OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Molnupiravir – Generic

DRUG CLASS

Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Molnupiravir	2492423-29-5	C13-H19-N3-O7

ANNOTATED BIBLIOGRAPHY

References updated: 31 January 2022

Abbreviations used: COVID-19, coronavirus disease, 2019; ICU, intensive care unit; IFN, interferon; IL, interleukin; MERS, Middle East respiratory syndrome; NHC, N-hydroxycytidine; SARS-CoV-2, severe acute respiratory syndrome-coronavirus 2.

• Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. [PMC free article: PMC7159299] [PubMed: 31986264]

  (Among 41 adults with COVID-19 pneumonia hospitalized in Wuhan China in December 2019-January 2020, 37% had serum AST elevations [62% of those in the ICU and 25% of those not] with concurrent elevations in proinflammatory cytokines [IL1B, IL6, IL2, IFN gamma], and 15% died).
• Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, et al. China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720. [PMC free article: PMC7092819] [PubMed: 32109013]

  (Among1099 patients hospitalized with COVID-19 at 552 hospitals in China through January 2020, the median age was 47 years, 42% were women, 2.4% were admitted to an ICU, 1.4% died and ALT elevations arose in 4.1%).
• Qiu H, Wander P, Bernstein D, Satapathy SK. Acute on chronic liver failure from novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Liver Int. 2020;40:1590–1593. [PubMed: 32369658]

  (56 year old woman with decompensated alcoholic cirrhosis developed worsening jaundice and liver function when admitted with SARS-CoV-2 infection [bilirubin rising from 9.4 to ~17.8 mg/dL, ALT from 94 to ~275 U/L, AST from 184 to ~880 U/L, Alk P from 128 to ~195 U/L, INR from 1.92 to 2.6], improving back towards baseline as the infection resolved).
• Wander P, Epstein M, Bernstein D. COVID-19 presenting as acute hepatitis. Am J Gastroenterol. 2020;115:941–942. [PMC free article: PMC7172489] [PubMed: 32301760]

  (59 year old woman with HIV infection developed fatigue and jaundice [bilirubin 0.6 mg/dL, ALT 697 U/L, Alk P 145 U/L, INR 1.08] and then developed fever and cough with positive tests for SARS-CoV-1, liver tests falling over the next week as she recovered from COVID-19 ).
• Bertolini A, van de Peppel IP, Bodewes FAJA, Moshage H, Fantin A, Farinati F, Fiorotto R, et al. Abnormal liver function tests in COVID-19 patients: relevance and potential pathogenesis. Hepatology. 2020;72(5):1864–1872. [PMC free article: PMC7404414] [PubMed: 32702162]

  (Review of the prevalence and potential causes of abnormal liver tests in patients with SARS-CoV-2 infection, ALT elevations being reported in 4-39% of patients with higher rates in patients with more severe disease).
• Hundt MA, Deng Y, Ciarleglio MM, Nathanson MH, Lim JK. Abnormal liver tests in COVID-19: A retrospective observational cohort study of 1827 patients in a major U.S. hospital network. Hepatology. 2020 Oct;72(4):1169–1176. [PMC free article: PMC9258788] [PubMed: 32725890]

  (Among 1877 patients hospitalized with SARS-CoV-2 infection, serum ALT levels were elevated before hospitalization in 19%, at admission in 42% and a peak during hospitalization in 62%, with 21% being greater than 5 times ULN; elevations correlated with disease severity and its risk factors: male sex, older age, higher BMI and diabetes).
• Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, et al. Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrob Agents Chemother. 2021;65:e02428–20. [PMC free article: PMC8092915] [PubMed: 33649113]

  (Among 64 healthy adults participating in a double-blind dose and safety trial, adverse events were less frequent with molnupiravir [50 to 1600 mg daily] than placebo and there were no clinically significant findings or dose related trends in laboratory values).
• Zhou S, Hill CS, Sarkar S, Tse LV, Woodburn BMD, Schinazi RF, Sheahan TP, et al. β-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but Is also mutagenic to mammalian cells. J Infect Dis. 2021;224:415–419. [PMC free article: PMC8136050] [PubMed: 33961695]

  (In cell culture, N-hydroxycytidine [NHC] had potent [EC₅₀ 0.3 µM] activity against SARS-CoV-2 replication and created mutant viral genomes in a dose dependent manner, while ribavirin and favipiravir had minimal effects on replication and only at high concentrations; NHC also resulted in mutations in host genes in a mammalian cell culture system while ribavirin and favipiravir had minimal or no mutagenic effects).
• Gordon CJ, Tchesnokov EP, Schinazi RF, Götte M. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template. J Biol Chem. 2021 Jul;297:100770. [PMC free article: PMC8110631] [PubMed: 33989635]

  (Studies with the SARS-CoV-2 RNA dependent RNA polymerase complex suggested that molnupiravir causes mutations in viral genomes by incorporation into the viral RNA template).
• Kabinger F, Stiller C, Schmitzová J, Dienemann C, Kokic G, Hillen HS, Höbartner C, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28:740–746. [PMC free article: PMC8437801] [PubMed: 34381216]

  (In vitro assays demonstrated that molnupiravir is converted to N-hydroxycytidine [NHC] which can be used by the SARS-CoV-2 RNA dependent RNA polymerase to create negative strand viral RNA which is then used as a template for positive strand viral RNA, and since NHC can base pair with either cytidine or adenine, it can thus create mutations in subsequent negative strand synthesis).
• Khoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R, Downs N, et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J Antimicrob Chemother. 2021;76:3286–3295. [PMC free article: PMC8598307] [PubMed: 34450619]

  (Among 18 outpatients with documented SARS-CoV-2 infection started on molnupiravir [300, 400 or 800 mg] or placebo twice daily for 5 days within 5 days of onset, all patients tolerated therapy well with no serious adverse events; 1 of 12 patients on active drug had a mild, transient ALT elevation).
• Fischer WA 2nd, Eron JJ Jr, Holman W, Cohen MS, Fang L, Szewczyk LJ, Sheahan TP, 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. [PMC free article: PMC10763622] [PubMed: 34941423]

  (Among 202 unvaccinated patients with documented SARS-CoV-2 infection enrolled within 7 days of onset of symptoms who were treated with oral molnupiravir [200, 400 or 800 mg] or placebo twice daily for 5 days, the median time to clearance of nasal swab SARS-CoV-2 RNA was shorter with 800 mg daily [15 days] than placebo [14 days] and adverse event rates were lower with active drug, ALT elevations occurring in 2.8% vs 3.2% and there were no serious adverse events).
• Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A, et al. MOVe-OUT Study Group. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2021 Dec 16; Epub ahead of print. [PMC free article: PMC8693688] [PubMed: 34914868]

  (Among 1433 outpatients at high risk of complications of COVID-19 started on oral molnupiravir or placebo within 5 days of onset of symptoms or signs, rates of hospitalization [6.8% vs 9.7%] and deaths within 29 days [0.1% vs 1.3%] were less with molnupiravir than placebo, while adverse event rates were similar [30%vs 33%]; no mention of ALT elevations or hepatotoxicity).
• Whitley R. Molnupiravir – A step toward orally bioavailable therapies for Covid-19. N Engl J Med. 2021 Dec 16; Epub ahead of print. [PMC free article: PMC8693684] [PubMed: 34914869]

  (Editorial in response to Jayk Bernal [2021] mentions that response rates with molnupiravir were greater in the interim analysis [50%] than the final analysis [30%] of the MOVe-OUT trial, and that starting antiviral therapy early appears to be crucial in achieving a response in COVID-19).
• Couzin-Frankel J. Antiviral pills could change pandemic's course. Science. 2021;374(6569):799–800. [PubMed: 34762459]

  (News report of the promise of antivirals including Paxlovid and molnupiravir as a means of treatment for early SARS-CoV-2 infection; no discussion of adverse events).
• Molnupiravir for treatment of COVID-19. Med Lett Drug Ther. 2022;64:10–11. [PubMed: 35134041]

  (Concise review of the mechanism of action, clinical efficacy, safety and indications of molnupiravir shortly after its Emergency Use Authorization in the US mentions mild adverse events arising during the 5 day treatment including diarrhea, nausea and dizziness and potential risks of embryofetal toxicity and impaired bone and cartilage growth; no mention of ALT levels or liver injury).
• Law MF, Ho R, Law KWT, Cheung CKM. Gastrointestinal and hepatic side effects of potential treatment for COVID-19 and vaccination in patients with chronic liver diseases. World J Hepatol. 2021;13:1850–1874. [PMC free article: PMC8727202] [PubMed: 35069994]

  (Summary of the therapies for COVID-19 therapy and their potential for causing liver injury mentions that ALT elevations have occurred in some patients treated with molnupiravir).