Treatments of Interest for COVID-19
(Updated September 22, 2021)
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
Investigational synthetic form of vasoactive intestinal polypeptide hypothesized to protect alveolar type 2 cells from viral injury.85
In an unpublished case-control study (n=51), treated patients had better survival and clinical improvement. Side effects include hypotension and diarrhea. Based on data from this study, the manufacturer has applied for an EUA for aviptadil.
Aviptadil is currently being studied for COVID-19 respiratory failure (Intravenous Aviptadil for Critical COVID-19 with Respiratory Failure [COVID-AIV)], NCT04311697). See www.clinicaltrials.gov.
Aviptadil is also available through an Expanded Access protocol. For more information, see https://www.neurorxpharma.com/our-services/usa-licensed-physicians/.
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, it 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
Clinical trials are planned on the use of chloroquine to prevent COVID-19 in healthcare workers. See www.clinicaltrials.gov.
A Brazilian study of chloroquine phosphate 600 mg twice daily vs 450 mg twice daily stopped the high-dose arm due to higher instance of QT prolongation >500 milliseconds (18.9% vs 11.1%) and mortality (39% vs 15%).41 All patients received azithromycin.41
When used with azithromycin (and other QT-prolonging medications), QT prolongation is of increased concern.2,4,6
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 (not yet peer-reviewed), 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=0.04), 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; p=0.01).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 EUA does not replace clinical trials.70 Convalescent plasma should not be considered the standard of care and enrollment in prospective clinical trials is encouraged.70 See clinicaltrials.gov and https://covidcp.org/ for more information.
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, because the clinical trials they were supporting are complete.71 However, the CONCOR-Donor study of immunity after infection is ongoing. Learn more here: https://cancovid19plasma.ca/concor-donor/.
Recovered patients interested in donating their plasma can do so through the American Red Cross (https://www.redcrossblood.org/donate-blood/dlp/plasma-donations-from-recovered-covid-19-patients.html), or they can locate a donation center at http://www.aabb.org/tm/donation/Pages/Blood-Bank-Locator.aspx. Mobile blood drives in their area may be another option. In Canada, see https://www.blood.ca/en/convalescentplasma.
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 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 clearanceis 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.
Ciclesonide (Alvesco) is also being studied for treatment of COVID-19. See www.clinicaltrials.gov for more information.
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.
Fluvoxamine’s mechanism in COVID-19 may involve action at the sigma-1 receptor, which regulates cytokine production.101
In a preliminary placebo-controlled study (n=152), outpatients treated with fluvoxamine starting within seven days of symptom onset had a reduced risk of clinical deterioration (dyspnea, oxygen saturation <92% on room air) at day 15 (0/80 patients vs 6/72 patients). The study used an escalating dose, based on tolerability: 50 mg at bedtime on day 1, then 100 mg twice daily x 2 days, then 100 mg three times daily through day 15.101 Fluvoxamine inhibits CYP1A2 and CYP2C19.101 Gastrointestinal and central nervous system side effects are common.27
Is a more potent inhibitor of SARS-CoV-2 than chloroquine in vitro.2 Also has immunomodulating effects.27
Early enthusiasm for hydroxychloroquine was based on a widely publicized open-label, randomized study in hospitalized patients testing positive for SARS-CoV-2.2 Six of 26 hydroxychloroquine patients were lost to follow-up: one due to death, three due to intensive care admission, one due to side effects (nausea), and one who left the hospital. Viral clearance at day six was 70% in the 20 remaining hydroxychloroquine patients vs 12.5% of the control patients (n = 16).2 Six treated patients also received azithromycin to prevent bacterial infection.2 In the combination group, viral clearance was 100% at day six vs 57.1% in the hydroxychloroquine-alone group.2 Also see subsequent observational data under “Azithromycin,” above.
In larger, open-label and cohort studies, despite some small, inconsistent benefit on clinical signs and symptoms, there was no benefit on viral clearance, length of stay, need for intensive care or mechanical ventilation, or mortality.29,39,42,43,49,60,66 In one study, thirty percent of hydroxychloroquine patients had adverse effects.42 In another study, the combination of hydroxychloroquine and azithromycin was associated with cardiac arrest.66 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.
One large (n = 2,541) retrospective U.S. cohort study found reduced mortality with hydroxychloroquine +/- azithromycin vs usual care.75 Some patients with high cardiac risk were excluded. Select patients with severe COVID-19 and minimal cardiac risk also received azithromycin. Hydroxychloroquine was started within 48 hours of hospital admission in almost all patients. This study had several limitations. For example, the outcomes of almost 300 patients were not included in the analysis, and there were differences between treatment groups that could not be adequately adjusted for (e.g., baseline disease severity, other treatments received).
In a placebo-controlled study in outpatients, hydroxychloroquine did not improve symptoms.11 Forty-three percent of hydroxychloroquine patients had side effects vs 22% of placebo patients. Four hydroxychloroquine patients were hospitalized, and there was one outpatient death in this group. In the placebo group, ten placebo patients were hospitalized, one of which died (p=0.29).
The NIH’s placebo-controlled ORCHID trial (n=479) found no benefit in patients with severe COVID-19.100 The WHO has discontinued the hydroxychloroquine arm of the Solidarity Trial because interim results suggested little mortality benefit for hospitalized patients.74
The hydroxychloroquine arm of the large RECORD study was stopped due to lack of efficacy.74
The FDA has 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
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 mechanical 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 is unavailable.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.
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)
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
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; 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).
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Cite this document as follows: Clinical Resource, Treatments of Interest for COVID-19. Pharmacist’s Letter/Prescriber’s Letter. October 2020.