NOTE: The National Institutes of Health (NIH) provides guidance on treating nonhospitalized patients with mild to moderate coronavirus disease 2019 (COVID-19) who are at high risk of progressing to severe disease. The NIH recommends using 1 of the following therapeutics:

• Preferred therapies (Adults and Pediatrics, listed in order of preference)
  • nirmatrelvir; ritonavir
  • remdesivir
• Alternative therapies (Adults only)
  • molnupiravir

The NIH recommends using molnupiravir ONLY if none of the preferred therapies are available, feasible to administer, or clinically appropriate (e.g., due to drug interactions, renal or hepatic dysfunction).[65314]

NOTE: Health care providers should choose an authorized therapeutic option with activity against the circulating variants in their state, territory, or US jurisdiction. Current variant frequency data are available at: https://covid.cdc.gov/covid-data-tracker/#variant-proportions.

No dosage adjustments are needed.

No dosage adjustments are needed.

Molnupiravir is an investigational oral antiviral medication with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is not an FDA-approved medication; however, it has been authorized for emergency use to treat adults with a current diagnosis of mild to moderate coronavirus disease 2019 (COVID-19) who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative FDA approved or authorized COVID-19 treatment options are unavailable or not clinically appropriate. Molnupiravir is NOT authorized for initiation of treatment in patients hospitalized due to COVID-19; however, should a patient require hospitalization after starting treatment, the patient may complete the full 5-day course at the health care providers' discretion. The drug is also NOT authorized for use as a pre-exposure or post-exposure prophylaxis to prevent COVID-19. Animal data suggest that treatment with molnupiravir may cause fetal harm when administered to pregnant individuals; therefore, prior to starting treatment, health care providers must assess whether a person of childbearing potential is pregnant. Additionally, both female and sexually active male drug recipients must be instructed to correctly and consistently use a reliable method of contraception.[67209]

The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend molnupiravir as an alternative treatment option for nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease. Molnupiravir should ONLY be prescribed when preferred treatment options cannot be used. Start molnupiravir as soon as possible after positive test results for SARS-CoV-2 and within 5 days of symptom onset. Although the drug is not authorized for use in patients hospitalized due to severe COVID-19, it may be used in patients who are hospitalized for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19 and are at high risk of progressing to severe disease.[65314]

For storage information, see the specific product information within the How Supplied section.

NOTE: Molnupiravir is not an FDA-approved medication; however, it has been authorized for emergency use to treat adults with a current diagnosis of mild to moderate coronavirus disease 2019 (COVID-19) who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative FDA approved or authorized COVID-19 treatment options are unavailable or not clinically appropriate. Under the Emergency Use Authorization (EUA), prescribing healthcare providers are required to document that information consistent with the "Fact Sheet for Patients and Caregivers" was communicated to the patient or caregiver prior to the patient receiving treatment; such information includes the following:

• Molnupiravir is an unapproved drug authorized for emergency use
• Other therapeutics are currently approved or authorized for the same use as molnupiravir
• There are benefits and risks to taking molnupiravir
• There is a pregnancy registry
• Persons 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
• Males of reproductive potential who are sexually active with persons 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

NOTE: Healthcare providers also MUST ensure that the following MANDATORY requirements are met before prescribing molnupiravir:

• The prescriber MUST assess whether a person of childbearing potential is pregnant or not, if clinically indicated
• If considering use of molnupiravir during pregnancy, the prescriber MUST communicate to the patient the known and potential benefits and risks of molnupiravir use during pregnancy
• If the decision is made to use molnupiravir during pregnancy, the prescriber MUST document that the known and potential benefits and risks of molnupiravir use during pregnancy were discussed with the patient
• The prescriber MUST document that a pregnant individual was made aware of the pregnancy registry at https://covid-pr.pregistry.com or 1-800-616-3791.

NOTE: Molnupiravir may ONLY be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state law to prescribe drugs in the antiinfective therapeutic class.

NOTE: Under the EUA, healthcare providers are required to report all medication errors and serious adverse events potentially related to molnupiravir therapy within 7 calendar days from the healthcare provider's awareness of the event.[67209]

Molnupiravir is a prodrug with antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Molnupiravir is hydrolyzed during or after absorption to form the cytidine nucleoside analog, N4-hydroxycytidine (NHC), which distributes into cells. Once inside the cells, NHC is phosphorylated to form the active ribonucleoside triphosphate (NHC-TP). Viral RNA polymerase (nsp12) then incorporates NHC-TP (as NHC-monophosphate [NHC-MP]) into SARS-CoV-2 RNA. This causes an accumulation of errors in the viral genome leading to inhibition of viral replication (i.e., viral error catastrophe or viral lethal mutagenesis).

In cell culture assays, NHC was active against SARS-CoV-2 (USA-WA1/2020 isolate) with 50% effective concentrations (EC₅₀) ranging from 0.67 to 2.7 microMolar in A-549 cells and 0.32 to 2 microMolar in Vero E6 cells. Similar activity was observed against SARS-CoV-2 variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621), and Omicron (B.1.1.529/BA.1, BA.1.1, BA.2, BA.4, and BA.5) with mean EC₅₀ values of 0.55 to 3 microMolar. NHC had non-antagonistic antiviral activity with remdesivir against SARS-CoV-2 in cell culture.

No amino acid substitutions in SARS-CoV-2 associated with resistance to NHC have been identified in Phase 2 clinical trials evaluating molnupiravir for treatment of COVID-19. Studies to evaluate selection of resistance to NHC with SARS-CoV-2 in cell culture have not been completed.

In clinical trials, encoded amino acid changes (substitutions, deletions, or insertions) were more likely to be detected in viral sequences in subjects treated with molnupiravir as compared to placebo. In some subjects, amino acid changes in the spike protein occurred at positions targeted by monoclonal antibodies and vaccines. The clinical and public health significance of these changes are unknown.

In vitro data does not indicate cross-resistance with remdesivir. In cell culture, NHC retained activity against virus with polymerase (nsp12) substitutions (e.g., F480L, V557L, and E802D) associated with decreased remdesivir susceptibility.

In the Phase 3 MOVe-OUT trial, a subset of molnupiravir and placebo recipients developed post-treatment increases in SARS-CoV-2 RNA shedding levels (i.e., viral RNA rebound) in nasopharyngeal samples on Day 10, Day 15, and/or Day 29. Approximately 1% of patients in both study groups had evidence of recurrent COVID-19 symptoms coinciding with a rebound in viral RNA levels in nasopharyngeal samples. However, post-treatment viral RNA rebound was not associated with the primary clinical outcome of hospitalization or death through Day 29 after the single 5-day course of molnupiravir. Additionally, post-treatment viral RNA rebound was not associated with the detection of cell culture infectious virus in nasopharyngeal swab samples.[67209]

Molnupiravir is administered orally. During or after absorption, molnupiravir is hydrolyzed to the cytidine nucleoside analog, N4-hydroxycytidine (NHC). NHC is the primary circulating component, with an apparent volume of distribution of 142 L. NHC is not bound to plasma proteins, but rather enters into cells were it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC is eliminated by metabolism to uridine and cytidine through the same pathways involved in endogenous pyrimidine metabolism. NHC has an apparent clearance of 76.9 L/hour and an effective half-life of approximately 3.3 hours. The fraction of dose excreted as NHC in the urine is up to 3%.[67209]

Affected cytochrome P450 isoenzymes: None

Molnupiravir and NHC are not substrates of CYP enzymes or the drug transporters P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Additionally, they are not inhibitors or inducers of major drug metabolizing enzymes or transporters.[67209]