molnupiravir (Investigational)

1-10%

Diarrhea (2%)

Nausea (1%)

Dizziness (1%)

≤2%

• Selected Grade 3 and 4 laboratory abnormalities in chemistry (ALT, AST, creatinine, and lipase) and hematology (hemoglobin, platelets, and leukocytes)

Required reporting for serious adverse events and medication errors

Prescribers and/or the provider’s designee are/is responsible for mandatory reporting of all serious adverse events and medication errors potentially drug-related within 7 calendar days from the onset of the event

Serious adverse events are defined as

• Death or a life-threatening adverse event;
• A medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly;
• Inpatient hospitalization or prolongation of existing hospitalization;
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or
• A congenital anomaly/birth defect

FDA recommends that such reports use FDA Form 3500

Contraindications

None have been identified based on the limited available data on the emergency use authorized under this EUA

Cautions

There are limited clinical data available; serious and unexpected adverse events may occur that have yet to be reported

May cause fetal harm when administered to pregnant females

Bone and cartilage toxicity

• Not authorized for use in patients aged <18 years owing to possible effects on bone and cartilage growth
• Bone and cartilage toxicity was observed in rats after repeated dosing
• Safety and efficacy have not been established in pediatric patients

Pregnancy

Not recommended during pregnancy

Based on animal data, fetal harm may occur when administered to pregnant females

No available human data are available on use in pregnant females to evaluate the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Verify pregnancy status in females of childbearing potential

Prescribing healthcare provider must communicate the known and potential benefits and the potential risks of using molnupiravir during pregnancy to the pregnant individual

May only be prescribed to pregnant individuals after the prescribing healthcare provider has determined that the benefits would outweigh the risks for that individual patient

If used during pregnancy, prescribing healthcare provider must document potential risks and benefits were communicated

Clinical considerations

• There are maternal and fetal risks (eg, preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, fetal death) associated with untreated COVID-19 in pregnancy

Pregnancy surveillance program

• Program monitors pregnancy outcomes in individuals exposed to molnupiravir during pregnancy
• Prescribing healthcare provider must document that pregnant individuals were made aware of the COVID pregnancy registry, OR
• Merck Sharp & Dohme’s pregnancy surveillance program at 1-877-888-4231 or pregnancyreporting.msd.com

Contraception

• Females of childbearing potential: Use a reliable method of contraception correctly and consistently, as applicable during treatment and for 4 days after final dose
• Males with partners of childbearing potential: Use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after final dose; risk beyond 3 months after last dose is unknown; studies on the risks >3 months are ongoing

Animal data

• Oral administration to pregnant rats during organogenesis resulted in embryofetal lethality and teratogenicity at 8x the human NHC exposures at the recommended human dose (RHD) and reduced fetal growth at ≥3x the human NHC exposure at the RHD
• Oral administration to pregnant rabbits during organogenesis resulted in reduced fetal body weights at 18x the human NHC exposure at the RHD

Lactation

There are no data on the presence of molnupiravir or its metabolites in human milk

NHC was detected in the plasma of nursing pups from lactating rats administered molnupiravir

It is unknown whether molnupiravir affects the breastfed infants or has effects on milk production

Not recommended during treatment and for 4 days after final dose

Consider interrupting breastfeeding, and consider pumping and discarding breast milk during treatment and for 4 days after final dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Orally bioavailable prodrug of nucleoside analogue beta-D-N4-hydroxycytidine (NHC)

Metabolized to cytidine nucleoside analogue, NHC, which distributes into cells where NHC is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP)

NHC-TP incorporation into SARS-CoV-2 RNA by the viral RNA polymerase results in an accumulation of errors in the viral genome, leading to inhibition of replication

Absorption

Peak plasma time: 1.5 hr

Peak plasma concentration: 2,330 ng/mL (patients); 2,970 ng/mL (healthy subjects)

AUC: 8,260 ng·hr/mL (patients); 8,330 ng·hr/mL (healthy subjects)

Effect of food: 35% reduction in peak plasma concentration, no effect on AUC

Distribution

Protein bound: 0%

Vd: 142 L

Metabolism

NHC eliminated by metabolism to uridine and/or cytidine through the same pathways involved in endogenous pyrimidine metabolism

Elimination

Clearance: 76.9 L/hr

Half-life: 3.3hr

Excretion: Urine (3%)

Oral Administration

Take orally, with or without food

Missed dose

• <10 hours: Take missed dose as soon as possible, and resume normal dosing schedule
• >10 hours: Skip dose, and take the next dose at the regularly scheduled time
• Do not double dose to make up for missed dose

Nasogastric or orogastric tube (>12 F)

1. Open 4 capsules and transfer contents into a clean container with a lid
2. Add 40 mL of water to container
3. Put lid on container and shake for 3 minutes to mix capsule contents and water thoroughly (capsule contents may not dissolve completely); prepared mixture may have visible undissolved particulates and are acceptable for administration
4. Flush NG/OG tube with 5 mL of water before administration
5. Using a catheter tip syringe, draw up entire contents from container and administer immediately through the NG/OG tube; do not keep mixture for future use
6. If any portion of capsule contents are left in the container, add 10 mL of water to container, mix, and using same syringe draw up the entire contents of the container and administer through the NG/OG; repeat as needed until no capsule contents remain in container or syringe
7. Flush NG/OG tube with 5 mL of water twice (10 mL total) after administration of mixture

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)