Viral replication

Understanding peak viral replication

Study design:

In a post exposure prophylaxis study, a modeling analysis was performed in a cohort of patients who developed incident SARS-CoV-2 infection. That analysis compared magnitude of peak viral load, time from viral shedding onset to peak, and time from peak to shedding cessation across three symptom groups. The analysis estimated and compared the time from peak viral load to onset of mild or moderate symptoms for people in the symptomatic groups. Peak viral load generally occurred within 1-2 days of symptom onset. Viral replication peaks rapidly, followed by a slow decrease, suggesting that the period for effective antiviral intervention is very narrow.1

Select study limitations:

Self-sampling technique or degradation of sample could yield false negatives. Analysis was limited to a 14 day observation period, which underestimates viral shedding. Daily swabbing could have missed peak viral load in those with shorter viral shedding duration. Detectable viral RNA does not equal culture positivity or infectiousness. Study relied on Ct values as a proxy for viral RNA levels. The viral shedding model used assumed that viral load followed a piecewise linear trend whereas the true trajectories might be more curved.

Viral load believed to occur within a 10-day time frame, with peak viral load occurring within days 1-2 and then decreasing over ten days.Viral load believed to occur within a 10-day time frame, with peak viral load occurring within days 1-2 and then decreasing over ten days.

Visualization of peak viral replication early in disease course is for illustrative purposes only, based on the Stankiewicz study. Not drawn to scale.

EUA, emergency use authorization; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RNA, ribonucleic acid; Ct, cycle threshold.

References: 1. Stankiewicz Karita HC, et al. JAMA Network Open. 2022;5(1):e2142796. doi:10.1001/jamanetworkopen.2021.42796 2. Bernal AJ et al. N Engl J Med. 2022;386(6):509-520.

Authorized Use

  • LAGEVRIO™ (molnupiravir) is authorized for use under an Emergency Use Authorization (EUA) for the treatment of adults with mild-to-moderate coronavirus disease 2019 (COVID-19):
    • who are at high risk for progression to severe COVID-19 including hospitalization or death, and
    • for whom alternative COVID-19 treatment options approved or authorized by the FDA are not accessible or clinically appropriate
  • LAGEVRIO is not approved for any use, including the treatment of COVID-19, but is authorized for emergency use by the FDA under an Emergency Use Authorization (EUA).
  • The emergency use of LAGEVRIO is only authorized for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic under Section 564(b)(1) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1) unless the declaration is terminated or authorization revoked sooner.

Limitations of Authorized Use

  • LAGEVRIO is not authorized:
    • for use in patients who are less than 18 years of age
    • for initiation of treatment in patients hospitalized due to COVID-19. Benefit of treatment with LAGEVRIO has not been observed in subjects when treatment was initiated after hospitalization due to COVID-19
    • for use for longer than 5 consecutive days
    • for pre-exposure or post-exposure prophylaxis for prevention of COVID-19
  • LAGEVRIO 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 therapeutic class to which LAGEVRIO belongs (ie, anti-infectives).

Selected Safety Information

Contraindications

  • No contraindications have been identified based on the limited available data on the emergency use of LAGEVRIO authorized under this EUA.

Warnings and Precautions

  • There are limited clinical data available for LAGEVRIO. Serious and unexpected adverse events may occur that have not been previously reported with LAGEVRIO use.
  • LAGEVRIO is not recommended for use during pregnancy. Based on findings from animal reproduction studies, LAGEVRIO may cause fetal harm when administered to pregnant individuals. There are no available human data on the use of LAGEVRIO in pregnant individuals to evaluate the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
  • LAGEVRIO is authorized to be prescribed to a pregnant individual only after the healthcare provider has determined that the benefits would outweigh the risks for that individual patient. If the decision is made to use LAGEVRIO during pregnancy, the prescribing healthcare provider must document that the known and potential benefits and the potential risks of using LAGEVRIO during pregnancy were communicated to the pregnant individual.
  • There is a pregnancy registry that monitors pregnancy outcomes in individuals exposed to LAGEVRIO during pregnancy. The prescribing healthcare provider must document that a pregnant individual was made aware of the pregnancy registry at https://covid-pr.pregistry.com or 1-800-616-3791. Pregnant individuals exposed to LAGEVRIO or their healthcare providers can also report the exposure by contacting Merck Sharp & Dohme LLC, Rahway, NJ, USA at 1-877-888-4231.
  • Advise individuals of childbearing potential of the potential risk to a fetus and to use an effective method of contraception correctly and consistently during treatment with LAGEVRIO and for 4 days after the final dose.
  • Prior to initiating treatment with LAGEVRIO, assess whether an individual of childbearing potential is pregnant or not, if clinically indicated.
  • Hypersensitivity reactions, including anaphylaxis, have been reported with LAGEVRIO. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue LAGEVRIO and initiate appropriate medications and/or supportive care.
  • LAGEVRIO is not authorized for use in patients less than 18 years of age because it may affect bone and cartilage growth. The safety and efficacy of LAGEVRIO have not been established in pediatric patients.

Adverse Reactions

  • The most common adverse reactions occurring in ≥1% of subjects in the LAGEVRIO treatment group in the Phase 3 double-blind MOVe-OUT study were diarrhea (2% versus placebo at 2%), nausea (1% versus placebo at 1%), and dizziness (1% versus placebo at 1%) all of which were Grade 1 (mild) or Grade 2 (moderate).

     

    Serious adverse events occurred in 7% of subjects receiving LAGEVRIO and 10% receiving placebo; most serious adverse events were COVID-19 related. Adverse events leading to death occurred in 2 (<1%) of the subjects receiving LAGEVRIO and 12 (2%) of subjects receiving placebo.

Drug interactions

  • No drug interactions have been identified based on the limited available data on the emergency use of LAGEVRIO. No clinical drug-drug interaction trials of LAGEVRIO with concomitant medications, including other treatments for mild-to-moderate COVID-19, have been conducted.

Pregnancy/Breastfeeding

  • There are no data on the presence of LAGEVRIO or its metabolites in human milk. It is unknown whether LAGEVRIO has an effect on the breastfed infant or effects on milk production. Based on the potential for adverse reactions in the infant from LAGEVRIO, breastfeeding is not recommended during treatment with LAGEVRIO and for 4 days after the final dose. A lactating individual may consider interrupting breastfeeding and may consider pumping and discarding breast milk during treatment and for 4 days after the last dose of LAGEVRIO.

Males of Reproductive Potential

  • Nonclinical studies to fully assess the potential for LAGEVRIO to affect offspring of treated males have not been completed. Advise sexually active individuals 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 of LAGEVRIO. The risk beyond three months after the last dose of LAGEVRIO is unknown.

Required Reporting for Serious Adverse Events and Medication Errors

  • The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory reporting of all serious adverse events and medication errors potentially related to LAGEVRIO within 7 calendar days from the healthcare provider’s awareness of the event.

     

    Submit adverse event and medication error reports, using FDA Form 3500, to FDA MedWatch using one of the following methods:

In addition, please provide a copy of all FDA MedWatch forms to:
Merck Sharp & Dohme LLC, Rahway, NJ, USA by:
Fax: 215-616-5677
Email: dpoc.usa@merck.com

 

Before prescribing LAGEVRIO, please read the accompanying Fact Sheet for Healthcare Providers, including Mandatory Requirements for Administration of LAGEVRIO Under Emergency Use Authorization. The FDA Letter of Authorization and the Fact Sheet for Patients and Caregivers also are available.

Authorized Use

  • LAGEVRIO™ (molnupiravir) is authorized for use under an Emergency Use Authorization (EUA) for the treatment of adults with mild-to-moderate coronavirus disease 2019 (COVID-19):
    • who are at high risk for progression to severe COVID-19 including hospitalization or death, and
    • for whom alternative COVID-19 treatment options approved or authorized by the FDA are not accessible or clinically appropriate
  • LAGEVRIO is not approved for any use, including the treatment of COVID-19, but is authorized for emergency use by the FDA under an Emergency Use Authorization (EUA).
  • The emergency use of LAGEVRIO is only authorized for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic under Section 564(b)(1) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1) unless the declaration is terminated or authorization revoked sooner.

Limitations of Authorized Use

  • LAGEVRIO is not authorized:
    • for use in patients who are less than 18 years of age
    • for initiation of treatment in patients hospitalized due to COVID-19. Benefit of treatment with LAGEVRIO has not been observed in subjects when treatment was initiated after hospitalization due to COVID-19
    • for use for longer than 5 consecutive days
    • for pre-exposure or post-exposure prophylaxis for prevention of COVID-19
  • LAGEVRIO 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 therapeutic class to which LAGEVRIO belongs (ie, anti-infectives).
  • LAGEVRIO™ (molnupiravir) is authorized for use under an Emergency Use Authorization (EUA) for the treatment of adults…
  • LAGEVRIO™ (molnupiravir) is authorized for use under an Emergency Use Authorization (EUA) for the treatment of adults with mild-to-moderate coronavirus disease 2019 (COVID-19):
    • who are at high risk for progression to severe COVID-19 including hospitalization or death, and
    • for whom alternative COVID-19 treatment options approved or authorized by the FDA are not accessible or clinically appropriate

Selected Safety Information for LAGEVRIO (molnupiravir)

Contraindications

  • No contraindications have been identified based on the limited available data on the emergency use of LAGEVRIO authorized under this EUA.

Warnings and Precautions

  • There are limited clinical data available for LAGEVRIO. Serious and unexpected adverse events may occur that have not been previously reported with LAGEVRIO use.
  • LAGEVRIO is not recommended for use during pregnancy. Based on findings from animal reproduction studies, LAGEVRIO may cause fetal harm when administered to pregnant individuals. There are no available human data on the use of LAGEVRIO in pregnant individuals to evaluate the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
  • LAGEVRIO is authorized to be prescribed to a pregnant individual only after the healthcare provider has determined that the benefits would outweigh the risks for that individual patient. If the decision is made to use LAGEVRIO during pregnancy, the prescribing healthcare provider must document that the known and potential benefits and the potential risks of using LAGEVRIO during pregnancy were communicated to the pregnant individual.
  • There is a pregnancy registry that monitors pregnancy outcomes in individuals exposed to LAGEVRIO during pregnancy. The prescribing healthcare provider must document that a pregnant individual was made aware of the pregnancy registry at https://covid-pr.pregistry.com or 1-800-616-3791. Pregnant individuals exposed to LAGEVRIO or their healthcare providers can also report the exposure by contacting Merck Sharp & Dohme LLC, Rahway, NJ, USA at 1-877-888-4231.
  • Advise individuals of childbearing potential of the potential risk to a fetus and to use an effective method of contraception correctly and consistently during treatment with LAGEVRIO and for 4 days after the final dose.
  • Prior to initiating treatment with LAGEVRIO, assess whether an individual of childbearing potential is pregnant or not, if clinically indicated.
  • Hypersensitivity reactions, including anaphylaxis, have been reported with LAGEVRIO. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue LAGEVRIO and initiate appropriate medications and/or supportive care.
  • LAGEVRIO is not authorized for use in patients less than 18 years of age because it may affect bone and cartilage growth. The safety and efficacy of LAGEVRIO have not been established in pediatric patients.

Adverse Reactions

  • The most common adverse reactions occurring in ≥1% of subjects in the LAGEVRIO treatment group in the Phase 3 double-blind MOVe-OUT study were diarrhea (2% versus placebo at 2%), nausea (1% versus placebo at 1%), and dizziness (1% versus placebo at 1%) all of which were Grade 1 (mild) or Grade 2 (moderate).

     

    Serious adverse events occurred in 7% of subjects receiving LAGEVRIO and 10% receiving placebo; most serious adverse events were COVID-19 related. Adverse events leading to death occurred in 2 (<1%) of the subjects receiving LAGEVRIO and 12 (2%) of subjects receiving placebo.

Drug interactions

  • No drug interactions have been identified based on the limited available data on the emergency use of LAGEVRIO. No clinical drug-drug interaction trials of LAGEVRIO with concomitant medications, including other treatments for mild-to-moderate COVID-19, have been conducted.

Pregnancy/Breastfeeding

  • There are no data on the presence of LAGEVRIO or its metabolites in human milk. It is unknown whether LAGEVRIO has an effect on the breastfed infant or effects on milk production. Based on the potential for adverse reactions in the infant from LAGEVRIO, breastfeeding is not recommended during treatment with LAGEVRIO and for 4 days after the final dose. A lactating individual may consider interrupting breastfeeding and may consider pumping and discarding breast milk during treatment and for 4 days after the last dose of LAGEVRIO.

Males of Reproductive Potential

  • Nonclinical studies to fully assess the potential for LAGEVRIO to affect offspring of treated males have not been completed. Advise sexually active individuals 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 of LAGEVRIO. The risk beyond three months after the last dose of LAGEVRIO is unknown.

Required Reporting for Serious Adverse Events and Medication Errors

  • The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory reporting of all serious adverse events and medication errors potentially related to LAGEVRIO within 7 calendar days from the healthcare provider’s awareness of the event.

     

    Submit adverse event and medication error reports, using FDA Form 3500, to FDA MedWatch using one of the following methods:

In addition, please provide a copy of all FDA MedWatch forms to:
Merck Sharp & Dohme LLC, Rahway, NJ, USA by:
Fax: 215-616-5677
Email: dpoc.usa@merck.com

 

Before prescribing LAGEVRIO, please read the accompanying Fact Sheet for Healthcare Providers, including Mandatory Requirements for Administration of LAGEVRIO Under Emergency Use Authorization. The FDA Letter of Authorization and the Fact Sheet for Patients and Caregivers also are available.

Contraindications

  • No contraindications have been identified based on…

Contraindications

  • No contraindications have been identified based on the limited available data on the emergency use of LAGEVRIO authorized under this EUA.

Warnings and Precautions

  • There are limited clinical data available for LAGEVRIO. Serious and unexpected adverse events may occur that have not been previously reported with LAGEVRIO use.