Molnupiravir

FDA Drug Information • Also known as: Lagevrio

Brand Names: Lagevrio
Dosage Form: POWDER
Product Type: BULK INGREDIENT

⚠ Boxed Warning (Black Box)

MANDATORY REQUIREMENTS FOR ADMINISTRATION OF LAGEVRIO UNDER EMERGENCY USE AUTHORIZATION In order to mitigate the risks of using this unapproved product under the EUA and to optimize the potential benefit of LAGEVRIO, the following steps are required. Use of LAGEVRIO under this EUA is limited to the following (all requirements must be met): Treatment of adults with mild-to-moderate 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 FDA are not accessible or clinically appropriate [see Limitations of Authorized Use (1) ] . As the prescribing healthcare provider, review the information contained within the “Fact Sheet for Patients and Caregivers” with your patient or caregiver prior to the patient receiving LAGEVRIO. Healthcare providers must provide the patient/caregiver with an electronic or hard copy of the “Fact Sheet for Patients and Caregivers” prior to the patient receiving LAGEVRIO and must document that the patient/caregiver has been given an electronic or hard copy of the “Fact Sheet for Patients and Caregivers”. The prescribing healthcare providers must inform the patient/caregiver that: LAGEVRIO is an unapproved drug that is authorized for use under this Emergency Use Authorization. Other therapeutics are currently approved for the same use as LAGEVRIO [ see Emergency Use Authorization (1) - Information Regarding Available Alternatives for the EUA Authorized Use ]. There are benefits and risks of taking LAGEVRIO as outlined in the “Fact Sheet for Patients and Caregivers.” There is a pregnancy registry. Females of childbearing potential should 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. Males of reproductive potential who are sexually active with females of childbearing potential should use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after the last dose. The prescribing healthcare provider must assess whether a female of childbearing potential is pregnant or not, if clinically indicated [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ]. Based on findings from animal reproduction studies, LAGEVRIO may cause fetal harm when administered to pregnant individuals. If LAGEVRIO is used during pregnancy, prescribing healthcare providers must communicate to the patient the known and potential benefits and the potential risks of LAGEVRIO use during pregnancy, as outlined in the “Fact Sheet for Patients and Caregivers” [see Warnings and Precautions (5.1 , 5.3) , Use in Specific Populations (8.1 , 8.3) and Nonclinical Toxicology (13.1) ]. If the decision is made to use LAGEVRIO during pregnancy, the prescriber must document that the known and potential benefits and the potential risks of LAGEVRIO use during pregnancy, as outlined in the “Fact Sheet for Patients and Caregivers,” were discussed with the patient. 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. The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory reporting of all medication errors and serious adverse events potentially related to LAGEVRIO within 7 calendar days from the healthcare provider’s awareness of the event [see Adverse Reactions (6.4) ]. For information on clinical studies of LAGEVRIO and other therapies for the treatment of COVID-19, see www.clinicaltrials.gov .

Description

11 DESCRIPTION LAGEVRIO capsules contain molnupiravir, a nucleoside analogue that inhibits SARS-CoV-2 replication by viral mutagenesis and is the 5´-isobutyrate ester of the ribonucleoside analog N4-hydroxycytidine (NHC). The chemical name for molnupiravir is {(2R,3S,4R,5R)-3,4-Dihydroxy-5-[(4Z)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl]oxolan-2-yl}methyl 2-methylpropanoate. It has an empirical formula of C 13 H 19 N 3 O 7 and its molecular weight is 329.31 g/mol. Its structural formula is: Molnupiravir is a white to off-white powder that is soluble in water. Each LAGEVRIO capsule, for oral use, contains 200 mg of molnupiravir and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and purified water. The capsule shell is made of hypromellose, red iron oxide and titanium dioxide. The capsule is printed with white ink made of butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong ammonia solution and titanium dioxide. LAGEVRIO structure

Dosage and Administration

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.

Side Effects (Adverse Reactions)

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...

Drug Interactions

7 DRUG INTERACTIONS 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) ].

Contraindications

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

Pregnancy and Breastfeeding

8.1 Pregnancy 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...

Overdosage

10 OVERDOSAGE There is no human experience of overdosage with LAGEVRIO. Treatment of overdose with LAGEVRIO should consist of general supportive measures including the monitoring of the clinical status of the patient. Hemodialysis is not expected to result in effective elimination of NHC.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied LAGEVRIO capsules are supplied as follows: Contents Description How Supplied NDC 200 mg molnupiravir Swedish Orange opaque capsules with corporate logo and “82” printed in white ink 40 count bottles NDC-0006-5055-06 NDC-0006-5055-07 NDC-0006-5055-09 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] .

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.