Molnupiravir (Monograph)

Brand name: Lagevrio
Drug class: Nucleosides and Nucleotides
Chemical name: (2R,3S,4R,5R)-3,4-Dihydroxy-5-[(4Z)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate
Molecular formula: C₁₃H₁₉N₃O₇

Medically reviewed by Drugs.com on Feb 25, 2023. Written by ASHP.

Introduction

Antiviral; prodrug of N4-hydroxycytidine (NHC), a cytidine nucleoside analog that has antiviral activity against SARS-CoV-2.

Uses for Molnupiravir

Coronavirus Disease 2019 (COVID-19)

Molnupiravir is available under an emergency use authorization (EUA) for the treatment of mild to moderate COVID-19 in adults with a current diagnosis of mild-to-moderate COVID-19 and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Consult molnupiravir EUA letter of authorization, EUA fact sheet for healthcare providers, and EUA fact sheet for patients and caregivers for additional information.

Molnupiravir is not authorized under the EUA for use in pediatric patients (younger than 18 years of age), patients requiring hospitalization due to COVID-19, for use as preexposure or postexposure prophylaxis, or for use >5 consecutive days.

Preferred therapies now include ritonavir-boosted nirmatrelvir or remdesivir, in order of preference.

If neither preferred therapies are available, treatment options include molnupiravir.

For the treatment of nonhospitalized patients (ambulatory patients) with mild to moderate COVID-19 at high risk of progression to severe COVID-19, IDSA suggests the use of molnupiravir within 5 days of symptom onset over no molnupiravir treatment in patients with no other treatment options. Consider patient-specific factors when selecting an appropriate treatment for COVID-19 in nonhospitalized outpatients including availability of treatment options, feasibility of parenteral medication administration, potential for drug-drug interactions, and regional prevalence of variants.

Based on clinical trial data to date, use of molnupiravir early in the disease process when viral loads are high confers maximum benefit; therefore, rapid diagnosis and treatment early in the disease course are critical.

The use of molnupiravir presents additional considerations and potential concerns regarding viral mutagenesis in immunocompromised individuals and safety in individuals of reproductive potential, for which more data are needed to quantify such effects.

Molnupiravir Dosage and Administration

General

Pretreatment Screening

• Information in the “Fact Sheet for Patients and Caregivers” should be reviewed with patients or caregivers prior to initiation of treatment.

• Verify pregnancy status in females of reproductive potential.

• If a decision is made to use molnupiravir during pregnancy, discussion with the patient on the risks and benefits of the use of molnupiravir during pregnancy, and the pregnancy surveillance program, must be documented.

• Females of childbearing potential should use a reliable method of contraception during and for 4 days after the last dose of molnupiravir.

• Males of reproductive potential who are sexually active with females of childbearing potential must use a reliable method of contraception during and for at least 3 months after the last dose of molnupiravir.

Patient Monitoring

• Monitor for signs and symptoms of hypersensitivity reactions or anaphylaxis.

Dispensing and Administration Precautions

• Completion of FDA MedWatch forms to report all medication errors and all serious adverse events potentially related to molnupiravir is mandatory. The FDA fact sheet for health care providers that is provided with the drug and available at the FDA website should be consulted for requirements and instructions regarding reporting of adverse reactions and medication errors.

Other General Considerations

• Patients should continue isolation in accordance with public health recommendations to maximize viral clearance and minimize transmission of SARS-CoV-2.

Administration

Oral Administration

Administer orally without regard to food.

Swallow capsules whole; do not open, break, or crush.

If a dose of molnupiravir is missed within 10 hours of the time it is usually taken, take the prescribed dose as soon as it is remembered. If a dose is missed by >10 hours, take the prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose.

Dosage

Adults

Treatment of Mild to Moderate COVID-19 in Nonhospitalized Patients

Oral

EUA permits use of 800 mg of molnupiravir orally every 12 hours for 5 days. Complete full 5-day treatment course. Safety and efficacy of administration beyond 5 consecutive days not established.

Administer molnupiravir as soon as possible after a diagnosis of COVID-19 is made and within 5 days of symptom onset.

If hospitalization occurs after molnupiravir therapy, treatment course may be continued per the clinician's discretion.

Special Populations

Hepatic Impairment

No dosage adjustment recommended.

Renal Impairment

No dosage adjustment recommended.

Geriatric Patients

No dosage adjustment recommended.

Cautions for Molnupiravir

Contraindications

• FDA EUA states none.

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

No available data on use of molnupiravir in pregnant women; however, based on animal findings (e.g., abortion, decreased fetal weight, decreased fetal growth, teratogenicity), may cause fetal harm.

Estimated background risk of major birth defects and miscarriage in the indicated population unknown. COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.

Avoid pregnancy during molnupiravir therapy. Verify pregnancy status prior to initiation of therapy in females of reproductive potential; advise such females to use effective contraceptive methods while receiving molnupiravir therapy and for 4 days after the last dose. In addition, sexually active males with partners of reproductive potential should use effective contraceptive methods while receiving molnupiravir and for ≥3 months after the last dose.

Use during pregnancy only if potential benefit outweighs potential risk for the woman and fetus. If the drug is used in a pregnant female, apprise patient of the potential hazard to the fetus.

Clinicians must document that a pregnant individual was informed of the manufacturer's pregnancy surveillance program at 1-877-888-4231 or via the manufacturer’s website (https://pregnancyreporting.msd.com). Pregnant females or females who become pregnant while receiving molnupiravir are encouraged to enroll in the manufacturer's pregnancy surveillance program.

Hypersensitivity Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported with molnupiravir. Immediately discontinue treatment for signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis and initiate appropriate treatments and/or supportive care.

Bone and Cartilage Toxicity

Molnupiravir is not authorized for use in pediatric patients <18 years of age; possible effect on bone and cartilage growth.

In animals, transformation of growth cartilage into new bone observed in femur and tibia.

EUA Requirements for Patient Monitoring and Mandatory FDA MedWatch Reporting

Safety and efficacy of molnupiravir not established. FDA EUA that permits use of molnupiravir for the treatment of mild to moderate COVID-19 in adults requires that the drug be administered using the dosages recommended in the EUA.

Only limited data available to date regarding adverse effects associated with use of molnupiravir. Serious and unexpected adverse events may occur that have not been previously reported with the drug.

Completion of FDA MedWatch forms to report all medication errors and all serious adverse events potentially related to molnupiravir is mandatory. The EUA Fact Sheet for Healthcare Providers that is provided with the drug and available at the manufacturer’s website should be consulted for requirements and instructions regarding reporting of adverse reactions and medication errors.

Specific Populations

Pregnancy

May cause fetal harm based on animal findings.

Encourage pregnant females or females who become pregnant while receiving molnupiravir to enroll in the manufacturer's pregnancy surveillance program. Patients or their clinicians should call 1-877-888-4231 to enroll.

Lactation

Not known whether molnupiravir or its metabolites are distributed into human milk; however, N4-hydroxycytidine (NHC) was detected in plasma of nursing pups when molnupiravir was administered to lactating rats. The effects of the drug on the breast-fed infant or on the production of milk are unknown.

Because of the potential for adverse reactions to molnupiravir in breast-fed infants, advise females not to breast-feed while receiving the drug and for 4 days after the final dose. Lactating females may consider pumping and discarding breast milk during molnupiravir therapy and for 4 days after the final dose.

Females and Males of Reproductive Potential

Avoid pregnancy during molnupiravir therapy. Verify pregnancy status prior to initiation of therapy in females of reproductive potential; advise such females to use effective contraceptive methods while receiving molnupiravir therapy and for 4 days after the last dose.

Sexually active males with partners of reproductive potential should use effective contraceptive methods while receiving molnupiravir and for ≥3 months after the last dose. The risk beyond 3 months after the last dose of molnupiravir is unknown.

In animal reproductive studies, no effects on fertility, mating performance, or early embryonic development observed.

Pediatric Use

Not authorized for use in pediatric patients <18 years of age.

Safety and efficacy not established in pediatric patients.

In a repeat-dose toxicity study in rats, impaired transformation of growth cartilage into new bone observed in the femur and tibia.

Geriatric Use

No difference in safety and tolerability observed between ambulatory geriatric patients and younger adults receiving molnupiravir for the treatment of COVID-19.

Hepatic Impairment

Effect of hepatic impairment on the pharmacokinetics of molnupiravir unknown; however, hepatic impairment unlikely to affect NHC exposure.

Renal Impairment

Mild or moderate renal impairment did not have a meaningful impact on pharmacokinetics of NHC. Pharmacokinetic profile of NHC not evaluated in patients with eGFR <30 mL/min per 1.73m² or in those requiring dialysis; however, severe renal impairment and end-stage renal disease (ESRD) not expected to have a significant effect on NHC exposure.

Common Adverse Effects

Most common adverse reactions occurring in ≥1% of patients include diarrhea, nausea, and dizziness. Post-authorization experience has identified additional adverse effects, including erythema, rash, urticaria, and hypersensitivity reactions through voluntary reporting.

Drug Interactions

Drug-drug interaction trials not conducted.

In vitro, molnupiravir and its active nucleoside analog (N4-hydroxycytidine [NHC]) are not substrates of CYP isoenzymes or P-glycoprotein (P-gp) and BCRP transporters.

In vitro, molnupiravir and NHC are not inhibitors of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 or inhibitors of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2K, MRP2, MDR1 and BCRP or inducers of CYP isoenzymes 1A2, 2B6, and 3A4.

Molnupiravir Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and AUC of molnupiravir increase in a dose-proportional manner without accumulation of serum concentrations.

Following twice-daily administration of 300, 600, or 800 mg of molnupiravir, the prodrug is generally not detectable, or detected at low concentrations, only at 30 minutes and 1 hour post-dose. Following twice-daily administration of 300, 600, or 800 mg of molnupiravir, plasma concentrations of the active nucleoside analog N4-hydroxycytidine (NHC) are detectable; however, no accumulation is observed after 5 days of administration.

Peak plasma concentrations of NHC are achieved in a median of 1–1.75 hours following administration of molnupiravir.

Food

Administration in a fed state decreased the rate of absorption, with a 36% reduction in mean C_max, but did not affect the extent of absorption compared with the fasted state, as demonstrated by the AUC.

Distribution

Extent

Apparent volume of distribution is 142 L.

Not known whether molnupiravir is distributed into human or animal milk.

Plasma Protein Binding

Molnupiravir appears not to bind significantly to plasma proteins.

Elimination

Metabolism

Not metabolized by CYP isoenzymes. Hydrolyzed to NHC (active nucleoside analog). NHC is eliminated by metabolism to uridine and/or cytidine through the same pathways involved in endogenous pyrimidine metabolism.

Elimination Route

Dialysis is not expected to remove NHC.

Half-life

The half-life of NHC is 3.3 hours.

Special Populations

The effects of sex, race, body weight, or disease severity on the pharmacokinetics of molnupiravir are unknown; hepatic or renal clearance is not expected to be a major route of NHC elimination.

Stability

Storage

Oral

Capsules

20–25ºC (excursions permitted between 15–30ºC).

Actions

• Molnupiravir is an isopropylester prodrug of the ribonucleoside analog β-D-N4-hydroxycytidine (also referred to as NHC; N-hydroxycytidine; EIDD-1931), which is a cytidine nucleoside analog with broad-spectrum antiviral activity against several RNA viruses (e.g., SARS-CoV-2, MERS-CoV, SARS-CoV, related zoonotic group 2b or 2c Bat-CoVs, Ebolavirus, Venezuelan equine encephalitis virus [VEEV]).

• Following incorporation of the active nucleoside analog NHC-TP into viral SARS-CoV-2 RNA by viral RNA-dependent RNA polymerase (RdRp, nsp12), an accumulation of errors in the viral genome results in inhibition of replication.

• In an in vitro SARS-CoV-2 virus neutralization assay in A-549 and Vero E6 cells, molnupiravir was active against SARS-CoV-2 (USA WA1/2020 isolate) with an average EC₅₀ of 0.67–2.66 µM and 0.32–2.03 µM, respectively. NHC had similar activity against SARS-CoV-2 variants B.1.1.7 (alpha), B.1351 (beta), P.1 (gamma), and B.1.617.2 (delta) with EC₅₀ values of 1.59, 1.77, 1.32, and 1.68 µM, respectively.

• In vitro, NHC retained activity against SARS-CoV-2 and recombinant mouse hepatitis virus with polymerase substitutions (e.g. F480L, V557L and E802D) associated with decreased remdesivir sensitivity, indicating a lack of cross-resistance.

Advice to Patients

• The Fact Sheet for Patients and Caregivers: Emergency Use Authorization (EUA) of Molnupiravir for the Treatment of Coronavirus Disease 2019 (COVID-19) must be provided to patients or caregivers prior to administration of molnupiravir.

• Inform patients or caregivers that FDA authorized the emergency use of molnupiravir, which is an investigational drug that has not received FDA approval, for use in certain adults with mild to moderate COVID-19 who are outpatients at high risk of progression to severe COVID-19, including hospitalization or death.

• Inform patients or caregivers about the significant known and potential risks and benefits of molnupiravir, and the extent to which such risks and benefits are unknown.

• Inform patients or caregivers of the signs and symptoms of a hypersensitivity reaction to molnupiravir (e.g., hives, rapid heartbeat, trouble breathing or swallowing, throat tightness, hoarseness, skin rash, or swelling of the mouth, lips, or face).

• Inform patients to stop taking molnupiravir if a hypersensitivity reaction occurs and to contact their healthcare provider immediately.

• If a dose of molnupiravir is missed and it is within 10 hours of the time it is usually taken, advise patients to take the prescribed dose as soon as possible. If a dose is missed by more than 10 hours, advise patients to take the prescribed dose at the next scheduled time; do not take an additional dose to replace the missed dose.

• Importance of advising patients to swallow capsules intact and not to break, chew, or open capsules.

• Importance of completing the full 5-day treatment course.

• Advise patients treated with molnupiravir that they should continue to self-isolate and use infection control measures according to CDC guidelines during therapy.

• Risk of fetal harm. Advise females of reproductive potential to use effective contraception during treatment with molnupiravir and for 4 days after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with molnupiravir and for at least 3 months after the last dose. Importance of females informing clinicians if they are or plan to become pregnant. Importance of encouraging pregnant females who receive molnupiravir to enroll in the manufacturer's pregnancy surveillance program.

• Importance of advising females to avoid breast-feeding during molnupiravir therapy and for 4 days after the last dose.

• Risk of adverse bone and cartilage effects; molnupiravir is not authorized for use in pediatric patients younger than 18 years of age.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Molnupiravir is not commercially available. FDA issued an emergency use authorization (EUA) for molnupiravir that allows use of the drug for the treatment of mild to moderate COVID-19 in certain nonhospitalized adults who are at high risk of progression to severe COVID-19, including hospitalization or death. The manufacturer (Merck) should be contacted for information on how to obtain molnupiravir for use under the EUA.

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