Who should receive outpatient therapy for COVID-19?
- Have mild-moderate COVID-19 illness AND
- Have a positive SARS-CoV-2 viral test result, AND
- Are at higher risk for progressing to severe COVID-19 and/or hospitalization.
- Higher risk includes older persons (i.e., age 50 and older) or any age with one or more conditions on the CDC list of Underlying Medical Conditions Associated with High Risk for Severe COVID-19.
- It is important to note that a broad group of patients qualify because the list includes common conditions such as diabetes, depression, obesity, physical inactivity, and current and former smokers among many others.
- The likelihood of developing severe COVID-19 increases when a person has multiple comorbidities.
- It is now recommended that providers consider the social determinants of health such as CDPH now recommends that providers consider the social determinants of health when evaluating a patient’s risk of progressing to severe COVID-19.
Currently recommended treatments
Four 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. They are effective against the Omicron variants.
In order of suggested use*:
- Paxlovid (antiviral, under EUA, taken orally for 5 days, must start within 5 days of symptom onset)
- Remdesivir (antiviral, FDA approved, given IV for 3 days, must start within 7 days of symptom onset)
- Molnupiravir and
Bebtelovimab (Equal ranking) - only authorized for use if alternative COVID-19 treatment options authorized
or approved by the FDA are not accessible or are not clinically appropriate.
- Molnupiravir (antiviral, under EUA, taken orally for 5 days, must start within 5 days of symptom onset)
- Bebtelovimab (monoclonal antibody, under EUA, given IV as single dose, must start within 7 days of symptom onset)
*From NIH COVID-19 Treatment Guidelines: Therapeutic Management of Nonhospitalized Adults With COVID-19.
Note: Pre-exposure prophylaxis with Evusheld is recommended for individuals if they are moderately or severely immunosuppressed or are unable to be vaccinated for COVID-19 – see Pre-exposure prophylaxis - Evusheld.
1) Paxlovid
Nirmatrelvir/ritonavir (Paxlovid) — nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use. Treatment started as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset.
If normal renal function, 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all three tablets taken together twice daily for 5 days. Alternate dosing is necessary for patients with reduced renal function.
Paxlovid is an oral protease inhibitor. Pfizer announced the results from a trial of 2,246 adults who received either Paxlovid or placebo. All patients had not received a COVID-19 vaccine and had not been previously infected with COVID-19. In the study, Paxlovid significantly reduced the proportion of people with COVID-19 related hospitalization or death from any cause by 88% compared to placebo among patients treated within five days of symptom onset.
- Currently under EUA
- Allocations to pharmacies (with a healthcare provider prescription) and clinical sites is determined by LA County DPH. See Procuring medication for your patients.
- Use in persons 12 years of age and older weighing at least 40 kg
- Many drug-drug interactions
- Paxlovid may lead to a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.
- 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 no contraindications to therapy.
- Clinicians who are not experienced in prescribing ritonavir-boosted drugs should refer to resources such as the EUA fact sheet for ritonavir-boosted nirmatrelvir (Paxlovid), the ISDA practice guideline on the management of drug interactions with Paxlovid, and the Liverpool COVID-19 Drug Interactions website for additional guidance.
- The FDA revised the EUA for Paxlovid in April 2022: new additional packaging configuration to be used for dosing and dispensing in patients with moderate renal impairment; different ritonavir tablet appearance. Dear Healthcare Provider Letter
- The FDA revised the EUA for Paxlovid in June 2022:
- To include a number of additional drugs for which concomitant use or use immediately after discontinuation is contraindicated. These medications include drugs that are highly dependent on CYP3A for clearance as well as drugs that are potent CYP3A inducers. PAXLOVID cannot be started immediately after discontinuation of the drugs in the latter category due to the delayed offset of the recently discontinued CYP3A inducer.
- To include new adverse reactions including hypersensitivity reactions, abdominal pain, nausea and malaise, new drug interactions and information related to rebound after Paxlovid as noted below.
- The FDA revised the EUA for Paxlovid in July 2022
- To expand prescribing authority to pharmacists. On 7/11
The California Department of Consumer Affairs waived any restrictions preventing pharmacists from aligning with prescribing guidance as noted in the Paxlovid EUA. Pharmacists can prescribe Paxlovid if:
- Sufficient information is available, such as through access to health records less than 12 months old or consultation with a health care provider in an established provider-patient relationship with the individual patient, to assess renal and hepatic function; and
- Sufficient information is available, such as through access to health records, patient reporting of medical history, or consultation with a health care provider in an established provider-patient relationship with the individual patient, to obtain a comprehensive list of medications (prescribed and non-prescribed) that the patient is taking to assess for potential drug interaction.
- The state-licensed pharmacist should refer an individual patient for clinical evaluation (e.g., telehealth, in-person visit) with a physician, advanced practice registered nurse, or physician assistant licensed or authorized under state law to prescribe drugs, if any of the following apply:
- Sufficient information is not available to assess renal and hepatic function.
- Sufficient information is not available to assess for a potential drug interaction.
- Modification of other medications is needed due to a potential drug interaction.
- PAXLOVID is not an appropriate therapeutic option based on the authorized Fact Sheet for Healthcare Providers or due to potential drug interactions for which recommended monitoring would not be feasible.
- To expand prescribing authority to pharmacists. On 7/11
The California Department of Consumer Affairs waived any restrictions preventing pharmacists from aligning with prescribing guidance as noted in the Paxlovid EUA. Pharmacists can prescribe Paxlovid if:
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
Rebound after Paxlovid
Reports about patients experiencing symptom reoccurrence after completion of Paxlovid treatment have been reported. In some of these cases, patients tested negative on a direct SARS-CoV-2 viral test and then tested positive again. In light of these reports, additional analyses of the Paxlovid clinical trial data have been performed by the FDA.
Key findings include:
- In the Paxlovid clinical trial, some patients (range 1-2%) had one or more positive SARS-CoV-2 PCR tests after testing negative, or an increase in the amount of SARS-CoV-2 detected by PCR, after completing their treatment course.
- This finding was observed in patients treated with the drug as well as patients who received placebo.
- Additional analyses show that most of the patients did not have symptoms at the time of a positive PCR test after testing negative, and, most importantly, there was no increased occurrence of hospitalization or death or development of drug resistance.
- These reports do not change the conclusions from the Paxlovid clinical trial which demonstrated a marked reduction in hospitalization and death.
- There is no evidence of benefit at this time for a longer course of treatment (e.g., 10 days rather than the 5 days recommended in the Provider Fact Sheet for Paxlovid) or repeating a treatment course of Paxlovid in patients with recurrent COVID-19 symptoms following completion of a treatment course.
- Health care providers and patients should refer to CDC recommendations regarding patient isolation and should wear a mask and isolate if they have any symptoms regardless of whether or not they have been treated with an antiviral agent.
The FDA is continuing to review data from clinical trials and will provide additional information as it becomes available.
Cases of rebound infection after Paxlovid treatment can be reported to FDA Medwatch using Form 3500 (online or download - please also provide a copy of this form to Pfizer Inc. at fax number: 1-866-635-8337). Rebound cases can also be reported to Pfizer at https://paxaes.pfizersafetyreporting.com/#/en.
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
2) Remdesivir
Remdesivir (Veklury) — IV infusion for a total of 3 days initiated as soon as possible and within 7 days of symptom onset
- FDA approved to include both inpatient and outpatient use including for pediatric patients 28 days of age and older weighing at least 3 kilograms.
- 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.
- 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: Press release FDA approval for children | Information for providers vekluryhcp.com | Information for patients wwwwww.veklury.com
3) Molnupiravir (equal in order of suggested use with Bebtelovimab)
Molnupiravir (Lagevrio) — 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. Merck announced results from a trial of 1,433 patients. Enrolled participants had not received a COVID-19 vaccination and had at least one risk factor associated with poor disease outcomes and symptom onset within five days prior to study enrollment. The risk of hospitalization for any cause or death through day 29 was lower with Molnupiravir (6.8%) than with placebo (9.7%), for a relative risk reduction of 30%.
- Currently under EUA
- 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.
- Allocations to pharmacies (with a healthcare provider prescription) and clinical sites is determined by LA County DPH. See Procuring medication for your patients.
- 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.
Molnupiravir sample prescription:
FDA: Letter of authorization | FAQs on the EUA | Fact sheet for health providers | Fact sheet for patient/caregivers
3) Bebtelovimab (equal in order of suggested use with Molnupiravir)
Bebtelovimab — single 175mg IV injection administered as soon as possible after diagnosis of COVID-19 and within 7 days of symptom onset.
- Bebtelovimab is a monoclonal antibody therapy with EUA. It should only be used if other treatments are not available or not clinically appropriate.
- Use in persons 12 years of age and older weighing at least 40 kg
- 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 no contraindications to therapy
- Requests for product can be sent to laemsadutyofficer@dhs.lacounty.gov.
- Appears to be effective against Omicron variants
FDA: EUA Letter of Authorization | Frequently Asked Questions for Bebtelovimab | Fact sheet for health care providers | Fact sheet for parents/caregivers
Pre-exposure prophylaxis
Evusheld
Evusheld (Tixagevimab/cilgavimab) (AstraZeneca) - has an EUA for pre-exposure prophylaxis against COVID-19. A combination of two long-acting anti-SARS-CoV-2 monoclonal antibodies administered via intramuscular injection, Evusheld is intended to protect individuals who are unable to mount an adequate immune response to COVID-19 vaccination or are unable to receive a COVID-19 vaccine due to severe adverse reaction.
As defined in the EUA, Evusheld is authorized as a pre-exposure prophylaxis in the following:
- 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 either:
- 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).
- 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 either:
According to the EUA, the medical conditions or treatments that may result in moderate to severe immune compromise and an inadequate immune response to COVID-19 vaccination include but are not limited to:
- Active treatment for solid tumor and hematologic malignancies
- Receipt of solid-organ transplant and taking immunosuppressive therapy
- Receipt of chimeric antigen receptor (CAR)-T-cell or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy)
- Moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome)
- Advanced or untreated HIV infection (people with HIV and CD4 cell counts <200 /mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)
- Active treatment with high-dose corticosteroids (i.e., ≥20 mg prednisone or equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, Cancer chemotherapeutic agents classified as severely immunosuppressive, tumor-necrosis (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory (e.g., B-cell depleting agents)
Important information about change in dose: On 2-24-22, the FDA revised the emergency use authorization for Evusheld (tixagevimab plus cilgavimab) to increase the dose (from an initial dosing of 150 mg of tixagevimab and 150 mg of cilgavimab) to 300 mg of tixagevimab and 300 mg of cilgavimab) due to concerns about lower efficacy against certain Omicron subvariants. Health care professionals should contact patients who received the previously authorized Evusheld dose to return for repeat dosing as follows:
- If the patient received their initial dose ≤ 3 months ago, the patient should receive an additional dose of 150 mg of tixagevimab and 150 mg of cilgavimab
- If the patient received their initial dose > 3 months ago, the patient should receive a dose of 300 mg of tixagevimab and 300 mg of cilgavimab.
The volume of each injection for the new, higher dose will be larger (3 mL instead of 1.5 mL) This means that the injections should be limited to large muscles on the body that can accommodate this volume (e.g., the gluteal muscles)
The EUA was recently updated to include new information on hypersensitivity reactions and the risk of cross-hypersensitivity with COVID-19 vaccines and related clinical recommendations.
- Providers are asked to consider consulting an allergist-immunologist for individuals with a history of a severe allergic reaction (e.g., anaphylaxis) to a COVID-19 vaccine.
- Evusheld should be administered under the supervision of a health care provider with appropriate medical support to manage severe allergic reactions
- Patients should be observed for at least one hour post admin to monitor for hypersensitivity reactions
- The EUA was also recently modified to recommend redosing every 6 months after the initial full dose has been completed. The repeat dosage of EVUSHELD in adults and pediatric individuals (12 years of age and older weighing at least 40 kg) is 300 mg of tixagevimab and 300 mg of cilgavimab administered every 6 months. Repeat dosing should be timed from the date of the most recent Evusheld dose.
Patients who do receive COVID-19 vaccination should wait at least 2 weeks before receiving Evusheld.
See CDC webpage for other factors to consider.
Evusheld sample prescription
FDA: Letter of authorization | FAQs on the EUA | Fact sheet for health providers | Fact sheet for patient/caregivers
