Lagevrio

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

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

5.1Embryo-Fetal Toxicity 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; therefore, LAGEVRIO is not recommended for use during pregnancy. When considering LAGEVRIO for a pregnant individual, the prescribing healthcare provider must communicate the known and potential benefits and the potential risks of using LAGEVRIO during pregnancy to the pregnant individual.

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.

Advise individuals of childbearing potential of the potential risk to a fetus and to use an effective method of contraception correctly and consistently, as applicable, during treatment with LAGEVRIO and for 4 days after the final dose [see Use in Specific Populations (8.1 , 8.3 and Nonclinical Toxicology (13.1) ] . Prior to initiating treatment with LAGEVRIO, assess whether an individual of childbearing potential is 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 whether the patient is pregnant based on 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 [see Box ] .

5.2Hypersensitivity Including Anaphylaxis

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.

No drug interactions have been identified based on the limited available data on the emergency use of LAGEVRIO authorized under this EUA. No clinical drug-drug interaction trials of LAGEVRIO with concomitant medications, including other treatments for mild-to-moderate COVID-19, have been conducted [see Clinical Pharmacology (12.3) ].

8.1Pregnancy Pregnancy Registry

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.

Risk Summary Based on animal data, 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; therefore, LAGEVRIO is not recommended during pregnancy [see Box and Warnings and Precautions (5.1) ] . In an animal reproduction study, oral administration of molnupiravir to pregnant rats during the period of organogenesis resulted in embryofetal lethality and teratogenicity at 8 times the human NHC (N4-hydroxycytidine) exposures at the recommended human dose (RHD) and reduced fetal growth at ≥ 3 times the human NHC exposure at the RHD.

Oral administration of molnupiravir to pregnant rabbits during the period of organogenesis resulted in reduced fetal body weights at 18 times the human NHC exposure at the RHD (see Data ). When considering LAGEVRIO for a pregnant individual, the prescribing healthcare provider must communicate the known and potential benefits and the potential risks of using LAGEVRIO during pregnancy to the pregnant individual. LAGEVRIO may only be prescribed to a pregnant individual after the prescribing 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 potential risks of using LAGEVRIO during pregnancy were communicated to the pregnant individual [see Box ] . There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk 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.

6.1Adverse Reactions from Clinical Studies

The following adverse reactions have been observed in the clinical study of LAGEVRIO that supported the EUA. The adverse reaction rates observed in these clinical trials cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Additional adverse events associated with LAGEVRIO may become apparent with more widespread use. Overall, more than 900 subjects have been exposed to LAGEVRIO 800 mg twice daily in clinical trials.

The safety assessment of LAGEVRIO is primarily based on an analysis from subjects followed through Day 29 in the Phase 3 study in non-hospitalized subjects with COVID-19 (MOVe-OUT) [see Clinical Studies (14) ] . The safety of LAGEVRIO was evaluated based on an analysis of a Phase 3 double-blind trial (MOVe-OUT) in which 1,411 non-hospitalized subjects with COVID-19 were randomized and treated with LAGEVRIO (N=710) or placebo (N=701) for up to 5 days.

Adverse events were those reported while subjects were on study intervention or within 14 days of study intervention completion/discontinuation. Discontinuation of study intervention due to an adverse event occurred in 1% of subjects receiving LAGEVRIO and 3% of subjects receiving placebo. 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%) subjects receiving LAGEVRIO and 12 (2%) of subjects receiving placebo. The most common adverse reactions in the LAGEVRIO treatment group in MOVe-OUT are presented in Table 1 , all of which were Grade 1 (mild) or Grade 2 (moderate). Table 1: Adverse Reactions Occurring in Greater Than or Equal to 1% of Subjects Receiving LAGEVRIO in MOVe-OUT Frequencies of adverse reactions are based on all adverse events attributed to study intervention by the investigator.

LAGEVRIO N=710 Placebo N=701 Diarrhea 2% 2% Nausea 1% 1% Dizziness 1% 1% Laboratory Abnormalities Selected Grade 3 and 4 laboratory abnormalities in chemistry (alanine aminotransferase, aspartate aminotransferase, creatinine, and lipase) and hematology (hemoglobin, platelets, and leukocytes) parameters all occurred at a rate of less than or equal to 2% and occurred at a similar rate across arms in MOVe-OUT.

6.2Post-Authorization Experience

The following adverse reactions have been identified during post-authorization use of LAGEVRIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders vomiting Immune System Disorders hypersensitivity, anaphylaxis, angioedema [see Warnings and Precautions (5.2) ] Skin and Subcutaneous Tissue Disorders erythema, pruritus, rash, urticaria