April 28, 2022

Clinician Advisory: Treatments for Outpatients with Mild to Moderate COVID-19 Who are at Increased Risk for Severe Outcomes of COVID-19

Requested Actions: 

• Encourage patients to be fully vaccinated and up-to-date with respect with COVID-19 vaccine booster recommendations. This provides the best and most efficient protection against severe disease. If you  are not able to vaccinate them at your site, refer them to this online vaccine finder or to the websites of most commercial chain pharmacies.
• Offer NIH-recommended treatment to patients with mild to moderate COVID-19 who are not hospitalized and who are at increased risk for severe COVID-19 outcomes.  Several treatment options are available.
• Assist patients in finding COVID therapeutics through the ASPR website for Test-to-Treat services and COVID therapeutics locator. 

Background & Highlights:

• Outpatient therapy for COVID-19 in high-risk patients can benefit individual patient health while also mitigating the collective impact of severe illness on the healthcare system.   Timely initiation can reduce the risk of hospitalization by up to 90%.   
• For outpatient treatment, oral nirmatrelvir/ritonavir (Paxlovid) and intravenous remdesivir are the preferred options; however, remdesivir access is currently limited to hospital settings due logistical constraints imposed by intravenous administration.  
• Alternative agents should be considered when preferred agents are contraindicated or not available.   For example:
  1. Paxlovid (primarily its ritonavir component) inhibits CYP3A4. Both protease inhibitor constituents in Paxlovid are CYP3A4 substrates as well.   Consequently, Paxlovid is contraindicated in patients taking drugs that are highly metabolized by CYP3A4 where elevated concentrations can be life-threatening.  It is also contraindicated in patients taking potent CYP3A4 inducers which may reduce the eff­ectiveness of Paxlovid and may contribute to the development of drug resistance. See Additional Resources section below for drug interaction detection and management guidance.  
  2. Paxlovid is not recommended for patients with severely impaired hepatic function (Child-Pugh Class C);
  3. Paxlovid is not recommended for patients with eGFR<30; renal dosing guidelines have been established for patients with lesser degrees of renal insufficiency.
  4. Oral antivirals are not authorized for initiation if the patient is more than 5 days out from the onset of symptoms.  Bebtelovimab is authorized and remdesivir is approved for initiation up through day 7.
  5. Molnupiravir is not recommended for use in pregnant patients.  
• Evusheld (tixagevimab/cilgavimab) is a monoclonal antibody preparation authorized for pre-exposure prophylaxis among immunosuppressed patients who are unlikely to respond to vaccine or among patients unable to complete vaccination due to severe adverse reactions. For more information, see the EUA Fact Sheet.  

Additional Resources:

• CDC. Health Advisory (April 25, 2022): Updated Information on Availability and Use of Treatments for Outpatients with Mild to Moderate COVID-19 Who are at Increased Risk for Severe Outcomes of COVID-19.  
• NIH.  Therapeutic Management of Nonhospitalized Adults with COVID-19.  
• Drug-drug Interaction Resources
  1. University of Liverpool.  COVID-19 Drug Interactions.    
  2. Science Table (COVID-19 Advisory for Ontario [Canada]). Nirmatrelvir/Ritonavir (Paxlovid): What Prescribers and Pharmacists Need to Know.
• FDA. Emergency Use Authorization Fact Sheets for Healthcare Providers
  1. Paxlovid
  2. Molnupiravir
  3. Bebtelovimab
  4. Evusheld
• Gilead.  Highlights of [Remdesivir (Veklury)] Prescribing Information.
• Washington State Department of Health.  COVID-19 Therapeutics Information for Health Care Providers.   
• CDC.  COVID-19 Vaccine Boosters.