Molnupiravir

2 DOSAGE AND ADMINISTRATION 2.1 Dosage for Emergency Use of LAGEVRIO in Adult Patients 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. 2.2 Dosage Adjustments in Specific Populations 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) ] . 2.3 Administration via Nasogastric (NG), Orogastric (OG) and Gastrostomy (G) Tubes that are 12F or Larger or via Gastrojejunostomy (GJ) Tubes that are 14F or Larger Open four (4) capsules and transfer contents into a clean container with a lid. Add 40 mL of water to the container. 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. Flush the tube with 5 mL of water prior to administration. 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. 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. Flush the tube with 5 mL of water twice (10 mL total) after administration of the mixture.

6 ADVERSE REACTIONS 6.1 Adverse 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. 6.2 Post-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 6.4 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, 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: [email protected] 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.

12.3 Pharmacokinetics 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. Table 2: Pharmacokinetics of NHC After Multiple Oral Administration of 800 mg LAGEVRIO Every 12 Hours NHC Geometric Mean (%CV) Values were obtained from a Phase 1 study of healthy subjects, unless otherwise indicated. Pharmacokinetics in Patients AUC 0-12hr (ng*hr/mL) Values were obtained from population PK analysis. 8260 (41.0) C max (ng/mL) 2330 (36.9) C 12hr (ng/mL) 31.1 (124) Pharmacokinetics in Healthy Subjects AUC 0-12hr (ng*hr/mL) 8330 (17.9) C max (ng/mL) 2970 (16.8) C 12hr (ng/mL) 16.7 (42.8) AUC Accumulation Ratio 1.09 (11.8) Absorption T max (hr) Median [min - max] 1.50 [1.00 – 2.02] Effect of Food 35% reduction in C max , no effect on AUC Distribution Plasma Protein Binding ( in vitro ) 0% Apparent Volume of Distribution (L) 142 Elimination Effective t 1/2 (hr) 3.3 Apparent Clearance (L/hr) 76.9 Fraction of dose excreted in urine over the time interval of 0-12 hours 3% (81.6%) 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.