Active COVID-19, Clinical Pathway — All Settings

Molnupiravir

Background

Molnupiravir is a prodrug which is metabolized into a ribonucleoside analogue with antiviral activity against SARS-CoV-2. The mechanism of action is through uptake by viral RNA-dependent RNA-polymerase and integration into the viral RNA genome, where it promotes lethal mutations in the viral genome affecting infectivity and replication. Molnupiravir is expected to retain activity against the omicron variant.

The efficacy of molnupiravir was evaluated in the MOVe-OUT study, a phase III randomized controlled trial which compared a 5- day course of molnupiravir to placebo in adult (age 18 and over) outpatients with mild to moderate COVID-19 who were at high risk of progression to severe disease. Patients were randomized within 5 days of symptom onset and test positivity, and vaccinated patients were excluded. An interim analysis demonstrated that molnupiravir was associated with a significant reduction in a composite outcome of all-cause hospitalization or death at 29 days (7.3% in the molnupiravir group and 14.1% in the placebo group). However, for reasons that are yet unexplained, the effect size was more modest in the final analysis that included the full study population. Overall, the composite study outcome of hospitalization or death at 29 days following randomization was documented in 6.8% of subjects randomized to molnupiravir versus 9.7% of patients randomized to placebo, a relative risk reduction of 30%. Based on these data, molnupiravir received Emergency Use Authorization (EUA) from the FDA on 12/23/21. Additional information for healthcare providers can be found on the healthcare provider fact sheet .

Due to the mechanism of action of molnupiravir, there is a theoretical risk of metabolism by the human host cell and incorporation into human DNA, potentially leading to mutagenesis in the host. Studies are inconsistent as to the extent of this risk, and adverse events were not detected clinically in the phase III trials, but further investigation is ongoing.

Indication

Given that molnupiravir has marginal clinical benefits even in older adults, and significant potential toxicities, it is unlikely to be beneficial for most CHOP patients. Use of molnupiravir can only be considered if other therapies are unavailable (e.g., nirmatrelvir-ritonavir), and should only be used after careful weighting of the risk/benefit ratio with shared decision making between the patient/family and provider. Additional information for healthcare providers can be found on the healthcare provider fact sheet . Please review the alternative therapies in the Therapies by Illness Severity table.

Inclusion:

Age ≥ 18 years (not authorized or available for children due to bone/cartilage toxicity) AND
Positive SARS-CoV-2 PCR or antigen test AND
Mild-moderate symptoms of COVID-19 AND
Within 5 days of symptom onset (but as soon as possible after symptom onset) AND
Able to swallow pills (tabs cannot be crushed) AND
High risk for progression to severe disease (see “Risk Stratification” below) AND
Not pregnant AND
No other alternative COVID-19 therapy (e.g., nirmatrelvir-ritonavir)

Exclusion:

Hospitalized due to severe or critical COVID-19 (note that if a patient is hospitalized during the 5 days of treatment, treatment can be completed using home supply per the healthcare provider’s discretion)

High risk criteria

Data informing risk stratification to identify young adults at highest risk of severe disease are limited. The table linked below summarizes pediatric patients who appear at highest risk for severe disease, which are broadly generalizable to young adults cared for at CHOP. If a prescriber elects to use molnupiravir, we recommend prioritizing these patients, presuming they meet the inclusion criteria above. In addition, molnupiravir may be considered in all individuals classified as high-risk for severe disease by the CDC .

Risk strata	Recommendation
High risk patients: Moderate to severe immunocompromise OR Not fully vaccinated with a high-risk comorbid condition	Consider molnupiravir if no contraindication, review Prescribing Steps
Moderate or uncertain risk patients: all other patients per the CDC high-risk criteria	Molnupiravir not recommended at CHOP, but use is permitted under the EUA

¹ Fully vaccinated is defined as an immunocompetent patient ≥ 14 days after the second dose of either mRNA vaccine against COVID-19 OR a single dose of the Johnson and Johnson vaccine

Adverse events

Pregnancy/contraception: Toxicity to the fetus is a potential risk based on animal studies. No human data are available to characterize the frequency of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Molnupiravir is therefore not recommended for use in pregnant females.
Bone/cartilage growth: Molnupiravir may affect bone and cartilage growth based on animal studies, thus it is not authorized in children < 18 years old.
Other side effects: Minor side effects potentially due to molnupiravir include diarrhea (2%), nausea (1%), and dizziness (1%).

Prescribing Steps

Any provider may prescribe molnupiravir in the outpatient setting. Outpatient retail pharmacies are responsible for ordering and stocking molnupiravir. As of 4/15/22, the CHOP outpatient pharmacy does not stock molnupiravir.

Review the eligibility criteria above and the information in the healthcare provider fact sheet to ensure the patient is eligible to receive Paxlovid under the EUA.
Assess pregnancy status in females of childbearing age. This may be done through the first day of last menstrual period in individuals who have regular menstrual cycles, is using a reliable method of contraception correctly and consistently or have had a negative pregnancy test. A pregnancy test is recommended if the individual has irregular menstrual cycles, is unsure of the first day of last menstrual period or is not using effective contraception correctly and consistently.
- Use of molnupiravir is not recommended for pregnant females. Use may be considered in pregnancy only when benefit outweighs risk.
Review this website to identify a pharmacy supplying molnupiravir.
Discuss the risks and benefits of molnupiravir with the patient/family and provide the Provide the Fact Sheet for Patients and Parents/Caregivers . The caregiver should be informed of the following:
- Molnupiravir is not approved by the FDA but has FDA EUA status.
- There are no available alternative medical treatments that are FDA approved for high-risk patients with mild-moderate COVID-19. There ARE alternative products that are authorized for the same use as molnupiravir.
- There are benefits and risks to taking molnupiravir, as outlined in the “Fact Sheet for Patients and Caregivers”
- Females of childbearing potential should abstain from sex or use a reliable method of contraception while receiving and for 4 days after receiving molnupiravir.
- Males of reproductive potential who are sexually active with females of childbearing potential should abstain from sex or use a reliable method of contraception during treatment and for at least 3 months after the last dose of molnupiravir, as studies evaluating the risk to offspring have not been completed.
- Based on findings from animal studies, molnupiravir may cause fetal harm. Use of molnupiravir is not recommended for pregnant females. Use may be considered in pregnancy only when benefit outweighs risk.
- If a healthcare provider chooses to prescribe molnupiravir to a pregnant woman, the prescriber must document the known and unknown risks to molnupiravir use during pregnancy. The prescriber must also document that the individual was made aware of the Merck pregnancy surveillance program (1-877-888-4231 or pregnancyreporting.msd.com). If the patient agrees to participate in the surveillance program and allows the prescribing healthcare provider to disclose patient specific information, the healthcare provider must disclose the patient name and contact information to Merck.
Obtain verbal consent AND document this discussion using the smartphrase: .MOLNUPIRAVIREUA
Counsel the patient that they should complete the full 5-day treatment course, as it is unknown whether shorter courses may confer a greater risk of emergence of molnupiravir-resistant mutations, particularly if the patient is immunocompromised.
Order molnupiravir using the Epic order. You will also need to indicate a “do not dispense after” date, which should be dated 5 days after the patients symptom onset to align with the EUA criteria for use. Finally, you must answer all questions to ensure the regulatory steps for prescribing molnupiravir are adhered to.
Prescribers must report all medication errors and adverse events (death, serious adverse events1) considered potentially related to Paxlovid within 7 days of the event to FDA MedWatch . It is the responsibility of the person prescribing molnupiravir to report these errors and adverse events.

¹Serious adverse events include any of the following occurring while receiving remdesivir: death, life-threatening event, event resulting in hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.

Dosing and Administration

Category	Dose/Duration	Comments
Adults ≥ 18 years and older	Molnupiravir 800 mg PO (4 x 200 mg tablets) every 12 hours x 5 days If the patient misses a dose of molnupiravir within 10 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 10 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose. Molnupiravir tablets cannot be crushed.	No dose adjustment is recommended based on renal or hepatic impairment. There are no known serious drug interactions. There are no data evaluating potential for secretion of molnupiravir into breastmilk. However, because of potential toxicities to the infant, breastfeeding is not recommended for females receiving molnupiravir during treatment and for 4 days after the final dose.

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