Therapeutic Options for COVID-19 Patients

• Nirmatrelvir/ritonavir is an oral antiviral treatment that combines a SARS-CoV-2 protease inhibitor (nirmatrelvir) with ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor. Ritonavir acts as a pharmacological booster to increase the levels of nirmatrelvir. It is authorized for the treatment of mild-to-moderate COVID-19 in patients at high risk for severe illness from COVID-19. Treatment must be started within five days of symptom onset and is given as a five-day treatment course. In the EPIC-HR trial, ritonavir-boosted nirmatrelvir (Paxlovid) reduced the risk of hospitalization or death by 88% compared to placebo in nonhospitalized adults with laboratory-confirmed SARS-CoV-2 infection.

NOTE: The following are limitations to the use of Paxlovid:

• Paxlovid is not authorized for use in patients younger than 12 years.
• Paxlovid is not recommended for use in patients with severe renal impairment (GFR<30ml/min) or hepatic impairment (Child-Pugh Class C).
• For patients with moderate renal impairment (GFR 30-60ml/min), the dose of nirmatrelvir should be reduced from 300mg to 150mg (refer to FDA: Fact Sheet for Providers below).

Due to the co-administration with ritonavir, it is critical to evaluate the patient medication regimen for potentially serious drug-drug interactions prior to prescribing Paxlovid. Please refer to guidance on Antiviral Therapy Resources for Providers.

There have been recent case reports of COVID-19 rebound following treatment with Paxlovid. These cases of COVID-19 rebound had negative test results after Paxlovid treatment and resolution of symptoms, followed by recurrence of symptoms and positive viral antigen and/or PCR testing. The limited information currently available suggests that these patients typically have mild illness that resolves within days without additional COVID-19 treatment, but patients should still be counseled to follow isolation guidance. More information for providers is available at CDC Health Alert Network: COVID-19 Rebound After Paxlovid Treatment. Health care providers are encouraged to report cases of COVID-19 rebound to Pfizer using Pfizer's COVID-19 Treatment Adverse Event Reporting online tool and to the FDA using MedWatch: The FDA Safety Information and Adverse Event Reporting Program.

• Molnupiravir is an oral nucleoside analogue that inhibits SARS-CoV-2 replication by inducing viral mutagenesis. It is authorized for the treatment of mild to moderate COVID-19 in patients at high risk for severe illness from COVID-19. Treatment must be started within five days of symptom onset and is given as a five-day treatment course. In the MOVe-OUT trial, molnupiravir reduced the rate of hospitalization or death by 30% compared to placebo.

NOTE: the following are limitations to the use of molnupiravir.

• Molnupiravir is not authorized for use in patients younger than 18 years.
• Molnupiravir is not recommended for use in pregnancy. Patients of childbearing potential should be advised to use effective contraception correctly and consistently, as applicable, for the duration of treatment and for four days after the last dose of molnupiravir.
• Molnupiravir is not recommended for use while breastfeeding. Breastfeeding is not recommended during treatment and for four days after the last dose of molnupiravir. A lactating individual may consider interrupting breastfeeding and may consider pumping and discarding breast milk during treatment and for four days after the last dose of molnupiravir.

More information can be found at Antiviral Therapy Resources for Providers.

• HHS: COVID-19 Therapeutics
  Resources for health care professionals on monoclonal antibodies for high-risk patients.
  • Monoclonal antibodies video and flyer for patients
  • FAQ on billing and reimbursement
  • High-risk patient guidance
  • Review of clinical evidence
  • Videos on counseling patients for monoclonal antibodies
     
• HHS/ASPR Federal Response to COVID-19: Monoclonal Antibody Clinical Implementation Guide (PDF)
  Outpatient administration guide for healthcare providers, updated Feb. 15, 2022.
   
• HHS/ASPR: The mAbs Calculator
  COVID-19 monoclonal antibody therapeutics calculator for infusion sites to inform staffing and resource decisions.
   
• CMS: COVID-19 Monoclonal Antibodies
  Information for health care providers on Medicare payment, billing, and coding for monoclonal antibody treatment. Note: On May 6, 2021, CMS increased the Medicare payment rate for administering monoclonal antibodies both in health care settings and at home or temporary lodging.
  • Visit CMS Increases Medicare Payment for COVID-19 Monoclonal Antibody Infusions for the full announcement.
     
• FDA: Exemption and Exclusion from Certain Requirements of the Drug Supply Chain Security Act During the COVID-19 Public Health Emergency
  Industry guidance on how prescription drug products related to the treatment of COVID-19 (including monoclonal antibodies) can be exempted from certain requirements of the Drug Supply Chain Security Act (DSCSA).

Certain circulating SARS-CoV-2 viral variants may be associated with resistance to monoclonal antibodies. Health care providers should review the viral neutralization data in the authorized fact sheets for each mAb available under EUA for details regarding specific variants and resistance (see below). Information on the proportion of SARS-CoV-2 variants circulating in the U.S. is available on CDC COVID Data Tracker: Variant Proportions and will be updated regularly.

Please note that although sequencing information is helpful on a population level, individual patient results will not be reported back to the provider or submitting laboratory. Whole genome sequencing is not currently approved for use as a diagnostic test to make individual patient treatment decisions. In addition, the lengthy turnaround time for this type of testing means it is unsuitable for treatment decisions involving mAbs, which should be given as soon as possible once a patient has developed symptoms and tests positive.

• For questions on mAbs and variants, please contact the MDH Provider Hotline at 651-201-5414, option 3.
• Please visit the MDH Health Advisory: SARS-CoV-2 Variant Surveillance for questions on submitting specimens for genomic sequencing.

Bebtelovimab is available for use through HHS allocation and distribution. It received emergency use authorization on Feb. 11, 2022, for the treatment of mild to moderate COVID-19 in non-hospitalized patients.

Bebtelovimab became commercially available on Aug. 15, 2022. Facilities who have previously received monoclonal antibodies through the distributor (Amerisource Bergen) should have received an email from the distributor with instructions regarding commercial purchase. Facilities that have not previously received monoclonal antibodies and are interested in purchasing bebtelovimab should contact Amerisource Bergen at service@asdhealthcare.com to register for an account. Additional information on the transition of bebtelovimab to the commercial marketplace and the bebtelovimab dose replacement program for providers is available at ASPR: Bebtelovimab.

Bebtelovimab is authorized for use only in patients for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate. It is thought to be effective against the Omicron variant, including the BA.4 and BA.5 subvariants. It is administered by IV injection.

Tixagevimab/cilgavimab is available for use through HHS allocation and distribution.

• AstraZeneca: Evusheld (tixagevimab/cilgavimab)
  Website of the manufacturer of tixagevimab/cilgavimab. Visit additional links, resources, and guidance to facilities administering the treatment, including:
  • FDA letter of authorization
  • Fact sheet for U.S. health care providers
  • Fact sheet for patients and caregivers in English
• FDA: Evusheld Letter of Authorization (PDF)
  Letter for emergency use authorization of tixagevimab/cilgavimab, updated Feb. 24, 2022.
• FDA authorizes revisions to Evusheld dosing
  • FDA recommends repeat dosing every six months with a dose of 300mg of tixagevimab and 300mg of cilgavimab if patients need ongoing protection.
  • Please refer to the updated Evusheld Fact Sheet for Healthcare Providers for more details.
• COVID-19 Therapeutics Locator
  National map displaying locations that have received supplies of COVID-19 therapeutics, including tixagevimab/cilgavimab.

Patients with other medications or conditions that result in moderate to severe immune compromise may also be eligible. Please refer to the FDA's Fact Sheet for Healthcare Providers on tixagevimab/cilgavimab for updates to eligibility and dosing.

Providers with questions about the availability of tixagevimab/cilgavimab should contact the patient's specialist provider for information. Providers who are not currently receiving distributions of Evusheld, but are interested in small volume ordering (1-3 patient courses), may now place those orders directly with the federal government at EVUSHELD Small Volume Order Form. AstraZeneca has established a helpline for providers with questions about prescribing and ordering: 1-833-EVUSHLD (833-388-7453).

On Oct. 3, 2022, FDA updated the provider fact sheet to include information on the increased risk for developing COVID-19 when exposed to variants of SARS-CoV-2 that are not neutralized by Evusheld. Details are available in the FDA: Fact Sheet for Healthcare Providers for Evusheld. Patients receiving tixagevimab/cilgavimab should be counseled about this potential risk and should be advised about continuing all other COVID-19 mitigation efforts including vaccination of family and caregivers; diligent, high-quality mask wearing when recommended; and avoidance of large gatherings. Patients should also be advised to test for SARS-CoV-2 infection if they develop signs or symptoms of COVID-19 and should seek medical attention immediately if positive for consideration of antiviral treatment.

• As of Jan. 24, 2022, REGEN-COV (casirivimab/imdevimab) and bamlanivimab/etesevimab are no longer authorized for use due to lack of activity against circulating variants.
• As of March 30, 2022, sotrovimab is no longer authorized for use in Minnesota due to lack of activity against circulating variants.

It was previously approved only in hospitalized patients, but approval was expanded by the FDA on Jan. 21, 2022, to include use in non-hospitalized patients: FDA Takes Actions to Expand Use of Treatment for Outpatients with Mild-to-Moderate COVID-19. The approval was expanded again on April 25, 2022, to include pediatric patients ages 28 days and older and weighing at least 3 kg: Coronavirus (COVID-19) Update: FDA Approves First COVID-19 Treatment for Young Children.

Remdesivir has been studied in non-hospitalized patients with mild to moderate illness who are at high risk of progressing to more severe illness. A clinical trial (PINETREE) showed that three consecutive days of IV remdesivir resulted in an 87% reduction in the risk of hospitalization or death compared to placebo.

• Dosing is 200mg IV on day 1, followed by 100mg IV once daily on days two and three
• Treatment should be initiated as soon as possible and within seven days of symptom onset

More information:

• NIH COVID-19 Treatment Guidelines: Therapeutic Management of Nonhospitalized Adults with COVID-19
  Last updated Feb. 1, 2022, including recommendation for remdesivir
   
• Update: Distribution of Veklury® (remdesivir) (PDF)
  Process for hospitals to order supplies of remdesivir.
  10/1/20
  Hospitals interested in ordering VEKLURY can contact AmerisourceBergen Specialty Division (800-746-6273), Cardinal Specialty (855-855-0708), and/or McKesson Plasma and Biologics (877-625-2566). These are the current authorized distributors.

More information can be found at Antiviral Therapy Resources for Providers.

COVID-19 convalescent plasma (CCP) is human plasma obtained from donors who have recovered from COVID-19. It may contain antibodies to SARS-CoV-2 that suppress viral replication. As of Dec. 28, 2021, CCP with high titers of anti-SARS-CoV-2 antibodies is currently authorized for the treatment of COVID-19 in patients with immunosuppressive disease or who are receiving immunosuppressive treatment. It is authorized for use in either the outpatient or the inpatient setting. This authorization is based on the totality of the scientific evidence available that suggests the potential benefits of CCP outweigh the potential risks when used for this indication. However, additional data from randomized controlled clinical trials are needed.

Plasma donations must be tested by registered or licensed blood establishments for high titers of anti-SARS-CoV-2 antibodies as a manufacturing step to determine suitability before release, using one of the tests and qualifying results listed in the FDA EUA.

Clinical dosing may first consider starting with one high titer CCP unit (about 200mL), with administration of additional high titer CCP units based on the prescribing physician’s judgment and the patient's clinical response.

• FDA: Fact Sheet for Healthcare Providers: Emergency Use Authorization of COVID-19 Convalescent Plasma for Treatment of COVID-19

Tocilizumab is an interleukin (IL)-6 inhibitor that can be used in hospitalized patients with progressive severe or critical COVID-19 illness that demonstrate elevated markers of inflammation. For a more complete review of the evidence, benefits/harms and treatment criteria, refer to the National Institutes of Health (NIH) and Infectious Disease Society of America (IDSA) COVID-19 treatment guidelines below:

• IDSA Guidelines on the Treatment and Management of Patients with COVID-19
  Last updated March 23, 2022
   
• NIH COVID-19 Treatment Guidelines: Interleukin-6 Inhibitors
  Last updated Dec. 16, 2021

Baricitinib is a Janus kinase (JAK) inhibitor that can be used in hospitalized patients with severe COVID-19 disease and elevated inflammatory markers, but not requiring mechanical ventilation. It can also be given in conjunction with remdesivir to hospitalized patients with severe disease who are unable to receive corticosteroids due to a contraindication. For a more complete review of the evidence, benefits/harms and treatment criteria, refer to the NIH and IDSA COVID-19 treatment guidelines below:

• IDSA Guidelines on the Treatment and Management of Patients with COVID-19
  Last updated March 23, 2022
   
• NIH COVID-19 Treatment Guidelines: Kinase Inhibitors: Baricitinib and Other Janus Kinase Inhibitors, and Bruton's Tyrosine Kinase Inhibitors
  Last updated Dec. 16, 2021