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Mechanism of Action
NOTE: Information on medical conditions and factors associated with an increased risk for progression to severe COVID-19 can be obtained on the Centers for Disease Control and Prevention (CDC) website at www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Health care providers are advised to consider the benefit-risk for each individual patient.
NOTE: Due to the Omicron variant (B.1.1.529/BA.1) becoming the dominant variant in many parts of the United States, the National Institutes of Health (NIH) has issued a statement to provide guidance on treating nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease. The NIH recommends using 1 of the following therapeutics with expected activity against the Omicron variant (listed in order of preference):
Molnupiravir should ONLY be prescribed when none of the other above options can be used.
NOTE: There may be logistical or supply constraints that make it impossible to offer the available therapy to all eligible patients, making patient triage necessary. Health care providers should prioritize their use for patients at highest risk of clinical progression. Information on which individuals might receive the greatest benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention can be obtained from www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies.
NOTE: Due to a lack of clinical benefit, starting molnupiravir in patients who are hospitalized because of COVID-19 is NOT authorized. However, should a patient require hospitalization after starting treatment with molnupiravir, the patient may complete the full 5-day regimen at the health care providers discretion.
NOTE: Molnupiravir is NOT authorized for use as pre-exposure or post-exposure prophylaxis to prevent COVID-19.
800 mg (four 200 mg capsules) by mouth every 12 hours for 5 days. Initiate treatment as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. Instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations; treatment for longer than 5 consecutive days is not authorized.
1,600 mg per day PO.
Use not authorized.
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 mild to moderate coronavirus disease 2019 (COVID-19) in adults with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death, and for whom alternative FDA 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. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend molnupiravir as a treatment option for nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease; however, molnupiravir should ONLY be prescribed when all other treatment options cannot be used.
NOTE: Molnupiravir is expected to be active against the Omicron SARS-CoV-2 variant (B.1.1.529/BA.1), although in vitro and in vivo data are currently limited.
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 as a treatment for mild to moderate COVID-19 in adults with positive SARS-CoV-2 viral testing who are at high risk for progressing to severe COVID-19, including hospitalization or death, and for whom alternative treatment options are not accessible or clinically appropriate. Under the Emergency Use Authorization (EUA), prescribing health care 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:
NOTE: Health care providers also MUST ensure that the following MANDATORY requirements are met before prescribing molnupiravir:
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, health care providers are required to report all medication errors and serious adverse events potentially related to molnupiravir therapy within 7 calendar days from the health care provider's awareness of the event.
The safety of molnupiravir was evaluated in a Phase 3 clinical trial (MOVe-OUT) involving non-hospitalized patients with COVID-19. Study subjects were randomized to receive either molnupiravir (n = 710) or placebo (n = 701) for up to 5 days. Adverse events were reported during treatment and for 14 days after completion or discontinuation of therapy. The most common adverse reactions for molnupiravir, as compared to placebo, were diarrhea (2% vs 2%, respectively), nausea (1% vs 1%), and dizziness (1% vs 1%). In all cases, these reactions in the molnupiravir group were Grade 1 (mild) or Grade 2 (moderate) in severity. Serious adverse events occurred in 7% of molnupiravir patients and 10% of patients in the placebo group, with most serious adverse events being COVID-19 related. Adverse events leading to death occurred in 2 molnupiravir patients (less than 1%) and 12 placebo patients (2%). Discontinuations due to an adverse event occurred in 1% of patients receiving molnupiravir and 3% of patients receiving the placebo. Grade 3 and 4 laboratory abnormalities were observed in up to 2% of patients treated with molnupiravir and placebo. These laboratory abnormalities included both chemistry (alanine aminotransferase, aspartate aminotransferase, creatinine, and lipase) and hematology (hemoglobin, platelets, and leukocytes).
Molnupiravir is not recommended for use during pregnancy. There are no human data available regarding use of molnupiravir in pregnant patients to evaluate the risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. However, animal data suggest maternal use of molnupiravir may cause fetal harm. In an animal reproduction study, oral administration of molnupiravir to pregnant rats during organogenesis resulted in embryofetal lethality and teratogenicity at 8-times the human N4-hydroxycytidine (NHC) exposure at the recommended human dose (RHD). Additionally, reduced fetal growth was observed at equal to or greater than 3-times the human NHC exposure at the RHD. Oral administration to pregnant rabbits during organogenesis resulted in reduced fetal body weights at 18-times the human NHC exposure at the RHD. When evaluating treatment options for pregnant patients with COVID-19, health care providers should consider that untreated 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. If considering use of molnupiravir in a pregnant patient, the prescribing health care provider MUST communicate to the pregnant patient the known and potential benefits and risks of using molnupiravir during pregnancy. If the decision is made to use molnupiravir during pregnancy, the prescribing health care provider MUST document that the known and potential benefits and risks were communicated to the pregnant patient. Molnupiravir may ONLY be prescribed to a pregnant patient after the prescribing health care provider has determined that the benefits would outweigh the risks for that individual patient. There is a pregnancy surveillance program that monitors pregnancy outcomes in patients exposed to molnupiravir during pregnancy. The prescribing health care provider MUST document that the pregnant patient was made aware of Merck Sharp and Dohme's pregnancy surveillance program at 1-877-888-4231 or pregnancyreporting.msd.com. If the pregnant patient agrees to participate in the pregnancy surveillance program and allows the health care provider to disclose patient specific information, the prescribing health care provider MUST provide the patient's name and contact information to Merck Sharp and Dohme; however, the patient may also report the exposure.
There are no data available regarding the presence of molnupiravir or its metabolites in human milk, the effects on the breast-fed infant, or the effects on milk production. Due to the potential for adverse reactions in the infant, breast-feeding is not recommended during treatment with molnupiravir or for 4 days after the last dose. Lactating mothers may consider interrupting breast-feeding or pumping and discarding breast milk during this time period.
Based on data from animal studies, exposure to molnupiravir during pregnancy is associated with a reproductive risk. Prior to initiating treatment, assess whether persons of childbearing potential are pregnant or not, if clinically indicated. Pregnancy status does not need to be confirmed in patients who have undergone permanent sterilization, are currently using an intrauterine system or contraceptive implant, or in whom pregnancy is not possible. In all other patients, assess pregnancy status based on the first day of last menstrual period in persons who have regular menstrual cycles, is using a reliable method of contraception correctly and consistently, or have had a negative pregnancy test. Pregnancy testing is recommended if the person has irregular menstrual cycles, is unsure of the first day of last menstrual period, or is not using effective contraception correctly and consistently.
Prescribing health care providers MUST inform patients of the contraception requirements associated with molnupiravir treatment. Persons who are capable of becoming pregnant must be instructed to use a reliable method of contraception correctly and consistently during treatment and for 4 days after the last dose. Advise sexually active persons with partners of childbearing potential to use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after the last dose. The risk beyond 3 months after the last molnupiravir dose is unknown; studies to evaluate this risk are ongoing.
Molnupiravir is not authorized for use in pediatric patients (i.e., neonates, infants, and children younger than 18 years), as animal data suggest the drug may affect bone and cartilage growth. In a 3-month study, bone and cartilage toxicity changes resulting in impaired transformation of growth cartilage into new bone were observed in the femur and tibia of rats at 5-times the human NHC exposure at the RHD. Growth cartilage is not present in mature skeletons; therefore, these bone and cartilage findings are not relevant for adults.
Molnupiravir is authorized for use as an oral therapy, given over 5 days, to treat mild to moderate COVID-19 in adults at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative treatment options are not accessible or clinically appropriate. The drug is NOT authorized for initiation of treatment in patients hospitalized due to COVID-19; nor is it authorized for use as pre-exposure or post-exposure prophylaxis to prevent COVID-19. In order to minimize antimicrobial resistance and transmission of SARS-CoV-2, instruct patients to complete the full 5-day treatment course and continue isolation in accordance with public health recommendations. Should a patient require hospitalization after starting treatment, the patient may complete the full 5-day treatment course at the discretion of the health care provider. Use of molnupiravir for longer than 5 consecutive days is NOT authorized.
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 with 50% effective concentrations (EC50) ranging from 0.67 to 2.66 microMolar in A-549 cells and 0.32 to 2.03 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), and Delta (B.1.617.2) with EC50 values of 1.59, 1.77, 1.32, and 1.68 microMolar, respectively. 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.
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%.
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.
Following twice daily administration molnupiravir 800 mg, the median time to reach peak plasma NHC concentrations (Tmax) is 1.5 hours (range: 1 to 2 hours). Peak plasma concentrations (Cmax), systemic exposure (AUC), and trough concentrations (C12) of NHC after administration of 800 mg molnupiravir every 12 hours to patients with COVID-19 were 2,330 ng/mL, 8,260 ng x hour/mL, and 31.1 ng/mL, respectively. At the same dose, the Cmax, AUC, and C12 of NHC in health subjects were 2,970 ng/mL, 8,330 ng x hour/mL, and 16.7 ng/mL, respectively. Administration with food results in a 35% reduction in NHC Cmax; however, the AUC is not significantly affected.
The pharmacokinetics of molnupiravir and NHC have not been evaluated in patients with moderate and severe hepatic impairment. NHC is not expected to undergo significant hepatic elimination; therefore, hepatic impairment is unlikely to affect NHC exposure.
Renal clearance is not a meaningful route of elimination for NHC. Data from a population pharmacokinetic analysis found that mild to moderate renal impairment did not significantly influence the pharmacokinetics of NHC. The pharmacokinetics of molnupiravir and NHC have not been evaluated in patients with an eGFR less than 30 mL/minute/1.73 m2 or on dialysis.
Data from a population pharmacokinetic analysis found that age does not significantly influence the pharmacokinetics of NHC.
Data from a population pharmacokinetic analysis found that gender does not significantly influence the pharmacokinetics of NHC.
Data from a population pharmacokinetic analysis found that race or ethnicity does not significantly influence the pharmacokinetics of NHC.
Data from a population pharmacokinetic analysis found that disease severity does not significantly influence the pharmacokinetics of NHC.
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