COVID-19 Outpatient Treatment

Who should receive outpatient therapy for COVID-19?

Clinicians should prescribe COVID-19 treatment to the extent possible to outpatients who meet all of the following:

Have mild or moderate COVID-19
Are within 5 days of symptoms onset for Paxlovid and molnupirivir or 7 days of symptom onset for IV remdesivir
Have one or more risk factors for severe COVID-19 including:
- Age over 50 years, especially those 65 and older, regardless of the presence of a medical condition
- Being unvaccinated or not being up to date on COVID-19 vaccinations
- Being in a racial or ethnic minority group
- Having common underlying health conditions and behaviors such as physical inactivity, obesity, depression, smoking (former or present), and disabilities. See CDC comprehensive discussion.

For more information, see the CDC webpage Interim Clinical Considerations for COVID-19 Treatment in Outpatients.

To view the IDSA COVID-19 Risk Continuum graphic see Understanding Risk for Severe COVID-19 webpage.

The following factors should NOT be reasons to withhold COVID-19 treatment:

Being fully or partially vaccinated
Having a history of prior SARS-CoV-2 infection
Presence of only mild disease. Patients with mild symptoms are included in criteria for outpatient treatment according to the FDA EUA and NIH recommendations.
A lack of recent renal or liver function tests. The FDA EUA does not require assessment of laboratory results.

Clinicians should have a low threshold to prescribe COVID-19 therapeutics given the broad range of individuals who are at higher risk for severe COVID-19 and can benefit from COVID-19 treatment.

Outpatient Treatments for COVID-19

Three antiviral therapies are currently FDA approved or authorized for outpatient treatment of COVID-19 infection and recommended by the NIH COVID-19 Treatment Guidelines Panel. They are not approved for pre- or post-exposure prophylaxis. Importantly, they retain full activity against the current variant mix in California.

Note: The FDA has removed the requirement for a positive SARS-CoV-2 viral test in order to prescribe these medications. Although the agency still strongly recommends the use of viral testing to help diagnose COVID-19 this change allows for providers to consider treatment in the rare instances where an individual with a known exposure who develops signs and symptoms consistent with COVID-19 presents with a negative test. See FDA product specific FAQs for more information.

Antiviral Medication (in order of preference)	FDA Status	Mode/duration of Administration	Start time from symptom onset	Age/Weight	Fact sheets/FAQs
1. Paxlovid	FDA EUA	Oral twice daily for 5 days	≤5 days	Age ≥12 who weigh ≥40kg	Providers Patient/caregivers FAQs
2. Remdesivir	FDA Approved	IV infusion daily for 3 days	≤7 days	Adults and children age ≥28 days who weigh ≥3kg	Providers Patients FAQs
3. Molnupiravir	FDA EUA	Oral twice daily for 5 days	≤5 days	Adults ≥18 (not recommended in pregnancy)	Providers Patient/caregivers FAQs

HHS Side-by-Side Overview of Therapeutics

See Side-by-Side Overview of Therapeutics for additional information.

Paxlovid

Paxlovid (nirmatrelvir 300 mg with ritonavir 100 mg), given within 5 days of symptom onset, is the preferred treatment for adults and pediatric patients (12 years of age and older weighing at least 40 kg) with symptomatic COVID-19 and risk factors for progression. It is taken orally twice a day for 5 days.

Studies have shown that Paxlovid:

Reduces the risk for hospitalization and death by 50-88% among unvaccinated people and by 45–50% among vaccinated or previously infected people.^1,2,3 Recent studies in highly COVID-19 immune populations conducted during omicron circulation show significant reductions in hospitalizations among patients aged 18 and older with risk factors for severe disease (see Table below).
May decrease the risk of developing post-COVID symptoms. ^4,5,6,7 The extent and scale of impact that long COVID may have on individual and population health are yet to be revealed and may be quite significant.
Decreases SARS-CoV-2 viral load faster compared with people not treated, suggesting the potential for decreased transmission and isolation time for test-result-based isolation protocols.¹
Has been shown to be safe, including in older adults.^1,8 Risks are minimal, especially when weighed against benefits.

Most commonly used medications can be safely co-administered with Paxlovid

Paxlovid can alter the concentrations of other drugs, so it is important to assess for potential drug-drug interactions.
Many commonly used medications can be safely co-administered with Paxlovid despite its drug-drug interaction potential. See NIH guidance Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications and the Liverpool COVID-19 Drug Interactions website
The Infectious Disease Society of America offers guidance on simple steps that can be taken to avoid significant interactions with commonly prescribed medications, such as brief suspension or dose reduction.

The potential for COVID-19 rebound is not a reason to avoid prescribing Paxlovid

COVID-19 rebound is the term used to describe a recurrence of symptoms and/or SARS CoV-2 antigen positivity which can occur between 2 and 8 days after initial recovery. The etiology of this phenomenon is not known. Recent small studies suggest that rebound may happen when people have a strong immune response to COVID-19; neither the development of resistance nor the absence of neutralizing antibody were likely causes of rebound ^{9, 10}
Rebound has been observed in the minority of patients treated with Paxlovid or molnupiravir^11,12 It also occurs in patients who did not receive COVID-19 therapeutics ^13,14 A preprint by Deo et al found that 1 out of 8 people who did not receive COVID-19 therapy experienced rebound. Those that rebounded were more likely to be older. Among those that rebounded, only 10% had symptoms.
Rebound is typically mild. Recent studies suggest that patients who experience rebound have an extremely low probability of developing severe COVID-19. Retreatment is not currently recommended.

FDA Paxlovid patient eligibility checklist PDF

Paxlovid package information

Standard packaging for patients with normal renal function:
- 300 mg nirmatrelvir;100 mg ritonavir - Each carton contains 30 tablets divided in 5 daily-dose blister cards.
- Each blister card contains 4 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each). Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.
New packaging option for patients with reduced renal function: See Dear Healthcare Provider Letter
- 150 mg nirmatrelvir; 100 mg ritonavir - Each carton contains 20 tablets divided in 5 daily-dose blister cards.
- Each blister card contains 2 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each). Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.

Paxlovid sample prescriptions

Prescription for patients with normal renal function

Prescription for patients with reduced renal function

FDA: Letter of authorization | FAQs on the EUA | FDA letter: new medication packaging for patients with moderate renal impairment | Fact sheet for health providers | Fact sheet for patient/caregivers

Other resources: Pharmacist Authority to Prescribe

Remdesivir

Remdesivir (Veklury) is the only treatment approved for children under 12 years of age. It is given as an IV infusion for a total of 3 days initiated as soon as possible and within 7 days of symptom onset.

In clinical trials, remdesivir reduced the risk of hospitalization or death by 87% among high-risk unvaccinated patients with COVID-19 treated within 7 days of symptom onset (Gottlieb, 2021).

Given the emergence of variants resistant to mAbs, providing remdesivir in the outpatient setting may be of particular importance for facilities and providers that see large numbers of immunosuppressed patients such as transplant and oncology centers, or high-risk pediatric populations. Providers are encouraged to order remdesivir to have on hand for patients unable to take Paxlovid.

FDA approved for the treatment of COVID-19 in adults and pediatric patients (28 days of age and older weighing at least 3 kilograms) who are:
- Hospitalized, or
- Not hospitalized and have mild-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization and death.
  Note: In December 2022, the FDA revised the remdesivir labeling to remove having a positive SARS-CoV-2 viral test result from the indication.
For information regarding purchasing or how to access remdesivir, please email remdesivir@amerisourcebergen.com, or call 1-800-746-6273 or reach out directly to your AmerisourceBergen representative.
HHS is asking providers who administer outpatient Veklury (remdesivir) to add their infusion site to the COVID-19 Therapeutics Locator in order to improve public awareness and product access. Only information provided by the infusion site will be visible on the locator. Infusion sites can opt out of being on the locator at any time. Infusion sites can learn more and opt into the therapeutics locator here.
CMS has created the Healthcare Common Procedure Coding System (HCPCS) code J0248 for reimbursement when administered in an outpatient setting. This code is available for use by all payers and is effective for dates of service on or after December 23, 2021. Additional information is available here.

FDA: Prescribing information | Press release FDA approval for children
Information for providers vekluryhcp.com |
Information for patients wwwwww.veklury.com

Molnupiravir

Molnupiravir (Lagevrio) is authorized as an alternative therapy when Paxlovid and remdesivir are not available, feasible to use, or clinically appropriate. It is given as 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days. Treatment started as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset.

Molnupiravir is a nucleoside analogue that inhibits SARS-CoV-2 replication by viral mutagenesis.
Due to concern for side effects and decreased risk reduction compared to other available medications, molnupiravir should only be used if other treatments are not available or not clinically appropriate.
Guidance is now available on the provider fact sheet for the preparation and administration of molnupiravir via nasogastric and orogastric tube.
Several studies have shown a risk reduction in severe disease after molnupiravir treatment with the most significant benefit in those at highest risk or elderly (≥75 years of age). In addition, there is evidence of more rapid symptom resolution and viral load reductions in people treated with molnupiravir. See table below.
Use in adults 18 and older only. Not recommended in pregnancy. If the provider and patient choose to use the product during pregnancy, it is advised that the patient be registered in the Merck Pregnancy Surveillance Program.
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.
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.
Providers should carefully review the Fact sheet for health providers before prescribing to ensure that the patient’s condition warrants treatment, that there are no drug interactions, and that there are contraindications to therapy.

FDA Molnupiravir patient eligibility checklist PDF

Molnupiravir sample prescription:

FDA: Letter of authorization | FAQs on the EUA | Fact sheet for health providers | Fact sheet for patient/caregivers

Summary of Effectiveness

Table: Summary of studies analyzing the effectiveness of oral antivirals during omicron
Study	Population	Drug	Time analyzed	Outcomes
Ganatra et al., 2022	1,130 patients receiving nirmatrelvir/ritonavir and 1:1 propensity score matched controls 18 yrs or older, fully vaccinated outpatients	Paxlovid	December – April 2022	45% relative risk reduction in all-cause ED visits, hospitalizations, or death 60% relative risk reduction in hospitalizations and 100% reduction in deaths
Najjar-Debbiny et al. 2022	180,351 patients 18 years or older at high risk for severe COVID-19 75.1% COVID-19 vaccinated	Paxlovid	January - February 2022	46% risk reduction of hospitalizations or death Most benefit in older patients, patients with cardiovascular disease, patients with neurological disease, and immunosuppressed patients
Najjar-Debbiny et al, 2022	2,261 molnupiravir recipients matched with 2661 controls; with at least one RF for severe COVID-19 (≥60 or ≥18 with comorbidities) 77.3% COVID-19 vaccinated	Molnupiravir	January-February 2022	Nonsignificant 17% risk reduction of composite outcome (severe disease/death) Significant decrease in risk seen in subgroup analyses; >75 years of age regardless of vaccination: HR= 0.54 (0.34–0.86) females, regardless of vaccination: HR= 0.41 (0.22–0.77) patients with inadequate COVID-19 vaccination HR=0.45 (0.25–0.82)
Arbel et al., 2022	109,213 patients 40 years or older at high risk for severe disease (42,819 65 years or older) 78% of patients had prior immunity (vaccination, prior infection, or hybrid immunity)	Paxlovid	January - March 2022	In 65 year or older patients: 73% risk reduction of hospitalizations 80% risk reduction of death No significant benefit in younger adults
Dryden-Peterson et al., 2022	44,551 patients 50 years old or older 90% vaccinated	Paxlovid	January - July 2022	45% risk reduction of combined outcome of hospitalization and death In incompletely vaccinated individuals there was an 81% risk reduction of combined outcome of hospitalization and death
Wong et al. 2022	1,856 molnupiravir-receiving patients, 890 nirmatrelvir/ritonavir and 2,746 control patients Hospitalized within 3 days before or after COVID diagnosis	Paxlovid and molnupiravir	February -April 2022	52% risk reduction of all-cause mortality with molnupiravir 66% risk reduction of all-cause mortality with nirmatrelvir/ritonavir
Wong et al., 2022	5,383 molnupiravir receiving patients and 6,464 nirmatrelvir/ritonavir 1:10 propensity score matched controls <50% vaccinated Molnupiravir group older and higher % vaccinated vs. nirmatrelvir/ritonavir group	Paxlovid and molnupiravir	February – June 2022	24% risk reduction of all-cause mortality with molnupiravir 66% risk reduction of all-cause mortality with nirmatrelvir/ritonavir 24% reduced risk of hospitalization with nirmatrelvir/ritonavir Similar effects of nirmatrelvir/ritonavir across vaccination status and age
Radcliffe et al. 2022	122 solid organ transplant recipients 49 (40%) received molnupiravir 24 (20%) received sotrovimab 48 (39%) untreated 48% ≥3 doses of an mRNA vaccine series or two doses of Ad26.COV2.S	Molnupiravir	January – February 2022	44% risk reduction of hospitalization or death
Butler et al. 2022	25,529 molnupiravir plus usual care vs 12525 usual care alone Outpatients ≥ 50 or ≥18 years with co-morbidities Highly vaccinated group (94% overall had received ≥3 doses of COVID-19 vaccine)	Molnupiravir	December 2021-April 2022	1% hospitalization or death in both groups (no difference) with a trend towards benefit in ≥65 Faster recovery in treatment group (median, 9 days vs. 15 days). Faster reduction of viral load in treatment group (undetectable viral load by Day 5 8% molnupiravir vs. 3% usual care)

Pre-exposure prophylaxis

On January 1-26-23 the FDA revised the Emergency Use Authorization for Evusheld (tixagevimab/cilgavimab) to limit its use to when the combined frequency of non-susceptible SARS-CoV-2 variants nationally is less than or equal to 90%. Based on this revision, Evusheld is not currently authorized for use in the U.S. until further notice by the Agency. See FDA announcement.

Evusheld is a combination of two long-acting anti-SARS-CoV-2 monoclonal antibodies administered via intramuscular injection that was used for pre-exposure prophylaxis to protect against SARS-CoV-2 infection. It lost FDA authorization for use in January 2023 due the high prevalence of variants resistant to Evusheld.

With the loss of the only pre-exposure prophylaxis medication to prevent COVID-19, it is important that that persons who are moderately to severely immunocompromised, those who might have an inadequate immune response to COVID-19 vaccination, and those with contraindications to receipt of COVID-19 vaccines, be counseled to exercise caution and recognize the need for additional preventive measures. In addition, they should be advised to have a personal COVID-19 care plan that includes prompt testing at the onset of COVID-19 symptoms and rapid access to antivirals if SARS-CoV-2 infection is detected. See CDC MMWR Information for Persons Who Are Immunocompromised Regarding Prevention and Treatment of SARS-CoV-2 Infection in the Context of Currently Circulating Omicron Sublineages — United States, January 2023

Information for providers with Evusheld product. The U.S. Government recommends that facilities and providers with Evusheld retain all product in the event that SARS-CoV-2 variants which are neutralized by Evusheld become more prevalent in the U.S. in the future. Retained product must be appropriately held in accordance with storage conditions detailed in the authorized Fact Sheet for Health Care Providers (PDF) and the Letter of Authorization (PDF). Also see: Expiration Dating Extension - COVID-19 Therapeutics

Post-exposure prophylaxis

At this time there are no therapeutics authorized for post-exposure prophylaxis that are active against Omicron

Procuring medication for your patients

If you are interested in becoming a therapeutics provider, please contact DPH-Therapeutics@ph.lacounty.gov.
This information is intended for medical providers. Information for the public is available here.
Patients who are unable to access oral COVID-19 therapeutics through their own provider or who do not have health insurance can be referred to a Test to Treat program or the DPH Public Health Call Center/Tele-Health service, which provides testing, consultation, and prescriptions. 1-833-540-0473 - open 7 days a week, 8:00 am-8:30 pm.

CLICK HERE for sites offering Test to Treat (Paxlovid and Molnupiravir only)

To search by zip code for locations that offer Test-to-Treat (testing, medical visits, and medication), use the federal Get medication for COVID-19 locator.

Patients who are unable to access oral COVID-19 therapeutics through their own provider or who do not have health insurance can be referred to a Test to Treat program or the DPH Public Health Call Center/Tele-Health service which provides testing, consultation, and prescriptions. 1-833-540-0473 - open 7 days a week 8:00 am-8:30 pm.

CLICK HERE for sites carrying Paxlovid and Molnupiravir

To search by zip code for locations that fill prescriptions use the federal Get medication for COVID-19 locator.

Patients who are unable to access oral COVID-19 therapeutics through their own provider or who do not have health insurance can be referred to a Test to Treat program or the DPH Public Health Call Center/Tele-Health service which provides testing, consultation, and prescriptions. 1-833-540-0473 - open 7 days a week 8:00 am-8:30 pm.

CLICK HERE for information about procuring Remdesivir

Facilities can order directly from manufacturer: vekluryhcp.com

Reimbursement and Billing

California’s Department of Health Care Services (DHCS) will still accept claims for individuals enrolled in the COVID-19 Uninsured Group Program. Individuals must apply for the COVID-19 Uninsured Group Program through a Medi-Cal Qualified Provider (QP). QPs are providers of the following programs: Presumptive Eligibility for Pregnant Women, Breast and Cervical Cancer Treatment Program, Hospital Presumptive Eligibility, and Child Health and Disability Prevention. Providers must submit applications via the COVID-19 Uninsured Group Application Portal. Providers can submit their COVID-19 testing, testing-related, and treatment claims to DHCS for claims processing.

Cost Sharing

COVID-19 Therapeutics: Fees for Oral Antivirals

Provider Assessment
1. Bill insurance if/when available
2. For uninsured and underinsured, encourage use of free, low-cost care (e.g., HRSA, State-run clinics)
3. May share cost (full fee or co-pay) with patients
Testing
1. Encourage use of ICATT sites that provide free testing
  1. Most Walgreens and CVS T2T sites are enrolled in ICATT (working towards all sites)
  2. Otherwise non-ICATT sites may charge patients
  3. Patients are able to use (free) at-home test
Medication
1. Free for all. No cost sharing with patients
Dispensing Fee
1. No cost sharing with patients

COVID-19 Therapeutics: Fees for monoclonal antibodies

Provider Assessment
1. Bill insurance if/when available
2. For uninsured and underinsured, encourage use of free, low-cost care (e.g., HRSA, State-run clinics)
3. May share cost (full fee or co-pay) with patients
Medication
1. Free for all. No cost sharing allowable
Administration Fee
1. Bill insurance if/when available
2. For uninsured and underinsured, encourage use of free, low-cost care (e.g. HRSA, State-run clinics)
3. May share cost (full fee or co-pay) with patients

Resources

Resources and contact information

LA County DPH COVID-19 medication resources for patients:
- Webpage: English | Spanish
- Fact sheet: English | Spanish (see webpage for other languages)
- COVID-19 Medicines Toolkit: including messages and images for social media emails and webpages
NIH COVID-19 Treatment Guidelines - comprehensive COVID-19 treatment guidelines
ASPR (Assistant Secretary for Preparedness and Response) COVID-19 Therapeutics webpage
CDPH SARS-CoV-2 Antiviral Therapeutics webpage
Federal COVID-19 Therapeutics Locator
FDA Emergency Use Authorization webpage: COVID-19 drugs and non-vaccine biological products
COVID-19 variant tracker CDC webpage
Webinars
- CDC Webinar: Updates to COVID-19 Testing and Treatment for the Current SARS-CoV-2 Variants-Recorded on 1-24-23. View archived recording | See slides
- CDC/IDSA Clinician Calls - slides and recordings and registration for future meetings
- CDC Clinician Outreach and Community Activity (COCA) Webinars and other resources

Contact Information

Call the California COVID-19 Provider Therapeutics Warmline at 1-866-268-4322 (866-COVID-CA) for clinical consultation regarding patient testing and treatment including management of drug-drug interactions.
For questions related to ordering Paxlovid or Molnupiravir please contact DPH-Therapeutics@ph.lacounty.gov.