The COVID-19 pandemic continues to test health systems across the US. Even with vaccinations readily available and mostly accessible, the US surpassed 1 million total deaths due to COVID-19 in May 2022.1 To prevent future surges in hospital admissions due to the virus, the FDA approved several outpatient options under emergency use authorizations (EUA) for patients who have mild-to-moderate COVID-19 and are at risk for progressing to severe COVID-19. Although these therapies should not replace vaccination or masking, they provide patients with an extra tool for protection against a potentially increasing severity of illness or hospitalization.2 As COVID-19 variants continue to surface, treatments must continue to evolve. Physicians and advanced practice clinicians (APCs) must be able to rapidly evaluate developing data and become proficient with each novel treatment. This article outlines outpatient therapies developed to combat the COVID-19 pandemic.
Molnupiravir and a combination of nirmatrelvir and ritonavir (nirmatrelvir/ritonavir) are oral antiviral agents designed for patients with mild-to-moderate COVID-19 (for example, no hypoxia) at risk for progressing to severe COVID-19, hospitalization, or death.3,4 Molnupiravir may only be used in adults, while nirmatrelvir/ritonavir may be used in patients 12 years of age and older weighing at least 40 kg.2-4 They may be prescribed to patients with positive results of direct SARS-CoV-2 viral testing and at least one risk factor for disease progression (see Risk factors for progression to severe COVID-19).2-4 Providers must be diligent when prescribing these medications because they are most effective when given within 5 days of symptom onset.3,4
Physicians and APCs should be extra vigilant regarding important counseling points and medication safety issues surrounding these drugs. Current guidelines from the National Institutes of Health (NIH) and Infectious Diseases Society of America encourage the use of the nirmatrelvir and ritonavir combination over molnupiravir for patients who are at high risk of progressing to severe COVID-19.2,5
The combination nirmatrelvir/ritonavir and molnupiravir have regimens with high pill burdens (the number of pills a patient needs to take each day). The full course of nirmatrelvir/ritonavir consists of 5 blister cards, each containing a full daily dose with descriptions and yellow and blue coloring indicating morning or evening administration. For patients with moderate renal impairment (eGFR between 30 and 59), a package with fewer nirmatrelvir tablets is available.3
Molnupiravir's dosing regimen is the most straightforward, with four capsules by mouth twice daily for 5 days.4 Nirmatrelvir/ritonavir consists of two separate pills, but administration may be simpler than molnupiravir as the tablets are dispensed in pre-packaged blister cards. In addition, Nirmatrelvir/ritonavir has a lower pill burden, with three tablets by mouth twice daily for 5 days.3 Patients with moderate renal impairment take two nirmatrelvir/ritonavir tablets twice a day.
Confirming patients' understanding of dosing regimens is crucial for efficacy and patient safety.
Risk factors for progression to severe COVID-192
Age 65 years or older
Overweight or obesity (BMI above 25)
Chronic kidney disease
Immunosuppressive disease or immunosuppressive treatment
Cardiovascular disease or hypertension
Chronic lung disease
Sickle cell disease
Neurodevelopmental disorders or other conditions that confer medical complexity∗
Having a medical-related technologic dependence†
∗Examples include genetic or metabolic syndromes and severe congenital anomalies
†Examples include tracheostomy, gastrostomy, or positive pressure ventilation which are not related to COVID-19
Warnings and adverse reactions
Patients should be aware of the common adverse reactions associated with nirmatrelvir/ritonavir and molnupiravir. The most common adverse reactions of nirmatrelvir/ritonavir are dysgeusia (metallic taste often reported), diarrhea, hypertension, and myalgia.3 Molnupiravir may cause diarrhea, nausea, and dizziness.4
Patients receiving nirmatrelvir/ritonavir should have a comprehensive medication review by their healthcare team to screen for potential drug interactions (see Common drug interactions with nirmatrelvir/ritonavir). Nirmatrelvir/ritonavir strongly interacts with CYP3A4, an enzyme involved in drug metabolism.3 Due to this interaction, some medications may need to be held during treatment. Clinicians should be aware of these interactions; however, patients should not stop taking medications without guidance.
Bebtelovimab is a monoclonal antibody indicated for patients 12 years of age and older weighing at least 40 kg.2,7 As of November 2022, the current Omicron variant is expected to be resistant to bebtelovimab. This agent was recommended for patients who could not receive remdesivir or nirmatrelvir/ritonavir.2 Patients must have mild-to-moderate COVID-19 with positive results of direct SARS-CoV-2 viral testing and risk factors for progression to severe COVID-19 to receive this antibody.2,7 Although several monoclonal antibodies have been developed, several others have had their EUA revoked with the emergence of new COVID-19 variants. Bebtelovimab was the last monoclonal antibody with an EUA. On November 30th, 2022, the FDA released a statement removing bebtelovimab's EUA based on the most recent resistance data of the Omicron variant, stating it is not expected to neutralize Omicron subvariants BQ.1 and BQ.1.1. The rationale of the FDA stated, “Given that a COVID-19 infection is likely to be caused by a non-susceptible SARS-CoV-2 variant, and consistent with the terms and conditions of the Letter of Authorization, bebtelovimab is not currently authorized for emergency use in any U.S. region at this time.”8 No clinical efficacy data exists for this monoclonal antibody against the Omicron variant. Currently, the FDA recommends that bebtelovimab should be retained on site, if already in stock, in the event that a bebtelovimab-susceptible SARS-CoV-2 variant should arise.2,7,8,9
Administration and monitoring2,7
Bebtelovimab may be prepared and administered in an outpatient setting. Bebtelovimab is administered by I.V. push over at least 30 seconds, followed by a 0.9% sodium chloride flush.7 Patients should be monitored during and for 1 hour after administration of bebtelovimab for possible infusion-related reactions.7 Serious hypersensitivity reactions, including anaphylaxis, can occur with administration of bebtelovimab.2,7 The most common adverse reactions associated with bebtelovimab are infusion-related reactions, pruritus, and rash (see Infusion-related reactions).2,7 Patients should be informed that infusion-related reactions may occur during the infusion and up to 24 hours after.
Common drug interactions with nirmatrelvir/ritonavir3
|HMG-CoA reductase inhibitors
||Increased concentration of atorvastatin, rosuvastatin, lovastatin, and simvastatin. Temporary discontinuation of atorvastatin and rosuvastatin may be considered. Lovastatin and simvastatin must be discontinued at least 12 hours before the use of nirmatrelvir/ritonavir for the 5 days of treatment and for 5 days after completing treatment.
||May have a varied effect on the concentration of warfarin. Increased concentration of rivaroxaban and apixaban.6 Monitor closely patients taking warfarin. Consider dose reduction of anti-Xa anticoagulants.
|Calcium channel blockers
||Increased concentration of certain calcium channel blockers. Consider dose reduction while taking nirmatrelvir/ritonavir.
||Decreases concentration of bupropion. Increases the concentration of trazodone. Monitor for signs of trazodone toxicity, such as nausea, dizziness, hypotension, and syncope. A lower dose of trazodone should be considered with the concurrent use of nirmatrelvir/ritonavir.
||Lurasidone and pimozide are contraindicated due to life-threatening reactions such as cardiac dysrhythmias. Quetiapine may be coadministered only if necessary, although this may warrant a dose reduction.
Patients should be advised to monitor for signs and symptoms of clinical worsening, including fever, hypoxia, increased respiratory difficulty, dysrhythmias, fatigue, or altered mental status, and may require hospitalization.2,7 It is unknown if these events are related to SARS-CoV-2 monoclonal antibody use or the progression of COVID-19.2
Remdesivir is a SARS-CoV-2 nucleotide analogue RNA polymerase inhibitor that inhibits viral replication by prematurely terminating RNA transcription.10 Since the pandemic's beginning, remdesivir has been reserved for hospitalized patients with COVID-19.2,10 However, remdesivir is effective in an outpatient setting for patients with positive results of direct SARS-CoV-2 viral testing and risk factors for progression to severe COVID-19.10 One study concluded that a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than a placebo.10
Remdesivir is administered by I.V. infusion and may only be administered in settings where there is immediate access to medications to treat a severe infusion or hypersensitivity reaction, such as anaphylaxis, and the ability to activate the emergency medical system, as necessary. Unlike monoclonal antibodies for COVID-19, remdesivir is given in three daily doses and must be initiated within 7 days of symptom onset. The infusion may be given over 30 to 120 minutes, and patients must be monitored for at least 1 hour after each infusion for hypersensitivity reactions.10 According to NIH guidelines, remdesivir is preferred second to nirmatrelvir/ritonavir for patients who do not require hospitalization or supplemental oxygen but who may be at high risk for progressing to severe COVID-19.2 Patients may receive remdesivir if they are 28 days of age and older and weighing at least 3 kg.
chest pain or discomfort
rash including urticaria
Tixagevimab combined with cilgavimab is the first and only IM injection indicated for pre-exposure prophylaxis against COVID-19.11 As COVID-19 variants continue to evolve, resistance to this agent is currently estimated to exceed 45% in all regions of the US as of November 2022.2 Due to a lack of alternative agents, tixagevimab plus cilgavimab is still recommended in qualifying patients.2 Unlike previous interventions, these monoclonal antibodies are for patients who are not currently infected with COVID-19 and have no known recent exposures to infected individuals.2 Patients may receive tixagevimab and cilgavimab if they are 12 years of age and older and weigh at least 40 kg.11 This medication is recommended in patients with moderate to severe immune compromise due to a medical condition, immunosuppressive medications, or treatments that may cause them not to mount an adequate immune response to COVID-19 vaccinations. It is also recommended in those for whom vaccination with any available COVID-19 vaccine is not recommended due to a history of severe adverse reaction to a COVID-19 vaccine(s) or COVID-19 vaccine component(s).2,11 Patients who have received the COVID-19 vaccination should wait at least 2 weeks after their last vaccination to receive tixagevimab/cilgavimab.11 Protection against COVID-19 will last up to 6 months, and then the dose must be repeated every 6 months.11
Administration and monitoring
Each tixagevimab/cilgavimab carton contains two single-dose vials: one of each monoclonal antibody. Do not shake the vials.11 Two syringes should be used, one for each vial, and given at different I.M. injection sites.11 Preferably, one injection is given in each gluteal muscle.11 The time allowed from vial puncture to administration should not exceed 4 hours.11 After administration, patients should be monitored for 1 hour for hypersensitivity reactions.11 Also, patients should be advised that adverse reactions, such as headaches, fatigue, and cough, may occur.11
1. Centers for Disease Control and Prevention. COVID data tracker. 2022. https://covid.cdc.gov/covid-data-tracker/#datatracker-home
Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19
) Treatment Guidelines. National Institutes of Health. www.covid19treatmentguidelines.nih.gov/
. Accessed February 22, 2022.
3. Pfizer Inc: Fact sheet for healthcare providers: Emergency Use Authorization for PAXLOVID(TM). US Food & Drug Administration (FDA). Silver Spring, MD. 2021.
4. Merck Sharp & Dohme Corp: Fact sheet for healthcare providers: Emergency Use Authorization for MOLNUPIRAVIR. US Food & Drug Administration (FDA). Silver Spring, MD. 2021.
5. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the treatment and management of patients with COVID-19
. Clin Infect Dis
. [e-pub Apr. 27, 2020]
6. Product Information: ELIQUIS(R) oral tablets, apixaban oral tablets. Bristol-Myers Squibb (per manufacturer). Princeton, NJ. 2012.
7. US Food and Drug Administration (FDA). Fact sheet for healthcare providers: emergency use authorization for bebtelovimab. 2022. https://www.fda.gov/media/156152/download
. Accessed February 14, 2022.
8. US Food and Drug Admnistration (FDA). FDA Announces Bebtelovimab is Not Currently Authorized in Any US Region. https://www.fda.gov/drugs/drug-safety-and-availability/fda-announces-bebtelovimab-not-currently-authorized-any-us-region
. Published November 30, 2022. Accessed December 12, 2022.
9. Cathcart AL, Havenar-Daughton C, Lempp FA, et al. The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv. 2021. Updated manuscript submitted and online pre-print publication pending
10. Gottlieb RL, Vaca CE, Paredes R, et al GS-US-540-9012 (PINETREE) Investigators. Early remdesivir to prevent progression to severe Covid-19
in outpatients. N Engl J Med
. Published online December 22, 2021. doi:10.1056/NEJMoa2116846
11. AstraZeneca Pharmaceuticals LP: Fact sheet for healthcare providers: Emergency Use Authorization (EUA) for EVUSHELD(TM) (tixgevimab co-packaged with cilgavimab). US Food & Drug Administration (FDA). Silver Spring, MD. 2021