an oral antiviral. Clinical trials are underway for COVID-19 treatment and for prophylaxis in nursing home outbreaks.112
In mild to moderate COVID-19, it may speed clinical improvement.111,112 Adverse effects include diarrhea, psychiatric symptoms, and lab abnormalities (increased uric acid, increased transaminases, decreased neutrophil count, increased triglycerides).112
It is currently approved in several countries for influenza and COVID-19.112 Approval is pending in Canada.
See “Selective Serotonin Reuptake Inhibitors,” below.
Early enthusiasm for hydroxychloroquine was based on a widely publicized open-label study.2
Subsequent studies, many with significant limitations, did not consistently show clinically meaningful benefit, and adverse effects were common.11,29,39,42,43,49,60,66,74,75,100
When used with azithromycin (and other QT-prolonging medications), QT prolongation is of increased concern.2,6 Information on managing QT prolongation risk in these patients is available at https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047521.
The FDA revoked its EUA for hydroxychloroquine because it is unlikely to be effective, based on data from the EUA and elsewhere.73 In addition to efficacy concerns, the FDA’s revocation of its EUA for hydroxychloroquine was based on adverse effects; its known and potential benefits no longer outweigh the known and potential side effects (e.g., serious cardiac events and other serious side effects).33 Due to the risk of arrhythmias, the FDA recommends against hydroxychloroquine use for COVID-19 outside of a clinical trial.33
NIH guidance recommends against use of hydroxychloroquine for treatment of COVID-19 in hospitalized or nonhospitalized patients.50
Hydroxychloroquine was not effective for prevention of SARS-CoV-2 infection in an eight-week placebo-controlled trial of healthcare providers at two urban tertiary care hospitals (n=132).87
Icatibant (Firazyr, generics [U.S])
SARS-CoV-2 uses ACE2 to enter cells. Because the resulting loss of ACE2 function might lead to bradykinin accumulation, there is interest in use of icatibant (a bradykinin antagonist) for severe COVID-19.
In a small case-control study, icatibant 30 mg every six hours x 3 was associated with improved oxygenation in hypoxic patients.81
See www.clinicaltrials.gov for ongoing studies.
High IL-6 levels are associated with higher COVID-19 disease severity, especially in nonsurvivors.13 Tocilizumab reduces inflammatory markers (e.g., C-reactive protein) in patients with severe COVID-19.116
A meta-analysis of 27 randomized trials of IL-6 antagonists (mostly tocilizumab) vs usual care or placebo found an association between IL-6 use and lower 28-day mortality in patients also receiving a corticosteroid, especially among patients on supplemental or high-flow oxygen, or non-invasive mechanical ventilation. For patients receiving corticosteroids plus tocilizumab, mortality rate was 20%, and the OR for the association with mortality was 0.77 (95% CI 0.68 to 0.87). For patients receiving tocilizumab and corticosteroids, 25% of patients progressed to invasive mechanical ventilation or death vs 33% for placebo/usual care. Tocilizumab did not seem to increase the risk of secondary infections, even when used with a corticosteroid.125
Data from the open-label REMAP-CAP study suggest that tocilizumab (n=353) reduces mortality (28% tocilizumab vs 35.8% standard care) if given within 24 hours of starting respiratory support (invasive or non-invasive mechanical ventilation, high-flow oxygen) or vasopressors.116 About 85% of patients also received a corticosteroid; mean time from admission to randomization was 1.2 days; and most patients were receiving respiratory support at enrollment. The tocilizumab dose was 8 mg/kg (max 800 mg), and the dose could be repeated in 12 to 24 hours if improvement was insufficient. Among patients randomized to tocilizumab, 92% received at least one dose, and 29% received a second dose. About 2% of the control group received an immunomodulator outside of the study protocol.
Results from an arm of the open-label RECOVERY trial suggests that adding tocilizumab (n=2,022) to standard care reduces mortality in hospitalized patients requiring oxygen or respiratory support who have baseline CRP ≥75 mg/L.115 Tocilizumab-treated patients were more likely to be discharged alive within 28 days (57% vs 50%). Among patients receiving mechanical ventilation at baseline, tocilizumab did not increase the chance of cessation. Tocilizumab dosing was stratified as follows: 800 mg (>90 kg), 600 mg (>65 kg to 90 kg), or 400 mg (>40 kg to 65 kg). A second dose could be given 12 to 24 hrs later if no improvement. Over 80% of patients were also receiving a corticosteroid, and mean time from admission to randomization was two days. Among patients randomized to tocilizumab, 84% received at least one dose, whereas 4% of the usual care group received at least one dose of tocilizumab or sarilumab. Almost 30% of the tocilizumab group received more than one dose.
Three placebo-controlled studies (COVACTA, EMPACTA, REMDACTA) did not find a mortality benefit for tocilizumab.124 In EMPACTA, tocilizumab reduced a composite endpoint of need for mechanical ventilation or death (12% vs 19.3%).124 Median time to hospital discharge or “ready for discharge” was reduced by 1.5 days.124 In COVACTA, median time to discharge or “ready for discharge” was 20 days in the tocilizumab group vs 28 days in the placebo group.124
Based on data from RECOVERY and the three placebo-controlled trials, tocilizumab has received Emergency Use Authorization (U.S.) for treatment of COVID-19 in hospitalized patients ≥2 years of age receiving systemic corticosteroids and supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.124 Tocilizumab is given as a one-hour infusion of 12 mg/kg (<30 kg) or 8 mg/kg (≥30 kg), to a maximum of 800 mg. If clinical signs and symptoms do not improve or worsen, the dose can be repeated after at least eight hours.124 There is insufficient evidence to assess the benefit of a second dose.50
The EUA fact sheet for tocilizumab for healthcare providers is available at https://www.fda.gov/media/150321/download. Give patients/caregivers the fact sheet available at https://www.fda.gov/media/150320/download.
The NIH recommends the addition tocilizumab to dexamethasone +/- remdesivir in patients with respiratory decompensation within three days of admission requiring high-flow oxygen, invasive or noninvasive mechanical ventilation, or ECMO.50 This includes patients within the first 24 hours of intensive care admission or patients not admitted to intensive care with CRP ≥75 mg/L. Some experts would add tocilizumab to patients with rapidly increasing oxygen needs and CRP ≥75 mg/L who do not yet require high-flow oxygen or noninvasive ventilation.50
Baricitinib may be an alternative to tocilizumab for many patients (see below).50 However, tocilizumab has more evidence of a mortality benefit, and there is limited data for using baricitinib in mechanically-ventilated patients.135 Do not combine tocilizumab with baricitinib due to infection risk.50
Some patients received sarilumab in REMAP-CAP (patients received noninvasive or invasive mechanical ventilation or high-flow oxygen and/or pressors).116 Based on limited evidence, it appears to work as well as tocilizumab at a single dose of 400 mg.77 Consider it for adults only if tocilizumab can't be used.50 To make an intravenous sarilumab solution using the subcutaneous syringe formulation, add 400 mg to 100 mL of normal saline. Infuse over one hour.50 Stability is four hours.136 Infuse with a 0.2 micron in-line filter.136
IL-6 antagonists may cause increased infections, neutropenia, thrombocytopenia, and elevated liver enzymes.1,34-38 There are several cases of tocilizumab-associated worsening of COVID-19, perhaps due to immunosuppression, despite an associated reduction in inflammatory markers.80
Ivermectin has several mechanisms that make it an attractive option for study for prevention and treatment of COVID-19. However, it has not previously demonstrated clinically significant antiviral efficacy for any virus in humans.32 A dose of 200 mcg/kg (the usual oral dose) may not produce levels high enough in the lungs to inhibit coronavirus.108
A small (n=72) study comparing ivermectin, ivermectin plus doxycycline, and placebo found no symptom benefit for patients with mild disease despite faster viral clearance and reduction of inflammatory markers.107 Another small study (n=60) of ivermectin 200 mcg/kg/day for five days showed statistically insignificant clinical improvement at day five (14/30 vs 11/30; p=0.43) and day ten (22/30 vs 16/30, p=0.10) in patients with severe disease compared to usual care (no placebo).131 The largest double-blind, placebo-controlled study to date (n=400) found no benefit of ivermectin 300 mcg/kg/day for five days for symptom resolution in mild disease.122 A retrospective cohort study (n=280) suggests lower mortality, especially in patients with severe COVID-19 lung disease, but neither length of stay nor extubation rate were affected.12 In general, these and other studies of ivermectin for COVID-19 had limitations such as small sample size; varying dose; open-label, uncontrolled, or retrospective design; confounding medications; and unclear COVID-19 severity and outcome measures.12,50
Meta-analyses that showed a mortality benefit included a large preprint study that has since been retracted.127-129,132 Meta-analyses that did not include the retracted study could not find benefit for mortality, recovery, or viral clearance, or as prophylaxis.133,134
The American Medical Association, American Society of Health-System Pharmacists, and the American Pharmacists Association oppose ivermectin use for COVID-19 except in a clinical trial.138 Canadian groups (e.g., Health Canada, CPhA) also oppose its use.
NIH guidance recommends neither for nor against ivermectin for COVID-19 treatment due to insufficient evidence.50 However, in endemic areas, ivermectin can be considered for strongyloidiasis prophylaxis in patients receiving dexamethasone plus tocilizumab as a treatment for COVID-19.50
Ivermectin (oral) is well-tolerated when used as directed for its approved indication (strongyloidiasis) or off-label for lice and scabies.50 Adverse effects include nausea, diarrhea, dizziness, itching.50 Overdose, such as happens when people self-medicate with ivermectin intended for animals or take more than the usual dose, can cause vomiting, hypotension, ataxia, seizures, coma, and death.130 It can also interact with warfarin, possibly by inhibiting vitamin K-dependent clotting factors.27
Janus Kinase Inhibitors (Baricitinib [Olumiant], tofacitinib [Xeljanz])
Interest in Janus kinase inhibitors for treatment of COVID-19 is based on their potential to block the effects of IL-6 and other cytokines. They might also prevent SARS-CoV-2 from entering cells.20
In the ACTT-2 study (n=1,033), oral baricitinib 4 mg once daily x 14 days (or until discharge) with remdesivir reduced recovery time by one day vs remdesivir plus placebo (median recovery time seven days vs eight days; rate ratio 1.16, 95% CI 1.01 to 1.32; p=0.03).20 Among patients requiring high-flow or noninvasive ventilation at baseline, median recovery time was ten days for the combination vs 18 days with remdesivir plus placebo (rate ratio 1.51, 95% CI 1.10 to 2.08).20 Mortality at day 28 was not significantly lower with the combination (5.1% vs 7.8%)(HR 0.65, 95% CI 0.39 to 1.09).20 Mortality in the control group was relatively low.20
ACTT-2 was not designed to evaluate baricitinib's safety and efficacy in patients receiving dexamethasone, which has been shown to improve mortality in patients on supplemental oxygen.20,31 However, patients who received corticosteroids after randomization had a higher incidence of infection.20 ACTT-4 will study remdesivir/baricitinib vs remdesivir/dexamethasone.
The COV-BARRIER study (n=1,525) showed no benefit of baricitinib 4 mg once daily for 14 days until discharge over placebo for reduction of the combined primary outcome of progression to high-flow oxygen, non-invasive or mechanical ventilation, or death in patients on supplemental oxygen.99 It did reduce a secondary outcome of 28-day all-cause mortality (8.1% vs 13.1%), driven by patients not requiring mechanical ventilation. Most patients also received corticosteroids. Patients with serious non-COVID infections, who were immunocompromised, or who were receiving invasive mechanical ventilation or ECMO were excluded. Risk of secondary infection was not increased vs placebo. Preliminary data from a COV-BARRIER substudy suggest that baricitinib may reduce mortality in patients on mechanical ventilation or ECMO.135
Based on ACTT-2 and COV-BARRIER, baricitinib has received EUA to treat COVID-19 in patients ≥2 years of age who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.103 These studies were limited to adults. Pediatric dosing is based on studies for other uses.103
The NIH recommends the addition of baricitinib to dexamethasone ± remdesivir in patients on high-flow oxygen or noninvasive ventilation with clinical progression or inflammatory markers within three days of admission.50 Some experts would add baricitinib to patients with inflammatory signs and rapidly increasing oxygen needs while on dexamethasone, but who do not yet require high-flow oxygen or noninvasive ventilation.50
Tocilizumab may be an alternative to baricitinib for many patients (see above).50 Tocilizumab has more evidence of a mortality benefit. Consider that there is limited data for using baricitinib in mechanically-ventilated patients.20,135 Do not combine baricitinib with tocilizumab due to infection risk.50
The EUA fact sheet for baricitinib for healthcare providers is available at https://www.fda.gov/media/143823/download. Give patients/caregivers the fact sheet available at https://www.fda.gov/media/143824/download.
See the EUA (link below) for information on dosing for renal impairment, low blood counts, and aminotransferase elevations, as well as safe handling.
A subsequent study (STOP-COVID)(n=289) compared tofacitinib 10 mg twice daily to placebo for 14 days until discharge in patients hospitalized for <72 hours. Most patients also received corticosteroids and supplemental oxygen, but not remdesivir, invasive or noninvasive mechanical ventilation, or ECMO. Patients with active non-COVID infections or who were immunocompromised were excluded. Tofacitinib decreased the composite risk of death or respiratory failure vs placebo (18.1% vs 29% [RR 0.63, 95% CI 0.41 to 0.97, p=0.04], but not duration of ICU or hospital stay. Death from any cause at day 28 was 2.8% in the tofacitinib group vs 5.5% in the placebo group (HR 0.49, 95% CI 0.15 to 1.63). Risk of secondary infection was not increased vs placebo.126
Consider tofacitinib for non-critically ill patients if baricitinib is unavailable.50,126
The baricitinib EUA carries warnings about VTE risk.103 VTE was similar in the two treatment arms of ACTT-2 (21 patients [baricitinib] vs 16 patients [placebo]; 4.1% vs 3.1%, 95% CI -1.3 to 3.3).20 All patients received VTE prophylaxis unless contraindicated, as is recommended in the EUA.20,103 Similarly, VTE risk was not increased in COV-BARRIER or STOP-COVID.99 Patients with recurrent VTE, or history within 12 weeks (COV-BARRIER; ACTT-2), or any VTE history (STOP-COVID) were excluded from these studies.99,126
Interest in linagliptin use for COVID-19 treatment is based on its in vitro inhibition of SARS-CoV-2 cysteine protease, an enzyme involved in viral replication.121
Lopinavir/ritonavir has not demonstrated anti-SARS-CoV-2 activity in humans.15 A small study suggested benefit (reduced composite endpoint of ARDS or death) for 2003 SARS vs historical control.17
Results from a randomized, open-label study (n=199) suggested it might reduce complications such as acute kidney injury, secondary infections, or need for mechanical ventilation in patients with COVID-19 pneumonia.15 However, time to clinical improvement was not reduced (main outcome measure).15 Gastrointestinal adverse effects may limit use.15,30
In an arm of the RECOVERY trial, 1,616 patients were randomized to open-label lopinavir-ritonavir. Compared to usual care (n=3,424), lopinavir-ritonavir did not improve 28-day mortality (p=0.60) or affect the composite endpoint of mechanical ventilation or death (composite endpoint; p=0.092).58
The WHO has discontinued the lopinavir/ritonavir arm of the Solidarity Trial because interim results suggest no mortality benefit for hospitalized patients.74
Studies in mice suggest that ARBs can reduce lung damage caused by SARS-CoV.22
Clinical trials are underway for treatment of COVID-19. See www.clinicaltrials.gov for more information.
Molnupiravir is nucleoside analog prodrug. It is converted in the body to NHC (beta-D-N4-hydroxycytidine) triphosphate. Viral RNA-polymerase uses NHC triphosphate as a substrate instead of uridine and cytidine triphosphates. The resulting mutation is lethal to the virus.140
Molnupiravir, when given within five days of symptom onset in mild-to-moderate COVID-19 seems to reduce the risk of hospitalization by about 30% (NNT = 35).145,146
Molnupiravir seems to be well-tolerated.145 However, like other nucleoside analogs, molnupiravir is potentially mutagenic, so there are concerns about embryofetal toxicity (e.g., skeletal malformations) and changes to the viral spike protein.146
In the U.S., molnupiravir has received EUA for treatment of mild to moderate test-confirmed COVID-19 in adults (≥18 years) at high risk of COVID-19 hospitalization or death.141 Molnupiravir is not for initiation of treatment in hospitalized COVID-19 patients.141 This drug is also under priority review by Health Canada.
The EUA fact sheet for molnupiravir for healthcare providers is available at https://www.fda.gov/media/155054/download. Give patients the fact sheet available at https://www.fda.gov/media/155055/download.
Monoclonal antibodies (SARS-CoV-2 neutralizing antibodies)
AstraZeneca (AZD7442), Eli Lilly (bamlanivimab, etesevimab), GlaxoSmithKline (VIR-7831; COMET-Ice Study), Regeneron (casirivimab/imdevimab), and others are testing monoclonal antibodies against COVID-19.
Casirivimab/imdevimab, bamlanivimab/etesevimab, and sotrovimab have received EUA in the U.S., and casirivimab/imdevimab, bamlanivimab, and sotrovimab have been authorized by interim order in Canada.
For NIH guidance on prioritization of COVID-19 monoclonal antibodies, see https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-the-prioritization-of-anti-sars-cov-2-monoclonal-antibodies/.
Bamlanivimab +/- Etesevimab (Eli Lilly)
Nirmatrelvir is a SARS-CoV2-specific protease inhibitor.102 Ritonavir is added to inhibit its metabolism.102
When started within five days of symptom onset (300 mg x 1, then 100 mg twice daily for five days), there was an 89% reduction in hospitalization or death vs placebo.102 There were no deaths in the Paxlovid group.102
Adverse effects (mostly mild) occurred in about 20% of patients in the ritonavir and placebo groups.102 Anticipate CYP3A4 drug interactions and others due to inclusion of ritonavir.27
In the U.S., Paxlovid has received EUA for treatment of mild to moderate test-confirmed COVID-19 in patients (≥12 years and ≥40 kg) at high risk of COVID-19 hospitalization or death. Paxlovid is not for initiation of treatment in hospitalized COVID-19 patients.147 The drug is also under priority review by Health Canada.
Remdesivir has in vitro activity against SARS-CoV-2.40
In a cohort of 53 evaluable patients receiving oxygen support, or with oxygen saturation ≤94% on room air, remdesivir was associated with clinical improvement in regard to oxygen support requirements in 68% of patients.40 Mortality was 13%, which is less than in other case series and cohorts.40 Most of the patients (65%) were receiving mechanical ventilation or ECMO at baseline.40 Viral load was not evaluated,40 but in a previous case report, virologic improvement was seen.8
In a double-blind, placebo-controlled trial (ACTT-1) (n = 1,062), remdesivir seemed to shorten time to recovery (10 days vs 15 days; p <0.001), but mortality at day 29 was not statistically different (11.4% vs 15.2%; HR 0.73, 95% CI 0.52 to 1.03).72 Shortened recovery time was statistically significant only in patients who received treatment within ten days of symptoms onset.72
Five days vs ten days of remdesivir were compared in the open-label SIMPLE-Severe study. Included patients had oxygen saturation ≤94% on room air and radiologic evidence of pneumonia.82 Most patients were receiving some kind of supplemental oxygen (mostly low-flow).82 Patients receiving mechanical ventilation or ECMO were excluded.82 There was no significant difference between five days and ten days in regard to clinical status at day 14.82 An unpublished comparison of remdesivir-treated patients (n=312) to a matched cohort of patients receiving standard care (n=818) showed recovery and mortality benefit for remdesivir.79
A five-day course of remdesivir was associated with a statistically significant (but perhaps not clinically significant) improvement in clinical status on a seven-point ordinal scale in patients with moderate COVID-19 (radiographic evidence of pulmonary infiltrates and oxygen saturation >94% on room air) vs standard care in an open-label, randomized study (n=584). Most patients were not on any kind of supplemental oxygen. Viral load was not assessed. Patients randomized to a 10-day course (actual median treatment duration six days) did not benefit. The clinical status score used in this study could have underestimated benefit in this population with nonsevere disease.24
In the open-label WHO SOLIDARITY trial, 2,743 patients were randomized to remdesivir.91 The primary goal was to assess its effect on in-hospital mortality.91 Most patients (~75%) were receiving some kind of oxygen at randomization.91 Remdesivir did not reduce mortality, reduce the need for mechanical ventilation, or reduce length of stay vs similar care without remdesivir.91 There was a small, nonsignificant mortality benefit for patients not on mechanical ventilation at study entry (RR 0.86, 99% CI 0.67 to 1.11).91 SOLIDARITY’s results do not negate ACTT-1, as SOLIDARITY was not placebo-controlled and ACTT-1 was designed to assess time to recovery.53
WHO guidelines weakly suggest against remdesivir because it lacks important effects on patient-centered outcomes such as mortality, need for mechanical ventilation, or time to clinical improvement. But because the quality of evidence is low or very low, important clinical benefit cannot be excluded. Furthermore, because COVID-19 is potentially fatal and remdesivir is well-tolerated, some patients will choose to receive it.104
The FDA has approved remdesivir (Veklury) for treatment of COVID-19 in hospitalized patients ≥12 years of age who weigh ≥40 kg, based on data from the ACTT trial and Gilead’s SIMPLE studies.24,57,72,82
Remdesivir and dexamethasone can be used together in patients requiring increasing supplemental oxygen, and can be considered for those who have been recently intubated.50 The rationale for combination therapy is that remdesivir provides antiviral activity while dexamethasone provides anti-inflammatory activity.50 The combination has not been specifically studied.50
Ten days’ treatment with remdesivir has not been shown to be more effective than five days (see SIMPLE-Severe, above),82 but treatment can be extended to ten days if improvement is not substantial by day five.50 Remdesivir can be discontinued at discharge.50
Remdesivir should be continued to complete the course for patients who progress to a high-flow oxygen device, mechanical ventilation, or ECMO.50 However, its benefit in these patients is unclear based on current data (see studies above).
In Canada, remdesivir (Veklury) has received marketing authorization with conditions pending the results of additional clinical trials. Its approved indication is treatment of COVID-19 pneumonia requiring supplemental oxygen in patients ≥12 years of age who weigh ≥40 kg.59
The most common adverse effects of remdesivir are nausea and transaminase elevations.57,59 Discontinue if ALT >10 x ULN with symptoms suggestive of liver injury (Canada: discontinue if ALT reaches 5 x ULN).57,59
Product labeling recommends against use in severe renal impairment due to accumulation of cyclodextrin which may cause liver or renal toxicity.47,59,61 However, five days’ treatment seems well-tolerated in severe renal impairment or hemodialysis.61 The aqueous formulation contains twice as much cyclodextrin as the powder.61
Coadministration of remdesivir and chloroquine or hydroxychloroquine is not recommended based on in vitro data showing that these drugs might interfere with the metabolic activation and antiviral activity of remdesivir.53 In Simple-Severe, recovery rate at day 14 for patients who received hydroxychloroquine plus remdesivir was lower than in patients who received remdesivir alone remdesivir alone. Concomitant hydroxychloroquine use was associated with a higher risk of adverse events.79
Another potential drug interaction involves inhibition of remdesivir elimination from hepatocytes by P-glycoprotein inhibitors. This interaction could result in hepatotoxicity.76
Selective serotonin reuptake inhibitors
Statins might ameliorate COVID-19-mediated inflammation and prevent lung injury by affecting ACE2 expression.25
In a meta-analysis of almost 9,000 COVID-19 patients in studies looking at the risk of severe COVID-19 illness or mortality in statin users vs nonusers, statin use was associated with a reduced risk of severe or fatal COVID-19 (HR 0.7, 95% CI 0.53 to 0.94).25
NIH guidelines recommend against use specifically for COVID-19 treatment outside of a clinical trial.50
See www.clinicaltrials.gov for more information on planned or ongoing studies.
Interest based on reports of microvascular pulmonary thrombosis in COVID-19 patients.
Studies are underway to treat ARDS in COVID-19 patients.See www.clinicaltrials.gov.
Intravenous vitamin C is being studied for treatment of severe COVID-19 disease based on previous data in sepsis and ARDS. However, there is no clear evidence of benefit even for these conditions, in which it has been studied alone or with thiamine +/- hydrocortisone in sepsis.48
In an open-label study, oral vitamin C 8,000 mg daily, alone or with zinc gluconate, did not reduce symptom duration in outpatients.93
The NIH recommends neither for nor against vitamin C for COVID-19 due to insufficient evidence.50
See www.clinicaltrials.gov for information on ongoing clinical trials.
Interest in vitamin D stems from its effects on the immune system and pulmonary ACE2 expression.109,110
In a cohort (n=186) of patients with severe COVID-19, 59% were vitamin-D deficient, but risk factors for vitamin D deficiency may also be risk factors for severe COVID-19 (e.g., obesity, poverty).109
The NIH recommends neither for nor against vitamin D for COVID-19 due to insufficient evidence.50
Studies are planned or underway using vitamin D for prevention or as a treatment adjunct. See www.clinicaltrials.gov for more information.
Zinc has in vitro activity against SARS-CoV.47
In an open-label study, oral zinc gluconate 50 mg daily, alone or with vitamin C, did not reduce symptom duration in outpatients.93
The NIH recommends against use of zinc for COVID-19 prevention above the recommended dietary allowance outside of a clinical trial, and recommends neither for nor against its use for treatment, due to insufficient evidence.50
Studies of zinc, alone or in combination (e.g., with vitamin C, vitamin D) to prevent or treat COVID-19 disease are planned or ongoing. See www.clinicaltrials.gov for more information.
Abbreviations: ACE = angiotensin-converting enzyme; ALT = alanine aminotransferase; ARB = angiotensin receptor blocker; ARDS = acute respiratory distress syndrome; BMI = body mass index; ECMO = extracorporeal membrane oxygenation; EUA = Emergency Use Authorization; ICU = intensive care unit; IDSA = Infectious Diseases Society of America; IL = interleukin; NIH = National Institutes of Health; NSAIDs = nonsteroidal anti-inflammatory drugs; SARS = severe acute respiratory syndrome; SARS-CoV-2 = the virus that causes COVID-19 disease; SSRI = selective serotonin reuptake inhibitor; tPA = tissue plasminogen activator; TNF = tumor necrosis factor; U.K. = United Kingdom; ULN = upper limit of normal; VTE = venous thromboembolism; WHO = World Health Organization
Levels of Evidence
In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.
Good-quality patient-oriented evidence.*
Inconsistent or limited-quality patient-oriented evidence.*
Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.
*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).
RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]
Prepared by the Editors of Therapeutic Research Center (361022); last modified January 2022.
- Product monograph for Kevzara. Sanofi Genzyme. Mississauga, ON L4W 4V9. August 2019.
- Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;56:105949.
- Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020;14:72-3.
- FDA. Fact sheet for health care providers emergency use authorization (EUA) of chloroquine phosphate supplied from the strategic national stockpile for treatment of COVID-19 in certain hospitalized patients. Revoked. June 15, 2020. https://www.fda.gov/media/136535/download. (Accessed September 15, 2020).
- Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res 2020;177:104762.
- Cortegiani A, Ippolito M, Ingoglia G, et al. Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for the treatment of COVID-19. J Crit Care 2020;59:176-90.
- Bermejo-Martin JF, Kelvin DJ, Eiros JM, et al. Macrolides for the treatment of severe respiratory illness caused by novel H1N1 swine influenza viral strains. J Infect Dev Ctries 2009;3:159-61.
- Ko WC, Rolain JM, Lee NY, et al. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents 2020;55:105933. doi: 10.1016/j.ijantimicag.2020.105933.
- Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open 2020;3:e2013136.
- Veiga VC, Prats JAGG, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randmised controlled trial. BMJ 2021;372:n84. http://dx.doi.org/10.1136/bmj.n84.
- Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med 2020;173:623-31.
- Rajter JC, Sherman MS, Fatteh N, et al. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the Ivermectin in COVID Nineteen Study. Chest 2021;159:85-92.
- Cortegiani A, Ippolito M, Greco M, et al. Rationale and evidence on the use if tocilizumab in COVID-19: a systematic review. Pulmonology 2021;27:52-66.
- RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet 2021;397:2049-59.
- Cao B, Wang Y, Wen W, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med 2020;382:1787-99.
- Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934-43.
- Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004;59:252-6.
- FDA. FDA issues emergency use authorization for convalescent plasma as potential promising COVID-19 treatment, another achievement in administration’s fight against pandemic. August 23, 2020. https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment. (Accessed September 16, 2020).
- Dimopoulos G, de Mast Q, Markou N, et al. Favorable anakinra responses in severe COVID-19 patients with secondary hemophagocytic lymphohistiocytosis. Cell Host Microbe 2020;28:117-23.e1.
- Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med 2021;384:795-807.
- Product monograph for bamlanivimab. Eli Lilly Canada. Toronto, ON M5X 1B1. April 2021.
- Kuster G, Pfister O, Burkard T, et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J 2020;41:1801-3.
- Diorio C, Anderson EM, McNerney KO, et al. Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome. Pediatr Blood Cancer 2020;67:e28693.
- Spinner CD, Gottleib RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA 2020;324:1048-57.
- Kow CS, Hasan SS. Meta-analysis of effect of statins in patients with COVID-19. Am J Cardiol 2020;134:153-5.
- McCreary EK, Pogue JM. Coronavirus disease 2019 treatment: a review of early and emerging options. Open Forum Infect Dis 2020;7:ofaa105.
- Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2021. http://www.clinicalkey.com. (Accessed December 8, 2021).
- Gautret P, Lagier JC, Parola P et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow-up: a pilot observational study. Travel Med Infect Dis 2020;34:101663.
- Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zheijang Univ 2020;49:215-19.
- Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020;323:1488-94.
- RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med 2021;384:693-704.
- Banerjee K, Nandy M, Dalai CK, Ahmed SN. The battle against COVID 19 pandemic: what we need to know before we “test fire” ivermectin. Drug Res (Stuttg) 2020;70:337-40.
- FDA. Frequently asked questions on the revocation of the Emergency Use Authorization for hydroxychloroquine sulfate and chloroquine phosphate. June 19, 2020. https://www.fda.gov/media/138946/download. (Accessed September 15, 2020).
- Product information for Kevzara. Sanofi-Aventis. Bridgewater, NJ 08807. April 2018.
- Product information for Actemra. Genentech. South San Francisco, CA 94080. March 2021.
- Product information for Sylvant. EUSA Pharma. Hertfordshire, U.K. HP2 4TZ. December 2019.
- Product monograph for Actemra. Mississauga, ON L5N 5M8. January 2021.
- Product monograph for Sylvant. Janssen. Toronto, ON M3C 1L9. March 2018.
- Chen Z, Hu JM, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020.03.22.20040758. https://doi.org/10.1101/2020.03.22.20040758. (Accessed September 17, 2020).
- Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med 2020;382:2327-36.
- Borba MG, Val FF, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open 2020;3(4.23):e208857.
- Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open-label, randomized, controlled trial. BMJ 2020;369. doi: 10.1136/bmj.m1849.
- Mahevas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with COVID-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ 2020;369. doi: 10.1136/bmj.m1844.
- Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med 2021;384:20-30.
- WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JA, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA 2020;324:1330-41.
- Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Last updated November 9, 2021. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/. (Accessed November 9, 2021).
- te Velthuis AJ, van den Worm SH, Sims AC, et al. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc inonophores block the replication of these viruses in cell culture. PLoS Pathog 2010;6:e1001176.
- Surani S, Sharma M. Revisiting the role of vitamin C in sepsis. Is it a forlorn hope or is there still dearth of data? Open Respir Med J 2019;13:55-7.
- Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Med (NY) 2020;1:114-27.
- NIH. Coronavirus disease 2019 (COVID-19). Treatment guidelines. Last updated October 27, 2021. https://covid19treatmentguidelines.nih.gov/. (Accessed November 18, 2021).
- World Health Organization. Corticosteroids for COVID-19. Living guidance. September 2, 2020. https://www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1. (Accessed November 19, 2021).
- Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA 2020;324:1298-306.
- FDA. Frequently asked questions for Veklury (remdesivir). February 4, 2021. https://www.fda.gov/media/137574/download. (Accessed May 16, 2021).
- FDA. Remdesivir EUA letter of authorization. October 22, 2020. https://www.fda.gov/media/137564/download. (Accessed May 16, 2021).
- Rogosnitzky M, Berkowitz E, Jadad AR. Delivering benefits at speed through real-world repurposing of off-patent drugs: the COVID-19 pandemic as a case point. JMIR Public Health Surveill 2020;6:e19199.
- Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA 2020;324:1307-16.
- Product information for Veklury. Gilead Sciences. Foster City, CA 94404. October 2020.
- RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet 2020;396:1345-52.
- Product monograph for Veklury. Gilead Sciences Canada. Mississauga, ON L5N 2W3. August 2021.
- Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 2020;382:2411-8.
- Thakare S, Gandhi C, Modi T, et al. Safety of remdesivir in patients with acute kidney injury or CKD. Kidney Int Rep 2021;6:206-10.
- Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582-9.
- Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci USA 2020;117:9490-6.
- Ye M, Fu D, Ren Y, et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol 2020;92:1890-901.
- Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020;2:e325-31.
- Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020;323:2493-502.
- Freedberg DE, Conigliaro J, Wang TC, et al. Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study. Gastroenterology 2020;159:1129-31.e3.
- The Writing Committee for the REMAP-CAP Investigators, Angus DC, Derde L, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA 2020;324:1317-29.
- Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from Covid-19. N Engl J Med 2021;384:1015-27.
- FDA. Fact sheet for health care providers. Emergency use authorization (EUA) of COVID-19 convalescent plasma for treatment of COVID-19 in hospitalized patients. February 4, 2021. https://www.fda.gov/media/141478/download. (Accessed February 19, 2021).
- Canadian Blood Services. COVID-19 and convalescent plasma. https://www.blood.ca/en/plasma/covid-19-and-convalescent-plasma. (Accessed July 17, 2021).
- Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19-final report. N Engl J Med 2020;383:1813-26.
- FDA. Letter to Gary L. Disbrow, Deputy Assistant Secretary, Director, Medical Countermeasures Programs, BARDA, in response to request for revocation of Emergency Use Authorization for chloroquine phosphate and hydroxychloroquine. June 15, 2020. https://www.fda.gov/media/138945/download. (Accessed September 15, 2020).
- Bagozzi D. WHO discontinued hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19. News release. July 4, 2020. https://www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19. (Accessed September 18, 2020).
- Arshad S, Kilgore P, Chaudry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis 2020;97:396-403.
- Leegwater E, Strik A, Wilms EB, et al. Drug induced liver injury in a patient with coronavirus disease 2019: potential interaction of remdesivir with P-glycoprotein inhibitors. Clin Infect Dis 2021;72:1256-8.
- The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19. The REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial. https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2.full.pdf. (Accessed September 10, 2021).
- Jeronimo CM, Farias ME, Val FF, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a randomized, double-blind, phase IIa, placebo-controlled trial. Clin Infect Dis 2021;72:e373-81.
- Gilead press release. Gilead presents additional data on investigational antiviral remdesivir for the treatment of COVID-19. July 10, 2020. https://www.gilead.com/news-and-press/press-room/press-releases/2020/7/gilead-presents-additional-data-on-investigational-antiviral-remdesivir-for-the-treatment-of-covid-19. (Accessed September 18, 2020).
- Radbel J, Narayanan N, Bhatt PJ. Use of tocilizumab for COVID-19-induced cytokine release syndrome: a cautionary case report. Chest 2020;158:e15-9.
- van de Veerdonk FL, Kouijzer IJ, de Nooijer AH, et al. Outcomes associated with use of kinin B2 receptor antagonist among patients with COVID-19. JAMA Netw Open 2020 Aug;3(8):e2017708. doi: 10.1001/jamanetworkopen.2020.17708.
- Goldman JD, Lye DC. Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med 2020;383:1827-37.
- American Society of Hematology. COVID-19 and convalescent plasma: frequently asked questions. March 23, 2021. https://www.hematology.org/covid-19/covid-19-and-convalescent-plasma. (Accessed June 18, 2021).
- Pau AK, Aberg J, Baker J, et al. Convalescent plasma for the treatment of COVID-19: perspectives of the National Institutes of Health COVID-19 treatment guidelines panel. Ann Intern Med 2021;174:93-5>.
- Reis G, Dos Santos Moreira-Silva EA, Medeiros Silva DC, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomized, platform clinical trial. Lancet Glob Health 2021 Oct 27. doi: 10.1016/S2214-109X(21)00448-4.
- FDA. Clinical memorandum re: EUA request. COVID-19 convalescent plasma. https://www.fda.gov/media/141480/download. (Accessed May 20, 2021).
- Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial. JAMA Intern Med 2021;181:195-202.
- FDA. Fact sheet for health care providers. Emergency use authorization (EUA) of casirivimab and imdevimab. November 2021. https://www.fda.gov/media/145611/download. (Accessed November 20, 2021).
- FDA. Fact sheet for health care providers. Emergency Use Authorization (EUA) of bamlanivimab and etesevimab. December 3, 2021. https://www.fda.gov/media/145802/download. (Accessed December 7, 2021).
- Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild or moderate COVID-19: a randomized clinical trial. JAMA 2021;325:632-44.
- WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19-interim WHO Solidarity trial results. New Engl J Med 2021;384:497-511.
- Ramakrishnan S, Nicolau DV Jr., Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med 2021;9:763-72.
- Thomas S, Patel D, Bittel B, et al. Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: the COVID A to Z randomized clinical trial. JAMA Netw Open 2021;4:e210369. doi: 10.1001/jamanetworopen.2021.0369.
- Yeramaneni S, Doshi P, Sands K, et al. Famotidine use is not associated with 30-day mortality: a coarsened exact match study 7158 hospitalized COVID-19 patients from a large healthcare system. Gastroenterology 2021;160:919-21.e3.
- Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020;371:m3939.
- RECOVER Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. June 16, 2021. https://www.medrxiv.org/content/10.1101/2021.06.15.21258542v1.full.pdf. (Accessed July 16, 2021).
- FDA. Coronavirus (COVID-19) update: FDA revokes Emergency Use Authorization for monoclonal antibody bamlanivimab. April 16, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-monoclonal-antibody-bamlanivimab. (Accessed April 16, 2021).
- NIH. Statement-NIH-sponsored ACTIV-3 trial closes LY-CoV555 sub-study. October 26, 2020. https://www.niaid.nih.gov/news-events/statement-nih-sponsored-activ-3-trial-closes-ly-cov555-sub-study. (Accessed February 19, 2021).
- Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomized, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med 2021 Aug 31. doi: 10.1016/S2213-2600(21)00331-3.
- Self WH, Semler MW, Leither LM, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. JAMA 2020;324-2165-76.
- Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA 2020;324:2292-300.
- Pfizer press release. Pfizer seeks Emergency Use Authorization for novel COVID-19 oral antiviral candidate. November 16, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-seeks-emergency-use-authorization-novel-covid-19. (Accessed November 23, 2021).
- FDA. Fact sheet for healthcare providers. Emergency Use Authorization (EUA) of baricitinib. October 2021. https://www.fda.gov/media/143823/download. (Accessed November 21, 2021).
- Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19. BMJ 2020;370:m3379.
- Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial of convalescent plasma in COVID-19 severe pneumonia. N Engl J Med 2021;384:619-29.
- FDA. Fact sheet for health care providers. Emergency Use Authorization (EUA) of bamlanivimab. March 18, 2021. http://pi.lilly.com/eua/bamlanivimab-eua-factsheet-hcp.pdf. (Accessed March 18, 2021).
- Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis 2020;103:214-6.
- Schmith VD, Zhou J, Lohmer LRL. The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19. Clin Pharmacol Ther 2020;108:762-5.
- De Smet D, De Smet K, Herroelen P, et al. Serum 25(OH)D level on hospital admission associated with COVID-19 stage and mortality. Am J Clin Pathol 2021;155:381-8.
- Mahdavi AM. A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: implications for a potential treatment for COVID-19. Rev Med Virol 2020;30:e2119.
- Udwadia ZF, Singh P, Barkate H, et al. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis 2020;103:62-71.
- Joshi S, Parkar J, Ansari A, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis 2021;102:501-8.
- Eli Lilly press release. Lilly's neutralizing antibody bamlanivimab (LY-CoV555) prevented COVID-19 at nursing homes in the BLAZE-2 trial, reducing risk by up to 80 percent for residents. January 21, 2021. https://investor.lilly.com/node/44291/pdf. (Accessed January 25, 2021).
- Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomized, double-blinded, adaptive, placebo-controlled, multicenter trial. Lancet Respir Med 2021;9:924-32.
- RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet 2021;397:1637-45.
- The REMAP-CAP Investigators. Interluekin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med 2021;384:1491-502.
- Anon. RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVIID-19. March 5, 2021. https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19. (Accessed March 11, 2021).
- Lopes MI, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomized, double-blinded, placebo-controlled clinical trial. RMD Open 2021;7:e001455.
- Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.17. Nature 2021;593:130-5.
- Product monograph for casirivimab and imdevimab. Hoffman-La Roche Limited. Mississauga, ON L5N 5M8. June 2021.
- Rao PPN, Pham AT, Shakeri A, et al. Drug repurposing: dipeptidyl peptidase IV (DPP4) inhibitors as potential agents to treat SARS-CoV-2 (2019-nCoV) infection. Pharmaceuticals (Basel) 2021;14:44. doi: 10.3390/ph14010044.
- Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized clinical trial. JAMA 2021;325:1426-35.
- FDA. Fact sheet for health care providers. Emergency use authorization (EUA) of sotrovimab. November 2021. https://www.fda.gov/media/149534/download. (Accessed November 21, 2021).
- FDA. Fact sheet for healthcare providers: Emergency use authorization (EUA) for Actemra (tocilizumab). June 2021. https://www.fda.gov/media/150321/download. (Accessed June 24, 2021).
- WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA 2021;326:499-518.
- Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N Engl J Med 2021;385:406-15.
- Hill A, Garratt A, Levi J, et al. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection. Open Forum Infect Dis 2021 July 6. doi.org/10.1093/ofid/ofab358.
- Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. Am J Ther2021;28:e434-60.
- Elgazzar A, Eltaweel A, Youssef SA, et al. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. (Withdrawn). https://assets.researchsquare.com/files/rs-100956/v3/706bc04e-fa7b-43fd-9c2a-15a41790f98e.pdf?c=1626390614. (Accessed July 28, 2021).
- FDA. Why you should not use ivermectin to treat or prevent COVID-19. September 3, 2021. https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-covid-19. (Accessed September 9, 2021).
- Okumus N, Demirturk N, Cetinkaya RA, et al. Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. BMC Infect Dis 2021;21:411.
- Kory P, Meduri GU, Varon J, et al. Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19. Am J Ther 2021;28:e299-318.
- Roman YM, Burela PA, Pasupuleti V, et al. Ivermectin for the treatment of COVID-19: a systematic review and meta-analysis of randomized controlled trials. Clin Infect Dis 2021 Jun 28. doi: 10.1093/cid/ciab591.
- Popp M, Stegemann M, Metzendorf MI. et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev 2021;(7):CD015017.
- Incyte press release. Lilly and Incyte’s baricitinib reduced deaths among patients with COVID-19 receiving invasive mechanical ventilation. August 3. 2021. https://s21.q4cdn.com/114423841/files/doc_news/Lilly-and-Incytes-baricitinib-reduced-deaths-among-patients-with-COVID-19-receiving-invasive-mechanical-ventilation-2021.pdf. (September 10, 2021).
- NHS. University Hospitals Birmingham. COVID-19 tocilizumab & sarilumab treatment protocol. September 9, 2021. https://www.uhb.nhs.uk/coronavirus-staff/clinical-info-pathways/clinical-info-pathways-downloads/c156-tocilizumab-treatment-protocol.pdf. (Accessed September 10, 2021).
- Product monograph for sotrovimab. GlaxoSmithKline. Mississauga, ON L5N 6L4. September 2021.
- Press release. AMA, APhA, ASHP statement on ending use of ivermectin to treat COVID-19. September 1, 2021. https://www.ama-assn.org/press-center/press-releases/ama-apha-ashp-statement-ending-use-ivermectin-treat-covid-19. (Accessed September 21, 2021).
- CDC. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings, 2016. https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB2016161. (Accessed September 22, 2021).
- Singh AK, Singh A, Singh R, Misra A. Molnupiravir in COVID-19: a systematic review literature. Diabetes Metab Syndr 2021;15:102329.
- FDA. Fact sheet for healthcare providers: emergency use authorization for molnupiravir. December 23, 2021. https://www.fda.gov/media/155054/download. (Accessed January 3, 2022).
- American Red Cross. Can I donate after receiving a COVID-19 vaccine? February 24, 2021. https://www.redcrossblood.org/local-homepage/news/article/covid-19-vaccination-guide-blood-donation.html. (Accessed November 20, 2021).
- Ezer N, Belga S, Daneman N, et al. Inhaled and intranasal ciclesonide for the treatment of COVID-19 in adult outpatients: CONTAIN phase II randomised controlled trial. BMJ 2021;375:e068060.
- Oskotsky T, Maric I, Tang A, et al. Mortality risk among patients with COVID-19 prescribed selective serotonin reuptake inhibitor antidepressants. JAMA Netw Open 2021;4:e2133090.
- FDA. Center for Drug Evaluation and Research. Antimicrobial Drugs Advisory Committee meeting briefing document (addendum). Molnupiravir: oral treatment of COVID-19. Meeting date: November 30, 2021. https://www.fda.gov/media/154422/download. (Accessed November 26, 2021).
- FDA. Center for Drug Evaluation and Research. FDA briefing document. Antimicrobial Drugs Advisory Committee meeting. November 30, 2021. https://www.fda.gov/media/154418/download. (Accessed December 8, 2021).
- FDA. Fact sheet for healthcare providers: emergency use authorization for Paxlovid. December 2021. https://www.fda.gov/media/155050/download. (Accessed January 3, 2022).
Cite this document as follows: Clinical Resource, Treatments of Interest for COVID-19. Pharmacist’s Letter/Prescriber’s Letter. October 2020.