Last Updated: April 20, 2023
Molnupiravir is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has shown antiviral activity against SARS-CoV-2 in vitro and in some clinical trials.1,2 NHC uptake by viral RNA-dependent RNA-polymerases results in viral mutations and lethal mutagenesis.3,4 On December 23, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for molnupiravir for the treatment of adults with mild to moderate COVID-19 who are within 5 days of symptom onset, who are at high risk of progressing to severe disease, and for whom alternative antiviral therapies are not accessible or clinically appropriate.5,6 Molnupiravir is expected to be active against the Omicron variant and its subvariants.6
As a mutagenic ribonucleoside antiviral agent, there is a theoretical risk that molnupiravir will be metabolized by the human host cell and incorporated into the host DNA, leading to mutations. Molnupiravir has been evaluated in 2 in vivo rodent mutagenicity assays. One study produced equivocal results. In the other study, there was no evidence for mutagenicity.6 The FDA concluded that, based on the available genotoxicity data and the 5-day duration of treatment, molnupiravir has a low risk for genotoxicity. In addition, there have been concerns about the potential effects of molnupiravir on SARS-CoV-2 mutation rates; the FDA has required that the manufacturer monitor genomic databases for the emergence of SARS-CoV-2 variants.
- The COVID-19 Treatment Guidelines Panel (the Panel) recommends using molnupiravir 800 mg orally (PO) twice daily for 5 days as an alternative therapy in nonhospitalized patients aged ≥18 years with mild to moderate COVID-19 who are at high risk of disease progression when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available, feasible to use, or clinically appropriate; treatment should be initiated as soon as possible and within 5 days of symptom onset (CIIa).
- The Panel recommends against the use of molnupiravir for the treatment of COVID-19 in pregnant patients unless there are no other options and therapy is clearly indicated (AIII). For more details, see Considerations in Pregnancy below.
- People who engage in sexual activity that may result in conception should use effective contraception during and following treatment with molnupiravir. For more details, see Considerations in Sexually Active Individuals below.
Molnupiravir 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. For the Panel’s recommendations on preferred and alternative antiviral therapies for outpatients with COVID-19, see Therapeutic Management of Nonhospitalized Adults With COVID-19.
The MOVe-OUT trial enrolled high-risk, unvaccinated, nonhospitalized adults and reported that molnupiravir reduced the rate of hospitalization or death among these patients by 31% compared to placebo.7 This trial was conducted in 2021 before the emergence of the Omicron variant and its subvariants. A secondary analysis of the patients who required hospitalization during the trial found a reduced need for respiratory interventions among those who received molnupiravir compared to those who received placebo.8 Molnupiravir has shown activity against the Omicron subvariants in vitro and in animal studies.2,9-11
The PANORAMIC trial enrolled participants during a period when the Omicron variant was circulating.12 The participants were nonhospitalized adults with COVID-19 who were at high risk of progressing to severe disease, and 94% had received at least 3 doses of a COVID-19 vaccine. The study found that the use of molnupiravir plus usual care did not reduce the primary composite outcome of hospitalization or death compared to usual care alone. The rates of this composite outcome were low (1%) in both arms. Molnupiravir plus usual care was superior to usual care alone for several secondary clinical endpoints. For example, patients who received molnupiravir plus usual care reported recovering from COVID-19 an estimated 4 days earlier than those who received usual care alone. However, because the PANORAMIC trial was an open-label study and the patients knew whether they were receiving molnupiravir or not, this may have affected their reported symptoms. As a result, these findings are less reliable than those from a placebo-controlled trial.
Although the different COVID-19 treatment options have not been directly compared in clinical trials, the Panel recommends using molnupiravir only when ritonavir-boosted nirmatrelvir and remdesivir are not available, feasible to use, or clinically appropriate (CIIa). Molnupiravir appears to have lower clinical efficacy than these other treatment options.
Some observational studies have evaluated the use of molnupiravir in nonhospitalized or hospitalized adults who are at high risk of progressing to severe disease, including some patients who received COVID-19 vaccines, but these studies have limitations.13-15 For treatment considerations for vaccinated individuals, see Therapeutic Management of Nonhospitalized Adults With COVID-19.
- Patients should complete the 5-day treatment course of molnupiravir. It is unknown whether a shorter course is less effective or associated with the emergence of molnupiravir-resistant mutations.
- If a patient requires hospitalization after starting treatment, the full treatment course of molnupiravir can be completed at the health care provider’s discretion.
- The FDA EUA for molnupiravir provides instructions for preparing and administering capsule contents through orogastric or nasogastric tubes.6
- There are no data on using combination antiviral therapies for the treatment of nonhospitalized patients with COVID-19. Clinical trials are needed to determine whether combination therapy has a role in the treatment of SARS-CoV-2 infection.
- Patients who are severely immunocompromised can experience prolonged periods of SARS-CoV-2 replication, which may lead to rapid viral evolution. There are theoretical concerns that using a single antiviral agent in these patients may produce antiviral-resistant viruses. Additional studies are needed to assess this risk. The role of combination antiviral therapy in treating patients who are severely immunocompromised is not yet known. See Special Considerations in People Who Are Immunocompromised for more information.
- There are limited data on the frequency of SARS-CoV-2 rebound in patients who have completed treatment with molnupiravir. During the MOVe-OUT trial, rates of symptomatic SARS-CoV-2 rebound were low (approximately 1%) in both those who received molnupiravir and those who received placebo.6
Monitoring, Adverse Effects, and Drug-Drug Interactions
The most common adverse effects of molnupiravir are diarrhea, nausea, and dizziness. Based on in vitro studies, neither molnupiravir nor its active metabolite NHC are inhibitors or inducers of major drug-metabolizing enzymes or inhibitors of major drug transporters.
According to the FDA EUA, no drug-drug interactions have been identified for molnupiravir.
Considerations in Sexually Active Individuals
For individuals of childbearing potential, clinicians should assess the patient’s pregnancy status before initiating molnupiravir.
Patients of childbearing potential should be counseled about abstaining from sex or using reliable contraception for the duration of therapy and for up to 4 days after taking molnupiravir. Reproductive toxicity has been reported in animal studies of molnupiravir, and molnupiravir may be mutagenic during pregnancy.
The FDA EUA states that men of reproductive potential who are sexually active with individuals of childbearing potential should be counseled to abstain from sex or use a reliable method of contraception for the duration of treatment and for at least 3 months after the last dose of molnupiravir.
Considerations in Pregnancy
The Panel recommends against the use of molnupiravir for the treatment of COVID-19 in pregnant patients unless there are no other options and therapy is clearly indicated (AIII). See Pregnancy, Lactation, and COVID-19 Therapeutics for more information.
Considerations in Lactating People
Because the risk of adverse effects in infants is currently unknown, the FDA EUA fact sheet recommends against feeding an infant breast milk from a patient who is taking molnupiravir for the duration of the treatment course and for 4 days after the final dose. See Pregnancy, Lactation, and COVID-19 Therapeutics for more information.
Considerations in Children
The MOVe-OUT and PANORAMIC trials excluded participants aged <18 years. There are no data available on the use of molnupiravir in children aged <18 years. Molnupiravir is not authorized for use in those aged <18 years due to potential effects on bone and cartilage growth.
MOVe-OUT was a multinational, Phase 3 trial that evaluated the use of molnupiravir in unvaccinated, nonhospitalized adults with mild to moderate COVID-19 who were at high risk of progressing to severe COVID-19 and enrolled within 5 days of symptom onset.7 The trial was conducted in 2021 before the emergence of the Omicron variant and its subvariants. Pregnant people, lactating people, and children were excluded from the study. Patients were randomized to receive molnupiravir 800 mg PO every 12 hours for 5 days or placebo.
The primary composite endpoint was all-cause hospitalization (defined as a hospital stay >24 hours) or death by Day 29.
- The final analysis included 1,433 patients:
- The median age was 43 years (with 17% aged >60 years); 49% of patients were men, 57% were White, 50% were Hispanic/Latinx, and 5% were Black or African American.
- Four percent had a body mass index ≥30, and 16% had diabetes.
- The time from the onset of COVID-19 symptoms to randomization was ≤3 days in 48% of patients.
- By Day 29, the use of molnupiravir reduced the risk of hospitalization or death by 31%.
- Forty-eight of 709 patients (6.8%) in the molnupiravir arm and 68 of 699 patients (9.7%) in the placebo arm experienced hospitalization or death (adjusted difference -3.0%; 95% CI, -5.9% to -0.1%).
- One death occurred in the molnupiravir arm and 9 deaths occurred in the placebo arm.
- There were no significant differences between the arms in the proportion of patients who experienced adverse events or serious adverse events.
- A secondary analysis of data from the patients who were hospitalized during the trial revealed that the use of molnupiravir reduced the risk of requiring respiratory interventions (conventional or high-flow oxygen delivery, noninvasive ventilation, or mechanical ventilation) by 21%.8
Limitations and Interpretation
- When compared with placebo, the use of molnupiravir had a modest benefit in reducing the risk of hospitalization or death in unvaccinated, nonpregnant, high-risk adults with mild to moderate COVID-19. Molnupiravir also reduced the risk of pulmonary complications in these patients. However, this study was conducted before the emergence of the Omicron variant and its subvariants.
PANORAMIC was a large, multicenter, open-label, adaptive platform trial that was conducted in the United Kingdom.12 The study evaluated the use of molnupiravir in nonhospitalized adults who were at high risk of progressing to severe COVID-19. The participants were aged ≥50 years or ≥18 years with comorbid conditions, and they had either a positive SARS-CoV-2 reverse transcription polymerase chain reaction result or rapid antigen test result at baseline. Patients were enrolled within 5 days of symptom onset. Pregnant people, lactating people, children, and those of childbearing potential who were unwilling to use effective contraception were excluded from the study. Patients were randomized to receive molnupiravir 800 mg PO twice daily for 5 days plus usual care or usual care alone.
The primary endpoint was a composite of all-cause hospitalization (defined as ≥1 overnight hospital stay, ≥1 night at home with care and monitoring by hospital clinicians, or an overnight stay in an emergency room) or death within 28 days of randomization. The trial was conducted from December 8, 2021, to April 27, 2022, when the Omicron variant was the dominant variant in the United Kingdom.
- The final analysis included 25,708 patients. The mean age was 56.6 years (with 26.5% aged ≥65 years), 94% of patients were White, and 59% were women.
- Ninety-four percent of the patients had received ≥3 doses of a COVID-19 vaccine.
- Overall, 69% of patients had comorbidities, including 25% with lung disease, 15% with obesity, 12% with diabetes, 8% with heart disease, and 8.5% were immunocompromised.
- Twenty-four percent of patients were taking inhaled corticosteroids.
- The mean time from symptom onset to starting molnupiravir was 3 days (range 3–5 days). Among the patients who provided information on their molnupiravir use, 95% reported completing the 5-day treatment course.
- Data on the primary outcome was available for 25,054 patients (97%).
- In both arms, approximately 1% of patients were hospitalized or died. There were 103 hospitalizations and 3 deaths in the molnupiravir arm compared with 96 hospitalizations and 5 deaths in the usual care alone arm (aOR 1.06; 95% CrI, 0.81–1.41; probability of superiority 0.33).
- Subgroup analyses revealed no evidence for treatment interaction.
- Molnupiravir plus usual care was superior to usual care alone for several secondary clinical endpoints.
- The time from randomization to self-reported first recovery was significantly shorter among those who received molnupiravir (median of 9 days; IQR 5–23) than those who received usual care alone (median of 15 days; IQR 7–not reached).
- After adjusting for age and baseline comorbidities, molnupiravir significantly reduced the estimated median time to first recovery. The median time to first recovery was 10.4 days (95% CrI, 10.1–10.6) in the molnupiravir arm and 14.6 days (95% CrI, 14.2–15) in the usual care alone arm (HR 1.36; 95% BCI, 1.32–1.40; probability of superiority >0.99).
- The use of molnupiravir also significantly reduced the time to early sustained recovery (defined as recovery by Day 14 that was sustained until Day 28), the time to sustained recovery, the time to alleviation of all symptoms, the time to sustained alleviation of all symptoms, and the time to initial reduction of symptom severity.
- Serious adverse events occurred in 0.4% of patients in the molnupiravir arm and 0.3% of patients in the usual care alone arm. No serious adverse events related to molnupiravir were reported; 145 patients (1.1%) withdrew because of adverse effects attributed to molnupiravir.
Limitations and Interpretation
- The use of molnupiravir did not reduce the rate of progression to hospitalization or death among vaccinated, nonpregnant, high-risk adults, but it did reduce the time to improvement of symptoms. However, because the PANORAMIC trial was an open-label study and the patients knew whether they were receiving molnupiravir or not, this may have affected their reported symptoms. As a result, these findings are less reliable than those from a placebo-controlled trial.
- Fischer WA II, Eron JJ Jr, Holman W, et al. A Phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med. 2022;14(628):eabl7430. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34941423.
- Zou R, Peng L, Shu D, et al. Antiviral efficacy and safety of molnupiravir against Omicron variant infection: a randomized controlled clinical trial. Front Pharmacol. 2022;13:939573. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35784723.
- Zhou S, Hill CS, Sarkar S, et al. Beta-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells. J Infect Dis. 2021;224(3):415-419. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33961695.
- Kabinger F, Stiller C, Schmitzová J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28(9):740-746. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34381216.
- Centers for Disease Control and Prevention. People with certain medical conditions. 2023. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Accessed February 23, 2023.
- Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for Lagevrio (molnupiravir) capsules. 2023. Available at: https://www.fda.gov/media/155054/download.
- Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N Engl J Med. 2022;386(6):509-520. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34914868.
- Johnson MG, Puenpatom A, Moncada PA, et al. Effect of molnupiravir on biomarkers, respiratory interventions, and medical services in COVID-19: a randomized, placebo-controlled trial. Ann Intern Med. 2022;175(8):1126-1134. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35667065.
- Vangeel L, Chiu W, De Jonghe S, et al. Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022;198:105252. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35085683.
- Takashita E, Yamayoshi S, Simon V, et al. Efficacy of antibodies and antiviral drugs against Omicron BA.2.12.1, BA.4, and BA.5 subvariants. N Engl J Med. 2022;387(5):468-470. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35857646.
- Uraki R, Kiso M, Iida S, et al. Characterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2. Nature. 2022;607(7917):119-127. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35576972.
- Butler CC, Hobbs FDR, Gbinigie OA, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2023;401(10373):281-293. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36566761.
- Flisiak R, Zarębska-Michaluk D, Rogalska M, et al. Real-world experience with molnupiravir during the period of SARS-CoV-2 Omicron variant dominance. Pharmacol Rep. 2022;74(6):1279-1285. Available at: https://pubmed.ncbi.nlm.nih.gov/36001284.
- Yip CF, Lui GCY, Man Lai MS, et al. Impact of the use of oral antiviral agents on the risk of hospitalization in community coronavirus disease 2019 patients (COVID-19). Clin Infect Dis. 2023;76(3):e26-e33. Available at: https://pubmed.ncbi.nlm.nih.gov/36031408.
- Wong CKH, Au ICH, Lau KTK, et al. Real-world effectiveness of early molnupiravir or nirmatrelvir-ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's Omicron BA.2 wave: a retrospective cohort study. Lancet Infect Dis. 2022;22(12):1681-1693. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36029795.