Treatments of Interest for COVID-19

(Updated September 2022)

Please see the FDA announcement authorizing pharmacists to prescribe Paxlovid with certain limitations.

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:

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.

TREATMENTS OF INTEREST

Drug

Pertinent Information or Resources

Note that DOSES provided are examples only for ADULTS.

Treatments with the BEST Evidence

Corticosteroids, systemic

The open-label RECOVERY trial (n=2,104), in which 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).41 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, as inflammation is more common in advanced disease, while viral replication is at a 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.42 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.43 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 regarding death or need for respiratory support (mechanical ventilation or high-flow oxygen) at day 21.44 However, the study was likely underpowered to show a difference, and was stopped early pending the RECOVERY publication.

The Brazilian MetCOVID study (n=416) did not find a mortality benefit for a five-day course of methylprednisolone over placebo.45 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).46 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.

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.37

NIHguidelines 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.1 If a patient is discharged, due to bed scarcity, from the emergency department on supplemental oxygen, the corticosteroid can be continued, with close monitoring, for the duration of supplemental oxygen or ten days (whichever comes first).1

  • Limited studies of different dexamethasone doses have mixed findings on the benefits of daily doses >6 mg. The COVID STEROID 2 trial suggests that dexamethasone 12 mg once daily might benefit patients needing high levels of respiratory support, so some prescribers might use this dose for select patients.1

Corticosteroids are not recommended for COVID-19 patients not requiring treatment with supplemental oxygen.1,37

Harms of corticosteroids include hyperglycemia, agitation, confusion, and infection risk.37

IL-6 antagonist

Tocilizumab (Actemra); sarilumab (Kevzara)

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 (non-invasive or mechanical ventilation, high-flow oxygen) or vasopressors.54 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.55 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.56 In EMPACTA, tocilizumab reduced a composite end point of need for mechanical ventilation or death (12% vs 19.3%).56 Median time to hospital discharge or “ready for discharge” was reduced by 1.5 days.56 In COVACTA, median time to discharge or “ready for discharge” was 20 days in the tocilizumab group vs 28 days in the placebo group.56

Based on data from RECOVERY and the three placebo-controlled trials, tocilizumab has received Emergency Use Authorization (US) for treatment of COVID-19 in hospitalized patients ≥2 years of age receiving systemic corticosteroids and supplemental oxygen, non-invasive or mechanical ventilation, or ECMO.56 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.56 There is insufficient evidence to assess the benefit of a second dose.1

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.

NIH guidance recommends the addition of tocilizumab to dexamethasone +/- remdesivir in patients with rapidly increasing oxygen needs and systemic inflammation (e.g., CRP ≥75 mg/L), or requiring high-flow oxygen, invasive or non-invasive mechanical ventilation, or ECMO.1

Baricitinib may be an alternative to tocilizumab for many patients (see below).1 For patients on high-flow oxygen or non-invasive ventilation, the quality and totality of evidence support baricitinib.1  However, tocilizumab has more evidence of a mortality benefit, and there is limited data for using baricitinib in mechanically-ventilated patients.57 Do not combine tocilizumab with baricitinib due to infection risk.1

Some patients received sarilumab in REMAP-CAP (patients received noninvasive or invasive mechanical ventilation or high-flow oxygen and/or pressors).54 Based on limited evidence, it appears to work as well as tocilizumab at a single dose of 400 mg.58 Consider it for adults only if tocilizumab can’t be used.1 To make an intravenous sarilumab solution using the subcutaneous syringe formulation, add 400 mg to 100 mL of normal saline.1 Infuse over one hour.1 Stability is four hours.59 Infuse with a 0.2 micron in-line filter.59

IL-6 antagonists may cause elevated liver enzymes, and less commonly neutropenia, thrombocytopenia, secondary infections, bowel perforation.1

Janus Kinase Inhibitors (Baricitinib [Olumiant], tofacitinib [Xeljanz])

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).60 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).60 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).60 Mortality in the control group was relatively low.60

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.41,60 However, patients who received corticosteroids after randomization had a higher incidence of infection.60 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.61 It did reduce a secondary outcome of 28-day all-cause mortality (8% vs 13%), 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. A small (n=101) COV-BARRIER sub study suggests that baricitinib reduces mortality in patients on mechanical ventilation or ECMO vs placebo (39% vs 58% p=0.03).57

Baricitinib (Olumiant) is FDA-approved for adults hospitalized with COVID-19 severe enough to require supplemental oxygen, non-invasive or mechanical ventilation, or ECMO.62

Based on ACTT-2 and COV-BARRIER, baricitinib has received EUA to treat COVID-19 in patients ≥2 to <18 years of age who require supplemental oxygen, non-invasive or mechanical ventilation, or ECMO.63 These studies were limited to adults. Pediatric dosing is based on studies for other uses.63

NIH guidance recommends the addition of baricitinib to dexamethasone ± remdesivir in patients on conventional oxygen with rapidly increasing oxygen needs and inflammatory markers, high-flow oxygen, non-invasive or mechanical ventilation, or ECMO.1

Tocilizumab may be an alternative to baricitinib for many patients (see above).1 Tocilizumab has more evidence of a mortality benefit. There is limited data for using baricitinib in mechanically-ventilated patients.57,60 Do not combine baricitinib with tocilizumab due to infection risk.1

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 or 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.64

Consider tofacitinib in place of baricitinib if baricitinib is unavailable.1,64

Baricitinib carries warnings about VTE risk.62,63 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).60 All patients received VTE prophylaxis unless contraindicated.60 Similarly, VTE risk was not increased in COV-BARRIER or STOP-COVID.61 Patients with recurrent VTE, or history within 12 weeks (COV-BARRIER; ACTT-2), or any VTE history (STOP-COVID) were excluded from these studies.61,64

Molnupiravir

(Lagevrio)

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.65

Molnupiravir, 800 mg every 12 hours orally for five days, started within five days of symptom onset in mild to moderate COVID-19 seems to reduce the risk of hospitalization by about 30% (NNT = 35).67

The most common side effects are diarrhea (2%), nausea (1%), and dizziness (1%).67 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.68 Men should use reliable contraception until three months after the last dose, and people of childbearing potential should use reliable contraception until four days after the last dose.67

In the US, molnupiravir has received EUA for treatment of mild to moderate test-confirmed COVID-19 in adults (≥18 years) at high risk of severe disease. Molnupiravir is not for initiation in patients requiring hospitalization for treatment of COVID-19.67 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.

For NIH guidance on prioritization of molnupiravir (and other outpatient COVID-19 therapies), see https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies/.

The NIH also has guidance for choosing among outpatient therapies for appropriate patients: https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-therapies-for-high-risk-nonhospitalized-patients/.

In Canada, provinces may have different prioritization for use of outpatient COVID-19 therapies based on product availability.

Monoclonal antibodies (SARS-CoV-2 neutralizing antibodies)

Distribution to US states and territories is based on the prevalence of susceptible variants. For updates, see https://www.phe.gov/emergency/events/COVID19/therapeutics/distribution/Pages/data-tables.aspx.

In the US, variants can be tracked at https://covid.cdc.gov/covid-data-tracker/#variant-proportions.

For NIH guidance on prioritization of COVID-19 monoclonal antibodies (and other outpatient therapies), see https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies/.

The NIH also has guidance for choosing among outpatient therapies for appropriate patients: https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-therapies-for-high-risk-nonhospitalized-patients/.

In Canada, provinces may have different prioritization for use of outpatient COVID-19 therapies based on product availability.

Bebtelovimab (US)

Bebtelovimab is NOT for patients requiring hospitalization for treatment of COVID-19 or those requiring supplemental oxygen (or increased flow rate in patients on chronic oxygen).69 It should be given as soon as possible, within seven days of symptom onset.69 It is authorized for use when other approved or authorized treatments are not available or appropriate. For more help with patient selection, see our US algorithm, MAbs” for COVID-19: Patient Assessment, or the links to the EUA fact sheet, below.

Authorization was based on a phase II study (BLAZE-4) in which bebtelovimab was used as monotherapy or with bamlanivimab/etesevimab.69 Treatment was started within three days of a positive test result. Most patients were infected with the Delta or Alpha variants and none were infected with Omicron.69 In the placebo-controlled part of the study in mostly low-risk unvaccinated patients (n=380), bebtelovimab reduced median time to symptom resolution (6 days vs 8 days) and reduced day 5 viral load.69,70 In another portion of the trial, 150 mostly high-risk patients were randomized to bebtelovimab alone or bebtelovimab with bamlanivimab/etesevimab.69 About 1/5 of patients had received at least one COVID-19 vaccine dose. Hospitalization or death occurred in two (4%) patients in the combo treatment group, and three (3%) in the monotherapy group. One patient in the bebtelovimab arm died. An additional 176 mostly high-risk patients received combination therapy (open-label).69 About 31% of these patients had received at least one COVID-19 vaccine dose. Three patients required hospitalization for COVID-19, and none died.

  • The rate of hospitalization and death through day 29 in patients who received bebtelovimab monotherapy or combination therapy was generally lower than the placebo rate in previous studies of monoclonal antibodies for high-risk patients, but conclusions are limited because of different circulating variants and patient populations in those studies.71

In vitro, it is active against Omicron variants, including Omicron BA.4/BA.5.69

Bebtelovimab is given as a one-time IV push.147 Monitor for at least an hour after injection.69

The EUA fact sheet for healthcare providers is available at https://www.fda.gov/media/156152/download. Give patients the fact sheet available at https://www.fda.gov/media/156153/download.

Tixagevimab/cilgavimab (Evusheld)

Tixagevimab/cilgavimab is for PRE-exposure prophylaxis of COVID-19 in moderately to severely immunocompromised patients not expected to have responded to vaccination, and for patients for whom vaccination is contraindicated.72,73 For help with patient selection, see our US algorithm, “MAbs” for COVID-19: Patient Assessment, or the links to the EUA fact sheet and Canadian product monograph, below.

Authorization/approval was based on the ongoing Phase III PROVENT (preexposure) and STORM CHASER (postexposure) trials.72,73 PROVENT patients were unvaccinated and at high risk due to age (≥60 years), comorbidities (e.g., obesity, heart or lung disease, immunocompromise), living situation, or occupation. After a follow-up of three to 166 days after a single dose, symptomatic infection occurred in 0.2% of treated patients vs 1% of placebo patients (NNT = 125). STORM CHASER patients were adults exposed to COVID-19 within the previous 8 days. Although it did not prevent symptomatic COVID-19 within 30 days of randomization (hence it is not authorized for post-exposure prophylaxis), there were more symptomatic COVID-19 infections in the placebo group after day 29.

  • Although authorized for patients ≥12 years of age weighing ≥40 kg, studies only included patients ≥18 years of age.72,73
  • In PROVENT, more patients in the treatment group experienced adverse cardiac events than in the placebo group (~0.6% vs 0.2%).72,73 Almost all of these patients had cardiac risk factors or a cardiac event history.73
  • Few patients in PROVENT (<4%) were immunocompromised.72,73

Evusheld protection may last for six months.72 NIH guidance recommends it be given in repeat doses every six months if ongoing protection is needed.1

In vitro, it has reduced activity against the Omicron BA.4/BA.5 variant.72 In the US, dosing has been increased to account for reduced susceptibility, and a dosage increase is an option in Canada.72,73

The EUA fact sheet for tixagevimab/cilgavimab for healthcare providers is available at https://www.fda.gov/media/154701/download. Give patients the fact sheet available at https://www.fda.gov/media/154702/download.

The Canadian product monograph for tixagevimab/cilgavimab is available at Health Canada’s Drug Product Database (https://health-products.canada.ca/dpd-bdpp/index-eng.jsp).

Casirivimab/imdevimab (Regen-COV)

In the US, casirivimab/imdevimab is not authorized/available for use in regions where nonsusceptible variants (e.g., Omicron) predominate.74

Casirivimab/imdevimab is NOT for patients requiring hospitalization for COVID-19 or those requiring supplemental oxygen (or increased flow rate in patients on chronic oxygen).74,75 It should be given as soon as possible, within ten days of symptom onset (US).74 For more help with patient selection, see our US algorithm, “MAbs” for COVID-19: Patient Assessment, or the links to the EUA fact sheet and Canadian product monograph, below.

The EUA was based on an phase I/II/III placebo-controlled study.74 Treatment was started within three days of a positive test result, and median duration of symptoms before starting treatment was three days.74 One percent of those who received the study drug at a dose of 1,200 mg (n=736) required emergency department care or hospitalization vs 3.2% of the placebo patients.74 This was based on a low number of events (24 in the placebo group and seven in the treatment group).74 Viral clearance was greater in the treatment group vs placebo.74

For the 2,400 mg dose (authorized in Canada), 1.3% of patients who received the study drug required emergency department care or hospitalization vs 4.6% of placebo patients. This was based on 18 events in the treatment group and 62 events in the placebo group.75 The lower dose authorized in the US (1,200 mg), is based on the drug’s flat dose-response curve.74

In the US, casirivimab/imdevimab had also received EUA for post-exposure prophylaxis in high-risk patients.74

Casirivimab/imdevimab is given as an infusion, or subcutaneously (US) if infusion is not feasible or would delay treatment.74,75(With subcutaneous administration, viral load reduction is similar to the intravenous route, but clinical efficacy data are limited; the intravenous route is strongly recommended.74) Casirivimab/imdevimabappears well tolerated, but patients must be monitored for one hour after administration for reactions.74,75

The EUA fact sheet for casirivimab/imdevimab for healthcare providers is available at https://www.fda.gov/media/145611/download. Give patients the fact sheet available at https://www.fda.gov/media/143893/download.

The Canadian product monograph is available at Health Canada’s Drug Product Database (https://health-products.canada.ca/dpd-bdpp/index-eng.jsp).

Bamlanivimab +/- Etesevimab (Eli Lilly)

In the US, bamlanivimab/etesevimab is not authorized/available for use in regions where nonsusceptible variants (e.g., Omicron) predominate.78 Because of the prevalence of resistant variants, the FDA has revoked the EUA for bamlanivimab monotherapy.76

Bamlanivimab +/- etesevimab is NOT for patients (EUA: ≥2 years of age) requiring hospitalization for COVID-19 (EUA: or those requiring supplemental oxygen, or increased flow rate in patients on chronic oxygen).77,78 (A study in patients hospitalized for COVID-19 [ACTIV-3] was closed due to lack of benefit.79) It should be given as soon as possible, within ten days of symptom onset.77,78 For more help with patient selection, see our US algorithm, “MAbs” for COVID-19: Patient Assessment, or the links to the EUA fact sheet and Canadian product monograph, below.

Original authorization was based on data from a study in recently diagnosed outpatients (BLAZE-1).77,78 Bamlanivimab 700 mg/etesevimab 1,400 mg reduced the need for a hospital visit vs placebo (0.8% [combo] vs 5.8% [placebo]).80 The treatment group had 2% lower mortality than the placebo group.78 In a post-hoc analysis, among patients ≥65 years of age or with BMI ≥35 kg/m2, hospitalizations in the bamlanivimab/etesevimab and placebo groups were 0% and 13.5% (7/52), respectively.80

In the US, bamlanivimab/etesevimab had also received EUA for post-exposure prophylaxis in high-risk patients.78

Bamlanivimab +/- etesevimab is given as a one-time infusion. They appear well tolerated, but patients must be monitored (US: for one hour) after the infusion for reactions.77,78

The EUA fact sheet for bamlanivimab/etesevimab for healthcare providers is available at https://www.fda.gov/media/145802/download. Give patients the fact sheet available at https://www.fda.gov/media/145803/download.

The Canadian product monograph for bamlanivimab is available at Health Canada’s Drug Product Database (https://health-products.canada.ca/dpd-bdpp/index-eng.jsp).

Sotrovimab (GlaxoSmithKline)

In the US, sotrovimab is not authorized for use in regions where nonsusceptible variants predominate.81

Sotrovimab is NOT for patients requiring hospitalization for treatment of COVID-19 or those requiring supplemental oxygen (or increased flow rate in patients on chronic oxygen).81,82 It should be given as soon as possible, within seven days of symptom onset (US).81 For more help with patient selection, see our US algorithm, “MAbs” for COVID-19: Patient Assessment, or the links to the EUA fact sheet and Canadian product monograph, below.

Authorization was based on the COMET-ICE and COMET-TAIL (US) trials.81,82 Patients were enrolled in COMET-ICE within five days of symptom onset.81 Among the one thousand fifty-seven patients included in the COMET-ICE intent-to-treat population, 1% of patients in the treatment group (n=6) required emergency department care or hospitalization vs 6% of the placebo group (n=30) (NNT = 20).81 Viral load data was available for a subset of patients in which the decrease in viral load was greater in treatment group.81 Two placebo patients died.81In vitro, it is active against Omicron BA.1 variants, but has reduced susceptibility to the Omicron BA.2 variant.81

Sotrovimab is given as a one-time infusion.81,82 It appears well tolerated, but patients must be monitored for at least one hour after the infusion for reactions.81,82

The EUA fact sheet for sotrovimab for healthcare providers is available at https://www.fda.gov/media/149534/download. Give patients the fact sheet available at https://www.fda.gov/media/149533/download.

The Canadian product monograph for sotrovimab is available at Health Canada’s Drug Product Database (https://health-products.canada.ca/dpd-bdpp/index-eng.jsp).

Nirmatrelvir/Ritonavir (Paxlovid)

Nirmatrelvir is a SARS-CoV2-specific protease inhibitor.99 Ritonavir is added to inhibit its metabolism.99

When started within five days of symptom onset (nirmatrelvir 300 mg/ritonavir 100 mg twice daily for five days [oral]), there was an 87% reduction in hospitalization or death vs placebo (NNT = 18).99 There were no deaths in the Paxlovid group.99 Included patients had no history of COVID-19 infection or vaccination, and study enrollment was completed prior to the emergence of the Omicron variant.66

Paxlovid is authorized for treatment of mild to moderate test-confirmed COVID-19 in patients (US: ≥12 years and ≥40 kg; Canada: adults [≥18 years old]) at high risk of severe COVID-19.99,100 Paxlovid is not for initiation in patients requiring hospitalization for treatment of COVID-19.99,100

The most common side effects were dysgeusia (bad taste) (6%), diarrhea (3%), hypertension (1%), and myalgia (1%).99,100

  • If dysgeusia occurs, suggestions for patients include choosing foods with only a few ingredients; avoidance of spicy foods; and avoidance of preservative-heavy, very sweet foods.101

Paxlovid has the potential to interact with CYP3A4 substrates due to the ritonavir component, but for many patients the interaction will not be clinically significant with only five days of treatment, or can be managed, and will not constitute a contraindication. Help with Paxlovid drug interaction screening and management is available:

Paxlovid requires a dose reduction (150 mg/100 mg twice daily) if eGFR is ≥30 to <60 mL/min/1.73m2, and should be avoided in patients with severe kidney or liver impairment.99,100

The EUA fact sheet for healthcare providers is available at https://www.fda.gov/media/155050/download. Give patients the fact sheet available at https://www.fda.gov/media/155051/download.

The Canadian product monograph for Paxlovid is available at Health Canada’s Drug Product Database (https://health-products.canada.ca/dpd-bdpp/index-eng.jsp).

For NIH guidance on prioritization of Paxlovid (and other outpatient COVID-19 therapies), see https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies/.

The NIH also has guidance for choosing among outpatient therapies for appropriate patients: https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-therapies-for-high-risk-nonhospitalized-patients/.

In Canada, provinces may have different prioritization for use of outpatient COVID-19 therapies based on product availability.

Remdesivir

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).83 Shortened recovery time was statistically significant only in patients who received treatment within ten days of symptoms onset.83

  • In ACTT-1, most patients had severe disease at enrollment, defined as oxygen saturation ≤94% on room air, need for invasive or noninvasive oxygen supplementation, or respirations ≥24 breaths/minute.83 Most patients were receiving oxygen.83 Remdesivir seemed to provide the most benefit for patients receiving low-flow oxygen at baseline, but this may be a reflection of subgroup sample size, and it cannot be concluded that other patients won’t benefit.83

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.84 Most patients were receiving some kind of supplemental oxygen (mostly low-flow).84 Patients receiving mechanical ventilation or ECMO were excluded.84 There was no significant difference between five days and ten days in regard to clinical status at day 14.84

  • A later comparison of remdesivir-treated patients (n=286) to a matched cohort of patients receiving standard care (n=852) showed a risk-adjusted mortality benefit for remdesivir (HR 0.6, 95% CI 0.40 to 0.9, p<0.01).85

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.86

In the open-label WHO SOLIDARITY trial, 2,743 patients were randomized to remdesivir.87 The primary goal was to assess its effect on in-hospital mortality.87 Most patients (~75%) were receiving some kind of oxygen at randomization.87 Remdesivir did not reduce mortality, reduce the need for mechanical ventilation, or reduce length of stay vs similar care without remdesivir.87 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).87 SOLIDARITY’s results do not negate ACTT-1, as SOLIDARITY was not placebo-controlled and ACTT-1 was designed to assess time to recovery.88

In patients hospitalized for treatment of COVID-19, remdesivir monotherapy (i.e., without dexamethasone) should be reserved for patients who require minimal supplemental oxygen.1

  • It may also be appropriate for inpatients not requiring oxygen, but with high risk of progression, based on conflicting evidence of faster time to recovery.1

Remdesivir and dexamethasone (or immunomodulator combination) are used together in patients requiring conventional oxygen (based on the ACTT-1 trial) and can be considered in patients requiring high-flow oxygen or non-invasive ventilation.1

  • Remdesivir should be continued to complete the course for patients who progress from conventional oxygen to high-flow oxygen, non-invasive or mechanical ventilation, or ECMO.1

Treatment with remdesivir for >5 days has not been shown to be more effective.84,89 Remdesivir can be discontinued at discharge, especially if the patient is not discharged on supplemental oxygen.1

In patients with mild to moderate COVID-19, but not hospitalized for treatment of COVID-19, remdesivir for three days (200 mg, then 100 mg on days 2 and 3) is an option.1 This recommendation is based on the PINETREE study (NNT = 22 to prevent one hospitalization [i.e., ≥24 hours of acute care]).1 Patients should be monitored for an hour post-dose.1

The NIH has guidance for choosing among outpatient therapies for appropriate patients: https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-therapies-for-high-risk-nonhospitalized-patients/.

The most common adverse effects of remdesivir are nausea and transaminase elevations.88,90 Discontinue if ALT >10 x ULN with symptoms suggestive of liver injury (Canada: hold while ALT is ≥5 x ULN, and stop if ALT elevation is accompanied by other signs or symptoms suggestive of liver injury).88,90

Product labeling recommends against use in severe renal impairment due to accumulation of cyclodextrin which may cause liver or renal toxicity.88,90,91 However, five days’ treatment seems well-tolerated in severe renal impairment or hemodialysis.91 The aqueous formulation contains twice as much cyclodextrin as the powder.88

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.88 In Simple-Severe, recovery rate at day 14 for patients who received hydroxychloroquine plus remdesivir was lower than in patients who received remdesivir alone. Concomitant hydroxychloroquine use was associated with a higher risk of adverse events.92 Another potential drug interaction involves inhibition of remdesivir elimination from hepatocytes by P-glycoprotein inhibitors. This interaction could result in hepatotoxicity.93

The FDA has approved remdesivir (Veklury) for treatment of COVID-19 in patients ≥28 days of age who weigh ≥3 kg who are hospitalized for treatment of COVID-19, or who are not hospitalized for treatment of COVID-19 but have mild- to moderate symptoms and at high-risk of progression to severe disease.88

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, and outpatients at high risk of hospitalization or death.90

Treatments with Limited or Emerging Evidence

Anakinra (Kineret)

Some institutions use anakinra in the treatment of COVID-19-related multisystem inflammatory syndrome in children.1

Anakinra was not effective for hospitalized or critically ill patients with moderate or severe COVID-19 pneumonia in REMAP-CAP or CORIMUNO-ANA-1.1,28 The SAVE-MORE trial suggested benefit (lower risk of clinical progression vs placebo), but these patients were pre-selected for having elevated levels of plasma-soluble urokinase plasminogen activator receptor, an assay for which is not available in most institutions.1

NIH guidelines recommend neither for nor against use of anakinra for treatment of COVID-19, due to insufficient evidence.1

Colchicine, outpatients

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 slightly reduced the composite primary end point 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.31 Patients with severe kidney or liver disease were excluded. More cases of pulmonary embolism occurred in the colchicine group (11 vs 2).31 Limitations include the statistical analysis and study termination before the pre-planned number of patients were recruited.

NIH guidelines recommend against use of colchicine for treatment of COVID-19 in outpatients, except in a clinical trial.1

Convalescent Plasma (COVID-19), high-titer

In hospitalized patients, convalescent plasma has not shown definitive mortality benefit or clinically meaningful improvement.33-36

In ambulatory patients, benefit is uncertain due to study limitations, but benefit cannot be excluded.37

There is very limited data (case reports, case series) on convalescent plasma for pediatric patients.1

Risks include transfusion reactions, allergic reactions, fluid overload, cardiac events, hypotension requiring pressors, thrombosis, and transfusion-related acute lung injury.37

The FDA has issued an EUA for use of high-titer convalescent plasma for outpatients or hospitalized patients with impaired immunity, based in part on data from the Mayo-Clinic-led expanded access program.38

NIH guidelines recommend use of only convalescent plasma collected after emergence of the Omicron variant.1

NIH guidelines recommend against use of convalescent plasma in immunocompetent hospitalized patients.1

NIH guidelines recommend neither for nor against use high-titer convalescent plasma in immunocompromised patients.1

  • If used (e.g., in severe or progressive disease despite other therapies), try to use a vaccinated donor who recently recovered from a variant similar to the one likely infecting the patient.1

IDSA recommends against use of high-titer convalescent plasma in hospitalized patients, but suggests use within eight days of symptom onset for ambulatory patients at high-risk of progression if no other treatment options are available.37

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.

Convalescent plasma is no longer being collected by Canadian Blood Services or by the American Red Cross.39,40

Corticosteroids, inhaled

Inhaled corticosteroids should be continued in asthma or COPD patients with COVID-19.1

Inhaled ciclesonide was studied in two RCTs in outpatients. 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).48 In a subsequent study using ciclesonide 320 mcg twice daily, time to symptom resolution was not reduced vs placebo, but need for a hospital visit or admission was reduced (1% vs 5.4% (OR 0.18, 95% CI 0.04 to 0.85) based on a small number of events.47

Two open-label studies using inhaled budesonide also had conflicting results.1

NIH guidelines recommend neither for nor against inhaled corticosteroids for COVID-19 treatment due to insufficient evidence.1

Favipiravir

Favipiravir is an oral antiviral.53

In mild to moderate COVID-19 (but not severe COVID-19), it may speed clinical improvement.53 Adverse effects include nausea, diarrhea, and lab abnormalities (increased uric acid, increased transaminases).53

Favipiravir is being investigated in clinical trials in the US and Canada. See clinicaltrials.gov to find current studies.

Treatments with No Clinically Important Benefit

Colchicine, inpatients

The large RECOVERY trial discontinued its colchicine arm in hospitalized COVID-19 patients due to futility regarding mortality benefit.32

NIH guidelines recommend against use in hospitalized patients.1

Famotidine

In a retrospective US 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.49 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.50

In a placebo-controlled study (n=55) in nonhospitalized patients, famotidine did not reduce time to symptom resolution by study day 28 (p=0.4).51 Time to 50% symptom reduction was 8.2 days in the famotidine group vs 11.4 days in the placebo group.

In an open-label study in hospitalized patients, famotidine reduced time to recovery and discharge, but did not affect mortality or need for intensive care or mechanical ventilation.52

The IDSA suggests against use of famotidine for COVID-19.37

Fluvoxamine

Based on the large (n=1,497) randomized, placebo-controlled TOGETHER trial in high-risk outpatients, smaller studies, and other data, the FDA declined EUA for fluvoxamine. Reasons include lack of clinically meaningful benefit, study limitations, paucity of evidence to support its mechanism of action in treatment of COVID-19, and availability of other treatements.29,30

Hydroxy-chloroquine or chloroquine and/or azithromycin

Early enthusiasm for hydroxychloroquine plus azithromycin was based on a widely publicized open-label study.2 Subsequent studies, many with significant limitations, did not consistently show clinically meaningful benefit of hydroxychloroquine, chloroquine, or azithromycin, and adverse effects were common.3-12

The FDA revoked EUA for chloroquine and hydroxychloroquine because they are unlikely to be effective, based on data from the EUA and elsewhere.13 In addition to efficacy concerns, the FDA’s revocation of EUA for chloroquine and hydroxychloroquine was based on adverse effects; the known and potential benefits no longer outweigh the known and potential side effects (e.g., serious cardiac events and other serious side effects).14

When azithromycin is used with hydroxychloroquine or chloroquine (and other QT prolonging medications), QT prolongation is of increased concern.2,15

NIH guidelines recommend against the use of azithromycin, chloroquine, or hydroxychloroquine in inpatients or outpatients for the treatment of COVID-19.1

Ivermectin

Ivermectin has not previously demonstrated clinically significant antiviral efficacy for any virus in humans.16 A dose of 200 mcg/kg (the usual oral dose) may not produce levels high enough in the lungs to inhibit coronavirus.17

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.1,18-21

Meta-analyses that showed a mortality benefit included a large preprint study that has since been retracted.22 Meta-analyses that did not include the retracted study could not find benefit for mortality, recovery, or viral clearance, or as prophylaxis.23,24

The American Medical Association, American Society of Health-System Pharmacists, the American Pharmacists Association, and the NIH oppose ivermectin use for COVID-19 except in a clinical trial.1,25 Canadian groups (e.g., Health Canada, CPhA) also oppose its use.

Ivermectin can be used for empiric treatment of strongyloidiasis in patients receiving dexamethasone plus tocilizumab who have lived in an area where Strongyloides is endemic.1

Ivermectin (oral) is well-tolerated when used as directed for its approved indication (strongyloidiasis) or off-label for lice and scabies.1 Adverse effects include nausea, diarrhea, dizziness, itching.1 In the I-TECH study, 5.8% of ivermectin patients developed diarrhea, which lead to hypovolemic shock in one patient.21 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.26 Ivermectin can also interact with warfarin, possibly by inhibiting vitamin K-dependent clotting factors.27

Statins

Data shows conflicting benefit of statins on outcomes in hospitalized COVID-19 patients.97.98

Patients taking statins who develop COVID-19 should continue to take them unless there is a reason to stop.1

Vitamins C, vitamin D, and Zinc

Interest in intravenous vitamin C for treatment of severe COVID-19 disease was based on previous data in sepsis and ARDS.1 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.94

In an open-label study, oral vitamin C 8,000 mg daily, alone or with zinc gluconate 50 mg daily, did not reduce symptom duration in outpatients.95

One high-quality, prospective clinical study in patients hospitalized with moderate to severe COVID-19 shows that taking a single oral dose of vitamin D3 200,000 IU does not affect hospital length of stay, in-hospital mortality, admission to intensive care, or need for ventilation when compared with placebo. Most patients in this study were vitamin D sufficient.96

Abbreviations: ALT = alanine aminotransferase; ARDS = acute respiratory distress syndrome; BMI = body mass index; DOAC = direct-acting oral anticoagulant; ECMO = extracorporeal membrane oxygenation; EUA = Emergency Use Authorization; ICU = intensive care unit; IDSA = Infectious Diseases Society of America; NIH = National Institutes of Health; SARS = severe acute respiratory syndrome; SARS-CoV-2 = the virus that causes COVID-19 disease; 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.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

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).

[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. https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]

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  3. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial. Ann Intern Med. 2020 Oct 20;173(8):623-631. Erratum in: Ann Intern Med. 2021 Mar;174(3):435.
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Cite this document as follows: Clinical Resource,Treatments of Interest for COVID-19. Pharmacist’s Letter/Prescriber’s Letter. July 2022.[380702]





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