COVID-19 MANAGEMENT AND TREATMENT

• ACRONYMS AND DEFINITIONS

• AAP - American Academy of Pediatrics
• CDC - Center for Disease Control and Prevention
• DIC - Disseminated intravascular coagulation
• EUA - Emergency use authorization
• MIS - Multisystem inflammatory syndrome
• NIH - National Institute of Health
• SARS-CoV-2 - Severe acute respiratory syndrome coronavirus 2

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• COVID-19 REVIEW

• Epidemiology - COVID-19 is a viral infection that first appeared in Wuhan, China, in December 2019. The virus went on to cause one of the most deadly pandemics in human history, and to date, it continues to mutate, infect, and kill thousands of people. The virus spreads easily and rapidly, and people of all ages are affected.

• Pathology - COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus is spread through infected respiratory droplets when they are breathed in or land on a person's eyes, nose, or mouth. The virus can also be transmitted through objects when a person touches a contaminated surface and then touches their eyes, nose, or mouth. Like other upper respiratory viruses, SARS-CoV-2 initially infects epithelial cells of the upper respiratory tract. Infected epithelial cells necrose, and inflammation ensues, causing typical upper respiratory symptoms (e.g. cough, congestion). In some people, the virus progresses to involve the lower airways where it infects pulmonary capillary endothelial cells; this triggers an influx of WBCs and inflammation that leads to alveolar edema and hypoxia. SARS-CoV-2 also infects and kills T lymphocytes, and most patients with severe disease have lymphopenia. In some individuals, the coagulation cascade becomes activated, causing DIC and/or thrombosis. Children may develop a rare condition called multisystem inflammatory syndrome (MIS) that is poorly understood but has features similar to Kawasaki disease. MIS typically presents 2 - 6 weeks following SARS-CoV-2 infection, and in some cases, the initial infection may be asymptomatic. MIS is marked by acute inflammation of multiple organs, which may include the heart, gastrointestinal tract, lungs, blood cells, skin, mucous membranes, kidneys, and nervous system.

• Symptoms - the typical incubation period for SARS-CoV-2 is 4 - 6 days, but it may be as long as 2 weeks in some cases. Symptoms of COVID-19 include the following: fever, cough, headache, sore throat, congestion, fatigue, muscle aches, shortness of breath, loss of smell/taste, and gastrointestinal upset (nausea, diarrhea, vomiting). Children have fewer symptoms than adults, and between 20 - 45% are asymptomatic. Most symptoms resolve within 10 days, and severe illness is seen in 1 - 6% of patients. Symptoms of MIS include persistent fever, conjunctivitis, swollen hands and feet, and cracked lips.

• Diagnosis - two widely available tests are used to diagnose COVID-19: nucleic acid amplification tests (NAATs) and antigen tests. NAATs detect the presence of viral RNA in an upper respiratory sample, and they are very sensitive and specific. Most NAATs are performed in a lab, so results may not be available for days. Antigen tests detect the presence of SARS-CoV-2 antigens in a specimen. These tests are less sensitive than NAATs, but their specificity is high, which means a positive test makes COVID infection likely. Antigen tests can be performed with simple kits that give results in minutes, and they are cheaper than NAATs. SARS-CoV-2 antibody tests are available, but they are not helpful in diagnosing acute infection. See NIH testing recommendations for more.

• Prevention - COVID-19 can be prevented through vaccination (≥ 6 months old), wearing masks, social distancing (6 feet away from others), and avoiding crowded spaces. [1,2,3,4]

• Quarantine - quarantine recommendations from the CDC are available here - CDC COVID quarantine recommendations

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• DISEASE CATEGORIES (NIH DEFINED)

• Mild COVID - individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging


• Moderate COVID - individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation (SpO2) ≥ 94% on room air at sea level


• Severe COVID - individuals who have SpO2 < 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300 mm Hg, a respiratory rate > 30 breaths/min, or lung infiltrates > 50%

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• MANAGEMENT GUIDELINES

• Overview
• The National Institute of Health (NIH) has created a website where they provide COVID treatment recommendations. The guidelines are continually updated based on new evidence and therapies as they become available. Links to different parts of the guidance are provided below, along with select guidelines from the CDC and AAP.

• General management recommendations
• COVID-19 overview [NIH]
• Testing recommendations [NIH]
• Prevention recommendations [NIH]
• COVID disease definitions (e.g. mild, moderate, severe) [NIH]

• Outpatient management
• General management recommendations [NIH]
• Treatment recommendations for nonhospitalized adults [NIH]
• Review of evidence for different therapies including those that are not recommended (e.g. ivermectin, chloroquine, fluvoxamine) [NIH]
• Quarantine and isolation recommendations [CDC]

• Inpatient management
• Therapy recommendations for hospitalized adults [NIH]
• Critical care recommendations [NIH]

• Special populations
• Special population recommendations (pregnancy, children, cancer, transplant, HIV, influenza) [NIH]

• Multisystem inflammatory syndrome (MIS) recommendations
• MIS recommendations [NIH]
• MIS criteria [CDC]
• MIS management recommendations [AAP]

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• NIRMATRELVIR (PAXLOVID®)

• EUA indications
• Treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression (see high-risk criteria below) to severe COVID-19, including hospitalization or death. Treatment should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset.

• Patient eligibility checklist
• On 5/4/2022, the FDA published a "Paxlovid Patient Eligibility Screening Checklist Tool for Prescribers" to help determine which patients should receive Paxlovid. The tool includes guidance on common drug interactions.
• FDA Paxlovid screening tool (pdf)

• Mechanism of action
• Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing polyprotein precursors, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro in a biochemical assay with a Ki value of 3.1 nM and an IC₅₀ value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography.
• Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

• Side effects
• In the EPIC-HR trial (N=2224), Paxlovid side effects that occurred at an incidence ≥ 1% and more than placebo are presented in the table below

Paxlovid side effects
Side effect	Paxlovid	Placebo
Taste perversion	6%	<1%
Diarrhea	3%	2%
Hypertension	1%	<1%
Myalgia	1%	<1%

• Contraindications
• History of significant hypersensitivity reaction to the drug
• Concomitant CYP3A4 sensitive substrates. Ritonavir is a CYP3A4 strong inhibitor, and it may increase exposure to CYP3A4 substrates (see drug interactions below). Paxlovid should not be given with the following drugs:
• Alpha1-adrenoreceptor antagonist: alfuzosin
• Analgesics: pethidine, piroxicam, propoxyphene
• Antianginal: ranolazine
• Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
• Anti-gout: colchicine
• Antipsychotics: lurasidone, pimozide, clozapine
• Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
• HMG-CoA reductase inhibitors: lovastatin, simvastatin
• PDE5 inhibitor: sildenafil (Revatio®) when used for pulmonary arterial hypertension (PAH)
• Sedative/hypnotics: triazolam, oral midazolam
• Concomitant CYP3A4 strong inducers may increase the metabolism of Paxlovid and reduce its effectiveness. Paxlovid cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer.
• Anticancer drugs: apalutamide
• Anticonvulsant: carbamazepine, phenobarbital, phenytoin
• Antimycobacterials: rifampin
• Herbal products: St. John’s Wort (hypericum perforatum)

• Precautions
• Hepatotoxicity
• Hepatotoxicity including liver enzyme elevations, hepatitis, and jaundice have occurred in patients receiving ritonavir. Use caution when prescribing to patients with liver disease.

• HIV-1 resistance
• Ritonavir is a protease inhibitor used to treat HIV. There may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

• Kidney disease
• CrCl ≥ 60 ml/min: no dose adjustment necessary
• CrCl 30 - 59 ml/min: dosing is nirmatrelvir 150 mg and ritonavir 100 mg twice daily for 5 days
• CrCl < 30 ml/min: not recommended

• Liver disease
• Child-Pugh A or B: no dose adjustment necessary
• Child-Pugh C: has not been studied. Not recommended.

• Drug interactions
• Paxlovid contains ritonavir, which is included to inhibit the metabolism of nirmatrelvir, the active drug. Ritonavir is a CYP3A4 strong inhibitor, and therefore, it has many significant drug interactions. Paxlovid should not be taken with certain drugs (see contraindications above), and there are a number of other drugs where it should be used with caution. See the Paxlovid PI [sec 7] for more.
• The University of Liverpool has published a website that offers guidance on drug interactions associated with COVID-19 drugs, including Paxlovid. The website is available here - University of Liverpool COVID-19 drug interactions.

• Dosing
• Dosage form
• Nirmatrelvir 150 mg tablet and ritonavir 100 mg tablet
• Comes in carton with 5 daily-dose blister cards. Each card contains four nirmatrelvir 150 mg tablets and two ritonavir 100 mg tablets.
• Dosing
• Nirmatrelvir 300 mg (two 150 mg tablets) + ritonavir 100 mg (one 100 mg tablet) twice daily for 5 days
• Treatment should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset
• May take without regard to food
• Do not crush, cut, or chew tablets
• No dosage adjustment is required when co-administered with other products containing ritonavir or cobicistat. Patients on ritonavir- or cobicistat-containing HIV or HCV regimens should continue their treatment as indicated.
• Missed doses
• If a dose is missed within 8 hours of the time it is usually taken, take it as soon as possible and resume the regular dosing schedule. If a dose is missed by more than 8 hours, do not take the missed dose and instead take the next dose at the regularly scheduled time. Do not double the dose to make up for a missed dose.
• Dosing in kidney disease
• CrCl ≥ 60 ml/min: no dose adjustment necessary
• CrCl 30 - 59 ml/min: dosing is nirmatrelvir 150 mg and ritonavir 100 mg twice daily for 5 days
• CrCl < 30 ml/min: not recommended
• Dosing in liver disease
• Child-Pugh A or B: no dose adjustment necessary
• Child-Pugh C: has not been studied. Not recommended. [6]

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• MOLNUPIRAVIR (LAGEVRIO™)

• EUA indications
• Treatment of mild-to-moderate COVID-19 in adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, who are at high risk for progression (see high-risk criteria below) to severe COVID-19, including hospitalization or death and for whom alternative COVID-19 treatment options authorized by FDA are not accessible or clinically appropriate. Treatment should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset.

• Mechanism of action
• Molnupiravir is a prodrug with antiviral activity against SARS-CoV-2. It is metabolized to the cytidine nucleoside analogue, NHC which distributes into cells where NHC is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP incorporation (as NHC-monophosphate [NHC-MP]) into SARS-CoV-2 RNA by the viral RNA polymerase (nsp12) results in an accumulation of errors in the viral genome leading to inhibition of replication. The mechanism of action (known as viral error catastrophe or viral lethal mutagenesis) is supported by biochemical and cell culture data, studies of SARS-CoV-2 infection in animal models, and analyses of SARS-CoV-2 genome sequences in human subjects treated with molnupiravir.

• STUDY
  Molnupiravir vs Usual Care for COVID-19 in a Highly Vaccinated (94%) Population, Lancet (2023) [PubMed abstract]
• Design: Randomized, open-label trial (N=26,411 | length = 28 days) in patients (mean age 56.6 years) with confirmed COVID-19 for ≤ 5 days who were older than 50 or older than 18 with relevant comorbidities. 94% of participants had received at least 3 doses of a COVID vaccine.
• Treatment: Molnupiravir 800 mg twice daily for 5 days vs Usual care
• Primary outcome: All-cause hospitalization or death within 28 days of randomization
• Results:
• Primary outcome: Molnupiravir - 1%, Usual care - 1% (odds ratio 1.06, 95% Bayesian credible interval [0.81 - 1.41])
• Findings: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalizations or death among high-risk vaccinated adults in the community.

• Side effects
• Side effects that occurred in ≥ 1% of subjects in the molnupiravir and placebo groups were diarrhea (2% vs 2%), nausea (1% vs 1%), and dizziness (1% vs 1%)

• Contraindications
• None known

• Precautions
• Pregnancy risks (male and female)
• Based on findings from animal reproduction studies, molnupiravir may cause fetal harm. There are no data available from human studies. Molnupiravir is not recommended during pregnancy unless it has been determined the potential benefits outweigh the risks and the patient provides informed consent. If pregnancy status is unknown, pregnancy testing should be performed before treatment.
• Females of childbearing potential should use a reliable method of contraception correctly and consistently, as applicable, for the duration of treatment and for 4 days after the last dose of molnupiravir.
• The effect of molnupiravir on sperm cells is unknown. Males of reproductive potential who are sexually active with females of childbearing potential should use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after the last dose.

• Bone and cartilage toxicity
• Molnupiravir may affect bone and cartilage growth; therefore, it is not recommended in patients under 18 years of age

• Kidney disease
• No dose adjustment is recommended for any degree of renal impairment

• Liver disease
• No dose adjustment is recommended for any degree of liver disease

• Drug interactions
• Molnupiravir has no known drug interactions

• Dosing
• Dosage form
• 200 mg capsule
• Dosing
• 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days, with or without food
• Treatment should be initiated as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset.
• Missed doses
• If a dose is missed within 10 hours of the time it is usually taken, take it as soon as possible and resume the regular dosing schedule. If a dose is missed by more than 10 hours, do not take the missed dose and instead take the next dose at the regularly scheduled time. Do not double the dose to make up for a missed dose. [7]

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• ANTIBODY TREATMENTS

• Recommended therapies
• As of November 30th, 2022, no antibody treatments are authorized for use in the U.S.

• EUA indications
• Bamlanivimab plus etesevimab
• Treatment - treatment of mild to moderate COVID in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct COVID viral testing, and who are at high risk for progression (see high-risk criteria below) to severe COVID-19, including hospitalization or death. Drug should be given as soon as possible after a positive test and within 10 days of symptom onset.
• Post-exposure prophylaxis - see postexposure prophylaxis criteria below


• Bebtelovimab
• Treatment - treatment of mild to moderate COVID in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct COVID viral testing, and who are at high risk for progression (see high-risk criteria below) to severe COVID-19, including hospitalization or death. Drug should be given as soon as possible after a positive test and within 7 days of symptom onset.


• Casirivimab plus imdevimab (REGEN-COV®)
• Treatment - treatment of mild to moderate COVID in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct COVID viral testing, and who are at high risk for progression (see high-risk criteria below) to severe COVID-19, including hospitalization or death. Drug should be given as soon as possible after a positive test and within 10 days of symptom onset.
• Post-exposure prophylaxis - see postexposure prophylaxis criteria below


• Sotrovimab
• Treatment - treatment of mild to moderate COVID in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct COVID viral testing, and who are at high risk for progression (see high-risk criteria below) to severe COVID-19, including hospitalization or death. Drug should be given as soon as possible after a positive test and within 10 days of symptom onset. [5]

• Postexposure prophylaxis criteria
• Adults and pediatric patients (12 years of age and older weighing at least 40 kg) who are at high risk of progression to severe COVID-19, including hospitalization or death, and are not fully vaccinated^✝ or who are not expected to mount an adequate immune response to complete COVID vaccination (for example, individuals with immunocompromising conditions including those taking immunosuppressive medications) and meet one of the following criteria:
• Have been exposed to an individual infected with COVID consistent with close contact criteria per CDC
• Are at high risk of exposure to an individual infected with COVID because of occurrence of COVID infection in other individuals in the same institutional setting (for example, nursing homes, prisons) [5]
• ^✝Individuals are considered to be fully vaccinated 2 weeks after their second vaccine dose in a 2-dose series (such as the Pfizer or Moderna vaccines), or 2 weeks after a single-dose vaccine (such as Johnson & Johnson's Janssen vaccine)

• Postexposure prophylaxis
• Casirivimab + imdevimab and bamlanivimab + etesevimab have EUAs for COVID postexposure prophylaxis. The two studies that led to their approval are detailed below. For bamlanivimab + etesevimab, only bamlanivimab was used in the study, but the EUA is for the combination drug.

• STUDY
  Casirivimab + Imdevimab (REGEN-COV) vs Placebo for the Prevention of COVID in Household Contacts, NEJM (2021) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=1505 | length = 28 days) in asymptomatic healthy patients (≥ 12 years old and adults) who were household contacts of an index patient (defined as the first person with a diagnosis of COVID in the household). Subjects were eligible to participate if they anticipated living with the index patient for at least 28 days. Participants underwent randomization within 96 hours after collection of the index patient’s positive COVID diagnostic test sample, and persons with previous COVID infection were excluded.
• Treatment: REGEN-COV 1200 mg (600 mg each of casirivimab and imdevimab) subcutaneously vs Placebo
• Primary outcome: Development of symptomatic COVID infection through day 28 in participants who did not have COVID infection (as measured by reverse-transcriptase–quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity)
• Results:
• Primary outcome: REGEN-COV - 1.5%, Placebo - 7.8% (p<0.001)
• Findings: Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load.

• STUDY
  Bamlanivimab vs Placebo for the Prevention of COVID in Skilled Nursing and Assisted Living Facilities, JAMA (2021) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=966 | length = 8 weeks) among residents and staff living in skilled nursing and assisted living facilities with at least 1 confirmed COVID index case
• Treatment: Bamlanivimab 4200 mg IV one time vs Placebo within 7 days of the reported confirmed case
• Primary outcome: Cumulative incidence within 8 weeks of randomization of COVID-19, defined as detection of SARS-CoV-2 by RT-PCR and presence of mild or worse disease severity within 21 days of detection
• Results:
• Primary outcome: Bamlanivimab - 8.5%, Placebo - 15.2% (p<0.001)
• Findings: Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy.

• Side effects
• In single-dose trials, all three antibody infusions were well tolerated. Infusion-related reactions were observed in around 1% of patients, and serious reactions, including anaphylaxis, have been reported in < 1% of patients.
• Other side effects occurred at a low incidence and were similar to placebo [5]

• Contraindications / Precautions
• The only contraindication to antibody infusions is a history of hypersensitivity reactions to the product
• Precautions include hypersensitivity reactions and possible worsening of COVID after infusion, which is likely related to COVID progression and not the drug

• Kidney disease - kidney disease is not expected to affect antibody clearance

• Liver disease
• Bamlanivimab or etesevimab - mild liver disease (Child-Pugh A) does not affect clearance; has not been studied in moderate or severe liver disease.
• Casirivimab and imdevimab - has not been studied
• Sotrovimab - has not been studied [5]

• Drug interactions
• Antibody treatments are not renally excreted, nor are they metabolized by hepatic enzymes; therefore, they are unlikely to have significant drug interactions [5]

• Bamlanivimab plus etesevimab (adults and children ≥ 12 years and weighing at least 40 kg)
• Treatment: bamlanivimab 700 mg and etesevimab 1400 mg administered together via IV infusion as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset
• Post-Exposure Prophylaxis: bamlanivimab 700 mg and etesevimab 1400 mg administered together via IV infusion as soon as possible following exposure to SARS-CoV-2

• Bebtelovimab (adults and children ≥ 12 years and weighing at least 40 kg)
• Treatment: 175 mg administered as a single intravenous injection over at least 30 seconds. Administer bebtelovimab as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 7 days of symptom onset. See bebtelovimab fact sheet for more.

• Casirivimab plus imdevimab - REGEN-COV® (adults and children ≥ 12 years and weighing at least 40 kg)
• Treatment: casirivimab 600 mg and imdevimab 600 mg administered by subcutaneous injection or together as an IV infusion as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset
• Post-Exposure Prophylaxis: casirivimab 600 mg and imdevimab 600 mg administered by subcutaneous injection or together as an IV infusion as soon as possible following exposure to SARS-CoV-2. If ongoing exposure for longer than 4 weeks is expected, repeat dosing of casirivimab 300 mg and imdevimab 300 mg by subcutaneous injection or intravenous infusion once every 4 weeks may be appropriate.

• Sotrovimab (adults and children ≥ 12 years and weighing at least 40 kg)
• Treatment: sotrovimab 500 mg IV as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 10 days of symptom onset [5]

• Other studies
• Casirivimab plus Imdevimab (REGEN-COV®) for Inpatient COVID, Lancet (2022) [PubMed abstract]

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• REMDESIVIR (VEKLURY®)

• Indications: In January 2022, the FDA granted an EUA to the viral RNA polymerase inhibitor remdesivir for the outpatient treatment of COVID in adults and pediatric patients (12 years of age and older and weighing at least 88 lbs (40 kg)) with mild-to-moderate COVID-19 who are at high risk for progression to severe COVID-19. On April 22, 2022, the FDA expanded its EUA to include pediatric patients 28 days of age and older weighing at least 7 pounds (3 kg). Remdesivir should be given as soon as possible and within 7 days of symptom onset. [Veklury PI]
• Dosing: Remdesivir is administered as an IV infusion, and dosing for adult outpatients is as follows: 200 mg IV on Day 1 followed by 100 mg IV on Days 2 and 3.
• Precautions / side effects: Hypersensitivity reactions, including anaphylaxis, have occurred, and remdesivir should only be administered in a setting that is equipped to handle these situations. Patients should be monitored for at least an hour after the end of the infusion. The most common side effects seen in trials were increases in liver enzymes (AST, ALT) and nausea. The remdesivir prescribing information recommends checking liver function tests before and during therapy. It should not be given to patients with a GFR < 30 ml/min. See remdesivir prescribing information for more.
• Efficacy: Remdesivir vs Placebo for Outpatient COVID in High-risk Adults, NEJM (2022) [PubMed abstract]

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• HIGH-RISK CRITERIA

• Overview
• High-risk criteria from the EUA and CDC website are listed below. The NIH has also issued recommendations for the prioritization of outpatient treatments when supplies are limited. That guidance is available here - NIH prioritization of outpatient COVD treatments.


• High-risk criteria (from EUA and CDC website)
• Older age (for example age ≥ 65 years of age)
• Obesity or being overweight (for example, adults with BMI >25 kg/m2, or if age 12-17, have BMI ≥ 85th percentile for their age and gender based on CDC growth charts)
• Pregnancy
• Chronic kidney disease
• Chronic liver disease
• Diabetes
• Cancer
• Tuberculosis
• Mental health condition including substance use disorders
• Solid organ or blood stem cell transplant
• Immunosuppressive disease or immunosuppressive treatment
• Cardiovascular disease (including congenital heart disease) or hypertension
• Cerebrovascular disease (e.g. stroke)
• Chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension)
• Sickle cell disease or thalassemia
• Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies)
• Dementia or other neurological conditions
• Down syndrome
• Smoking, current or former
• Having a medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19))

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• PRE-EXPOSURE PROPHYLAXIS

• Evusheld®
• On December 8, 2021, the FDA granted an EUA to the long-acting monoclonal antibody treatment Evusheld® (tixagevimab co-packaged with cilgavimab) for the pre-exposure prophylaxis of COVID-19 in certain high-risk adults and pediatric patients 12 years and older weighing at least 40 kg (88 lbs). On 1/26/2023, the FDA issued an update stating that Evusheld was no longer authorized for emergency use because it is unlikely to be active against the current predominant COVID variants. [FDA Evusheld dosing update]
• Evusheld® is given as two separate consecutive IM injections, with one containing 300 mg of tixagevimab and the other 300 mg of cilgavimab. The injections may be repeated in 6 months. [Evusheld® PI]
• The NIH recommendations for using Evusheld® are available here - NIH statement on the use of Evusheld®
• A study published in 2022 found that Evusheld® was effective in preventing severe COVID or death in unvaccinated patients recently diagnosed with mild to moderate COVID [PMID 35688164]

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• BIBLIOGRAPHY

• 1 - CDC website
• 2 - PMID 34261902 - Coronavirus disease 2019 in children, Curr Opin Infect Dis (2021)
• 3 - PMID 32648899 - Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19), JAMA (2020)
• 4 - PMID 32766824 - A Pediatric Infectious Disease Perspective on COVID-19, Clin Infect Dis (2021)
• 5 - Manufacturer's prescribing information
• 6 - Fact sheet for healthcare providers: emergency use authorization for Paxlovid
• 7 - Fact sheet for healthcare providers: emergency use authorization for Molnupiravir