Questions-and-Answers-Treatment-Information-for-Providers-and-Facilities Questions and Answers: Treatment Information for Providers and Facilities

Questions and Answers: Treatment Information for Providers and Facilities

Updates as of April 20, 2022:

  • On February 11, 2022, the FDA issued an EUA for the monoclonal antibody bebtelovimab for the treatment of mild to moderate COVID-19.
  • On February 24, 2022, the FDA revised the EUA for tixagevimab/cilgavimab (Evusheld) to change the initial dose for the authorized use as pre-exposure prophylaxis from 150 mg of tixagevimab and 150 mg of cilgavimab administered to 300 mg of tixagevimab and 300 mg of cilgavimab.  
  • Beginning on March 7, 2022, the U.S. Department of Health and Human Services (HHS) began distributing the oral antiviral treatments, Paxlovid and molnupiravir, directly to federally-qualified health centers (FQHCs), pharmacy-based clinics, and long-term health facilities as part of the new federal Test to Treat program.
  • With recent data showing that sotrovimab is not effective against the Omicron BA.2 subvariant, the FDA updated the EUA for sotrovimab so that it is no longer authorized for use in any U.S. state or territory at this time.
  • On April 1, the NIH updated the guidelines on the preferred and alternative therapies for non-hospitalized patients

Introduction 

Frequently Asked Questions About Outpatient Treatments for SARS-CoV-2 

Treatment for Acute Infection

1. What anti-SARS-CoV-2 outpatient treatment options are available?

2. Who is a candidate for anti-SARS-CoV-2 outpatient treatment?

3. Can children be prescribed anti-SARS-CoV-2 outpatient treatments?

4. Can a patient who is hospitalized due to COVID-19 receive anti-SARS-CoV-2 outpatient treatment?

Post-Exposure Prophylaxis

5. What SARS-CoV-2 post-exposure prophylaxis options are available?

Pre-Exposure Prophylaxis

6. What SARS-CoV-2 pre-exposure prophylaxis options are available?

General Questions

7. How do I determine if my patient qualifies for anti-SARS-CoV-2 outpatient treatment or prophylaxis? 

8. Are there recommendations for which therapies should be preferred in nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease?

9. Where can I find guidance on patient prioritization for outpatient therapeutics when there are logistical or supply constraints?

10. Where can I find information on the side effects of available COVID-19 therapeutics and criteria for use, preparation, and administration?

11. My patient qualifies for anti-SARS-CoV-2 treatment or prophylaxis. What should I do next?

12. How will my facility be reimbursed for the cost of administering anti-SARS-CoV-2 treatment or prophylaxis?

 

Introduction 

Several COVID-19 outpatient therapeutic options are available in the United States, including those for treatment of acute infection, pre-exposure prophylaxis, and post-exposure prophylaxis. Treatments can be ordered for eligible patients based on exposure status, symptoms, and risk factors for severe disease progression, as outlined in the NIH treatment guidelines for non-hospitalized patients. Ultimately, COVID-19 treatments play an important role in preventing illness and helping people recover from COVID-19, with the goal of saving lives, reducing hospitalizations, and releasing pressure on stressed hospital systems.  For more information about the available outpatient treatments, please refer to the U.S. Department of Health and Human Services (HHS) Side-by-Side Overview of Therapies (PDF).

Overview of COVID-19 Outpatient Treatment Options

SARS-CoV-2 Negative (-)

Not Exposed

Exposed

Pre-Exposure Prophylaxis (PrEP)

Post-Exposure Prophylaxis (PEP)

Long-Acting Monoclonal Antibody

  • Tixagevimab/cilgavimab (Evusheld)

Currently no authorized treatments

SARS-CoV-2 Positive (+)

Mild to Moderate Illness in Individual at High Risk for Disease Progression

Treatment options, in order of preference:

1. Niramtrelivr/ritonavir (Paxlovid)

2. Remdesivir (Veklury)

If above options are unavailable or not medically appropriate, can consider (in alphabetical order):

3. Bebtelovimab

4. Molnupiravir (Lagevrio)

Anti-SARS-CoV-2 Monoclonal Antibody (mAb) Treatments

Monoclonal antibodies are synthetic proteins that mimic the immune system's ability to fight off harmful antigens such as viruses. Monoclonal antibodies are directed against the spike protein of SARS-CoV-2 and block the virus' attachment and entry into human cells.

Early intervention with monoclonal antibody treatment reduces the risk of severe illness and hospitalization in high-risk patients with mild to moderate COVID-19. Additionally, specific monoclonal antibody treatments can be used to decrease the chances of developing COVID-19 after an infectious exposure (as a post-exposure prophylaxis) or before an infectious exposure (as a pre-exposure prophylaxis) in certain at-risk individuals.

Antiviral Treatments

Antiviral medications interfere with viral processes. Like monoclonal antibodies, antivirals reduce the risk of severe disease in individuals with mild to moderate COVID-19. They are currently only approved for treatment of COVID-19 disease and not as a pre- or post-exposure prophylaxis.

Frequently Asked Questions about Outpatient Treatments for SARS-CoV-2 

 

Treatment for Acute Infection  

 

1.    What are the outpatient treatment options for acute infection with COVID-19?

Monoclonal Antibody Treatments

There are four anti-SARS-CoV-2 monoclonal antibodies that have received Emergency Use Authorization (EUA) from the Food and Drug Administration (FDA). However, with the predominance of the Omicron variant and the BA.2 subvariant throughout the United States, only one anti-SARS-CoV-2 monoclonal antibody is currently authorized for treatment (bebtelovimab). Because they are ineffective against the Omicron variant and/or the Omicron BA.2 subvariant, bamlanivimab/etesevimab, casirivimab/imdevimab (REGEN-COV), and sotrovimab are not authorized for use in any U.S. states, territories, and jurisdictions at this time. 

 

Drug Route Age groups authorized for treatment Timing of Treatment Treatment Effectiveness Activity Against Variants Currently Circulating
Bebtelovimab 175 mg
given as a single intravenous injection
Intravenous12 years and older and weighing at least 40 kg

As soon as possible, but within 7 days of symptom onset

 

In low-risk adults, 34% relative reduction in viral load compared to placebo and a relative reduction in time to sustained symptom resolution compared to placebo. Currently there is no trial data to determine difference in clinical outcomes between placebo and treatment arms.Effective against Omicron, including BA.2 subvariant

 

For more information about the anti-SARS-CoV-2 monoclonal antibodies, please refer to the NIH's Table 3c. Characteristics of SARS-CoV-2 Antibody-based Products.  

 

Antiviral Treatments

There are currently two oral SARS-CoV-2 antivirals that have received EUAs from the FDA for outpatient treatment of acute COVID-19 infection - molnupiravir (branded as Lagevrio) and nirmatrelvir/ritonavir (branded as Paxlovid). Additionally, remdesivir (branded as Veklury) is a SARS-CoV-2 antiviral given intravenously or intramuscularly (for pediatric patients) that has  FDA approval as an inpatient treatment and has been added to the NIH outpatient treatment guidelines. Remdesivir has been granted supplemental New Drug Application (sNDA) approval as a treatment for mild to moderate disease in high-risk adult and pediatric outpatients 12 years and older weighing at least 40 kg. Its pediatric EUA was expanded to include hospitalized and non-hospitalized pediatric patients younger than 12 years of age as well.

Drug Route Age groups authorized for treatment Timing of Treatment Effectiveness Activity Against Variants Currently Circulating

Nirmatrelvir 300 mg with ritonavir 100 mg (Paxlovid)

Orally twice daily for 5 days

Oral12 years and older and weighing at least 40 kgAs soon as possible, but within 5 days of symptom onsetCompared to placebo, a relative risk reduction of 89% in hospitalizations or deaths.Effective against Omicron, including BA.2 subvariant

Remdesivir (Veklury)

200 mg IV on Day 1, followed by 100 mg IV daily on Days 2 and 3

For pediatric dosing, see EUA Factsheet (PDF)

Intravenous

FDA approved for use: 12 years and older and weighing at least 40 kg

FDA EUA for use: pediatric outpatients <12 years and/or children weighing 3.5 kg to 40 kg

As soon as possible, but within 7 days of symptom onsetCompared to placebo, a relative risk reduction of 87% in hospitalizations or deaths.Effective against Omicron, including BA.2 subvariant

Molnupiravir (Legevrio) 800 mg

Orally twice daily for 5 days

Oral18 years and olderAs soon as possible, but within 5 days of symptom onsetCompared to placebo, a relative risk reduction of 30% in hospitalizations or deaths.Effective against Omicron, including BA.2 subvariant

2.    Who is a candidate for anti-SARS-COV-2 outpatient treatment?

Monoclonal Antibody Treatments

Bebtelovimab is authorized for the treatment of mild to moderate COVID-19 in high-risk adult and pediatric patients (12 years of age and older weighing at least 40 kg):

  • with positive results of direct SARS-CoV-2 viral testing, and
  • who are at high risk for progression to severe COVID-19, including hospitalization or death, and
  • whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate.

High-risk criteria include older age, being overweight/obese, pregnancy, chronic kidney disease, diabetes, immunosuppression, cardiovascular disease or hypertension, chronic lung diseases, sickle cell disease, neurodevelopmental disorders, having a medical-related technological dependence, or other medical conditions or factors (for example, race or ethnicity) that may also place individual patients at high risk for progression to severe COVID-19.

Authorization for use of monoclonal antibody treatment is not limited to the medical conditions or factors listed above. For a complete list of risk factors, including information on the relative risk of severe disease, see the Centers for Disease Control and Prevention's (CDC) "Underlying Medical Conditions Associated with High Risk for Severe COVID-19."  Of note, the likelihood of developing severe COVID-19 increases when a person has multiple comorbidities.

Monoclonal antibodies should be administered as soon as possible after positive results of direct SARS-CoV-2 viral testing (antigen or PCR test). Bebtelovimab should be administered within 7 days of symptom onset. For more information on the use of bebtelovimab for the treatment of non-hospitalized patients with mild to moderate COVID-19, please see the NIH treatment guidelines.

There is no recommended deferral period for COVID-19 vaccination after monoclonal antibody treatment per revised guidance.

Antiviral Treatment

  • Nirmatrelvir/ritonavir (Paxlovid) is authorized (PDF) for the treatment of mild to moderate COVID-19 in adult and pediatric patients age 12 years and older weighing at least 40 kg with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19 including hospitalization or death. Treatment should be started within 5 days of symptom onset. For more information, particularly regarding potential drug-drug interactions and medications that may require dose adjustments when co-administered with nirmatrelvir/ritonavir (Paxlovid), please refer to the NIH page on ritonavir-boosted nirmatrelvir (Paxlovid).  Providers should use an drug interaction checker if there are questions about potential drug interactions.
  • Remdesivir (Veklury) has FDA approval for the treatment (PDF) of COVID-19 in mild to moderately ill adult and pediatric outpatients. In December 2021, the NIH released a statement with guidance on using IV remdesivir in adult and pediatric patients aged 12 years and older weighing at least 40 kg with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19 including hospitalization or death. On January 21, 2022, the FDA granted approval for treatment of COVID-19 in non-hospitalized adult and pediatric patients ages 12 years and older weighing at least 40 kg who are at high risk of progression to severe disease. The FDA also expanded the pediatric EUA (PDF) to include pediatric patients younger than 12 years of age who are hospitalized OR not hospitalized and have mild to moderate COVID-19 and are at high risk of disease progression. These authorizations allow Remdesivir to be administered in outpatient settings as daily intravenous infusions or injections (for pediatric patients) over three consecutive days. Treatment should be started within 7 days of symptom onset. For more information, please refer to the NIH page on remdesivir.
  • Molnupiravir (Lagevrio) is authorized (PDF) for the treatment of mild-to-moderate nonpregnant adults (18 years of age and older) with positive results of direct SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19 including hospitalization or death. Molnupiravir is only authorized for use when alternative FDA authorized or NIH suggested COVID-19 treatment options are not accessible or clinically appropriate. Treatment should be started within 5 days of symptom onset. For more information, please refer to the NIH page on Molnupiravir.

3.   Can children be prescribed anti-SARS-CoV-2 outpatient treatments? 

For guidance on outpatient treatments for individuals 12 years of age and older, please refer to the HHS Clinical Decision Aid (PDF).

Monoclonal Antibody Treatment

Bebtelovimab is authorized for use in individuals 12 years of age and older weighing at least 40 kg.

Antiviral Treatment

Paxlovid is authorized for use in children 12 years and older weighing at least 40kg.

Remdesivir is approved for use in children 12 years and older weighing at least 40kg. Remdesivir has received an EUA for treatment in younger outpatients; the EUA authorizes use in pediatric patients weighing 3.5 kg to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg. Providers should review pediatric dosages guidance prior to using. 

Molnupiravir is only authorized for use in individuals 18 years and older due to its potential impact on bone and cartilage development.

4.   Can a patient who is hospitalized for COVID-19 receive anti-SARS-CoV-2 monoclonal antibodies or oral antivirals that are authorized for outpatient treatment? 

Anti-SARS-CoV-2 monoclonal antibodies and oral antivirals are not authorized for use in patients who are:

  • Hospitalized due to COVID-19, OR
  • Require oxygen therapy due to COVID-19, OR
  • Require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related morbidity

All authorized treatments can be used to treat mild to moderate COVID-19 in patients who are hospitalized for a reason other than COVID-19. If a patient requires hospitalization after starting treatment, the full treatment course of nirmatrelvir/ritonavir (Paxlovid) or molnupiravir can be completed at the health care provider's discretion.

Treatments available for patients requiring hospitalization for COVID-19 include remdesivir as well as corticosteroids and other immunomodulatory drugs. Providers should refer to the NIH treatment guidelines for inpatients as well as the Infectious Diseases Society Of America treatment guidelines for guidance on management of patients hospitalized with COVID-19.

Post-Exposure Prophylaxis  

5.    What SARS-CoV-2 post-exposure prophylaxis options are available?

Although the monoclonal antibodies, bamlanivimab/etesevimab and casirivimab/imdevimab (REGEN-COV) received EUAs from the FDA for post-exposure prophylaxis against COVID-19, they are not currently authorized for use anywhere in the United States due to the prevalence of the Omicron variant. There are currently no FDA approved or authorized treatments for post-exposure prophylaxis of COVID-19.

Pre-Exposure Prophylaxis 

6.    What SARS-CoV-2 pre-exposure prophylaxis options are available?

Tixagevimab/cilgavimab (branded as Evusheld) is currently the only drug that has received an EUA from the FDA for pre-exposure prophylaxis against COVID-19 for individuals who are immunocompromised or have a medical contraindication for COVID-19 vaccines.

Evusheld may only be used in adults and pediatric individuals (12 years of age and older, weighing at least 40 kg):

  • Who are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to an individual infected with SARS-CoV-2 AND
    • Who have moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination OR
    • For whom vaccination with any available COVID-19 vaccine, according to the approved or authorized schedule, is not recommended due to a history of severe adverse reaction (e.g., severe allergic reaction) to a COVID-19 vaccine(s) and/or COVID-19 vaccine component(s).

The NIH treatment guidelines provide further recommendations on identifying patients that are eligible for Evusheld.

On February 24, 2022, the FDA revised the EUA for tixagevimab/cilgavimab (Evusheld) to change the initial dose from 150 mg of tixagevimab and 150 mg of cilgavimab administered as two separate consecutive intramuscular injections to 300 mg of tixagevimab and 300 mg of cilgavimab. The dosing regimen was revised as data has indicated that a higher dose of tixagevimab/cilgavimab (Evusheld) may be more likely to prevent infection by the COVID-19 Omicron subvariants BA.1 and BA.1.1. The new dose is based on pharmacokinetic/pharmacodynamic modeling for the Omicron BA.1 and BA.1.1 subvariants. Patients who have already received the previously authorized dose (150 mg of tixagevimab and 150 mg of cilgavimab) should receive an additional dose of Evusheld as soon as possible, with the dose based on the following criteria:

    • If the patient received their initial dose less than or equal to 3 months ago, the patient should receive a dose of 150 mg of tixagevimab and 150 mg of cilgavimab.
    • If the patient received their initial dose longer than 3 months ago, the patient should receive a dose of 300 mg of tixagevimab and 300 mg of cilgavimab.

 

Drug Route Age groups authorized for treatment Pre-Exposure Prophylaxis Effectiveness Activity Against Variants Currently Circulating

Tixagevimab 300 mg / 300 cilgavimab mg (Evusheld)

Given as two separate, consecutive injections

 

Intramuscular12 years and older and weighing at least 40 kgReduced the risk of developing symptomatic COVID-19 by 77% compared to placebo.Effective against Omicron, including the BA.2 subvariant

 

Evusheld is not a substitute for COVID-19 vaccination and should not be used in unvaccinated individuals for whom COVID-19 vaccination is recommended and who are anticipated to have an adequate response. Vaccination remains the most effective way to prevent SARS-CoV-2 infection, and it should be considered the first line of prevention.

In individuals who have recently received a COVID-19 vaccine, Evusheld should be administered ≥ 2 weeks after vaccination.

The EUA for Evusheld allows for repeat dosing once every 6 months using intramuscular injection. There is currently no safety or efficacy data on repeat dosing.

 

General Questions 

7.    How do I determine if my patient qualifies for anti-SARS-CoV-2 outpatient treatment or prophylaxis?

Providers should review the NIH treatment guidelines as well as the product fact sheets before prescribing COVID-19 outpatient therapeutics. The U.S. Department of Health and Human Services (HHS) has developed a  clinical implementation guide (PDF) as well as an outpatient therapeutics decision guide (PDF).

8.  Are there recommendations for which therapies should be preferred in nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease?

According to NIH guidelines, the following therapies are preferred for high-risk, non-hospitalized patients with mild to moderate COVID-19 (in order of preference):

  • Nirmatrelvir/ritonavir (Paxlovid)
  • Remdesivir

Nirmatrelvir/ritonavir (Paxlovid) and remdesivir are preferred treatments due to their 88% to 89% reduction in hospitalization or death in treated patients in randomized, placebo-controlled trials as well as their in vitro neutralization activities against the Omicron variant.

If none of the above therapies are available, feasible to deliver, or clinically appropriate, either bebtelovimab or molnupiravir may be used as alternative therapies.

9.   Where can I find guidance on patient prioritization for outpatients therapeutics when there are logistical of supply constraints? 

Currently there is adequate availability of COVID-19 therapeutics throughout the state. For that reason, all patients meeting criteria for treatment as presented in the product EUAs should be offered therapy.

If there are logistic or supply constraints in the future, the NIH treatment guides provide recommendations on patient prioritization for outpatient therapies, including prioritization tiers.

10.   Where can I find information on the side effects of available COVID-19 therapeutics and criteria for use, preparation, and administration? 

FDA documentation for each monoclonal antibody and antiviral product includes information on use criteria, preparation, contraindications, drug interactions, side effects and administration and product fact sheets can be found at the links below. Detailed COVID-19 clinical treatment guidelines are available from National Institutes of Health (NIH) and Infectious Disease Society of America (IDSA).

While not a complete list of contraindications, the following should be noted:

  • Molnupiravir is not authorized for use in patients less than 18 years of age because it may affect bone and cartilage growth. For more information on these precautions, please see the NIH section on Molnupiravir and the Molnupiravir Fact Sheet (PDF).
  • Paxlovid has significant and complex drug-drug interaction potential, primarily due to the ritonavir component of the combination. Review additional guidance from NIH on identifying and avoiding drug interactions.
  • Paxlovid is not recommended for patients with severe hepatic or renal impairment and different dosing is required for moderate renal impairment. Given the presence of ritonavir, Paxlovid may also increase the risk of HIV-1 resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1.
  • Remdesivir is not recommended in pediatric patients (greater than 28 days old) with eGFR less than 30 mL/min or in full-term neonates (at least 7 days to less than or equal to 28 days old) with serum creatinine greater than or equal to 1 mg/dL.

Product Fact Sheets

Anti-SARS-CoV-2 Monoclonal Antibodies

Antivirals

11.         My patient qualifies for anti-SARS-CoV-2 outpatient treatment or prophylaxis. What should I do next?

All medications for treatment or prophylaxis require a prescription by a licensed and authorized provider. Prescribing healthcare providers can locate sites where state-allocated COVID-19 therapeutics are available using the HHS Therapeutics Locator. The Therapeutics Locator is based on shipments and reported utilization and is not a guarantee of availability and the prescribing healthcare provider should ensure supply at the dispensing site.

Patients should be given an electronic or hard copy of the Fact Sheet for the drug prescribed.

12.         How will my facility be reimbursed for the cost of administering anti-SARS-CoV-2 outpatient treatment or prophylaxis?

The federal government has purchased supplies of Evusheld, bebtelovimab, Paxlovid, and molnupiravir and these products remain free of charge at this time. 

The additional cost of administering the treatment is billed through the usual claims process, based on each patient's health care coverage

The Centers for Medicare and Medicaid Services (CMS) created the Healthcare Common Procedure Coding System (HCPCS) code J0248 for the remdesivir antiviral medication when administered in the outpatient setting. 


Originally published on January 19, 2022