Get your patient on Lagevrio - Molnupiravir capsule (Molnupiravir)

The dosage in adult patients is 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days, with or without food [see Clinical Pharmacology (12.3) ] . Take LAGEVRIO as soon as possible after a diagnosis of COVID-19 has been made, and within 5 days of symptom onset [see Emergency Use Authorization (1) and Clinical Studies (14) ] .

Completion of the full 5-day treatment course and continued isolation in accordance with public health recommendations are important to maximize viral clearance and minimize transmission of SARS-CoV-2 [see Patient Counseling Information (17) ] .

LAGEVRIO is not authorized for use for longer than 5 consecutive days because the safety and efficacy have not been established.

If the patient misses a dose of LAGEVRIO 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.

Should a patient require hospitalization after starting treatment with LAGEVRIO, the patient may complete the full 5 day treatment course per the healthcare provider’s discretion.

No dosage adjustment is recommended based on renal or hepatic impairment or in geriatric patients [see Use in Specific Populations (8.5 , 8.6 , 8.7) ] .

1. Open four (4) capsules and transfer contents into a clean container with a lid.
2. Add 40 mL of water to the container.
3. Put the lid on the container and shake to mix the capsule contents and water thoroughly for 3 minutes.
   • NOTE : Capsule contents may not dissolve completely.
   • The prepared mixture may have visible undissolved particulates and are acceptable for administration.
4. Flush the tube with 5 mL of water prior to administration.
5. Using an appropriate syringe, draw up the entire contents from the container and administer immediately through the tube. If using a GJ tube, administer through the gastric port. Do not keep the mixture for future use.
6. If any portion of the capsule contents are left in the container, add 10 mL of water to the container, mix, and using the same syringe draw up the entire contents of the container and administer through the tube. Repeat as needed until no capsule contents are left in the container or syringe.
7. Flush the tube with 5 mL of water twice (10 mL total) after administration of the mixture.

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.

Data

Animal Data

In an embryofetal development (EFD) study in rats, molnupiravir was administered orally to pregnant rats at 0, 100, 250, or 500 mg/kg/day from gestation days (GDs) 6 to 17. Molnupiravir was also administered orally to pregnant rats at up to 1,000 mg/kg/day from GDs 6 to 17 in a preliminary EFD study. Developmental toxicities included post-implantation losses, malformations of the eye, kidney, and axial skeleton, and rib variations at 1,000 mg/kg/day (8 times the human NHC exposure at the RHD) and decreased fetal body weights and delayed ossification at ≥500 mg/kg/day (3 times the human NHC exposure at the RHD). There were no developmental toxicities at ≤250 mg/kg/day (less than the human NHC exposure at the RHD). Maternal toxicities included decreased food consumption and body weight losses, resulting in the early sacrifice of two of sixteen animals at 1,000 mg/kg/day, and decreased body weight gain at 500 mg/kg/day.

In an EFD study in rabbits, molnupiravir was administered orally to pregnant rabbits at 0, 125, 400, or 750 mg/kg/day from GDs 7 to 19. Developmental toxicity was limited to reduced fetal body weights at 750 mg/kg/day (18 times the human NHC exposures at the RHD). There was no developmental toxicity at ≤400 mg/kg/day (7 times the human NHC exposures at the RHD). Maternal toxicities included reduced food consumption and body weight gains, and abnormal fecal output at 750 mg/kg/day.

In a pre- and post-natal developmental study, molnupiravir was administered orally to female rats at doses up to 500 mg/kg/day (similar to the human NHC exposure at the RHD) from GD6 through lactation day 20. No effects were observed in offspring.

Risk Summary

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 (see Data ) . It is unknown whether molnupiravir 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 [see Warnings and Precautions (5.1 , 5.3) ].

Data

When molnupiravir was administered to lactating rats at ≥250 mg/kg/day in the pre- and post-natal development study, NHC was detected in plasma of nursing pups.

Based on animal studies, LAGEVRIO may cause fetal harm when administered to a pregnant individual.

Pregnancy Testing

Prior to initiating treatment with LAGEVRIO, assess whether an individual of childbearing potential is pregnant or not, if clinically indicated [see Warnings and Precautions (5.1) ].

Contraception

Females

Advise individuals of childbearing potential to use a reliable method of contraception correctly and consistently, as applicable for the duration of treatment and for 4 days after the last dose of LAGEVRIO [see Warnings and Precautions (5.1) ].

Males

While the risk is regarded as low, there is a theoretical risk for LAGEVRIO to affect offspring of treated males based on its mechanism of action. 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.

Molnupiravir was equivocal (neither clearly positive nor negative) in one in vivo mutagenicity assay of reticulocytes and RBCs which are used to reflect prior effects on hematopoietic stem cells in bone marrow. Molnupiravir was not mutagenic when assessed in in vivo assays of liver (somatic cells), bone marrow (somatic cells and stem cells), and sperm (male germ cells) from transgenic rats administered molnupiravir for 28 days [see Nonclinical Toxicology (13.1) ].

LAGEVRIO is not authorized for use in patients less than 18 years of age.
Bone and cartilage toxicity were observed in a 3-month, repeat-dose toxicology study in rats. The safety and efficacy of LAGEVRIO have not been established in pediatric patients [see Warnings and Precautions (5.3) and Nonclinical Toxicology (13.2) ] .

In MOVe-OUT, there was no difference in safety and tolerability between patients ≥65 years of age and younger patients who were treated with LAGEVRIO. No dosage adjustment is recommended based on age. The PK of NHC was similar in geriatric patients compared to younger patients [see Clinical Pharmacology (12.3) ] .

No dosage adjustment in patients with any degree of renal impairment is recommended. Renal clearance is not a meaningful route of elimination for NHC. Mild or moderate renal impairment did not have a meaningful impact on the PK of NHC. While the PK of NHC has not been evaluated in patients with eGFR less than 30 mL/min/1.73m ² or on dialysis, severe renal impairment, and end-stage renal disease (ESRD) are not expected to have a significant effect on NHC exposure [see Clinical Pharmacology (12.3) ] .

No dosage adjustment in patients with hepatic impairment is recommended. Preclinical data indicate that hepatic elimination is not expected to be a major route of NHC elimination therefore, hepatic impairment is unlikely to affect NHC exposure [see Clinical Pharmacology (12.3) ] .

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 ] .

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. Bone and cartilage toxicity was observed in rats after repeated dosing [see Nonclinical Toxicity (13.2) ] . The safety and efficacy of LAGEVRIO have not been established in pediatric patients [see Use in Specific Populations (8.4) ] .

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).

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.

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

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, using FDA Form 3500 (for information on how to access this form, see below). The FDA requires that such reports, using FDA Form 3500, include the following:

• Patient demographics and baseline characteristics (e.g., patient identifier, age or date of birth, gender, weight, ethnicity, and race)
• A statement " LAGEVRIO use for COVID-19 under Emergency Use Authorization (EUA)” under the “Describe Event, Problem, or Product Use/Medication Error” heading
• Information about the serious adverse event or medication error (e.g., signs and symptoms, test/laboratory data, complications, timing of drug initiation in relation to the occurrence of the event, duration of the event, treatments required to mitigate the event, evidence of event improvement/disappearance after stopping or reducing the dosage, evidence of event reappearance after reintroduction, clinical outcomes).
• Patient’s preexisting medical conditions and use of concomitant products
• Information about the product (e.g., dosage, route of administration, NDC #).

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

• Complete and submit the report online: www.fda.gov/medwatch/report.htm
• Complete and submit a postage-paid FDA Form 3500 (https://www.fda.gov/media/76299/download ) and return by:
  • Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or
  • Fax to 1-800-FDA-0178, or
• Call 1-800-FDA-1088 to request a reporting form

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

The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of LAGEVRIO.

^• Serious adverse events are defined as:

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

Molnupiravir is a prodrug with antiviral activity against SARS-CoV-2. It is metabolized to the cytidine nucleoside analogue, NHC which distributes into cells where NHC is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP incorporation (as NHC-monophosphate [NHC-MP]) into SARS-CoV-2 RNA by the viral RNA polymerase (nsp12) results in an accumulation of errors in the viral genome leading to inhibition of replication. The mechanism of action (known as viral error catastrophe or viral lethal mutagenesis) is supported by biochemical and cell culture data, studies of SARS-CoV-2 infection in animal models, and analyses of SARS-CoV-2 genome sequences in human subjects treated with LAGEVRIO.

The relationship between NHC and intracellular NHC-TP with antiviral efficacy has not been evaluated clinically.

Molnupiravir is a 5´-isobutyrate prodrug of NHC that is hydrolyzed during or after absorption. NHC, the primary circulating analyte, is taken up by cells and anabolized to NHC-TP. NHC is eliminated by metabolism to uridine and/or cytidine through the same pathways involved in endogenous pyrimidine metabolism. NHC pharmacokinetics are shown in Table 2 .

Plasma NHC concentrations in patients (N=5) following administration of molnupiravir via nasogastric or orogastric tube fell within the range of NHC concentrations following oral molnupiravir capsule administration under the same dosing regimen.

Specific Populations

Population PK analysis results indicated that age, sex, race, ethnicity, or disease severity do not meaningfully influence the PK of NHC.

Pediatric Patients

LAGEVRIO has not been studied in pediatric patients.

Patients with Renal Impairment

Renal clearance is not a meaningful route of elimination for NHC. In a population PK analysis, mild or moderate renal impairment did not have a meaningful impact on the PK of NHC. The PK of molnupiravir and NHC has not been evaluated in patients with eGFR less than 30 mL/min/1.73m ² or on dialysis.

Patients with Hepatic Impairment

The PK of molnupiravir and NHC has not been evaluated in patients with moderate and severe hepatic impairment. Preclinical data indicate that hepatic elimination is not expected to be a major route of NHC elimination; therefore, hepatic impairment is unlikely to affect NHC exposure.

Drug Interaction Studies

In vitro study results indicated that molnupiravir and NHC are not substrates of CYP enzymes or human P-gp and BCRP transporters. In vitro study results also indicated that molnupiravir and NHC are not inhibitors of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 or inhibitors of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2K, MRP2, MDR1 and BCRP or inducers of CYP1A2, 2B6, and 3A4. The interaction between molnupiravir with concomitant medications, including other treatments for mild-to-moderate COVID-19, has not been evaluated.

Antiviral Activity

NHC, the nucleoside analogue metabolite of molnupiravir, was active in cell culture assays against SARS-CoV-2 (USA-WA1/2020 isolate) with 50% effective concentrations (EC ₅₀ values) ranging between 0.67 to 2.7 µM in A-549 cells and 0.32 to 2.0 µM in Vero E6 cells. NHC had similar antiviral activity against SARS-CoV-2 variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621) and Omicron (B.1.1.529/BA.1, BA.1.1, BA.2, BA.4 and BA.5), with mean EC ₅₀ values of 0.55-3.0 μM. NHC had non-antagonistic antiviral activity with remdesivir against SARS-CoV-2 in cell culture.

Resistance

No amino acid substitutions in SARS-CoV-2 associated with resistance to NHC have been identified in Phase 2 clinical trials evaluating LAGEVRIO for the treatment of COVID-19. Studies to evaluate selection of resistance to NHC with SARS-CoV-2 in cell culture have not been completed. Resistance selection studies have been conducted with other coronaviruses (MHV and MERS-CoV) and showed a low likelihood of resistance development to NHC. Following 30 passages in cell culture, only a 2-fold decrease in susceptibility was observed and no NHC resistance-associated amino acid substitutions were identified.

In clinical trials, encoded amino acid changes (substitutions, deletions or insertions) were more likely to be detected in viral sequences in subjects treated with LAGEVRIO compared to placebo. In a small number of 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.

Cross-Resistance

NHC retained activity in cell culture against virus with polymerase (nsp 12) substitutions (e.g., F480L, V557L and E802D) associated with decreased remdesivir susceptibility, indicating a lack of cross-resistance.

Activity against SARS-CoV-2 in animal models

The antiviral activity of molnupiravir has been demonstrated in mouse, hamster, and ferret models of SARS-CoV-2 infection when dosing was administered prior to or within 1-2 days after viral challenge. In SARS-CoV-2 infected ferrets, molnupiravir significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and completely inhibited viral spread to untreated contact animals. In SARS-CoV-2 infected Syrian hamsters, molnupiravir reduced viral RNA and infectious virus titers in the lungs of animals. Histopathological analysis of lung tissue harvested after infection showed significantly reduced SARS-CoV-2 viral antigen levels and a lower abundance of pulmonary lesions in molnupiravir-treated animals compared with controls.

In Vitro Cytotoxicity

NHC, the nucleoside analogue metabolite of molnupiravir, had variable cytotoxicity against different mammalian cell types with CC ₅₀ values ranging from 7.5 µM (human lymphoid CEM cell line) to >100 µM, in 3-day exposure assays. Molnupiravir inhibited the proliferation of human bone marrow progenitor cells with CC ₅₀ values of 24.9 µM and 7.7 µM for erythroid and myeloid progenitor proliferation, respectively, in 14-day colony formation assays.

Viral RNA Rebound

Post-treatment increases in SARS-CoV-2 RNA shedding levels (i.e., viral RNA rebound) in nasopharyngeal samples were observed on Day 10, Day 15, and/or Day 29 in a subset of LAGEVRIO and placebo recipients in the Phase 3 MOVe-OUT trial. Approximately 1% of both LAGEVRIO and placebo recipients had evidence of recurrent COVID-19 symptoms coinciding with a rebound in viral RNA levels in nasopharyngeal samples.

Post-treatment viral RNA rebound was not associated with the primary clinical outcome of hospitalization or death through Day 29 following the single 5-day course of LAGEVRIO treatment. Post-treatment viral RNA rebound also was not associated with the detection of cell culture infectious virus in nasopharyngeal swab samples.

Carcinogenesis

Molnupiravir was not carcinogenic in a 6-month oral carcinogenicity study in RasH2 transgenic (Tg.RasH2) mice at any dose tested (30, 100 or 300 mg/kg/day).

Mutagenesis

Molnupiravir and NHC were positive in the in vitro bacterial reverse mutation assay (Ames assay) with and without metabolic activation. Molnupiravir was studied in two in vivo rodent mutagenicity models. The in vivo Pig-a mutagenicity assay gave equivocal results. Molnupiravir was negative in in vivo Big Blue® (cII Locus) transgenic rodent mutagenicity assays in somatic and germ cells. Molnupiravir was negative for induction of chromosomal damage in in vitro micronucleus (with and without metabolic activation) and in vivo rat micronucleus assays.

Based on the totality of the available genotoxicity data and the duration of treatment (5 days), molnupiravir is low risk for genotoxicity.

Impairment of Fertility

There were no effects on fertility, mating performance or early embryonic development when molnupiravir was administered to female or male rats at NHC exposures approximately 2 and 6 times, respectively, the human NHC exposure at the RHD.

Bone and cartilage toxicity changes resulting in impaired transformation of growth cartilage into new bone were observed in the femur and tibia of rats in a 3-month toxicity study at ≥ 500 mg/kg/day (5 times the human NHC exposure at the RHD). There was no bone or cartilage toxicity in a 1-month toxicity study in rats up to 500 mg/kg/day (4 and 8 times the human NHC exposure at the RHD in females and males, respectively), in dogs dosed for 14 days up to 50 mg/kg/day (similar to the human NHC exposure at the RHD), or in a 1-month toxicity study in mice up to 2,000 mg/kg/day (19 times the human NHC exposure at the RHD).

Growth cartilage is not present in mature skeletons, therefore the bone and cartilage findings are not relevant for adult humans but may be relevant for pediatric patients [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] .

Reversible, dose-related bone marrow toxicity affecting all hematopoietic cell lines was observed in dogs at ≥17 mg/kg/day (less than the human NHC exposure at the RHD). Mild decreases in peripheral blood cell and platelet counts were seen after 7 days of molnupiravir treatment progressing to more severe hematological changes after 14 days of treatment. Neither bone marrow nor hematological toxicity was observed in a 1-month toxicity study in mice up to 2,000 mg/kg/day (19 times the human NHC exposure at the RHD) and a 3-month toxicity study in rats up to 1,000 mg/kg/day (9 and 15 times the human NHC exposure at the RHD in females and males, respectively).

Storage and Handling

Store LAGEVRIO capsules at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] .